COMPOUNDS

Abstract

Compounds of general formula (I): wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5a, R.sup.5b X.sup.1, X.sup.2, Z and Y are as defined herein are positive modulators of the calcium-activated chloride channel (CaCC), TMEM16A. The compounds are useful for treating diseases and conditions affected by modulation of TMEM16A, particularly respiratory diseases and conditions.

##STR00001##

Claims

1.-32. (canceled)

33. A method for the treatment or prophylaxis of diseases and conditions affected by modulation of TMEM16A, the method comprising administering to a patient an effective amount of a compound according to formula (I): ##STR00524## wherein: R.sup.1 is H, CN, C(O)OR.sup.12, C.sub.1-3 alkyl, C.sub.2-3 alkenyl or C.sub.2-3 alkynyl, any of which alkyl, alkenyl or alkynyl groups are optionally substituted with one or more substituents, suitably one substituent, selected from fluoro, OR.sup.12, N(R.sup.12).sub.2, C(O)OR.sup.12, C(O)N(R.sup.12).sub.2, C(O)R.sup.12 and N(R.sup.13)C(O)R.sup.12; wherein each R.sup.12 and R.sup.13 is independently selected from H, C.sub.1-6 alkyl and C.sub.1-6 fluoroalkyl R.sup.2 is H or C.sub.1-6 alkyl optionally substituted with OR.sup.12; R.sup.3 is: C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from fluoro, CN, R.sup.14 OR.sup.14, OR.sup.15, N(R.sup.15).sub.2, C(O)OR.sup.15, C(O)N(R.sup.15).sub.2, N(R.sup.16)C(O)R.sup.15, N(R.sup.15)S(O).sub.2R.sup.14, N(R.sup.15)S(O).sub.2R.sup.16 and N(R.sup.15)C(O)OR.sup.16; or a 3- to 7-membered carbocyclic or heterocyclic ring system or a 6- to 10 membered aryl or 5- to 10-membered heteroaryl ring system, either of which is optionally substituted with one or more substituents selected from halo, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OR.sup.17 and N(R.sup.17).sub.2; wherein R.sup.14 is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OR.sup.17 and N(R.sup.17).sub.2; wherein each R.sup.17 is independently H, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl; each R.sup.15 and R.sup.16 is independently H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached combine to form a 3- to 10-membered carbocyclic or heterocyclic ring system optionally substituted with one or more substituents selected from halo, CN, OR.sup.9, N(R.sup.9).sub.2, C(O)OR.sup.9, C(O)N(R.sup.9).sub.2, C(O)R.sup.9, N(R.sup.9)C(O)R.sup.9 and C.sub.1-4 alkyl optionally substituted with halo, OR.sup.9 or N(R.sup.9).sub.2; or R.sup.1, R.sup.2 and R.sup.3 together with the carbon atom to which they are attached combine to form a bridged 5- to 10-membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from halo, CN, OR.sup.9, N(R.sup.9).sub.2, C(O)OR.sup.9, C(O)N(R.sup.9).sub.2, C(O)R.sup.9, N(R.sup.9)C(O)R.sup.9 and C.sub.1-4 alkyl optionally substituted with halo, OR.sup.9 or N(R.sup.9).sub.2; each R.sup.9 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; X.sup.1 is N; X.sup.2 is CR.sup.8 R.sup.8 is H, halo, OH, O(C.sub.1-4 alkyl), CN or NH.sub.2; Y is a bond or a straight C.sub.1-6 alkylene chain which is optionally substituted with one or more substituents R.sup.18, wherein two substituents R.sup.18 may be attached to the same or to different carbon atoms; wherein each R.sup.18 is independently C.sub.1-3 alkyl or C.sub.1-3 haloalkyl in which a —CH.sub.2— is optionally replaced with —NH— or —O— and wherein two R.sup.18 groups may combine with the atom or atoms to which they are attached to form a 3- to 6-membered carbocyclic or heterocyclic ring system; Z is —C(O)— or —C(O)NH—; R.sup.4 is a 6- to 14-membered aryl, 5- to 14-membered heteroaryl or a 5- to 10-membered carbocyclic ring system, any of which is optionally substituted with one or more substituents selected from: halo, CN, nitro, R.sup.19, OR.sup.19, OR.sup.6, SR.sup.6, NR.sup.6R.sup.7, C(O)R.sup.6, C(O)R.sup.19, C(O)OR.sup.6, C(O)N(R.sup.6)(R.sup.7), N(R.sup.7)C(O)R.sup.6; C.sub.1-6 alkyl or O(C.sub.1-6 alkyl), either of which is optionally substituted with one or more substituents selected from halo, CN, nitro, R.sup.19, OR.sup.6, SR.sup.6, NR.sup.6R.sup.7, C(O)R.sup.6 C(O)OR.sup.6, C(O)N(R.sup.6)(R.sup.7) and N(R.sup.7)C(O)R.sup.6; and when R.sup.4 is not fully aromatic in character, oxo; wherein R.sup.19 is 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OH, O(C.sub.1-4 alkyl), O(C.sub.10.4 haloalkyl); R.sup.6 is H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, benzyl, 3- to 7-membered carbocyclyl or 3- to 7-membered heterocyclyl; R.sup.7 is H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; or R.sup.6 and R.sup.7 together with the nitrogen atom to which they are attached may form a 4 to 7-membered heterocyclic ring optionally containing one or more further heteroatoms and optionally substituted with one or more substituents selected from oxo and halo; and each of R.sup.5a and R.sup.5b is independently H, C.sub.1-4 alkyl or halo

34. The method of claim 33, wherein the compound has a structure according to formula (Ia): ##STR00525## or a stereoisomer, a tautomer, a solvate or a salt thereof, wherein: R.sup.1 is H, CN, C(O)OR.sup.12, C.sub.1-3 alkyl, C.sub.2-3 alkenyl or C.sub.2-3 alkynyl, any of which alkyl, alkenyl or alkynyl groups are optionally substituted with one or more substituents selected from fluoro, OR.sup.12, N(R.sup.12).sub.2, C(O)OR.sup.12, C(O)N(R.sup.12).sub.2, C(O)R.sup.12 and N(R.sup.13)C(O)R.sup.12; wherein each R.sup.12 and R.sup.13 is independently selected from H, C.sub.1-6 alkyl and C.sub.10.6 fluoroalkyl R.sup.2 is H or C.sub.1-6 alkyl optionally substituted with OR.sup.12; R.sup.3 is: C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from fluoro, CN, R.sup.14 OR.sup.14, OR.sup.15, N(R.sup.15).sub.2, C(O)OR.sup.15, C(O)N(R.sup.15).sub.2, N(R.sup.16)C(O)R.sup.15, N(R.sup.15)S(O).sub.2R.sup.14, N(R.sup.15)S(O).sub.2R.sup.16 and N(R.sup.15)C(O)OR.sup.16; or a 3- to 7-membered carbocyclic or heterocyclic ring system or a 6- to 10 membered aryl or 5- to 10-membered heteroaryl ring system, either of which is optionally substituted with one or more substituents selected from halo, CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OR.sup.17 and N(R.sup.17).sub.2; wherein R.sup.14 is a 6- to 10-membered aryl or 5- to 10-membered heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, any of which is optionally substituted with one or more substituents selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, OR.sup.17 and N(R.sup.17).sub.2; wherein each R.sup.17 is independently H, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl; each R.sup.15 and R.sup.16 is independently H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; or R.sup.2 and R.sup.3 together with the carbon atom to which they are attached combine to form a 3- to 10-membered carbocyclic or heterocyclic ring system optionally substituted with one or more substituents selected from halo, CN, OR.sup.9, N(R.sup.9).sub.2, C(O)OR.sup.9, C(O)N(R.sup.9).sub.2, C(O)R.sup.9, N(R.sup.9)C(O)R.sup.9 and C.sub.1-4 alkyl optionally substituted with halo, OR.sup.9 or N(R.sup.9).sub.2; or R.sup.1, R.sup.2 and R.sup.3 together with the carbon atom to which they are attached combine to form a bridged 5- to 10-membered carbocyclic or heterocyclic ring system or phenyl, any of which is optionally substituted with one or more substituents selected from halo, CN, OR.sup.9, N(R.sup.9).sub.2, C(O)OR.sup.9, C(O)N(R.sup.9).sub.2, C(O)R.sup.9, N(R.sup.9)C(O)R.sup.9 and C.sub.1-4 alkyl optionally substituted with halo, OR.sup.9 or N(R.sup.9).sub.2; each R.sup.9 is independently selected from H, C.sub.1-6 alkyl or C.sub.1-6 haloalkyl; X.sup.1 is N; X.sup.2 is CR.sup.8 R.sup.8 is H, halo, OH, O(C.sub.1-4 alkyl), CN or NH.sub.2; each of R.sup.5a and R.sup.5b is independently H, C.sub.1-4 alkyl or halo; R.sup.10 is H, OH, halo, C.sub.1-6 alkyl, —O(C.sub.1-6 alkyl); each R.sup.11 is independently H, halo, OH, CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, —O(C.sub.1-6 alkyl) or C(O)O—(C.sub.1-6 alkyl); and n is 1 or 2.

35. The method of claim 33, wherein the compound has a structure according to formula (Id) or (Ie): ##STR00526## wherein R.sup.1, R.sup.2 and R.sup.3, are as defined in claim 33; R.sup.11a is H, halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl or C(O)O(C.sub.1-4 alkyl); R.sup.11b is H, halo, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl; and R.sup.11c is H, halo, CN, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl.

36. The method of claim 33, wherein the compound is selected from: N-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1); N-(1,1-Dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide (Compound 1.1); N-(1-Adamantyl)-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 1.2); N-(1-Adamantyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 1.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-methoxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 1.4); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethyl propyl)benzamide (Compound 1.5); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 1.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)pyridine-2-carboxamide (Compound 1.7); tert-Butyl N-[3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyl]carbamate (Compound 1.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (Compound 1.10); N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2); N-tert-Butyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.1); N-tert-Butyl-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.3); N-tert-Butyl-3-[[2-(3,5-difluoro-2-hydroxy-phenyl)acetyl]amino] benzamide (Compound 2.9); 3-[[2-(5-Bromo-2-hydroxy-phenyl) acetyl]amino]-N-tert-butyl-benzamide (Compound 2.10); N-tert-Butyl-3-[[2-(2,3-difluoro-6-hydroxy-phenyl)acetyl]amino] benzamide (Compound 2.11); N-tert-Butyl-3-[[2-(4,5-difluoro-2-hydroxy-phenyl)acetyl]amino] benzamide (Compound 2.12); N-(1,1-Dimethylpropyl)-3-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino] benzamide (Compound 2.13); N-tert-Butyl-3-[[2-(2-fluoro-6-hydroxy-phenyl)acetyl]amino]benzamide (Compound 2.15); N-tert-Butyl-3-[[2-[2-hydroxy-5-(trifluoro methyl)phenyl]acetyl]amino]benzamide (Compound 2.17); N-tert-Butyl-3-[[2-[2-hydroxy-4-(trifluoro methyl)phenyl]acetyl]amino]benzamide (Compound 2.19); N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3); N-(1,1-Dimethylpropyl)-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.1a); N-tert-Butyl-4-[[2-(4-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.2a); N-tert-Butyl-4-[[2-(2-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.3a); 4-[[2-(4-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 3.4a); 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 3.5a); 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl cyclobutyl)pyridine-2-carboxamide (Compound 3.6a); N-tert-butyl-4-[2-(2,5-dibromo-3-fluoro-6-hydroxyphenyl)acetamido]pyridine-2-carboxamide (Compound 3.7a); N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.5b); N-tert-Butyl-4-[[2-(4-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.6b); N-tert-Butyl-4-[[2-[2-hydroxy-4-(trifluoro methyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 3.7b); N-tert-Butyl-4-[[2-(2-hydroxy-5-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.8b); N-tert-Butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.11b); N-tert-Butyl-4-[[2-(3-hydroxyphenyl) acetyl]amino]pyridine-2-carboxamide (Compound 3.12b); N-tert-Butyl-4-[[2-(2-fluoro-5-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide (Compound 3.13b); N-tert-Butyl-4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.14b); N-tert-Butyl-4-[[2-(2-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.15b); N-tert-Butyl-4-[[2-(2-chloro-5-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide (Compound 3.16b); N-tert-Butyl-4-[[2-(3-chloro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 3.17b); N-tert-Butyl-4-[[2-(5-chloro-2-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.3); N-tert-Butyl-4-[[2-(3-chlorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 5.5); N-tert-Butyl-4-[[2-(3,4-dichlorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 5.8); N-tert-Butyl-4-[[2-(p-tolyl)acetyl] amino]pyridine-2-carboxamide (Compound 5.11); N-tert-Butyl-4-[[2-(2-fluorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 5.12); N-tert-Butyl-4-[[2-(m-tolyl)acetyl] amino]pyridine-2-carboxamide (Compound 5.14); N-tert-Butyl-4-[[2-(2,6-dichlorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 5.17); N-tert-Butyl-4-[[2-(4-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.18); N-tert-Butyl-4-[[2-(2-chlorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 5.20); N-tert-Butyl-4-[[2-(3-chloro-4-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 5.21); N-tert-butyl-4-[[1-(3-chlorophenyl) cyclopropanecarbonyl]amino]pyridine-2-carboxamide (Compound 5.31); N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.35); N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.37); N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 5.38); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl) benzamide (Compound 7); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1,1-dimethylbutyl)benzamide (Compound 7.1) 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1,1-dimethylbutyl)pyridine-2-carboxamide (Compound 7.2); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-cyclohexyl-benzamide (Compound 7.3); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-tetrahydropyran-4-yl-benzamide (Compound 7.4); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1,1,2-trimethylpropyl)benzamide (Compound 7.5); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1,1,2-trimethylpropyl)pyridine-2-carboxamide (Compound 7.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-isopropyl-pyridine-2-carboxamide (Compound 7.7); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(4-methyltetrahydropyran-4-yl)benzamide (Compound 7.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(4-methyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 7.9); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1-methylcyclobutyl)benzamide (Compound 7.10); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 7.11); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-sec-butyl-pyridine-2-carboxamide (Compound 7.13); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(2-hydroxy-1,1,2-trimethyl-propyl)pyridine-2-carboxamide (Compound 7.14); N-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 7.15); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide (Compound 7.16); tert-Butyl-3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (Compound 8.1); tert-Butyl (1r,5s,6s)-6-{4-[2-(5-chloro-2-hydroxyphenyl)acetamido]pyridine-2-amido}-3-azabicyclo[3.1.0]hexane-3-carboxylate (Compound 8.3); N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide (Compound 9); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide (Compound 9.2); N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 10); N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide (Compound 11); N-tert-Butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 15); N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide (Compound 18); N-tert-Butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide (Compound 19); N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 20); N-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide (Compound 22); 4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 23); 4-[[2-(3-Chlorophenyl)acetyl] amino]-N-(1-cyanocyclo propyl)pyridine-2-carboxamide (Compound 23.1); 4-[[2-(2-Chloro-5-fluoro-phenyl) acetyl] amino]-N-(1-cyanocyclo propyl)pyridine-2-carboxamide (Compound 23.2); N-tert-Butyl-4-[[2-[2-(difluoromethoxy) phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.4); N-tert-Butyl-4-[[2-[2-(difluoromethyl) phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.5); N-tert-Butyl-4-[[2-(3,4-difluorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 23.6); N-tert-Butyl-4-[[2-(3,5-difluorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 23.7); N-tert-Butyl-4-[[2-(2,3-difluorophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 23.8); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (Compound 23.9); N-tert-Butyl-4-[[2-[2-(trifluoromethyl) phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 23.12); 4-[[2-(2-Bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 23.13); N-tert-Butyl-4-[[2-(2-cyanophenyl) acetyl]amino]pyridine-2-carboxamide (Compound 23.14); 4-[[2-(2-Chloro-5-methoxy-phenyl)acetyl] amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 24); N-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino] pyridine-2-carboxamide (Compound 25); -[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 25.1); N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 26); N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl] amino]pyridine-2-carboxamide (Compound 27); N-tert-Butyl-4-[[2-[4-[(tert-butylamino)methyl]-5-chloro-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.1); N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.2); N-tert-Butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1-yl)methyl]-2-hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 27.3); N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (Compound 28); N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide (Compound 28.1); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 30.1); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide (Compound 30.2); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyclopropyl-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 30.3a); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-methyl-3-bicyclo[1.1.1] pentanyl)pyridine-2-carboxamide (Compound 30.4); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-3-bicyclo[1.1.1]pentanyl) pyridine-2-carboxamide (Compound 30.5); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluorocyclopropyl)pyridine-2-carboxamide (Compound 30.6); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (Compound 30.7); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-methylcyclopropyl)pyridine-2-carboxamide (Compound 30.8); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide (Compound 30.9); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2-fluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.10); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 30.11); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopentyl)pyridine-2-carboxamide (Compound 30.12); 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluoro-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 30.13); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide (Compound 31.2); 4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-N-[(1s,2s)-2-hydroxycyclohexyl] pyridine-2-carboxamide (Compound 31.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclo hexyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 31.3a); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 31.4); N-[(6-Amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl] amino]pyridine-2-carboxamide (Compound 32); 12-[[4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl] amino]dodecanoic acid (Compound 32.1); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-(3-pyridylmethyl)pyridine-2-carboxamide (Compound 32.2); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(2-pyridylmethyl)pyridine-2-carboxamide (Compound 32.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-(4-pyridylmethyl)pyridine-2-carboxamide (Compound 32.4); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-[(2-hydroxyphenyl) methyl]pyridine-2-carboxamide (Compound 32.5); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1,1-dimethyl-2-morpholino-ethyl)pyridine-2-carboxamide (Compound 32.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-2-carboxamide (Compound 32.7); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl] amino]-N-(3,3-difluoro-4-piperidyl)pyridine-2-carboxamide (Compound 32.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-(1H-imidazol-2-yl)pyridine-2-carboxamide (Compound 32.9); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl] pyridine-2-carboxamide (Compound 33); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 34); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl) tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35a); -[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35b); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(4-hydroxy-4-methyl-cyclohexyl) pyridine-2-carboxamide as a 6:4 mixture of stereoisomers (Compound 35.1); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-[(1s,2r)-2-(hydroxy methyl)cyclohexyl]pyridine-2-carboxamide (Compound 35.2); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-[(1s,3r)-3-hydroxycyclopentyl] pyridine-2-carboxamide (Compound 35.3); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-[2-hydroxy-1-(hydroxy methyl)-1-methyl-ethyl]pyridine-2-carboxamide (Compound 35.4); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(3-hydroxycyclohexyl)pyridine-2-carboxamide as a mixture of stereoisomers (Compound 35.6); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(3-phenoxypropyl)pyridine-2-carboxamide (Compound 35.7); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(1-methylcyclo propyl)pyridine-2-carboxamide (Compound 35.8); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-[1-methyl-1-(2-pyridyl) ethyl]pyridine-2-carboxamide (Compound 35.9); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(3-phenylpropyl)pyridine-2-carboxamide (Compound 35.10); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-[2-hydroxy-1-(2-pyridyl)ethyl] pyridine-2-carboxamide (Compound 35.11); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-[(5-methoxy-2-pyridyl)methyl]pyridine-2-carboxamide (Compound 35.12); Ethyl 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butanoate (Compound 35.13); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-(3-hydroxy-1,1-dimethyl-propyl)pyridine-2-carboxamide (Compound 35.14); N-Benzyl-4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide (Compound 35.15); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-phenyl-pyridine-2-carboxamide (Compound 35.16); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-[(1S,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 35.17); 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-[(1R,2S)-2-hydroxy cyclopentyl]pyridine-2-carboxamide (Compound 35.18); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-[(1S,2R)-2-hydroxy cyclopentyl]pyridine-2-carboxamide (Compound 35.19); 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl] amino]-N-(1-methylcyclohexyl)benzamide (Compound 35.20); N-(1,1-Dimethylprop-2-ynyl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.21); N-Cyclohexyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide (Compound 35.22); 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl] amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]benzamide (Compound 35.23); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclohexyl)pyridine-2-carboxamide (Compound 35.24); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide (Compound 35.25); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)oxetan-3-yl]pyridine-2-carboxamide (Compound 35.26); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-methoxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 35.27); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 36); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl)pyridine-2-carboxamide (Compound 37); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopentyl)pyridine-2-carboxamide (Compound 38); N-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 39); N-tert-Butyl-4-[[2-(2-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40); N-tert-Butyl-4-[[2-(2-chloro-5-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 40.1); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(2-hydroxyethyl) tetrahydropyran-4-yl]pyridine-2-carboxamide (Compound 42); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2-trifluoro ethylamino)propyl]pyridine-2-carboxamide (Compound 43); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1] hexanyl)pyridine-2-carboxamide (Compound 44); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(2,2-dimethylpropanoyl amino)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 45); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide (Compound 46); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46a); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 46b); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxamide (Compound 47); Methyl 4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-carboxylate (Compound 47.2); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-(3-cyanooxetan-3-yl)pyridine-2-carboxamide (Compound 47.3); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (Compound 48); N-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino] pyridine-2-carboxamide (Compound 48.1); N-[3-(tert-Butylamino)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide (Compound 49); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(methanesulfonamido)-1,1-dimethyl-propyl]pyridine-2-carboxamide (Compound 50); N-(3-Acetamido-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 51); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(hydroxymethyl)tetrahydro pyran-4-yl]pyridine-2-carboxamide (Compound 53); N-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 54); N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 55); N-tert-Butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl] amino]pyridine-2-carboxamide (Compound 56); N-tert-Butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide (Compound 58); 4-[[2-(3-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Compound 59); N-(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60); N-(1-Cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.1); N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide (Compound 60.2); N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 61); N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino] pyridine-2-carboxamide (Compound 62); 4-(Benzylcarbamoylamino)-N-tert-butyl-pyridine-2-carboxamide (Compound 64); N-tert-Butyl-4-[(2-chlorophenyl) methylcarbamoylamino]pyridine-2-carboxamide (Compound 64.5); N-tert-Butyl-4-[(3-chlorophenyl)methyl carbamoylamino]pyridine-2-carboxamide (Compound 64.7); N-tert-butyl-4-[(4-chlorophenyl)methyl carbamoylamino]pyridine-2-carboxamide (Compound 64.8); N-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide (Compound 65); N-tert-Butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.1); N-tert-Butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.2); N-tert-Butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.3); N-tert-Butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Compound 65.4); N-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 66); N-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 68); N-tert-Butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 69); N-tert-Butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 70); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide (Compound 71.1); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 72); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)-2-methoxy-1-methyl-ethyl]pyridine-2-carboxamide (Compound 73); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbut-2-ynyl) pyridine-2-carboxamide (Compound 73.1); 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)benzamide (Compound 74); N-tert-Butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 75); 4-[[2-(5-Chloro-4-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclo butyl)pyridine-2-carboxamide (Compound 76); 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 77); 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexanyl) pyridine-2-carboxamide (Compound 77.1); 4-[[2-(4-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 78); N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.1); N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (Compound 78.2); N-(1-Cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino] pyridine-2-carboxamide (Compound 81); N-(1-Cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 81.1); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide (Compound 81.2); N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino] pyridine-2-carboxamide (Compound 81.3); N-(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino] pyridine-2-carboxamide (Compound 81.4); 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl] pyridine-2-carboxamide (Compound 81.5); N-tert-Butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 82); 4-[(4-Acetamidobenzoyl)amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 83.29); N-tert-Butyl-6-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Compound 85); 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1-(methoxy methyl)ethyl]pyridine-2-carboxamide (Compound 86); N-tert-Butyl-4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 89); N-tert-Butyl-4-[[2-(4-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 90); N-tert-Butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Compound 91); 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 92); 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 92.1); 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 92.2); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Compound 93.1); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[(2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide (Compound 93.2); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide (Compound 93.3); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Compound 93.4); 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 93.5); and 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl) pyridine-2-carboxamide (Compound 94); and salts and solvates of any of the above.

37. The method of claim 33, wherein the compound is 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide (Compound 35a) or a salt or solvate thereof.

38. The method of claim 33, wherein the compound is 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Compound 36) or a salt or solvate thereof.

39. The method of claim 33, wherein the compound is N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl] amino] pyridine-2-carboxamide (Compound 5.36) or a salt or solvate thereof.

40. The method according to claim 33, wherein the disease or condition affected by modulation of TMEM16A is selected from respiratory diseases and conditions, dry mouth (xerostomia), intestinal hypermobility, cholestasis and ocular conditions.

41. The method according to claim 40, wherein the respiratory diseases and conditions are selected from cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, asthma and primary ciliary dyskinesia.

42. The method according to claim 40, wherein the dry mouth (xerostomia) results from Sjorgens syndrome, radiotherapy treatment or xerogenic drugs.

43. The method according to claim 40, wherein the intestinal hypermobility is associated with gastric dyspepsia, gastroparesis, chronic constipation or irritable bowel syndrome.

44. The method according to claim 40, wherein the ocular disease is dry eye disease.

45. The method according to claim 40, wherein the compound of general formula (I) is used in combination with an additional active agent useful in the treatment or prevention of respiratory conditions.

46. The method of claim 45, wherein the wherein the additional agent useful in the treatment or prevention of respiratory conditions is selected from: β2 adrenoreceptor agonists selected from metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, olodaterol, vilanterol and abediterol; antihistamines selected from histamine H.sub.1 receptor antagonists selected from loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H.sub.4 receptor antagonists; dornase alpha; corticosteroids selected from prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate; Leukotriene antagonists selected from montelukast and zafirlukast; anticholinergic compounds, muscarinic antagonists selected from ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium; CFTR repair therapies selected from CFTR potentiators, correctors or amplifiers, the CFTR potentiators, correctors or amplifiers selected from Ivacaftor, QBW251, VX659, VX445, VX561/CPT-656, VX152, VX440, GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI808, FDL-169 and FDL-176 and CFTR correctors selected from Lumacaftor and Tezacaftor; ENaC modulators, ENaC inhibitors selected from: amiloride, VX-371, AZD5634, QBW276, SPX-101, BI443651, ETD001 and compounds having a cation selected from: 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido) ethyl]-6-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidine-1-carbonyl)-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido) methyl]-6-{[2-(4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}piperidin-1-yl)ethyl]carbamoyl}-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-5-[4-({bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}methyl)piperidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3R)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-6-[(3S)-3-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}pyrrolidine-1-carbonyl]-1,3-diethyl-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{[(1r,4r)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium; 2-[({3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl}formamido)methyl]-1,3-diethyl-6-{[(1s,4s)-4-{bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}cyclohexyl]carbamoyl}-1H-1,3-benzodiazol-3-ium; and an anion selected from halide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methane sulfonate or p-toluene sulfonate; antibiotics; airway hydrating agents (osmoloytes) selected from hypertonic saline and mannitol; and mucolytic agents selected from N-acetyl cysteine.

Description

[1034] The invention is illustrated by the following non-limiting Examples and to the drawing in which:

[1035] FIG. 1 is an example trace from a whole-cell patch clamp (Qpatch) TMEM16A potentiator assay as used in Biological Example 95 and illustrates the methodology used in the assay.

EXAMPLES

[1036] The invention is illustrated by the following Examples.

General Conditions:

[1037] Mass spectra were run on LC-MS systems using electrospray ionization. These were run using either a Waters Acquity uPLC system with Waters PDA and ELS detectors or Shimadzu LCMS-2010EV systems. [M+H]+ refers to mono-isotopic molecular weights. NMR spectra were recorded on a Bruker Avance III HD 500 MHz with a 5 mm Broad Band Inverse probe, a Bruker Avance III HD 250 MHz or a 400 MHz Avance III HD Nanobay fitted with a 5 mm Broad Band Observed SmartProbe using the solvent as internal deuterium lock. Spectra were recorded at room temperature unless otherwise stated and were referenced using the solvent peak.

[1038] Referring to the examples that follow, compounds of the preferred embodiments were synthesized using the methods described herein, or other methods, which are known in the art.

[1039] The various starting materials, intermediates, and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.

[1040] Compounds were purified by flash column chromatography on normal phase silica on Biotage® Isolera systems using the appropriate SNAP cartridge and gradient. Alternatively, compounds were purified on reverse phase silica using Biotage® Isolera systems with the appropriate SNAP C18 cartridges and reverse phase eluent or by preparative HPLC (if stated otherwise).

Preparative HPLC Using Acidic pH, Early Elution Method

[1041] Purifications by were performed on a Gilson LC system using Waters Sunfire C18 columns (30 mm×100 mm, 10 μM; temperature: RT) and a gradient of 10-95% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 14.44 min then 95% B for 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

Preparative HPLC Using Acidic pH, Standard Elution Method

[1042] Purifications by preparative HPLC (acidic pH, standard elution method) were performed on a Gilson LC system using Waters Sunfire C18 columns (30 mm×100 mm, 10 μM; temperature: RT) and a gradient of 30-95% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 11 min then 95% B for 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

Preparative HPLC Using Basic pH, Early Elution Method

[1043] Purifications by preparative HPLC (basic pH, early elution method) were performed on a Gilson LC system using Waters Xbridge C18 columns (30 mm×100 mm, 10 μM; temperature: RT) and a gradient of 10-95% (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) over 14.44 min then 95% B for 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

Preparative HPLC Using Basic pH, Standard Elution Method

[1044] Purifications by preparative HPLC (basic pH, standard elution method) were performed on a Gilson LC system using Waters Xbridge C18 columns (30 mm×100 mm, 10 μM; temperature: RT) and a gradient of 30-95% (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) over 11 min then 95% B for 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.

[1045] If not indicated otherwise, the analytical HPLC conditions are as follows:

Method A

[1046] Column: Phenomenex Kinetix-XB C18 2.1×100 mm, 1.7 μm [1047] Column Temp 40° C. [1048] Eluents: A: H20 0.1% formic acid, B: acetonitrile, 0.1% formic acid [1049] Flow Rate: 0.6 mL/min [1050] Gradient: 0-5.3 mins 5-100% B, 5.3-5.8 mins 100% B, 5.8-5.82 mins 100-5% B, 5.82-7.00 mins 5% B

Method B

[1051] Column: Waters UPLC® CSH™ 018 2.1×100 mm 1.7 μm [1052] Column Temp 40° C. [1053] Eluents: A: 2 mM amm. Bicarbonate, buffered to pH10, B: acetonitrile [1054] Flow Rate: 0.6 mL/min [1055] Gradient: 0-5.3 mins 5-100% B, 5.3-5.8 mins 100% B, 5.8-5.82 mins 100-5% B, 5.82-7.00 mins 5% B

Method C

[1056] Column: Waters UPLC® BEH™ 018 2.1×100 mm 1.7 μm [1057] Column Temp 40° C. [1058] Eluents: A: 2 mM ammonium bicarbonate, buffered to pH10, B: acetonitrile [1059] Flow Rate: 0.6 mL/min [1060] Gradient: 0-5.3 mins 5-100% B, 5.3-5.8 mins 100% B, 5.8-5.82 mins 100-5% B, 5.82-7.00 mins 5% B

Method D

[1061] Column: Waters Atlantis dC18 2.1×100 mm 3 μm [1062] Column Temp 40° C. [1063] Eluents: A: H20+0.1% formic acid, B: acetonitrile+0.1% formic acid [1064] Flow Rate: 0.6 mL/min [1065] Gradient: 0-5 mins 5-100% B, 5-5.4 mins 100% B, 5.4-5.42 mins 100-5% B, 5.42-7.00 mins 5% B

Method E

[1066] Column: Kinetex Core-Shell C18 2.1×50 mm 5 μm [1067] Column Temp 40° C. [1068] Eluents: A: H20+0.1% formic acid, B: acetonitrile+0.1% formic acid [1069] Flow Rate: 1.2 mL/min [1070] Gradient: 0-1.20 mins 5-100% B, 1.20-1.30 mins 100% B, 1.30-1.31 mins 100-5% B

Method F

[1071] Column: Phenomenex Gemini-NX C18 2×50 mm 3 μm [1072] Column Temp 40° C. [1073] Eluents: A: 2 mM ammonium bicarbonate, buffered to pH10, B: acetonitrile [1074] Flow Rate: 1 mL/min [1075] Gradient: 0-1.80 mins 1-100% B, 1.80-2.10 mins 100% B, 2.10-2.30 mins 100-1% B

[1076] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed in vacuo, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, and NMR. Abbreviations used are those conventional in the art. If not defined, the terms have their generally accepted meanings.

Abbreviation

[1077] aq. aqueous [1078] br broad [1079] d doublet [1080] dd doublet of doublets [1081] DCM dichloromethane [1082] DIPEA diisopropylethylamine [1083] DMF N,N-dimethylformamide [1084] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [1085] EtOAc ethyl acetate [1086] HOAt 1-hydroxy-7-azabenzotriazole [1087] HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate [1088] HPLC high pressure liquid chromatography [1089] MeCN acetonitrile [1090] MeOH methanol [1091] MS mass spectrometry [1092] m multiplet [1093] min minute(s) [1094] mL milliliter(s) [1095] m/z mass to charge ratio [1096] NCS N-chlorosuccinimide [1097] NMR nuclear magnetic resonance [1098] PTFE polytetrafluoroethylene [1099] Rt retention time [1100] s singlet [1101] t triplet [1102] TBME methyl tert-butyl ether [1103] TBTU N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate [1104] TEA triethylamine [1105] TFA trifluoroacetic acid [1106] THF tetrahydrofuran [1107] T3P® 1,2. propylphosphonic anhydride

Preparation of Examples

Example 1

N-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

[1108] ##STR00037##

Step 1: Methyl 4-[[2-(2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate

[1109] ##STR00038##

[1110] To a solution of 2-(2-methoxyphenyl)acetic acid (218 mg, 1.31 mmol) in DMF (4 mL) was added HOAt (179 mg, 1.31 mmol), EDCI (328 mg, 1.71 mmol), DIPEA (574 μL, 3.29 mmol) and methyl 4-aminopyridine-2-carboxylate (200 mg, 1.31 mmol) and the mixture was stirred at room temperature for 6 hours 15 minutes. The resulting mixture was partitioned between H.sub.2O (30 mL) and DCM (30 mL) and the two phases separated. The aqueous was further extracted with DCM (30 mL) and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc in heptane to afford the titled compound as a pale yellow gum.

[1111] 1H NMR (500 MHz, Chloroform-d) δ 8.58 (d, J=5.5 Hz, 1H), 8.10 (s, 1H), 7.92 (dd, J=5.5, 2.2 Hz, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.37-7.32 (m, 1H), 7.29 (dd, J=7.4, 1.5 Hz, 1H), 7.04-6.97 (m, 2H), 3.98 (s, 3H), 3.97 (s, 3H), 3.75 (s, 2H).

[1112] LC-MS (Method E): Rt 0.96 mins; MS m/z 301.1=[M+H]+ (99% @ 215 nm)

Step 2: 4-[[2-(2-Hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid

[1113] ##STR00039##

[1114] A solution of methyl 4-[[2-(2-methoxyphenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (119 mg, 0.4 mmol) in DCM (1.2 mL) was cooled to 0° C. and treated with 1M BBr.sub.3 in DCM (2.38 mL, 2.38 mmol) over 15 minutes and stirred at 0° C. for 1 hr. After warming to room temperature and the reaction was stirred was further 19 hours. A further portion of 1M BBr.sub.3 in DCM (1.19 mL, 1.19 mmol) was added at room temperature and stirring continued for a further 72 hours. Water (25 mL) was slowly added to the reaction mixture and then the biphasic solution was concentrated in vacuo to yield the titled compound as a brown solid.

[1115] 1H NMR (500 MHz, Methanol-d4) δ 8.68-8.60 (m, 2H), 8.39 (dd, J=6.7, 2.4 Hz, 1H), 7.18 (dd, J=7.7, 1.6 Hz, 1H), 7.15-7.10 (m, 1H), 6.85-6.79 (m, 2H), 3.84 (s, 2H). (Compound purity 85%).

[1116] LC-MS (Method E): Rt 0.74 mins; MS m/z 273.0=[M+H]+ (92% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxamide

[1117] A solution of 4-[[2-(2-hydroxyphenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (138 mg, 0.43 mmol) in DMF (1.5 mL) was treated with EDCI (107 mg, 0.56 mmol), HOAt (59 mg, 0.43 mmol), DIPEA (113 μL, 0.65 mmol) and 2-methylpropan-2-amine (45 μL, 0.43 mmol). The reaction mixture was stirred for 21 hours at room temperature and then concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH, early elution method) and the product containing fractions freeze-dried to afford the titled compound as a white solid.

[1118] 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.49 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.13 (dd, J=7.5, 1.5 Hz, 1H), 7.07 (td, J=7.8, 1.7 Hz, 1H), 6.79 (dd, J=8.0, 0.9 Hz, 1H), 6.75 (td, J=7.4, 1.1 Hz, 1H), 3.65 (s, 2H), 1.39 (s, 9H).

[1119] LC-MS (Method A): Rt 2.86 mins; MS m/z 328.2=[M+H]+ (100% @ 215 nm)

Example 1.1

N-(1,1-Dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide

[1120] ##STR00040##

Step 1: Methyl 3-[[2-(2-methoxyphenyl)acetyl]amino]benzoate

[1121] ##STR00041##

[1122] 2-(2-Methoxyphenyl)acetic acid (1.09 g, 6.62 mmol) in DMF (1.5 mL) was treated with HOAt (900 mg, 6.62 mmol), EDCI (1.65 g, 8.6 mmol), DIPEA (2.89 mL, 16.54 mmol) and methyl 3-aminobenzoate (1.0 g, 6.62 mmol) and the mixture was stirred at room temperature for 3.5 hours. The resulting mixture was partitioned between H.sub.2O (30 mL) and DCM (30 mL) and the two phases separated. The aqueous was further extracted with DCM (30 mL) and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc in heptane to afford the titled compound as a beige crystalline solid.

[1123] 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.30 (t, J=1.8 Hz, 1H), 7.86-7.80 (m, 1H), 7.62 (dt, J=7.7, 1.2 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.28-7.19 (m, 2H), 6.98 (d, J=7.9 Hz, 1H), 6.90 (td, J=7.4, 0.9 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.64 (s, 2H).

[1124] LC-MS (Method E): Rt 1.10 mins; MS m/z 300.0=[M+H]+ (100% @ 215 nm)

Step 2: 3-[[2-(2-Hydroxyphenyl)acetyl]amino]benzoic acid

[1125] ##STR00042##

[1126] A solution of methyl 3-[[2-(2-methoxyphenyl)acetyl]amino]benzoate (step 1) (1.21 g, 4.04 mmol) in DCM (15 mL) was cooled to 0° C. and treated with 1M BBr.sub.3 in DCM (16.17 mL, 16.17 mmol) over 15 minutes. After completion of addition, the mixture was stirred at 0° C. for 1 hour and then stirred at room temperature for 19 hours. Water (50 mL) was slowly added to the mixture and the DCM concentrated in vacuo. The aqueous residue was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The recovered material was suspended in DCM (7.5 mL), cooled to 0° C. and treated with 1M BBr.sub.3 in DCM (7.0 mL, 7.0 mmol) over 10 minutes. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 4 hours. Water (100 mL) was slowly added to the reaction mixture and the DCM was concentrated in vacuo. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the titled compound as a straw-coloured solid.

[1127] 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 10.22 (s, 1H), 9.47 (s, 1H), 8.24 (t, J=1.7 Hz, 1H), 7.86-7.80 (m, 1H), 7.60 (dt, J=7.7, 1.2 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.14 (dd, J=7.5, 1.4 Hz, 1H), 7.07 (td, J=7.8, 1.7 Hz, 1H), 6.80 (dd, J=8.0, 0.9 Hz, 1H), 6.75 (td, J=7.4, 1.1 Hz, 1H), 3.61 (s, 2H).

[1128] LC-MS (Method E): Rt 0.93 mins; MS m/z 272.1=[M+H]+ (92% @ 215 nm)

Step 3: N-(1,1-Dimethylpropyl)-3-[[2-(2-hydroxyphenyl)acetyl]amino]benzamide

[1129] To a solution of 3-[[2-(2-hydroxyphenyl)acetyl]amino]benzoic acid (step 2) (70 mg, 0.24 mmol) in DMF (1 mL) was added EDCI (59 mg, 0.31 mmol), HOAt (32 mg, 0.24 mmol), DIPEA (62.2 μL, 0.36 mmol) and 2-methylbutan-2-amine (36.1 μL, 0.31 mmol) and the mixture stirred at room temperature for 17 hours. The resulting mixture was partitioned between water (5 mL) and DCM (5 mL). The organic layer was collected using a hydrophobic frit and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions lyophilised overnight to afford the titled compound as an off-white powder.

[1130] 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.49 (s, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.80-7.74 (m, 1H), 7.54 (s, 1H), 7.40 (dt, J=7.7, 1.2 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.14 (dd, J=7.5, 1.6 Hz, 1H), 7.06 (td, J=7.8, 1.7 Hz, 1H), 6.80 (dd, J=8.0, 1.0 Hz, 1H), 6.75 (td, J=7.4, 1.1 Hz, 1H), 3.60 (s, 2H), 1.77 (q, J=7.5 Hz, 2H), 1.30 (s, 6H), 0.80 (t, J=7.5 Hz, 3H). LC-MS (Method A): Rt 2.96 mins; MS m/z 341.2=[M+H]+ (99% @ 215 nm).

[1131] The compounds of the following tabulated Examples (Table 1) were prepared analogously to Example 1 by replacing 2-(2-methoxyphenyl)acetic acid (step 1) and methyl 4-aminopyridine-2-carboxylate (step 1) with the appropriate commercially available acid and amine and by replacing 2-methylpropan-2-amine (step 3) with the appropriate amine.

TABLE-US-00001 TABLE 1 Ex. Structure and Name 1H NMR, LCMS Retention Time, [M+HJ+, 1.2 [00043] 1H NMR (500 MHz, DMSO-d6) δ 10.20 (br. s, 1H), 9.81 (br. s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.78-7.72 (m, 1H), 7.55 (s, 1H), 7.44-7.37 (m, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.61 (s, 2H), 2.05 (s, 9H), 1.65 (s, 6H). LC-MS (Method A): Rt 3.86 mins; MS m/z 439.3/441.3 = [M + H]+ (100% @ 215 nm) 1.3 [00044] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (br. s, 1H), 9.83 (br. s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.91 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 2.06 (s, 9H), 1.67 (s, 6H). LC-MS (Method A): Rt 4.12 mins; MS m/z 440.3/442.3 = [M + H]+ (100% @ 215 nm) 1.4 [00045] 1H NMR (500 MHz, DMSO-d6) δ 10.63 (br. s, 1H), 9.82 (br. s, 1H), 8.47-8.41 (m, 2H), 8.18-8.13 (m, 1H), 7.80 (dd, J = 5.5, 2.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.14-7.08 (m, 1H), 6.82-6.77 (m, 1H), 3.66 (s, 2H), 3.44 (t, J = 6.3 Hz, 2H), 3.23 (s, 3H), 1.95 (t, J = 6.3 Hz, 2H), 1.40 (s, 6H). LC-MS (Method A): Rt 3.15 mins; MS m/z 406.3/408.3 = [M + H]+ (100% @ 215 nm) 1.5 [00046] 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.78 (br. s, 1H), 7.88 (t, J = 1.8 Hz, 1H), 7.82-7.70 (m, 1H), 7.54 (s, 1H), 7.43-7.39 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.61 (s, 2H), 1.77 (q, J = 7.5 Hz, 2H), 1.30 (s, 6H), 0.80 (t, J = 7.5 Hz, 3H). LC-MS (Method A): Rt 3.31 mins; MS m/z 375.2/377.2 = [M + H]+ (100% @ 215 nm) 1.6 Synthesis details given at the end of the table 1.7 [00047] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.84 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.97 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 2.18-2.08 (m, 2H), 1.55-1.32 (m, 10H), 1.32- 1.20 (m, 1H). LC-MS (Method A): Rt 3.78 mins; MS m/z 402.3/404.3 = [M + H]+ (100% @ 215 nm) 1.8 [00048] 1H NMR (500 MHz, Methanol-d4) δ 8.43 (d, J = 5.5 Hz, 1H), 8.13-8.11 (m, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.19 (d, J = 2.6 Hz, 1H), 7.09 (dd, J = 8.6, 2.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 3.71 (s, 2H), 3.15-3.09 (m, 2H), 2.06-2.01 (m, 2H), 1.46 (s, 6H), 1.37 (s, 9H). LC-MS (Method A): Rt 3.44 mins; MS m/z 491.3/493.3 = [M + H]+ (100% @ 215 nm) 1.9 [00049] 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.48 (s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.81-7.73 (m, 1H), 7.56 (s, 1H), 7.43-7.38 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.14 (dd, J = 7.5, 1.5 Hz, 1H), 7.06 (td, J = 7.8, 1.7 Hz, 1H), 6.80 (dd, J = 8.0, 1.0 Hz, 1H), 6.75 (td, J = 7.4, 1.1 Hz, 1H), 3.60 (s, 2H), 3.51 (s, 2H), 3.27 (s, 3H), 1.32 (s, 6H). LC-MS (Method A): Rt 2.70 mins; MS m/z 357.2 = [M + H]+ (99% @ 215 nm)

Example 1.6

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide

[1132] ##STR00050##

[1133] To a solution of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1)(800 mg, 2.61 mmol), 1-methylcyclobutanamine hydrochloride (381 mg, 3.13 mmol) and TEA (800 μL, 5.74 mmol) in DMF (15 mL) was added HATU (1.19 g, 3.13 mmol) and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed sequentially with aqueous 1M HCl, sat. aqueous NaHCO.sub.3, brine and 1M NaOH solution. The organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 50-100% ethyl acetate in heptanes afforded a pale yellow foam. The isolated material was recrystallised by dissolving in methanol (15 mL) and heating to reflux until all solids had dissolved. The mixture was allowed to cool slowly to room temperature. The resulting crystals were filtered to afford the titled compound as a pale yellow solid.

[1134] 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.81 (s, 1H), 8.47 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.15 (d, J=1.9 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 2.42-2.36 (m, 2H), 2.02-1.96 (m, 2H), 1.84-1.77 (m, 2H), 1.47 (s, 3H).

[1135] LC-MS (Method A): Rt 3.24 mins; MS m/z 374.3/376.3=[M+H]+ (100% @ 215 nm)

Example 1.10

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide

[1136] ##STR00051##

Step 1: 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide

[1137] ##STR00052##

[1138] A solution of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1 step 2) (3.0 g, 9.07 mmol), cyclohexanamine (1.25 mL, 10.89 mmol), EDCI (2.09 g, 10.89 mmol), HOAt (1.48 g, 10.89 mmol) and DIPEA (3.17 mL, 18.15 mmol) in DMF (30 mL) was stirred at room temperature for 19.5 hours. The resulting mixture was concentrated in vacuo and the residue partitioned between EtOAc (200 mL) and water (200 mL). The organic portion was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (2×100 mL), brine (2×100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as red/brown solid.

[1139] 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.38 (d, J=8.6 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.35-7.27 (m, 2H), 7.05-6.98 (m, 1H), 3.76 (s, 3H), 3.71 (s, 2H), 1.85-1.67 (m, 4H), 1.64-1.53 (m, 1H), 1.45-1.27 (m, 4H), 1.25-1.03 (m, 2H).

[1140] LC-MS (Method E): Rt 1.26 mins; MS m/z 402.0/404.1=[M+H]+ (89% @ 215 nm)

Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide

[1141] 1M BBr.sub.3 in DCM (21.26 mL, 21.26 mmol) was added to a stirred suspension of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (step 1) (3.2 g, 7.09 mmol) in DCM (50 mL) at 0° C. After addition the ice bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by slow addition of water (˜70 mL) and the mixture was partially concentrated in vacuo to remove volatile solvent. EtOAc (200 mL) was added followed by water (100 mL). The organic portion was separated and the aqueous layer extracted with EtOAc (100 mL). The combined organics were washed with sat. NaHCO.sub.3 (2×150 mL), brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography eluting with 10-100% MeCN in water with 0.1% formic acid to afford a dark brown/orange solid. The solid was dissolved in a minimum volume of boiling MeCN (˜100 mL) and allowed to stand overnight. The resulting crystals were collected by vacuum filtration and dried in a vacuum oven at 40° C. for 5 hours to afford the titled compound as pale beige needles.

[1142] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (br s, 1H), 9.81 (br s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.38 (d, J=8.6 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.83-3.70 (m, 1H), 3.66 (s, 2H), 1.85-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.63-1.54 (m, 1H), 1.45-1.25 (m, 4H), 1.21-1.07 (m, 1H).

[1143] LC-MS (Method A): Rt 3.46 mins; MS m/z 388.2/390.1=[M+H]+ (100% @ 215 nm)

Example 2

N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide

[1144] ##STR00053##

Step 1a: tert-Butyl N-[3-(tert-butylcarbamoyl)phenyl]carbamate

[1145] ##STR00054##

[1146] Commercially available 3-(tert-butoxycarbonylamino)benzoic acid (2.5 g, 10.54 mmol) in DMF (40 mL) was treated with HOAt (1.43 g, 10.54 mmol), EDCI (2.63 g, 13.7 mmol), TEA (1.9 mL, 13.7 mmol) and 2-methylpropan-2-amine (1.44 mL, 13.7 mmol) and stirred at room temperature for 2 hours. The resulting mixture was diluted with water (100 mL) with stirring and the resulting white suspension collected by filtration. The filter cake was washed with water (3×15 mL) and oven-dried to afford the titled compound as an off-white solid.

[1147] 1H NMR (500 MHz, Methanol-d4) δ 7.78-7.70 (m, 1H), 7.52-7.46 (m, 1H), 7.38-7.28 (m, 2H), 1.53 (s, 9H), 1.45 (s, 9H).

[1148] LC-MS (Method E): Rt 1.17 mins; MS m/z 293.0=[M+H]+ (100% @ 215 nm)

Step 1b: 3-Amino-N-tert-butyl-benzamide hydrochloride

[1149] ##STR00055##

[1150] tert-butyl N-[3-(tert-butylcarbamoyl)phenyl]carbamate (step 1a) (5.3 g, 18.13 mmol) was suspended in 1,4-dioxane (20 mL) and then 4M HCl in dioxane (9.59 mL, 271.92 mmol) was added. After stirring at room temperature for 24 hours, the resulting mixture was concentrated in vacuo and azeotroped with methanol. The resulting foam was dried in the vacuum oven at 40° C. for a further 3 hours to afford the titled compound as a light orange foam.

[1151] 1H NMR (500 MHz, DMSO-d6) δ 10.25 (br s, 2H), 7.91 (s, 1H), 7.76 (d, J=7.1 Hz, 1H), 7.71-7.68 (m, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.47-7.43 (m, 1H), 1.37 (s, 9H).

[1152] LC-MS (Method E): Rt 0.73 mins; MS m/z 193.1=[M+H]+ (99% @ 215 nm)

Step 2: 2-(5-Chloro-2-methoxy-phenyl)acetic acid

[1153] ##STR00056##

[1154] To a cooled (−10° C.), stirred solution of 2-(2-methoxyphenyl)acetic acid (2.0 g, 12.04 mmol) in THF (34.8 mL) was added dropwise sulfuryl chloride (1.37 mL, 16.85 mmol) over 15 mins and stirring continued for 1 hour. The reaction was quenched with ice cold water (34.8 mL) and extracted into EtOAc (3×50 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as a pink solid.

[1155] 1H NMR (250 MHz, DMSO-d6) δ 12.24 (s, 1H), 7.30 (d, J=2.7 Hz, 2H), 6.99 (d, J=8.8 Hz, 1H), 3.76 (s, 3H), 3.51 (s, 2H).

[1156] LC-MS (Method E): Rt 1.01 mins; MS m/z no characteristic mass ion observed

Step 3: N-tert-Butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzamide

[1157] ##STR00057##

[1158] To 2-(5-chloro-2-methoxy-phenyl)acetic acid (step 2) (114 mg, 0.57 mmol) in DMF (3 mL) was added HOAt (77 mg, 0.57 mmol), EDCI (142 mg, 0.74 mmol), DIPEA (248 μL, 1.42 mmol) and 3-amino-N-tert-butyl-benzamide hydrochloride (step 1b) (130 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned between water (8 mL) and (DCM (8 mL) and the phases separated using a PTFE-fritted phase separator. The organic layer was concentrated in vacuo and the crude product purified by chromatography on silica eluting with EtOAc in heptane. The product fractions were in vacuo to afford the titled compound as a white solid.

[1159] 1H NMR (500 MHz, Chloroform-d) δ 7.76-7.64 (m, 3H), 7.41-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.30-7.26 (m, 2H), 6.88 (d, J=8.6 Hz, 1H), 5.97 (br. s, 1H), 3.92 (s, 3H), 3.68 (s, 2H), 1.45 (s, 9H).

[1160] LC-MS (Method E): Rt 1.20 mins; MS m/z 375.0/377.0=[M+H]+ (94% @ 215 nm)

Step 4: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzamide

[1161] A solution of N-tert-butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzamide (step 3) (3.83 g, 10.2 mmol) in DCM (80 mL) was cooled to 0° C. and 1M BBr.sub.3 in DCM (20.4 mL, 20.4 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting mixture was diluted with water (10 mL) and the volatile solvent was removed in vacuo to afford a gummy residue. The residue was dissolved in EtOAc (60 mL) and saturated sodium bicarbonate (60 mL) and stirred for 1 hour to ensure full dissolution. The biphasic mixture was separated and the organic portion was washed with saturated sodium bicarbonate solution (80 mL), brine (80 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford a thick beige oil. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in heptane yielded a white foam. The material was azeotroped with MeCN (2×80 mL) then dissolved in boiling MeCN (˜30 mL) and allowed to cool to room temperature. After 3 hours, the resulting crystalline solid was collected by filtration and recrystallized again from boiling MeCN (40 mL) to afford the titled compound as a white crystalline solid.

[1162] 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.81 (s, 1H), 7.90 (t, J=1.7 Hz, 1H), 7.78-7.72 (m, 1H), 7.69 (s, 1H), 7.42 (dt, J=7.8, 1.1 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 1.36 (s, 9H).

[1163] LC-MS (Method A): Rt 3.19 mins; MS m/z 361.1/363.2=[M+H]+ (100% @ 215 nm)

[1164] The compounds of the following tabulated Examples (Table 2) were prepared analogously to Example 2 by replacing 2-(5-chloro-2-methoxy-phenyl)acetic acid (step 2) with the appropriate commercially available acid.

TABLE-US-00002 TABLE 2 1H NMR, LCMS Retention Time, Ex. Structure and Name [M + H]+, 2.1 [00058] 1H NMR (500 MHz, DMSO-d6) δ 10.17 (br. s, 1H), 9.49 (br. s, 1H), 7.94-7.86 (m, 1H), 7.79-7.73 (m, 1H), 7.69 (s, 1H), 7.44-7.37 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.00 (dd, J = 9.4, 3.2 Hz, 1H), 6.89 (td, J = 8.6, 3.2 Hz, 1H), 6.77 (dd, J = 8.8, 4.9 Hz, 1H), 3.61 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.83 mins; MS m/z 345.2 = [M + H]+ (99% @ 215 nm) 2.2 [00059] 1H NMR (500 MHz, DMSO-d6) δ 10.25 (br. s, 1H), 9.65 (br. s, 1H), 7.90 (t, J = 1.7 Hz, 1H), 7.79-7.73 (m, 1H), 7.69 (s, 1H), 7.47-7.39 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.09- 7.01 (m, 1H), 7.01-6.94 (m, 1H), 6.81-6.69 (m, 1H), 3.68 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.80 mins; MS m/z 345.2 = [M + H]+ (99% @ 215 nm) 2.3 [00060] 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 10.03 (br. s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.4-3679-7.73 (m, 1H), 7.70 (s, 1H), 7.47-7.38 (m, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.20-7.11 (m, 1H), 6.62-6.52 (m, 2H), 3.57 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.87 mins; MS m/z 345.2 = [M + H]+ (100% @ 215 nm) 2.4 [00061] 1H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.29 (br. s, 2H), 7.88 (t, J = 1.8 Hz, 1H), 7.77-7.71 (m, 1H), 7.69 (s, 1H), 7.42-7.36 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 8.1 Hz, 1H), 6.30 (d, J = 8.1 Hz, 2H), 3.59 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.36 mins; MS m/z 343.2 = [M + H]+ (99% @ 215 nm) 2.5 [00062] 1H NMR (500 MHz, DMSO-d6) δ 9.99 (br. s, 1H), 9.35 (br. s, 1H), 7.92- 7.85 (m, 1H), 7.80-7.73 (m, 1H), 7.70 (s, 1H), 7.44-7.38 (m, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.09 (dd, J = 7.4, 1.3 Hz, 1H), 7.00 (td, J = 7.8, 1.6 Hz, 1H), 6.81-6.77 (m, 1H), 6.70 (td, J = 7.4, 0.9 Hz, 1H), 2.87- 2.79 (m, 2H), 2.61-2.55 (m, 2H), 1.37 (s, 9H). LC-MS (Method A): Rt 2.83 mins; MS m/z 341.2 = [M + H]+ (100% @ 215 nm) 2.6 [00063] 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.44 (br. s, 1H), 7.89 (t, J = 1.8 Hz, 1H), 7.76-7.70 (m, 1H), 7.68 (s, 1H), 7.43-7.36 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.02 (t, J = 8.2 Hz, 1H), 6.49-6.43 (m, 2H), 3.71 (s, 3H), 3.61 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.76 mins; MS m/z 357.2 = [M + H]+ (100% @ 215 nm) 2.7 [00064] 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.67 (br. s, 1H), 7.97- 7.86 (m, 1H), 7.80-7.74 (m, 1H), 7.69 (s, 1H), 7.43-7.38 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 7.6, 1.3 Hz, 1H), 7.05 (td, J = 8.0, 1.4 Hz, 1H), 6.84-6.79 (m, 1H), 6.79-6.72 (m, 1H), 4.10 (q, J = 7.0 Hz, 1H), 1.49-1.21 (m, 12H). LC-MS (Method A): Rt 2.96 mins; MS m/z 341.2 = [M + H]+ (100% @ 215 nm) 2.8 [00065] 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.72 (br. s, 1H), 7.94-7.86 (m, 1H), 7.80-7.73 (m, 1H), 7.70 (s, 1H), 7.44-7.38 (m, 1H), 7.32 (t, J = 7.9 Hz, 1H), 6.86 (dd, J = 7.9, 1.5 Hz, 1H), 6.80-6.75 (m, 1H), 6.75-6.68 (m, 1H), 3.78 (s, 3H), 3.61 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.79 mins; MS m/z 357.3 = [M + H]+ (98% @ 215 nm) 2.9 [00066] 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.60 (br. s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.71 (s, 1H), 7.45-7.40 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.14-7.06 (m, 1H), 6.95-6.88 (m, 1H), 3.70 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.91 mins; MS m/z 363.2 = [M + H]+ (98% @ 215 nm) 2.10 [00067] 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.83 (s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.80-7.73 (m, 1H), 7.70 (s, 1H), 7.45-7.39 (m, 1H), 7.37- 7.29 (m, 2H), 7.23 (dd, J = 8.6, 2.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 3.61 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.14 mins; MS m/z 405.2/407.2 = [M + H]+ (100% @ 215 nm) 2.11 [00068] 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 10.01 (s, 1H), 7.89 (t, J = 1.8 Hz, 1H), 7.76-7.68 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.12 (q, J = 9.4 Hz, 1H), 6.61 (ddd, J = 8.9, 3.9, 1.6 Hz, 1H), 3.69 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.91 mins; MS m/z 363.2 = [M + H]+ (100% @ 215 nm) 2.12 [00069] 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.89 (t, J = 1.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.70 (s, 1H), 7.44-7.39 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.22 (dd, J = 11.4, 9.5 Hz, 1H), 6.75 (dd, J = 12.3, 7.2 Hz, 1H), 3.59 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.99 mins; MS m/z 363.2 = [M + H]+ (100% @ 215 nm) 2.13 [00070] 1H NMR (500 MHz, Methanol-d4) δ 7.88 (t, J = 1.8 Hz, 1H), 7.67 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.53 (s, 1H), 7.47-7.41 (m, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.16 (dd, J = 8.1, 6.9 Hz, 1H), 6.59-6.50 (m, 2H), 3.66 (s, 2H), 1.86 (q, J = 7.5 Hz, 2H), 1.38 (s, 6H), 0.90 (t, J = 7.5 Hz, 3H). LC- MS (Method A): Rt 3.08 mins; MS m/z 359.2 = [M + H]+ (100% @ 215 nm) 2.14 [00071] 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.58 (br. s, 1H), 7.90 (t, J = 1.6 Hz, 1H), 7.80-7.73 (m, 1H), 7.70 (s, 1H), 7.46-7.38 (m, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 6.35 (dd, J = 8.3, 2.5 Hz, 1H), 3.68 (s, 3H), 3.52 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.78 mins; MS m/z 357.3 = [M + H]+ (100% @ 215 nm) 2.15 [00072] 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 10.15 (br. s, 1H), 7.94-7.86 (m, 1H), 7.76-7.72 (m, 1H), 7.71 (s, 1H), 7.44-7.38 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.12-7.05 (m, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 8.8 Hz, 1H), 3.64 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.82 mins; MS m/z 345.2 = [M + H]+ (97% @ 215 nm) 2.16 [00073] 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.21 (br. s, 1H), 8.50 (br. s, 1H), 7.89 (t, J = 1.8 Hz, 1H), 7.79-7.73 (m, 1H), 7.70 (s, 1H), 7.41 (dt, J = 7.6, 1.1 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 6.68 (dd, J = 7.6, 1.8 Hz, 1H), 6.61 (dd, J = 7.6, 1.8 Hz, 1H), 6.57 (t, J = 7.6 Hz, 1H), 3.59 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.48 mins; MS m/z 343.2 = [M + H]+ (100% @ 215 nm) 2.17 [00074] 1H NMR (500 MHz, DMSO-d6) δ 11.12-9.35 (m, 2H), 7.90 (t, J = 1.8 Hz, 1H), 7.77-7.72 (m, 1H), 7.70 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.46- 7.38 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.69 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.27 mins; MS m/z 395.2 = [M + H]+ (100% @ 215 nm) 2.18 [00075] 1H NMR (500 MHz, DMSO-d6) δ 10.48 (br s, 1H), 10.22 (s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.79-7.74 (m, 1H), 7.73 (dd, J = 8.5, 2.2 Hz, 1H), 7.71 (s, 1H), 7.46-7.39 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.78 mins; MS m/z 385.2 = [M + H]+ (98% @ 215 nm) 2.19 [00076] 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 2H), 7.90 (t, J = 1.8 Hz, 1H), 7.80-7.73 (m, 1H), 7.70 (s, 1H), 7.47- 7.40 (m, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.12-7.08 (m, 1H), 7.08-7.05 (m, 1H), 3.69 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.30 mins; MS m/z 395.2 = [M + H]+ (100% @ 215 nm)

Example 3

N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1165] ##STR00077##

Step 1: 4-Amino-N-tert-butyl-pyridine-2-carboxamide

[1166] ##STR00078##

[1167] To a mixture of 4-aminopyridine-2-carboxylic acid (8.0 g, 57.92 mmol), TBTU (22.32 g, 69.5 mmol) and TEA (24.22 mL, 173.76 mmol) in DMF (100 mL) was added 2-methylpropan-2-amine (7.30 mL, 69.5 mmol). The resulting mixture was stirred at room temperature for 22 hours and then concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 3.5M methanolic ammonia in DCM and product fractions combined and concentrated in vacuo to yield the titled compound as a light yellow solid.

[1168] 1H NMR (500 MHz, Methanol-d4) δ 7.99 (d, J=5.6 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 6.62 (dd, J=5.6, 2.4 Hz, 1H), 1.45 (s, 9H).

[1169] LC-MS (Method F): Rt 1.47 mins; MS m/z 194.3=[M+H]+ (100% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1170] ##STR00079##

[1171] A solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (2.26 g, 11.27 mmol) in thionyl chloride (8.13 mL, 92.21 mmol) was heated at 70° C. for 30 minutes. After cooling to room temperature, excess thionyl chloride was removed in vacuo, azeotroping with toluene. The resulting residue was dissolved in DCM (5 mL) and added to a solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (step 1) (2.0 g, 10.25 mmol) and DIPEA (2.15 mL, 12.29 mmol) in DCM (25 mL). The mixture stirred at room temperature for 1 hour and then diluted with water (50 mL) and extracted with DCM. The combined organic extracts were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 0-50% EtOAc in heptane to afford the titled compound as a pale orange powder.

[1172] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J=5.6 Hz, 1H), 8.20 (dd, J=5.6, 2.2 Hz, 1H), 8.10 (br s, 1H), 7.98 (br s, 1H), 7.56 (d, J=2.1 Hz, 1H), 7.29-7.26 (m, 2H), 6.89 (d, J=9.5 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 2H), 1.47 (s, 9H).

[1173] LC-MS (Method E): Rt 1.21 mins; MS m/z 376.1/378.1=[M+H]+ (92% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1174] To a solution of N-tert-butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (2.7 g, 6.82 mmol, 95%) in DCM (10 mL) at 0° C. was added dropwise 1M BBr.sub.3 in DCM (27.3 mL, 27.3 mmol). Once addition was complete the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by slow addition of water (10 mL) and the DCM removed in vacuo. The resulting residue was dissolved in EtOAc and washed with sat. NaHCO.sub.3 solution (50 mL) and brine (50 mL). The organic portion was separated, dried Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 0-70% EtOAc in heptane to afford the product as an orange powder. This was further purified by reverse phase chromatography eluting with 0-100% MeCN in water with 0.1% formic acid to give the product as a colourless powder. The product was recrystallised from MeCN to afford the titled compound. A second crop was isolated by dropwise addition of water to the MeCN filtrate followed by heating and cooling of the mixture.

[1175] 1H NMR (500 MHz, DMSO-d6) δ 10.69 (br s, 1H), 9.82 (br s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.40 (s, 9H).

[1176] LC-MS (Method A): Rt 3.28 mins; MS m/z 362.1/364.1=[M+H]+ (99% @ 215 nm)

[1177] Compounds of the following tabulated Examples (Table 3a) were prepared analogously to Example 3 by replacing 2-methylpropan-2-amine (step 1) with the appropriate amine and by replacing 2-(5-chloro-2-methoxy-phenyl)acetic acid (step 2) with the appropriate commercially available acid.

TABLE-US-00003 TABLE 3a 1H NMR, LCMS Retention Time, Ex. Structure and Name [M + H]+, 3.1a [00080] 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.05 (br. s, 1H), 8.49-8.40 (m, 1H), 8.20-8.14 (m, 1H), 7.94 (s, 1H),7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.21-7.09 (m, 1H), 6.65-6.49 (m, 2H), 3.63 (s, 2H), 1.77 (q, J = 7.5 Hz, 2H), 1.34 (s, 6H), 0.81 (t, J = 7.5 Hz, 3H). LC-MS (Method A): Rt 3.25 mins; MS m/z 360.3 = [M + H]+ (100% @ 215 nm) 3.2a [00081] 1H NMR (500 MHz, DMSO-d6) δ 12.34-9.82 (m, 2H), 9.28- 9.21 (m, 1H), 9.00-8.96 (m, 1H), 8.84 (s, 1H), 8.62 (dd, J = 5.5, 2.2 Hz, 1H), 8.01-7.92 (m, 1H), 7.43-7.35 (m, 2H), 4.44 (s, 2H), 2.20 (s, 9H). LC-MS (Method A): Rt 3.00 mins; MS m/z 346.2 = [M + H]+ (100% @ 215 nm) 3.3a [00082] 1H NMR (500 MHz, Methanol-d4) δ 8.44-8.39 (m, 1H), 8.11- 8.07 (m, 1H), 7.91 (dd, J = 5.6, 2.2 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 6.91 (dd, J = 8.1, 1.0 Hz, 1H), 6.77 (dd, J = 8.2, 1.0 Hz, 1H), 3.96 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.17 mins; MS m/z 362.2/364.2 = [M + H]+ (98% @ 215 nm) 3.4a [00083] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 10.27 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.43 (s, 1H), 7.12 (s, 1H), 3.67 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.59 mins; MS m/z 440.0/441.9/443.9 = [M + H]+ (95% @ 215 nm) 3.5a [00084] 1H NMR (500 MHz, Methanol-d4) δ 8.48 (d, J = 5.5 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.4, 2.5 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.72 (s, 2H), 2.84-2.75 (m, 2H), 2.63-2.53 (m, 2H), 2.28-2.16 (m, 1H), 2.18-2.06 (m, 1H), 1.28 (s, 9H). LC-MS (Method A): Rt 3.40 mins; MS m/z 407.4 = [M + H]+ (98% @ 215 nm) 3.6a [00085] 1H NMR (500 MHz, Methanol-d4) δ 8.43 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 5.5, 2.0 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.15 (dd, J = 8.4, 2.5 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.72 (s, 2H), 2.50-2.39 (m, 2H), 2.17-2.07 (m, 2H), 1.97-1.85 (m, 2H), 1.55 (s, 3H), 1.28 (s, 9H). LC-MS (Method A): Rt 3.77 mins; MS m/z 396.4 = [M + H]+ (100% @ 215 nm) 3.7a [00086] 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.74 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 4.03 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.61 mins; MS m/z 502.1/504.1/506.1 = [M + H]+ (99% @ 215 nm)

Example 3.5b

N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1178] ##STR00087##

Step 1: N-tert-butyl-4-[[2-[2-methoxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1179] ##STR00088##

[1180] To a solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (70 mg, 0.36 mmol), TEA (127 μL, 0.72 mmol) and 2-[2-methoxy-5-(trifluoromethyl)phenyl]acetic acid (102 mg, 0.43 mmol) in 1,4-dioxane (1 mL) was added T3P® 50% solution in EtOAc (948 μL, 0.8 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned between water (25 mL) and EtOAc (25 mL). The organic layer was separated, washed with water (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with EtOAc in heptane to afford the titled compound as a pale yellow solid.

[1181] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.69-7.61 (m, 2H), 7.18 (d, J=8.5 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 2H), 1.40 (s, 9H).

[1182] LC-MS (Method E): Rt 1.23 mins; MS m/z 410.0=[M+H]+ (93% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1183] The titled compound was prepared from N-tert-butyl-4-[[2-[2-methoxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide (step 2) analogously to Example 3 step 3.

[1184] 1H NMR (500 MHz, DMSO-d6) δ 11.32-9.82 (m, 2H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.45 (dd, J=8.5, 2.1 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 3.76 (s, 2H), 1.40 (s, 9H).

[1185] LC-MS (Method A): Rt 3.41 mins; MS m/z 396.2=[M+H]+ (100% @ 215 nm)

[1186] Compounds of the following tabulated Examples (Table 3b) were prepared analogously Example 3.5b steps 1 and 2 by replacing 2-[2-methoxy-5-(trifluoromethyl)phenyl]acetic acid (step 1) with the appropriate commercially available acid.

TABLE-US-00004 TABLE 3b Ex. Structure and Name 1H NMR LCMS Retention Time, [M + H]+, 3.6b [00089] 1H NMR (500 MHz, Methanol-d4) δ 8.42 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H),7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.84 − 6.77 (m, 2H), 3.70 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.33 mins; MS m/z 362.1/364.1 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-4-[[2-(4-chloro-2-hydroxy- phenyl)acetyl]amino]pyridine-2-carboxamide 3.7b [00090] 1H NMR (500 MHz, DMSO-d6) δ 10.81 (brs, 1H), 10.30 (brs, 1H),8.44 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.16 − 7.00 (m, 2H), 3.75 (s, 2H), 1.40 (s, 9H LC-MS (Method A): Rt 3.44 mins; MS m/z 396.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-[2-hydroxy-4-(trifluoro methyl)phenyl]acetyl]amino]pyridine-2- carboxamide 3.8b [00091]   1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.06 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 6.76 (d, J = 3.0 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 6.67 (dd, J = 8.7, 3.0 Hz, 1H), 3.66 (s, 3H), 3.63 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.87 mins; MS m/z 358.2 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-4-[[2-(2-hydroxy-5-methoxy- phenyl)acetyl]amino]pyridine-2-carboxamide 3.9b [00092] 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.16 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.60 (dd, J = 8.1, 2.2 Hz, 1H), 4.07 (t, J = 7.4 Hz, 1H), 2.98 − 2.90 (m, 1H), 2.83 − 2.73 (m, 1H), 2.39 − 2.23 (m, 2H), 1.41 (s, 9H). LC-MS (Method A): Rt 3.00 mins; MS m/z 354.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[(6-hydroxyindane-1- carbonyl)amino]pyridine-2-carboxamide 3.10b [00093]   1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.49 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H), 4.11 (dd, J = 8.6, 5.3 Hz, 1H), 3.06 − 2.98 (m, 1H), 2.89 − 2.81 (m, 1H), 2.36 − 2.29 (m, 1H), 2.25 − 2.17 (m, 1H), 1.41 (s, 9H). LC-MS (Method A): Rt 3.26 mins; MS m/z 354.2 = [M + H]+ (96% @ 215 nm) N-tert-Butyl-4-[(7-hydroxyindane-1- carbonyl)amino]pyridine-2-carboxamide 3.11b [00094] 1H NMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 10.06 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.79 (dd, J = 5.5, 2.2 Hz, 1H), 4.07 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.84 mins; MS m/z 518.0/520.0/522.1 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-4-[[2-(2,5-dibromo-3-chloro-6-hydroxy- phenyl)acetyl]amino]pyridine-2-carboxamide 3.12b [00095] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.35 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.76 − 6.72 (m, 2H), 6.68 − 6.62 (m, 1H), 3.60 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 2.68 mins; MS m/z 328.2 = [M + H]+ (99% @ 215 nm). N-tert-Butyl-4-[[2-(3-hydroxyphenyl) acetyl]amino]pyridine-2-carboxamide 3.13b [00096] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.33 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 6.97 (t, J = 9.2 Hz, 1H), 6.75 (dd, J = 6.2, 3.0 Hz, 1H), 6.65 (ddd, J = 8.8, 4.0, 3.2 Hz, 1H), 3.70 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.74 mins; MS m/z 346.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(2-fluoro-5-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide 3.14b [00097] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.14 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.1, 2.0 Hz, 1H), 3.62 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.01 mins; MS m/z 362.2/364.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(4-chloro-3-hydroxy- phenyl)acetyl]amino]pyridine-2-carboxamide 3.15b [00098] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.10 (br s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.90 (dd, J = 8.2, 1.4 Hz, 1H), 6.84 (dd, J = 7.6, 1.4 Hz, 1H), 3.85 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 2.97 mins; MS m/z 362.2/364.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(2-chloro-3-hydroxy- phenyl)acetyl]amino]pyridine-2-carboxamide 3.16b [00099] 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.64 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 2.9 Hz, 1H), 6.70 (dd, J = 8.7, 2.9 Hz, 1H), 3.79 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.98 mins; MS m/z 362.2/364.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(2-chloro-5-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide 3.17b [00100] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.96 (br. s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 6.83 (t, J = 1.6 Hz, 1H), 6.73 − 6.68 (m, 2H), 3.64 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.12 mins; MS m/z 362.2/364.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(3-chloro-5-hydroxy- phenyl)acetyl]amino]pyridine-2-carboxamide

Example 4

N-tert-Butyl-3-[[2-(3-hydroxyphenyl)acetyl]amino]benzamide

[1187] ##STR00101##

[1188] A mixture comprising 3-amino-N-tert-butyl-benzamide hydrochloride (Example 2 step 1b) (50 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol), DIPEA (0.09 mL, 0.52 mmol) in DCM (1.25 mL) was treated with 2-(3-hydroxyphenyl)acetic acid (33 mg, 0.22 mmol) and stirred at room temperature for 1 hour. The resulting mixture was diluted with water (5 mL) and extracted with DCM (3×5 mL). The combined organics were passed through a PTFE phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were concentrated and dried in vacuo to afford the titled compound as a white solid.

[1189] 1H NMR (500 MHz, Methanol-d4) δ 7.90 (t, J=1.8 Hz, 1H), 7.72 (s, 1H), 7.69 (ddd, J=8.0, 2.1, 1.1 Hz, 1H), 7.49-7.45 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.19-7.13 (m, 1H), 6.87-6.81 (m, 2H), 6.73-6.68 (m, 1H), 3.63 (s, 2H), 1.46 (s, 9H).

[1190] LC-MS (Method B): Rt 2.56 mins; MS m/z 344.3=[M+NH.sub.3]+ (99% @ 215 nm)

[1191] The compounds of the following tabulated Examples (Table 4) were prepared analogously to Example 4 by replacing 2-(3-hydroxyphenyl)acetic acid with the appropriate commercially available acid.

TABLE-US-00005 TABLE 4 Ex. Structure and Name 1H NMR LCMS Retention Time, [M + H]+, 4.1 [00102] 1H NMR (500 MHz, Chloroform-d) δ 10.12 (s, 1H), 8.93 (s, 1H), 7.83 − 7.75 (m, 3H), 7.52 (d, J = 8.4 Hz, 1H), 7.47 − 7.43 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 5.96 (s, 1H), 4.14 (s, 2H), 1.46 (s, 9H). LC-MS (Method A): Rt 2.64 mins; MS m/z 351.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-3-[[2-(1H-indazol-3-yl)acetyl]amino]benzamide 4.2 [00103] 1H NMR (500 MHz, Chloroform-d) δ 8.67 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.61 − 7.57 (m, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.34 − 7.27 (m, 2H), 7.22 (dd, J = 9.5, 2.1 Hz, 2H), 6.98 (td, J = 9.0, 2.4 Hz, 1H), 5.97 (s, 1H), 3.82 (s, 2H), 1.44 (s, 9H). LC-MS (Method A): Rt 2.97 mins; MS m/z 368.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-3-[[2-(5-fluoro-1H-indol-3-yl)acetyl] amino]benzamide 4.3 [00104] 1H NMR (500 MHz, Methanol-d4) δ 7.86 (t, J = 1.7 Hz, 1H), 7.70-7.63 (m, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.9 Hz 6.75 (m, 2H), 3.70 (s, 2H), 1H), 7.19 (d, J = 7.5 Hz, 1H), 7.11 (td, J = 8.0, 1.6 Hz, 1H), 6.89 − 1.44 (s, 9H). LC-MS (Method A): Rt 2.72 mins; MS m/z 327.3 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-3-[[2-(2-hydroxyphenyl)acetyl]amino] benzamide 4.4 [00105] 1H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.71 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H), 7.54 (t, J = 1.9 Hz, 1H), 7.40 (s, 1H), 7.35 (dt, J = 7.7, 1.3 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.04 (td, J = 7.9, 4.7 Hz, 1H), 6.90 (ddd, J = 11.0, 7.9, 0.6 Hz, 1H), 5.93 (s, 1H), 3.81 (s, 2H), 2.47 (s, 3H), 1.43 (s, 9H). LC-MS (Method A): Rt 3.15 mins; MS m/z 382.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-3-[[2-(7-fluoro-2-methyl-1H-indol-3- yl)acetyl]amino]benzamide 4.5 [00106]   N-tert-Butyl-3-[[2-(1H-indol-3-yl)acetyl]amino]benzamide 1H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.19 (s, 1H), 7.89 (t, J = 1.8 Hz, 1H), 7.81 − 7.75 (m, 1H), 7.70 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.41 (dt, J = 7.9, 1.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.07 (td, J = 8.0, 7.0, 1.1 Hz, 1H), 6.98 (td, J = 7.5, 7.1, 0.9 Hz, 1H), 3.73 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 2.91 mins; MS m/z 350.2 = [M + H]+ (100% @ 215 nm) 4.6 [00107] 1H NMR (500 MHz, Chloroform-d) δ 7.72 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.44 − 7.38 (m, 3H), 7.38 − 7.31 (m, 4H), 7.13 (s, 1H), 5.95 (s, 1H), 3.76 (s, 2H), 1.45 (s, 9H). LC-MS (Method A): Rt 2.96 mins; MS m/z 311.2 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-3-[(2-phenylacetyl)amino]benzamide 4.7 [00108] 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.92 − 7.87 (m, 1H), 7.75 − 7.67 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.35 − 7.25 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.80 (t, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.01 mins; MS m/z 359.1 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-3-[[2-(2-fluoro-6-methoxy- phenyl)acetyl]amino]benzamide 4.8 [00109] 1H NMR (500 MHz, Chloroform-d) δ 7.75 (t, J = 1.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.10 (q, J = 9.2 Hz, 1H), 6.65 (ddd, J = 9.2, 3.4, 2.0 Hz, 1H), 5.97 (s, 1H), 3.90 (s, 3H), 3.79 (d, J = 1.6 Hz, 2H), 1.45 (s, 9H). LC-MS (Method A): Rt 3.19 mins; MS m/z 377.3 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-3-[[2-(2,3-difluoro-6-methoxy- phenyl)acetyl]amino]benzamide 4.9 [00110] 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.79 − 7.68 (m, 2H), 7.44 (dd, J = 14.6, 7.8 Hz, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 1.36 (s, 9H). LC-MS (Method A): Rt 3.45 mins; MS m/z 409.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-3-[[2-[2-methoxy-4-(trifluoromethyl) phenyl]acetyl]amino]benzamide

Example 5

N-tert-Butyl-4-[[2-(2-thienyl)acetyl]amino]pyridine-2-carboxamide

[1192] ##STR00111##

[1193] A solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (50 mg, 0.26 mmol), 2-(2-thienyl)acetic acid (37 mg, 0.26 mmol) and TEA (0.09 mL, 0.52 mmol) in 1,4-dioxane (2 mL) was treated with 50% T3P® solution in EtOAc (617 μL, 0.97 mmol) and stirred at room temperature under an inert atmosphere for 1 hour. The resulting mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). The organic portion was separated and concentrated in vacuo. Purification by preparative HPLC (acidic pH, standard elution method) and freeze drying of the product fractions afforded the titled compound as a white solid.

[1194] 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.41 (dd, J=5.0, 1.4 Hz, 1H), 7.03-6.94 (m, 2H), 3.95 (s, 2H), 1.40 (s, 9H)

[1195] LC-MS (Method A): Rt 3.19 mins; MS m/z 318.2=[M+H]+ (99% @ 215 nm).

Example 5.1

4-[[2-(2-Adamantyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1196] ##STR00112##

[1197] A solution of 2-(2-adamantyl)acetic acid (40 mg, 0.21 mmol) in thionyl chloride (160 μL, 1.82 mmol) was heated at 70° C. for 30 minutes. Excess thionyl chloride was removed in vacuo (azeotropic drying with DCM) and the residue was treated with a mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (40 mg, 0.21 mmol) and DIPEA (43 μL, 0.25 mmol) in DCM (1.5 mL) and stirred at room temperature for 1 hour. The resulting mixture was partitioned with water (5 mL) and DCM (5 mL). The phases were separated through a PTFE-fritted separator and the organic layer concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH, standard elution method) and the product fractions concentrated in vacuo to afford the titled compound as a white crystalline solid.

[1198] 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 2.54-2.51 (m, 2H), 2.27-2.19 (m, 1H), 1.94-1.87 (m, 2H), 1.87-1.83 (m, 1H), 1.83-1.77 (m, 3H), 1.77-1.71 (m, 2H), 1.71-1.65 (m, 4H), 1.54-1.49 (m, 2H), 1.39 (s, 9H).

[1199] LC-MS (Method A): Rt 4.29 mins; MS m/z 370.3=[M+H]+ (100% @ 215 nm)

[1200] The compounds of the following tabulated Examples (Table 5) were prepared analogously to either Example 5 (using T3P®) or Example 5.1 (using thionyl chloride) from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and the appropriate commercially available acid.

TABLE-US-00006 TABLE 5 Activating 1H NMR Ex. Structure and Name Reagent LCMS Retention Time, [M + H]+, 5.2 [00113] Thionyl Chloride 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 5.6 Hz, 1H), 8.21 (dd, J = 5.6, 2.2 Hz, 1H), 8.01- 7.93 (m, 2H), 7.55 (d, J = 2.1 Hz, 1H), 7.23 (dd, J = 8.9, 6.5 Hz, 1H), 6.74 − 6.67 (m, 2H), 3.93 (s, 3H), 3.69 (s, 2H), 1.47 (s, 9H). LC-MS (Method A):Rt 3.31 mins; MS m/z 360.2 = [M + H]+ (97% @ 215 nm) N-tert-Butyl-4-[[2-(4-fluoro-2-methoxy- phenyl)acetyl]amino]pyridine-2-carboxamide 5.3 [00114]   N-tert-Butyl-4-[[2-(5-chloro-2-fluoro- Thionyl Chloride 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.51 (dd, J = 6.4, 2.7 Hz, 1H), 7.40 (ddd, J = 8.7, 4.4, 2.8 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H), 3.83 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.61 mins; MS m/z 364.2/ 366.2 = [M + H]+ (97% @ 215 nm) phenyl)acetyl]amino]pyridine-2-carboxamide 5.4 [00115]   T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.58 (dd, J = 1.8, 0.7 Hz, 1H), 6.41 (dd, J = 3.1, 1.9 Hz, 1H), 6.36-6.24 (m, 1H), 3.81 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.97 mins; MS m/z 302.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(2-furyl)acetyl]amino] pyridine-2- carboxamide 5.5 [00116] T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.43- 7.41 (m, 1H), 7.39 − 7.31 (m, 2H), 7.31 − 7.27 (m, 1H), 3.75 (s, 2H), 1.39 (s, 9H) LC-MS (Method A): Rt 3.60 mins; MS m/z 346.2, 348.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(3-chlorophenyl) acetyl]amino]pyridine-2-carboxamide 5.6 [00117]   N-tert-Butyl-4-[[2-(1H-indol-3-yl)acetyl] T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.71 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.10 − 7.05 (m, 1H), 7.01 − 6.96 (m, 1H), 3.80 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.19 mins; MS m/z 351.2 = [M + H]+ (97% @ 215 nm) amino]pyridine-2-carboxamide 5.7 [00118]   N-tert-Butyl-4-[[2-(o-tolyl)acetyl]amino]pyridine-2- T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.27 − 7.22 (m, 1H), 7.20 − 7.12 (m, 3H), 3.75 (s, 2H), 2.28 (s, 3H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.46 mins; MS m/z 326.2 = [M + H]+ (98% @ 215 nm) carboxamide 5.8 [00119]   T3P ® 1H NMR (500 MHz, DMSO-d6) δ 11.62 (s, 1H), 9.26 (d, J = 5.5 Hz, 1H), 8.98 (d, J = 2.0 Hz, 1H), 8.84 (s, 1H), 8.61 (dd, J = 5.5, 2.2 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 8.3 Hz, 1H), 8.13 (dd, J = 8.3, 2.0 Hz, 1H), 4.59 (s, 2H), 2.20 (s, 9H). LC-MS (Method A): Rt 3.86 mins; MS m/z 380.1/ 382.1/384.1 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(3,4-dichlorophenyl) acetyl]amino]pyridine-2-carboxamide 5.9 [00120]   T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J = 5.5, 2.1 Hz, 1H), 7.42 -7.33 (m, 1H), 7.21 − 7.14 (m, 2H), 7.12 − 7.05 (m, 1H), 3.76 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.39 mins; MS m/z 330.2 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-4-[[2-(3-fluorophenyl)acetyl] amino]pyridine-2-carboxamide 5.10 [00121] Thionyl Chloride 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.33 − 7.28 (m, 2H), 7.03 − 6.99 (m, 1H), 3.75 (s, 3H), 3.71 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.61 mins; MS m/z 376.2/ 378.2 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-4-[[2-(5-chloro-2-methoxy- phenyl)acetyl]amino]pyridine-2-carboxamide 5.11 [00122] T3P ® 1H NMR (500 MHz, Methanol-d4) δ 8.42 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 3.68 (s, 2H), 2.31 (s, 3H), 1.47 (s, 9H). LC-MS (Method A):Rt 3.52 mins; MS m/z 326.2 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-4-[[2-(p-tolyl)acetyl]amino]pyridine-2- carboxamide 5.12 [00123]   N-tert-Butyl-4-[[2-(2-fluorophenyl) T3P ® 1H NMR (500 MHz, Methanol-d4) δ 8.43 (d, J = 5.3 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.36 (td, J = 7.6, 1.6 Hz, 1H), 7.31 (tdd, J = 7.4, 5.3, 1.8 Hz, 1H), 7.16 (td, J = 7.5, 1.1 Hz, 1H), 7.10 (ddd, J = 9.5, 8.3, 1.0 Hz, 1H), 3.82 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.30 mins; MS m/z 330.2 = [M + H]+ (98% @ 215 nm) acetyl]amino]pyridine-2-carboxamide 5.13 [00124] T3P ® 1H NMR (500 MHz, Methanol-d4) δ 8.43 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.36 (dd, J = 8.7, 5.4 Hz, 2H), 7.10 − 7.01 (m, 2H), 3.72 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.34 mins; MS m/z 330.2 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-4-[[2-(4-fluorophenyl) acetyl]amino]pyridine-2-carboxamide 5.14 [00125]   N-tert-Butyl-4-[[2-(m-tolyl)acetyl]amino]pyridine-2-carboxamide T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J = 5.5, 2.1 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.14 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 3.66 (s, 2H), 2.29 (s, 3H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.58 mins; MS m/z 326.2 = [M + H]+ (98% @ 215 nm) 5.15 [00126] T3P ® 1H NMR (500 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 7.90 (dd, J = 5.6, 2.2 Hz, 1H), 7.79 − 7.73 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.5, 1.6 Hz, 1H), 3.88 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 2.82 mins; MS m/z 353.1 = [M + H]+ (98% @ 215 nm) 4-[[2-(1,3-Benzoxazol-6-yl)acetyl]amino]-N-tert- butyl-pyridine-2-carboxamide 5.16 [00127]   N-tert-Butyl-4-[[2-(2-chloro-3-pyridyl) T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.35 (dd, J = 4.8, 1.8 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.90 (dd, J = 7.5, 1.8 Hz, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.44 (dd, J = 7.5, 4.8 Hz, 1H), 3.95 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.76 mins; MS m/z 347.1, 349.1 = [M + H]+ (97% @ 215 nm) acetyl]amino]pyridine-2-carboxamide 5.17 [00128] T3P ® 1H NMR (500 MHz, DMS0-d6) δ 10.95 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.78 (dd, J = 5.5, 2.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.40 − 7.32 (m, 1H), 4.11 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.66 mins; MS m/z 380.1/ 382.1/384.1 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-4-[[2-(2,6-dichlorophenyl) acetyl]amino]pyridine-2-carboxamide 5.18 [00129] T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.39 (dd, J = 10.5, 1.8 Hz, 1H), 7.20 (dd, J = 8.2, 1.6 Hz, 1H), 3.78 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.67 mins; MS m/z 364.1/ 366.1 = [M + H]+ (97% @ 215 nm) N-tert-Butyl-4-[[2-(4-chloro-3-fluoro- phenyl)acetyl]amino]pyridine-2-carboxamide 5.19 [00130] T3P ® 1H NMR (250 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.52 (t, J = 1.9 Hz, 1H), 7.41 (d, J = 1.9 Hz, 2H), 3.80 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.99 mins; MS m/z 380.1/ 382.1/384.1 = [M + H]+ (94% @ 215 nm) N-tert-Butyl-4-[[2-(3,5-dichloro phenyl)acetyl]amino]pyridine-2-carboxamide 5.20 [00131] T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.1 Hz, 1H), 7.50 − 7.40 (m, 2H), 7.36 − 7.28 (m, 2H), 3.92 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.44 mins; MS m/z 346.1/ 348.1 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(2-chlorophenyl) acetyl]amino]pyridine-2-carboxamide 5.21 [00132] T3P ® 1H NMR (500 MHz, Methanol-d4) δ 8.42 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.3, 2.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.62 (s, 2H), 1.47 (s, 9H). LC-MS (Method A): Rt 3.03 mins; MS m/z 362.1/ 364.1 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-4-[[2-(3-ch loro-4-hyd roxy- phenyl)acetyl]amino]pyridine-2-carboxamide 5.22 [00133]   N-tert-Butyl-4-(indane-1-carbonyl amino)pyridine-2- carboxamide Thionyl Chloride 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.30 (dd, J = 19.3, 7.3 Hz, 2H), 7.20 (t, J = 7.0 Hz, 1H), 7.16 (t, J = 7.0 Hz, 1H), 4.16 (t, J = 7.3 Hz, 1H), 3.10-3.03 (m, 1H), 2.94-2.86 (m, 1H), 2.39 − 2.27 (m, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.58 mins; MS m/z 338.2 = [M + H]+ (100% @ 215 nm) 5.23 [00134] T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.96-8.91 (m, 2H), 8.45 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.09-8.06 (m, 2H), 8.02 (s, 1H), 7.87 − 7.81 (m, 2H), 4.04 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 2.66 mins; MS m/z 364.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[(2-quinoxalin-6-ylacetyl)   amino]pyridine-2-carboxamide   5.24 [00135]   T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.02 (s, 1H), 7.92 − 7.86 (m, 3H), 7.86 − 7.84 (m, 1H), 7.84 − 7.81 (m, 1H), 7.54 − 7.45 (m, 3H), 3.90 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.74 mins; MS m/z 362.2 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-4-[[2-(2-naphthyl)   acetyl]amino]pyridine-2-carboxamide   5.25 [00136]   N-tert-Butyl-4-(2,3-dihydrobenzofuran-3- carbonylamino)pyridine-2-carboxamide T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.87 (dd, J = 5.5, 2.1 Hz, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.85 (dd, J = 9.0, 6.0 Hz, 1H), 4.70 (t, J = 9.2 Hz, 1H), 4.51 (dd, J = 9.3, 6.0 Hz, 1H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.32 mins; MS m/z 340.2 = [M + H]+ (98% @ 215 nm) 5.26 [00137]   N-tert-Butyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulene- 5-carbonylamino)pyridine-2-carboxamide T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.19 (dd, J = 7.2, 1.6 Hz, 1H), 7.12 (dtd, J = 14.9, 7.3, 1.6 Hz, 2H), 7.00 − 6.97 (m, 1H), 4.06 − 4.01 (m, 1H), 2.93 − 2.80 (m, 2H), 2.06 − 2.00 (m, 1H), 1.91 − 1.63 (m, 4H), 1.43 − 1.32 (m, 10H). LC-MS (Method A): Rt 4.09 mins; MS m/z 366.2 = [M + H]+ (96% @ 215 nm) 5.27 [00138]   N-tert-Butyl-4-(tetralin-1-carbonylamino)pyridine-2-carboxamide T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.85 (dd, J = 5.5, 2.1 Hz, 1H), 7.17 − 7.06 (m, 4H), 3.92 (t, J = 6.6 Hz, 1H), 2.84 − 2.69 (m, 2H), 2.11 − 1.95 (m, 3H), 1.73 − 1.63 (m, 1H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.73 mins; MS m/z 352.2 = [M + H]+ (99% @ 215 nm) 5.29 [00139]   N-tert-Butyl-4-[[2-(6-quinolyl)acetyl]amino]pyridine-2-carboxamide T3P ® 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.37 − 8.32 (m, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.74 (dd, J = 8.7, 2.0 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 3.95 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 1.98 mins;     MS m/z 363.2 = [M + H]+ (97% @ 215 nm) 5.31 [00140]   N-tert-butyl-4-[[1-(3-chlorophenyl) cyclopropanecarbonyl]amino]pyridine-2- carboxamide T3P ® 1H NMR (500 MHz, Methanol-d4) δ 8.41 (d, J = 5.5 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 5.6, 2.2 Hz, 1H), 7.52 − 7.47 (m, 1H), 7.40 (dd, J = 5.2, 2.7 Hz, 2H), 7.37 (ddt, J = 6.7, 4.4, 2.5 Hz, 1H), 1.66 -1.60 (m, 2H), 1.47 (s, 9H), 1.28 − 1.22 (m, 2H). LC-MS (Method A): Rt 4.01 mins; MS m/z 372.2/374.2 = [M + H]+ (100% @ 215 nm) 5.32 [00141]   N-tert-Butyl-4-[[2-(2,3-dihydro-1,4-benzodioxin-6- yl)acetyl]amino]pyridine-2-carboxamide Thionyl Chloride 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.77 (dd, J = 8.3, 1.9 Hz, 1H), 4.21 (s, 4H), 3.57 (s, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 3.23 mins; MS m/z 370.3/371.3 = [M + H]+ (98% @ 215 nm)

Example 5.33

N-(1,1-Dimethylprop-2-ynyl)-4-[(2-isochroman-1-ylacetyl)amino]pyridine-2-carboxamide

[1201] ##STR00142##

[1202] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-isochroman-1-ylacetic acid analogously to Example 5.1

[1203] 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.19 (tdd, J=12.4, 9.2, 5.5 Hz, 4H), 5.19 (dd, J=10.0, 3.1 Hz, 1H), 4.08-4.01 (m, 1H), 3.72 (ddd, J=11.4, 9.0, 4.1 Hz, 1H), 3.21 (s, 1H), 3.09 (dd, J=14.6, 3.4 Hz, 1H), 2.92-2.84 (m, 1H), 2.75-2.67 (m, 2H), 1.65 (s, 6H).

[1204] LC-MS (Method A): Rt 3.22 mins; MS m/z 378.3=[M+H]+ (100% @ 215 nm)

Example 5.34

4-[[2-(4,4-Difluorocyclohexyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1205] ##STR00143##

[1206] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-(4,4-difluorocyclohexyl)acetic acid analogously to Example 5.1

[1207] 1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 3.21 (s, 1H), 2.34 (d, J=7.1 Hz, 2H), 2.05-1.90 (m, 3H), 1.90-1.82 (m, 1H), 1.82-1.75 (m, 3H), 1.64 (s, 6H), 1.32-1.18 (m, 2H).

[1208] LC-MS (Method A): Rt 3.26 mins; MS m/z 364.3=[M+H]+ (97% @ 215 nm)

Example 5.35

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1209] ##STR00144##

[1210] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-[4-(trifluoromethyl)phenyl]acetic acid analogously to Example 5

[1211] 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H), 3.86 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

[1212] LC-MS (Method A): Rt 3.53 mins; MS m/z 390.2=[M+H]+ (100% @ 215 nm)

Example 5.36

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl] amino]pyridine-2-carboxamide

[1213] ##STR00145##

Step 1: 2-[3-(Trifluoromethyl)-1H-pyrazol-4-yl]acetic acid

[1214] ##STR00146##

[1215] Periodic acid (278 mg, 1.22 mmol) was added to MeCN (4.5 mL) and stirred at room temperature for 20 mins. To this solution was added 2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]ethanol (100 mg, 0.56 mmol) in MeCN (0.93 mL) and the mixture was cooled to 0° C. Pyridinium chlorochromate (8 mg, 0.04 mmol) was added and the mixture was warmed gradually to room temperature and stirred for 90 hours. The resulting mixture was diluted with excess water, acidified with 3M sulfuric acid and quenched with saturated aqueous sodium thiosulfate. After 3 days, the mixture was filtered and washed with water to afford the titled compound as a pale yellow solid.

[1216] 1H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 12.38 (s, 1H), 7.85 (s, 1H), 3.53 (s, 2H).

[1217] LC-MS (Method E): Rt 0.77 mins; MS m/z 195.0=[M+H]+ (95% @ 215 nm)

Step 2: N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetyl]amino] pyridine-2-carboxamide

[1218] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-[3-(trifluoromethyl)-1H-pyrazol-4-yl]acetic acid (step 1) analogously to Example 5.

[1219] 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 10.74 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.91 (s, 1H), 7.80 (dd, J=5.5, 2.1 Hz, 1H), 3.73 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1220] LC-MS (Method A): Rt 2.69 mins; MS m/z 380.2=[M+H]+ (100% @ 215 nm)

Example 5.37

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1221] ##STR00147##

[1222] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-[3-(trifluoromethyl)phenyl]acetic acid analogously to Example 5.

[1223] 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.72-7.69 (m, 1H), 7.66-7.61 (m, 2H), 7.61-7.55 (m, 1H), 3.88 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1224] LC-MS (Method A): Rt 3.51 mins; MS m/z 390.2=[M+H]+ (100% @ 215 nm)

Example 5.38

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1225] ##STR00148##

[1226] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-[2-(trifluoromethyl)phenyl]acetic acid analogously to Example 5.

[1227] 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.52 (dd, J=18.5, 7.7 Hz, 2H), 4.01 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1228] LC-MS (Method A): Rt 3.53 mins; MS m/z 390.2=[M+H]+ (100% @ 215 nm)

Example 5.39

4-[[2-(2,3-Dihydro-1,4-benzoxazin-4-yl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1229] ##STR00149##

[1230] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-(2,3-dihydro-1,4-benzoxazin-4-yl)acetic acid analogously to Example 5.

[1231] 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 6.74-6.67 (m, 2H), 6.59-6.52 (m, 2H), 4.26-4.21 (m, 2H), 4.17 (s, 2H), 3.52-3.47 (m, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1232] LC-MS (Method A): Rt 3.32 mins; MS m/z 379.2=[M+H]+ (90% @ 215 nm)

Example 6

N-tert-Butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1233] ##STR00150##

Step 1: 4-[[2-(5-Bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1234] ##STR00151##

[1235] 2-(5-Bromo-2-methoxy-phenyl)acetic acid (348 mg, 1.42 mmol) in thionyl chloride (1.25 mL, 14.2 mmol) was stirred at 70° C. under an inert atmosphere for 1 hour. The resulting solution was cooled to room temperature and concentrated in vacuo (azeotroping with toluene and DCM). The dry acid chloride was dissolved in anhydrous DCM (10 mL) and added drop wise to a solution of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (274 mg, 1.42 mmol) and DIPEA (0.5 mL, 2.84 mmol) in anhydrous DCM (10 mL). The reaction mixture was stirred under an inert atmosphere at room temperature. After 1 hour, the mixture was diluted with DCM (25 mL) and washed with water (2×25 mL). The organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting crude oil was purified by chromatography on silica eluting with EtOAc in heptane. The column was flushed with methanol and the eluent collected and concentrated in vacuo to afford a beige solid. The solid was re-purified by chromatography on silica eluting with 0-10% MeOH in DCM and the product fractions concentrated in vacuo and dried in a vacuum oven at 40° C. for 2 hours to afford the titled compound.

[1236] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.47-7.38 (m, 2H), 7.01-6.92 (m, 1H), 3.74 (s, 3H), 3.71 (s, 2H), 1.40 (s, 9H).

[1237] LC-MS (Method A): Rt 3.62 mins; MS m/z 420.2, 422.2=[M+H]+ (100% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-(5-cyano-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1238] ##STR00152##

[1239] A solution of 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 1) (75 mg, 0.18 mmol) in DMF (2 mL) was de-gassed with nitrogen for 5 minutes before addition of tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol). The mixture was purged with nitrogen for a further 5 minutes then treated with zinc cyanide (27 mg, 0.23 mmol). The resulting mixture was stirred at 100° C. for 16 hours. A further portion of zinc cyanide (27 mg, 0.23 mmol) and tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.02 mmol) was added, the mixture purged with nitrogen and stirring continued at 100° C. for a further 24 hours. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL), aqueous NaHCO.sub.3 (sat.) (20 mL) and brine (20 mL). The organics were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with EtOAc in heptane. The product fractions were concentrated in vacuo and dried in a vacuum oven to afford the titled compound as a yellow solid.

[1240] 1H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J=5.6 Hz, 1H), 8.39 (br.s, 1H), 8.20 (dd, J=5.6, 2.2 Hz, 1H), 8.04 (s, 1H), 7.75-7.69 (m, 1H), 7.63 (dd, J=8.6, 2.1 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 3.95 (s, 3H), 3.77 (s, 2H), 1.47 (s, 9H).

[1241] LC-MS (Method E): Rt 1.13 mins; MS m/z 367.1=[M+H]+ (95% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1242] ##STR00153##

[1243] To a solution of N-tert-butyl-4-[[2-(5-cyano-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (20 mg, 0.05 mmol) in DCM (2 mL) was added 1M BBr.sub.3 in DCM (164 μL, 0.16 mmol). The resulting mixture was stirred under an inert atmosphere for 2 hours. Additional 1M BBr.sub.3 in DCM (164 μL, 0.16 mmol) was added and the mixture stirred at room temperature for a further 16 hours. Further 1M BBr.sub.3 in DCM (164 μL, 0.16 mmol) was added and the mixture stirred for 24 hours at room temperature under nitrogen. The mixture was diluted with DCM (20 mL) and washed with water (2×20 mL). The organic portion was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with 0-100% MeCN in water with 0.1% formic acid. The product fractions were freeze-dried to afford the titled compound as a white solid.

[1244] 1H NMR (500 MHz, DMSO-d6) δ 10.78 (br s, 1H), 10.75 (s, 1H), 10.90-10.60 (m, 2H), 8.44 (d, J=5.5 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.4, 2.2 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 3.72 (s, 2H), 1.40 (s, 9H).

[1245] LC-MS (Method A): Rt 2.84 mins; MS m/z 353.3=[M+H]+ (94% @ 215 nm)

Example 7

3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl) benzamide

[1246] ##STR00154##

Step 1: Methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoate

[1247] ##STR00155##

[1248] A solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (1200 mg, 5.98 mmol), EDCI (1376 mg, 7.18 mmol), HOAt (814 mg, 5.98 mmol), DIPEA (2.61 mL, 14.95 mmol) and methyl 3-aminobenzoate (904 mg, 5.98 mmol) in DMF (5 mL) was stirred at room temperature for 17 hours. The reaction mixture was diluted with water (35 mL) and extracted with EtOAc (2×40 mL). The combined organic portions were washed with water (2×40 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 10-70% EtOAc in heptane. The product fractions were concentrated in vacuo to afford the titled compound as an off-white solid.

[1249] 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.29 (t, J=1.8 Hz, 1H), 7.82 (ddd, J=8.1, 2.1, 1.0 Hz, 1H), 7.63 (dt, J=7.7, 1.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.32-7.28 (m, 2H), 7.05-6.95 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.66 (s, 2H).

[1250] LC-MS (Method E): Rt 1.21 mins; MS m/z 334.1/336.1=[M+H]+ (96% @ 215 nm)

Step 2: 3-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]benzoic acid

[1251] ##STR00156##

[1252] 2 M LiOH (7.71 mL, 15.42 mmol) was added to a solution of methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoate (step 1) (1751 mg, 5.14 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature for 7 hours. The resulting mixture was concentrated in vacuo, diluted with water (8 mL) and acidified to pH 2 with aqueous 2M HCl. A precipitate formed which was collected by vacuum filtration and washed with Et.sub.2O (2×20 mL). The solid was dried in a vacuum oven at 40° C. for 3 hours to afford the titled compound as a pale beige solid.

[1253] 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.23 (s, 1H), 7.87-7.74 (m, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.31-7.27 (m, 2H), 7.03-6.95 (m, 1H), 3.76 (s, 3H), 3.66 (s, 2H).

[1254] LC-MS (Method E): Rt 1.07 mins; MS m/z 320.1/322.1=[M+H]+ (100% @ 215 nm)

Step 3: 3-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl) benzamide

[1255] ##STR00157##

[1256] A solution of 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoic acid (step 2) (70 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol), DIPEA (0.11 mL, 0.66 mmol) and 2,3,3-trimethylbutan-2-amine hydrochloride (33 mg, 0.22 mmol) in DMF (0.5 mL) was stirred at room temperature for 3 hours. The resulting mixture was diluted with EtOAc (5 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (5 mL) and the combined organic extracts were washed with water (5 mL), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions concentrated in vacuo to afford the titled compound as an off-white powder.

[1257] 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.85 (s, 1H), 7.74 (dt, J=6.8, 2.1 Hz, 1H), 7.37-7.32 (m, 2H), 7.32-7.26 (m, 2H), 7.09 (s, 1H), 7.02-6.98 (m, 1H), 3.76 (s, 3H), 3.65 (s, 2H), 1.39 (s, 6H), 0.97 (s, 9H).

[1258] LC-MS (Method E): Rt 1.32 mins; MS m/z 417.2/419.2=[M+H]+ (97% @ 215 nm)

Step 4: 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl) benzamide

[1259] To a cooled (0° C.) solution of 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-N-(1,1,2,2-tetramethylpropyl)benzamide (step 3) (53 mg, 0.13 mmol) in DCM (0.5 mL) was added 1M BBr.sub.3 in DCM (0.38 mL, 0.38 mmol) and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (2×8 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions concentrated in vacuo to afford the titled compound as an off-white powder.

[1260] 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.81 (br s, 1H), 7.86 (s, 1H), 7.75 (dt, J=6.6, 2.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.20 (d, J=2.7 Hz, 1H), 7.13-7.05 (m, 2H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 1.39 (s, 6H), 0.97 (s, 9H).

[1261] LC-MS (Method D): Rt 4.52 mins; MS m/z 403.2/405.2=[M+H]+ (100% @ 215 nm).

[1262] The compounds of the following tabulated Examples (Table 6) were prepared analogously to Example 7 from the appropriate amino ester and acid (step 1) and by replacing 2,3,3-trimethylbutan-2-amine hydrochloride (step 3) with the appropriate commercially available amine. The amide coupling step was carried out using either (i) EDCI/HOAt/DIPEA or (ii) TBTU/TEA or (iii) T3P®/TEA

TABLE-US-00007 TABLE 6 Coupling 1H NMR Ex. Structure and Name Reagents LCMS Retention Time, [M + H]+, 7.1 [00158]   3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.74 (br s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.84 − 7.71 (m, 1H), 7.56 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.61 (s, 2H), 1.78 − 1.64 (m, 2H), 1.37 − 1.20 (m, 8H), 0.86 (t, J = 7.3 Hz, 3H). LC-MS (Method D): Rt 4.40 mins; MS m/z 389.2/391.2 = [M + H]+ (98% @ 215 nm) N-(1,1-dimethylbutyl)benzamide 7.2 [00159]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- EDCI/ HOAt/ DIPEA 1H NMR (250 MHz, DMSO-d6) δ 10.69 (br s, 1H), 9.86 (br s, 1H), 8.44 (d, J = 5.8 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 1.80 − 1.63 (m, 2H), 1.35 (s, 6H), 1.32 − 1.16 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). LC-MS (Method A): Rt 3.79 mins; MS m/z 390.2/392 = [M + H]+ (100% @ 215 nm) N-(1,1-dimethylbutyl)pyridine-2-carboxamide 7.3 [00160]   EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.79 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.96 (t, J = 1.8 Hz, 1H), 7.80 − 7.75 (m, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.79 − 3.69 (m, 1H), 3.61 (s, 2H), 1.84- 1.68 (m, 4H), 1.64 − 1.57 (m, 1H), 1.36 − 1.23 (m, 4H), 1.17 − 1.06 (m, 1H). LC-MS (Method A): Rt 3.31 mins; MS m/z 387.2/389.2 = [M + H]+ 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- (100% @ 215 nm) N-cyclohexyl-benzamide 7.4 [00161] EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.80 (br s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.99 (t, J = 1.8 Hz, 1H), 7.87 − 7.69 (m, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.98 (m, 1H), 3.92 − 3.80 (m, 2H), 3.61 (s, 2H), 3.41 − 3.36 (m, 2H), 1.80 − 1.65 (m, 2H), 1.63 − 1.51 (m, 2H). LC-MS (Method A): Rt 2.57 mins; MS m/z 389.2/391.2 = [M + H]+ 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- (100% @ 215 nm) N-tetrahydropyran-4-yl-benzamide 7.5 [00162]   3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.80 (br s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.81 − 7.71 (m, 1H), 7.52 (s, 1H), 7.39 (dd, J = 6.5, 1.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.61 (s, 2H), 1.27 (s, 6H), 0.85 (d, J = 6.9 Hz, 6H). LC-MS (Method A): Rt 3.52 mins; MS m/z 389.3/391.3 = [M + H]+ (100% @ 215 nm) N-(1,1,2-trimethylpropyl)benzamide 7.6 [00163]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.71 (br s, 1H), 9.86 (br s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.66 (s, 2H), 2.36 − 2.28 (m, 1H), 1.32 (s, 6H), 0.88 (d, J = 6.9 Hz, 6H). LC-MS (Method A): Rt 3.74 mins; MS m/z 390.2/392.2 = [M + H]+ (99% @ 215 nm) N-(1,1,2-trimethylpropyl)pyridine-2-carboxamide 7.7 [00164]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- N-isopropyl-pyridine-2-carboxamide TBTU/ TEA 1H NMR (500 MHz, DMSO-d6) δ 10.69 (br s, 1H), 9.77 (br s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.16 − 4.03 (m, 1H), 3.66 (s, 2H), 1.18 (d, J = 6.6 Hz, 6H). LC-MS (Method A): Rt 2.89 mins; MS m/z 348.1/350.1 = [M + H]+ (99% @ 215 nm) 7.8 [00165]   3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.80 (s, 1H), 7.99 − 7.84 (m, 1H), 7.80 − 7.60 (m, 1H), 7.72 (s, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.67 − 3.52 (m, 6H), 2.26 − 2.19 (m, 2H), 1.58 − 1.49 (m, 2H), 1.38 (s, 3H). LC-MS (Method A): Rt 2.79 mins; MS m/z 403.2/405.2 = [M + H]+ (100% @ 215 nm) N-(4-methyltetrahydropyran-4-yl)benzamide 7.9 [00166]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- T3P ®/ TEA 1H NMR (500 MHz, DMSO-d6) δ 10.72 (br s, 1H), 9.74 (br s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.11 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.70 − 3.60 (m, 4H), 3.55 − 3.46 (m, 2H), 2.23 − 2.14 (m, 2H), 1.67-1.58 (m, 2H), 1.42 (s, 3H). LC-MS (Method A): Rt 2.90 mins; MS m/z 404.2/406.2 = [M + H]+ (96% @ 215 nm) N-(4-methyltetrahydropyran-4-yl)pyridine-2- carboxamide 7.10 [00167]   3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.80 (s, 1H), 8.32 (s, 1H), 7.95 (t, J = 1.8 Hz, 1H), 7.77-7.42 (m, 1H), 7.49-7.44 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.61 (s, 2H), 2.34 − 2.28 (m, 2H), 2.00 − 1.92 (m, 2H), 1.84 − 1.75 (m, 2H), 1.45 (s, 3H). LC-MS (Method A): Rt 3.15 mins; MS m/z 373.2/375.1 = [M + H]+ (99% @ 215 nm) N-(1-methylcyclobutyl)benzamide 7.11 [00168]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- TBTU/ TEA 1H NMR (500 MHz, DMSO-d6) δ 10.69 (br s, 1H), 9.86 (br s, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.06 − 3.95 (m, 1H), 3.89 − 3.83 (m, 2H), 3.66 (s, 2H), 1.75 − 1.61 (m, 4H). LC-MS (Method A): Rt 2.57 mins; MS m/z 390.2/392.2 = [M + H]+ (98% @ 215 nm) N-tetrahydropyran-4-yl-pyridine-2-carboxamide 7.12 [00169]   EDCI/ HOAt/ DIPEA 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.82 (br s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.41 (d, J = 3.4 Hz, 1H), 3.87 − 3.76 (m, 1H), 3.74 − 3.68 (m, 1H), 3.66 (s, 2H), 1.83 − 1.66 (m, 2H), 1.65 − 1.47 (m, 6H). LC-MS (Method A): Rt 2.45 mins; MS m/z 404.2/ 406.2 = [M + H]+ 4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-N- (100% @ 215 nm) [(1s,4s)-4-hydroxycyclohexyl]pyridine-2- carboxamide 7.13 [00170]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- N-sec-butyl-pyridine-2-carboxamide T3P ®/ TEA 1H NMR (500 MHz, DMSO-d6) δ 10.69 (br s, 1H), 9.82 (br s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.96-3.85 (m, 1H), 3.66 (s, 2H), 1.64 − 1.44 (m, 2H), 1.15 (d, J = 6.6 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS (Method A): Rt 3.16 mins; MS m/z 362.1/364.1 = [M + H]+ (98% @ 215 nm) 7.14 [00171]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- T3P ®/ TEA 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.81 (br s, 1H), 8.71 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.99 (s, 1H), 3.67 (s, 2H), 1.39 (s, 6H), 1.16 (s, 6H). LC-MS (Method A): Rt 3.01 mins; MS m/z 406.2/408.2 = [M + H]+ (99% @ 215 nm) N-(2-hydroxy-1,1,2-trimethyl-propyl)pyridine-2- carboxamide 7.15 [00172]   N-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-chloro-2- T3P ®/ TEA 1H NMR (500 MHz, DMSO-d6) δ 10.71 (br s, 1H), 9.82 (br s, 1H), 9.09 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 2.45 (s, 1H), 2.10 (s, 6H). LC-MS (Method A): Rt 3.21 mins; MS m/z 372.1/374.1 = [M + H]+ (98% @ 215 nm) hydroxy-phenyl)acetyl]amino]pyridine-2- carboxamide 7.16 [00173]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]- *T3P ®/ TEA 1H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.82 (br s, 1H), 9.59 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 3.68 (s, 2H), 2.69 − 2.62 (m, 2H), 2.59 − 2.53 (m, 2H), 2.11 − 1.93 (m, 2H). LC-MS (Method A): Rt 2.89 mins; MS m/z 385.1/387.1 = [M + H]+ (95% @ 215 nm) N-(1-cyanocyclobutyl)pyridine-2-carboxamide

Example 8

tert-Butyl-3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylate

[1263] ##STR00174##

Step 1: 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-piperidyl)benzamide

[1264] ##STR00175##

[1265] The titled compound was prepared analogously to Example 7 by replacing 2,3,3-trimethylbutan-2-amine hydrochloride (step 3) with tert-butyl 3-aminopiperidine-1-carboxylate.

[1266] 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 7.98 (s, 1H), 7.82-7.70 (m, 1H), 7.50-7.46 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.88-3.80 (m, 1H), 3.61 (s, 2H), 3.02-2.95 (m, 1H), 2.88-2.80 (m, 1H), 2.48-2.42 (m, 2H), 1.90-1.77 (m, 1H), 1.74-1.59 (m, 1H), 1.54-1.37 (m, 2H).

[1267] LC-MS (Method A): Rt 1.66 mins; MS m/z 388.2/390.2=[M+H]+ (96% @ 215 nm)

Step 2: tert-Butyl-3-[[3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoyl]amino]piperidine-1-carboxylate

[1268] To a solution of 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-piperidyl)benzamide (step 1)(19 mg, 0.05 mmol) in THF (0.5 mL) was added BOC anhydride (12 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 3 hr. Additional BOC anhydride (12 mg, 0.06 mmol) was added and stirring continued for a further hour. The reaction mixture was concentrated in vacuo and purification of the crude product by chromatography on silica eluting with EtOAc in heptane afforded the titled compound as an off-white powder.

[1269] 1H NMR (500 MHz, DMSO-d6) δ 10.26 (br s, 1H), 9.81 (br s, 1H), 8.24 (d, J=7.0 Hz, 1H), 7.99 (s, 1H), 7.83-7.74 (m, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.37 (m, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.05-3.67 (m, 3H), 3.61 (s, 2H), 3.03-2.70 (m, 2H), 1.91-1.81 (m, 1H), 1.76-1.67 (m, 1H), 1.60-1.46 (m, 1H), 1.45-1.31 (m, 10H).

[1270] LC-MS (Method A): Rt 3.41 mins; MS m/z 488.3/490.4=[M+H]+ (99% @ 215 nm)

Example 8.1

tert-Butyl-3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[1271] ##STR00176##

Step 1: Methyl 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate

[1272] ##STR00177##

[1273] 2-(5-Chloro-2-methoxy-phenyl)acetic acid (24.19 g, 120.59 mmol) was suspended in thionyl chloride (103.68 mL, 1427.48 mmol) and heated at 70° C. for 1.5 hours. After cooling to room temperature the mixture was concentrated in vacuo. The residue was then dissolved in DCM (135 mL) and re-concentrated. The resulting brown viscous oil was dissolved in DCM (135 mL) and added dropwise to a cooled (ice bath) suspension of methyl 4-aminopyridine-2-carboxylate (17.9 g, 117.65 mmol) and DIPEA (30.82 mL, 176.47 mmol) in DCM (225 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was diluted with water (180 mL) and stirred for 10 mins. The organic portion was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica eluting with EtOAc to afford the titled compound as an orange glassy solid.

[1274] 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.32-7.29 (m, 2H), 7.02-6.99 (m, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.71 (s, 2H).

[1275] LC-MS (Method E): Rt 1.04 mins; MS m/z 335.0/337.0=[M+H]+ (98% @ 215 nm)

Step 2: 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1276] ##STR00178##

[1277] To a solution of methyl 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (95%, 38.09 g, 108.1 mmol) in THF (200 mL) was added a 2M aqueous solution of lithium hydroxide hydrate (162.15 mL, 324.29 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The volatile organics were removed in vacuo and the aqueous residue cooled (ice-bath) and treated with the gradual addition of 3M aqueous HCl (150 mL). The resulting suspension was filtered, washed with water (3×200 mL), diethyl ether (2×250 mL), dried under suction and then further dried in a high vacuum oven at 40° C. to afford the titled compound as a beige solid.

[1278] 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.81 (dd, J=5.6, 2.2 Hz, 1H), 7.34-7.28 (m, 2H), 7.04-6.98 (m, 1H), 3.75 (s, 3H), 3.72 (s, 2H).

[1279] LC-MS (Method E): Rt 0.88 mins; MS m/z 320.9/323.0=[M+H]+ (97% @ 215 nm)

Step 3: tert-Butyl 3-[[4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[1280] ##STR00179##

[1281] A solution of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (70 mg, 0.22 mmol), EDCI (50 mg, 0.26 mmol), HOAt (36 mg, 0.26 mmol), DIPEA (0.08 mL, 0.44 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (27.2 μL, 0.26 mmol) in DMF (0.5 mL) was stirred at room temperature for 20 hours. The resulting mixture was diluted with EtOAc (5 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (5 mL) and the combined organic extracts washed with water (5 mL), brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as an off-white solid.

[1282] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (br s, 1H), 8.52 (br s, 1H), 8.46 (m, 1H), 8.19 (br s, 1H), 7.87-7.79 (m, 1H), 7.35-7.26 (m, 2H), 7.08-6.93 (m, 1H), 3.87-3.78 (m, 1H), 3.75 (s, 3H), 3.71 (s, 2H), 3.17-2.83 (m, 2H), 1.87-1.77 (m, 1H), 1.77-1.58 (m, 2H), 1.57-1.20 (m, 10H).

[1283] LC-MS (Method E): Rt 1.28 mins; MS m/z 503.3/505.2=[M+H]+ (93% @ 215 nm)

Step 4 and 5: tert-Butyl-3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

[1284] The titled compound was prepared analogously to Example 8 from tert-butyl 3-[[4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]piperidine-1-carboxylate (step 3).

[1285] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (br s, 1H), 9.83 (br s, 1H), 8.61-8.40 (m, 2H), 8.20 (s, 1H), 7.83 (dd, J=5.5, 2.0 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.90-3.76 (m, 2H), 3.66 (s, 2H), 3.57-3.49 (m, 1H), 3.11-2.80 (m, 1H), 1.87-1.76 (m, 1H), 1.75-1.57 (m, 2H), 1.45-1.27 (m, 10H).

[1286] LC-MS (Method A): Rt 3.51 mins; MS m/z 489.3/491.3=[M+H]+ (99% @ 215 nm)

[1287] The compounds of the following tabulated Examples (Table 7) were prepared analogously to Example 8 from the appropriate aryl acid and by replacing tert-butyl 3-aminopiperidine-1-carboxylate (Example 8, step 1) with the appropriate commercially available amine.

TABLE-US-00008 TABLE 7 Ex. Structure and Name 1H NMR; LCMS Retention Time, [M + H]+, 8.2 [00180] 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.81 (br s, 1H), 7.92 − 7.85 (m. 1H), 7.81-7.77 (m. 1H), 7.70 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 2.7 Hz, 1H), 7.10 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.66 − 3.54 (m, 4H), 3.08 (m, 2H), 2.29-2.21 (m, 2H), 1.45 − 1.36 (m, 11H), 1.35 (s, 3H). LC-MS (Method A): Rt 3.61 mins; MS m/z 524.2/526.2 = [M + Na]+ (99% @ 215 nm) tert-Butyl 4-[[3-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]benzoyl]amino]-4-methyl-piperidine-1-carboxylate 8.3 [00181] 1H), 8.85 (d, J = 4.9 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.66 (s, 2H), 3.52 (m, 2H), 2.54 − 2.52 (m, 1H), 1.95 − 1.82 (m, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.44 mins; MS m/z 487.2/489.2 = [M + H]+ (99% @ 215 nm) tert-Butyl (1r,5s,6s)-6-{4-[2-(5-chloro-2- hydroxyphenyl)acetamido]pyridine-2-amido}-3- azabicyclo[3.1.0]hexane-3-carboxylate

Example 9

N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide

[1288] ##STR00182##

Step 1: 3-Amino-N-tert-butyl-4-fluoro-benzamide

[1289] ##STR00183##

[1290] To a solution of 3-amino-4-fluoro-benzoic acid (205 mg, 1.32 mmol) in DCM (5 mL) was added sequentially 2-methylpropan-2-amine (306 μL, 2.91 mmol), DIPEA (0.92 mL, 5.29 mmol) and HATU (553 mg, 1.46 mmol) and the mixture was shaken at room temperature overnight. The resulting mixture washed with 2M HCl (5 mL) and sat. NaHCO.sub.3 solution (5 mL). The organic phase was separated by passing through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography on silica eluting with 0-100% EtOAc in heptane afforded the titled compound as an off-white solid.

[1291] 1H NMR (500 MHz, Chloroform-d) δ 7.25-7.19 (m, 1H), 6.99-6.95 (m, 2H), 5.82 (s, 1H), 3.82 (s, 2H), 1.45 (s, 9H).

[1292] LC-MS (Method E): Rt 0.95 mins; MS m/z 211.1=[M+H]+ (97% @ 215 nm)

Step 2: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-fluoro-benzamide

[1293] A suspension of 3-amino-N-tert-butyl-4-fluoro-benzamide (step 1) (105 mg, 0.5 mmol) and 5-chloro-3H-benzofuran-2-one (84 mg, 0.5 mmol) in toluene (3 mL) was heated to 110° C. in a sealed tube for 4 days. After cooling to room temperature, the mixture was concentrated in vacuo and crude residue was purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as an off-white powder.

[1294] 1H NMR (500 MHz, MeOD) δ 8.28 (dd, J=7.4, 2.1 Hz, 1H), 7.56-7.49 (m, 1H), 7.24-7.18 (m, 2H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.74 (s, 2H), 1.43 (s, 9H).

[1295] LC-MS (Method A): Rt 3.18 mins; MS m/z 379.1/381.1=[M+H]+ (97% @ 215 nm)

Example 9.1

N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-methyl-benzamide

[1296] ##STR00184##

[1297] The titled compound was prepared analogously to Example 9 by replacing 3-amino-4-fluoro-benzoic acid (step 1) with 3-amino-5-methyl-benzoic acid.

[1298] 1H NMR (500 MHz, Methanol-d4) δ 7.67 (s, 1H), 7.50 (s, 1H), 7.28 (s, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.6, 2.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 2.36 (s, 3H), 1.44 (s, 9H).

[1299] LC-MS (Method A): Rt 3.32 mins; MS m/z 375.2/377.2=[M+H]+ (99% @ 215 nm).

Example 9.2

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide

[1300] ##STR00185##

Step 1: 4-Amino-N-(1,1-dimethylpropyl)pyridine-2-carboxamide

[1301] ##STR00186##

[1302] To a mixture of 2-methylbutan-2-amine (1.69 mL, 14.48 mmol), TBTU (1023 mg, 3.19 mmol) and TEA (0.81 mL, 5.79 mmol) was added 4-aminopyridine-2-carboxylic acid (400 mg, 2.9 mmol) and the mixture was stirred at room temperature for 5 hours.

[1303] The resulting mixture was partitioned between water (40 mL) and DCM (40 mL). The phases were separated and the organic portion concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with MeCN in H.sub.2O with 0.1% ammonium hydroxide to afford the titled compound as a white solid.

[1304] 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.17 (d, J=2.3 Hz, 1H), 6.56 (dd, J=5.6, 2.4 Hz, 1H), 6.32 (s, 2H), 1.74 (q, J=7.5 Hz, 2H), 1.31 (s, 6H), 0.80 (t, J=7.5 Hz, 3H).

[1305] LC-MS (Method F): Rt 1.55 mins; MS m/z 208.3=[M+H]+ (100% @ 215 nm)

Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylpropyl)pyridine-2-carboxamide

[1306] The titled compound was prepared analogously to Example 9 (step 2) from 4-amino-N-(1,1-dimethylpropyl)pyridine-2-carboxamide and 5-chloro-3H-benzofuran-2-one.

[1307] .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.42 (d, J=5.6 Hz, 1H), 8.13-8.08 (m, 1H), 7.91 (dd, J=5.5, 2.2 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.09 (dd, J=8.6, 2.6 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 3.71 (s, 2H), 1.86 (q, J=7.5 Hz, 2H), 1.42 (s, 6H), 0.91 (t, J=7.5 Hz, 3H).

[1308] LC-MS (Method A): Rt 3.50 mins; MS m/z 376.0/378.0=[M+H]+ (98% @ 215 nm).

Example 10

N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1309] ##STR00187##

Step 1: N-tert-Butyl-4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1310] ##STR00188##

[1311] The titled compound was prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and commercially available 2-(5-tert-butyl-2-methoxy-phenyl)acetic acid analogously to Example 4.

[1312] 1H NMR (500 MHz, Chloroform-d) δ 8.45 (br s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.29 (d, J=5.3 Hz, 1H), 8.16 (br s, 1H), 7.57 (s, 1H), 7.34 (dd, J=8.6, 2.5 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.75 (s, 2H), 1.48 (s, 9H), 1.30 (s, 9H).

[1313] LC-MS (Method E): Rt 1.31 mins; MS m/z 398.2=[M+H]+ (85% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1314] The titled compound was prepared analogously to Example 3 (step 3) from N-tert-Butyl-4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide.

[1315] 1H NMR (500 MHz, Methanol-d4) δ 8.42 (d, J=5.5 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.91 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.15 (dd, J=8.4, 2.5 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 3.72 (s, 2H), 1.47 (s, 9H), 1.28 (s, 9H).

[1316] LC-MS (Method A): Rt 3.81 mins; MS m/z 384.3=[M+H]+ (97% @ 215 nm)

Example 11

N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide

[1317] ##STR00189##

Step 1: Methyl 5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoate

[1318] ##STR00190##

[1319] A mixture of 5-chloro-3H-benzofuran-2-one (75 mg, 0.44 mmol) and methyl 5-amino-2-methoxy-benzoate (81 mg, 0.44 mmol) in toluene (2 mL) was stirred at 100° C. in a sealed tube for 2 hours. The resulting mixture was allowed to cool to room temperature, toluene was added and the suspension was filtered, washing with toluene. The solid was dried in vacuo to afford the titled compound as an off-white solid.

[1320] 1H NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.72 (dd, J=9.0, 2.8 Hz, 1H), 7.14 (dd, J=8.6, 2.6 Hz, 1H), 7.08 (d, J=2.6 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.67 (s, 2H).

[1321] LC-MS (Method E): Rt 1.05 mins; MS m/z 350.0/351.9=[M+H]+ (98% @ 215 nm)

Step 2: 5-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoic acid

[1322] ##STR00191##

[1323] To a solution of methyl 5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoate (step 1) (105 mg, 0.29 mmol) in 1,4-dioxane (2 mL) was added aqueous 2M LiOH (0.29 mL, 0.59 mmol) and the mixture was shaken at room temperature for 5 hours. A further equivalence of aqueous 2M LiOH (0.15 mL, 0.29 mmol) was added and shaking continued for an hour. Dioxane was removed in vacuo and the resulting mixture acidified to pH 1 with 1M HCl (1 mL). The mixture was extracted with EtOAc (2×5 mL) and the combined extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as an off-white solid.

[1324] 1H NMR (500 MHz, DMSO-d6) δ 12.60 (br s, 1H), 10.05 (s, 1H), 9.79 (s, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.70 (dd, J=9.0, 2.8 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 7.07 (d, J=9.1 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.77 (s, 3H), 3.57 (s, 2H).

[1325] LC-MS (Method E): Rt 0.99 mins; MS m/z 336.0/338.0=[M+H]+ (99% @ 215 nm)

Step 3: N-tert-Butyl-5-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzamide

[1326] ##STR00192##

[1327] The titled compound was prepared from 5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzoic acid (step 2) analogously to Example 1 step 3.

[1328] 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.80 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J=8.9, 2.8 Hz, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.09 (dd, J=8.6, 2.7 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.86 (s, 3H), 3.56 (s, 2H), 1.36 (s, 9H).

[1329] LC-MS (Method A): Rt 3.34 mins; MS m/z 391.2/393.2=[M+H]+ (99% @ 215 nm)

Step 4: N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-hydroxy-benzamide

[1330] The titled compound was prepared from N-tert-butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-methoxy-benzamide (step 3) analogously to Example 3 step 3.

[1331] 1H NMR (500 MHz, DMSO-d6) δ 11.50 (br.s, 1H), 9.94 (s, 1H), 9.82 (s, 1H), 8.24 (s, 1H), 7.98-7.88 (m, 1H), 7.60-7.53 (m, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.56 (s, 2H), 1.38 (s, 9H).

[1332] LC-MS (Method A): Rt 3.29 mins; MS m/z 377.2/379.2=[M+H]+ (95% @ 215 nm)

Example 12

N-tert-Butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide

[1333] ##STR00193##

Step 1: 3-[[2-(5-Bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide

[1334] ##STR00194##

[1335] The titled compound was prepared analogously to Example 4 from 3-amino-N-tert-butyl-benzamide hydrochloride (Example 2 step 1b) and 2-(5-bromo-2-methoxy-phenyl)acetic acid.

[1336] 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.89 (s, 1H), 7.74 (d, 1H), 7.70 (s, 1H), 7.44-7.40 (m, 3H), 7.33 (t, J=7.9 Hz, 1H), 6.99-6.92 (m, 1H), 3.76 (s, 3H), 3.65 (s, 2H), 1.36 (s, 9H).

[1337] LC-MS (Method A): Rt 3.41 mins; MS m/z 419.2, 421.2=[M+H]+ (100% @ 215 nm)

Steps 2-3: N-tert-Butyl-3-[[2-(5-cyano-2-hydroxy-phenyl)acetyl]amino]benzamide

[1338] The titled compound was prepared analogously to Example 6 steps 2 and 3 from 3-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-benzamide (step 1).

[1339] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (br. S, 1H), 10.23 (s, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.80-7.72 (m, 1H), 7.70 (s, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.56 (dd, J=8.4, 2.2 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.33 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 3.66 (s, 2H), 1.36 (s, 9H).

[1340] LC-MS (Method A): Rt 2.66 mins; MS m/z 352.2=[M+H]+ (98% @ 215 nm)

Example 13

Methyl 3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoate

[1341] ##STR00195##

Step 1: 4-[[2-(5-Bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1342] ##STR00196##

[1343] A solution of 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6, step 1) (500 mg, 1.19 mmol) in DCM (25 mL) was treated with 1M BBr.sub.3 in DCM (3.57 mL, 3.57 mmol) and stirred at room temperature under nitrogen overnight. The resulting mixture was diluted with DCM (50 mL) and washed with water (25 mL×2). The organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude solid by C18 reverse phase chromatography eluting with 0-100% MeCN in water with 0.1% formic acid afforded the titled compound as a light yellow solid.

[1344] 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.86 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 7.24 (dd, J=8.6, 2.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.40 (s, 9H).

[1345] LC-MS (Method A): Rt 3.34 mins; MS m/z 406.1/408.1=[M+H]+ (90% @ 215 nm)

Step 2: Methyl 3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-hydroxy-benzoate

[1346] All reagents charged to Coware equipment (carbon monoxide generating system) according to the following procedure; To chamber A was added sodium carbonate (53 mg, 0.50 mmol), 4-[[2-(5-bromo-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 1) (75 mg, 0.16 mmol), XantPhos Pd-G3 (third generation (G3) Buchwald precatalyst) (8 mg, 0.01 mmol) and toluene (2 mL). The reaction mixture was de-gassed for 5 minutes and MeOH (0.25 mL) was added. To chamber B was added formic acid (19 μL, 0.50 mmol) in toluene (2 mL) followed by mesyl chloride (39 μL, 0.50 mmol). Both chambers were sealed and TEA (139 μL, 0.99 mmol) added to chamber B to generate carbon monoxide. The Coware equipment was heated at 75° C. for 7 hours. The resulting mixture was concentrated in vacuo, dissolved in EtOAc (20 mL) and washed with water (2×20 mL). The organic portion was concentrated in vacuo and purified by preparative HPLC (acidic pH, early elution method). The product fractions were isolated and freeze-dried to afford the titled compound as an off-white solid.

[1347] 1H NMR (500 MHz, DMSO-d6) δ 10.78 (br s, 1H), 10.55 (br s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.83-7.80 (m, 2H), 7.74 (dd, J=8.5, 2.2 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 3.79 (s, 3H), 3.72 (s, 2H), 1.40 (s, 9H).

[1348] LC-MS (Method A): Rt 2.94 mins; MS m/z 386.3=[M+H]+ (95% @ 215 nm)

Example 14

N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide

[1349] ##STR00197##

Step 1: Methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoate

[1350] ##STR00198##

[1351] The titled compound was prepared analogously to Example 6 (step 1) from methyl 3-amino-4-methoxy-benzoate and 2-(5-chloro-2-methoxy-phenyl)acetic acid.

[1352] 1H NMR (500 MHz, Chloroform-d) δ 8.98 (m, 1H), 8.28 (s, 1H), 7.77 (dd, J=8.6, 2.1 Hz, 1H), 7.31 (d, J=2.6 Hz, 1H), 7.24 (dd, J=8.7, 2.6 Hz, 1H), 6.86 (dd, J=8.7, 6.1 Hz, 2H), 3.90 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.71 (s, 2H).

[1353] LC-MS (Method E): Rt 1.20 mins; MS m/z 364.1/366.1=[M+H]+ (72% @ 215 nm)

Step 2: 3-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoic acid

[1354] ##STR00199##

[1355] To a solution of methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoate (step 1)(301 mg, 0.83 mmol) in 1,4-dioxane (4 mL) was added aqueous 2M LiOH (1.24 mL, 2.48 mmol) and the mixture was shaken at room temperature overnight. The dioxane was removed in vacuo and the resulting mixture acidified to pH 1 with 1M HCl. The mixture was washed with EtOAc (2×5 mL). The aqueous phase was concentrated in vacuo and the resultant solid sonicated with MeOH (20 mL). The suspension was filtered, washed with further MeOH (5 mL) and the combined filtrate concentrated in vacuo to give an off-white solid.

[1356] 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.56 (s, 1H), 7.68 (dd, J=8.5, 2.1 Hz, 1H), 7.35-7.20 (m, 3H), 7.13 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 2H), 3.80 (s, 3H).

[1357] LC-MS (Method E): Rt 1.08 mins; MS m/z 350.1/352.1=[M+H]+ (85% @ 215 nm)

Step 3: N-tert-Butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzamide

[1358] ##STR00200##

[1359] To a solution of 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzoic acid (step 2)(201 mg, 0.57 mmol) in DMF (2 mL) was added EDCI (110 mg, 0.57 mmol), HOAt (78 mg, 0.57 mmol), DIPEA (251 μL, 1.44 mmol) and 2-methylpropan-2-amine (79 μL, 0.75 mmol). The reaction mixture was shaken at room temperature overnight and then partitioned between DCM (6 mL) and water (6 mL). The organic layer collected using a hydrophobic frit and concentrated in vacuo. Chromatography on silica eluting with EtOAc in heptane afforded the titled compound as a colourless glass.

[1360] 1H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J=2.2 Hz, 1H), 8.36 (s, 1H), 7.64 (dd, J=8.6, 2.3 Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.25 (dd, J=8.8, 2.6 Hz, 1H), 6.87 (dd, J=10.9, 8.7 Hz, 2H), 5.99 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.70 (s, 2H), 1.43 (s, 9H).

[1361] LC-MS (Method E): Rt 1.20 mins; MS m/z 405.1/407.1=[M+H]+ (62% @ 215 nm)

Step 4: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-hydroxy-benzamide

[1362] The titled compound was prepared from N-tert-butyl-3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-4-methoxy-benzamide (step 3) analogously to Example 3 step 3.

[1363] 1H NMR (500 MHz, Methanol-d4) δ 8.23 (d, J=2.2 Hz, 1H), 7.48 (s, 1H), 7.39 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 3.72 (s, 2H), 1.43 (s, 9H).

[1364] LC-MS (Method A): Rt 2.93 mins; MS m/z 377.3/379.2=[M+H]+ (99% @ 215 nm).

Example 15

N-tert-Butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1365] ##STR00201##

Step 1: N-tert-Butyl-4-[[2-(2-methoxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1366] ##STR00202##

[1367] To a solution of 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6 step 1) (200 mg, 0.48 mmol) and potassium carbonate (132 mg, 0.95 mmol) in diglyme (5 mL) was added Pd(dppf).sub.2Cl.sub.2 (17 mg, 0.02 mmol) followed by 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane in THF (50%, 0.16 mL, 0.57 mmol). The resulting mixture was degassed with nitrogen for 5 minutes and then stirred in a pressure tube at 100° C. for 16 hours. The resulting mixture was diluted with EtOAc (25 mL) and washed with water (2×25 mL) and brine (2×25 mL). The organic portion was dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by chromatography on silica eluting with EtOAc in heptane. The product fractions were concentrated in vacuo to afford the titled compound as a beige solid.

[1368] 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.06-7.01 (m, 2H), 6.86 (d, J=8.2 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H), 2.23 (s, 3H), 1.40 (s, 9H).

[1369] LC-MS (Method E): Rt 1.22 mins; MS m/z 356.2=[M+H]+ (97% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-(2-hydroxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1370] The titled compound was prepared from N-tert-Butyl-4-[[2-(2-methoxy-5-methyl-phenyl)acetyl]amino]pyridine-2-carboxamide (step 1) analogously to Example 3 (step 3).

[1371] 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.25 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.87 (dd, J=8.1, 1.9 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H), 3.61 (s, 2H), 2.18 (s, 3H), 1.40 (s, 9H).

[1372] LC-MS (Method A): Rt 3.19 mins; MS m/z 342.3=[M+H]+ (100% @ 215 nm)

Example 16

N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-4-methoxy-benzamide

[1373] ##STR00203##

[1374] The titled compound was prepared from methyl 3-amino-4-methoxy-benzoate and 5-chloro-3H-benzofuran-2-one analogously to Example 11 steps 1-3.

[1375] 1H NMR (500 MHz, Methanol-d4) δ 8.36 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.6, 2.2 Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.12 (dd, J=8.6, 2.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 2H), 1.43 (s, 9H).

[1376] LC-MS (Method A): Rt 3.18 mins; MS m/z 391.2/393.2=[M+H]+ (95% @ 215 nm)

Example 17

N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide

[1377] ##STR00204##

Steps 1-2: 5-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzoic acid

[1378] ##STR00205##

[1379] The titled compound was prepared from methyl 5-amino-2-fluoro-benzoate and 2-(5-chloro-2-methoxy-phenyl)acetic acid analogously to Example 7 steps 1 and 2.

[1380] 1H NMR (500 MHz, DMSO-d6) δ 13.25 (br s, 1H), 10.29 (s, 1H), 8.14 (dd, J=6.6, 2.8 Hz, 1H), 7.83-7.76 (m, 1H), 7.32-7.28 (m, 2H), 7.25 (dd, J=10.5, 9.0 Hz, 1H), 7.03-6.98 (m, 1H), 3.77 (s, 3H), 3.65 (s, 2H).

[1381] LC-MS (Method E): Rt 1.04 mins; MS m/z 338.0, 340.1=[M+H]+ (95% @ 215 nm)

Step 3: N-tert-Butyl-5-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzamide

[1382] ##STR00206##

[1383] To a mixture of 5-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzoic acid (step 2) (100 mg, 0.28 mmol), TBTU (108 mg, 0.34 mmol) and TEA (0.08 mL, 0.56 mmol) in DMF (1.5 mL) was added 2-methylpropan-2-amine (35 μL, 0.34 mmol) and the mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated in vacuo and the residue was partitioned between water (10 mL) and DCM (10 mL). The organic phase was separated and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with EtOAc in heptane afforded the titled compound as a white solid.

[1384] 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.83 (s, 1H), 7.73 (dd, J=6.3, 2.7 Hz, 1H), 7.65 (ddd, J=8.8, 4.4, 2.8 Hz, 1H), 7.32-7.29 (m, 1H), 7.29-7.27 (m, 1H), 7.17 (t, J=9.4 Hz, 1H), 7.02-6.98 (m, 1H), 3.76 (s, 3H), 3.63 (s, 2H), 1.34 (s, 9H).

[1385] LC-MS (Method E): Rt 1.22 mins; MS m/z 393.2, 395.1=[M+H]+ (99% @ 215 nm)

Step 4: N-tert-Butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-2-fluoro-benzamide

[1386] The titled compound was prepared from N-tert-butyl-5-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-2-fluoro-benzamide (step 3) analogously to Example 7, step 4.

[1387] 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.84 (s, 1H), 7.83 (s, 1H), 7.73 (dd, J=6.3, 2.7 Hz, 1H), 7.66 (ddd, J=8.9, 4.4, 2.8 Hz, 1H), 7.24-7.13 (m, 2H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.59 (s, 2H), 1.34 (s, 9H).

[1388] LC-MS (Method A): Rt 3.30 mins; MS m/z 379.2/381.1=[M+H]+ (99% @ 215 nm)

Example 18

N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide

[1389] ##STR00207##

Step 1: 3-Amino-N-tert-butyl-5-fluoro-benzamide

[1390] The titled compound was prepared from 3-amino-5-fluoro-benzoic acid analogously to Example 9 step 1.

[1391] 1H NMR (500 MHz, Chloroform-d) δ 6.85-6.80 (m, 1H), 6.69 (dt, J=9.1, 1.8 Hz, 1H), 6.45 (dt, J=10.2, 2.2 Hz, 1H), 5.81 (s, 1H), 3.89 (s, 2H), 1.45 (s, 9H).

[1392] LC-MS (Method E): Rt 0.96 mins; MS m/z 211.1=[M+H]+ (100% @ 215 nm)

Steps 2-3: N-tert-Butyl-3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-benzamide

[1393] The titled compound was prepared from 3-amino-N-tert-butyl-5-fluoro-benzamide (step 1) analogously to Example 3 steps 2 and 3.

[1394] 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.81 (s, 1H), 7.81 (s, 1H), 7.75 (dt, J=11.2, 2.0 Hz, 1H), 7.66 (s, 1H), 7.32-7.24 (m, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.62 (s, 2H), 1.36 (s, 9H).

[1395] LC-MS (Method A): Rt 3.34 mins; MS m/z 379.1/381.1=[M+H]+ (97% @ 215 nm)

Example 19

N-tert-Butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide

[1396] ##STR00208##

Step 1: N-tert-Butyl-4-[[2-(3-methoxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide

[1397] ##STR00209##

[1398] The titled compound was prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and 2-(3-methoxy-2-pyridyl)acetic acid analogously to Example 5.

[1399] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.07 (dd, J=4.7, 1.3 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.42 (dd, J=8.3, 1.2 Hz, 1H), 7.30 (dd, J=8.3, 4.7 Hz, 1H), 3.88 (s, 2H), 3.81 (s, 3H), 1.40 (s, 9H).

[1400] LC-MS (Method A): Rt 2.11 mins; MS m/z 343.2=[M+H]+ (100% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-(3-hydroxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide

[1401] The titled compound was prepared from N-tert-Butyl-4-[[2-(3-methoxy-2-pyridyl)acetyl]amino]pyridine-2-carboxamide (step 1) analogously to Example 7, step 4.

[1402] 1H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 10.01 (br s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.95 (dd, J=4.4, 1.6 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.20-7.09 (m, 2H), 3.84 (s, 2H), 1.40 (s, 9H).

[1403] LC-MS (Method A): Rt 1.60 mins; MS m/z 329.1=[M+H]+ (98% @ 215 nm)

Example 20

N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1404] ##STR00210##

Step 1: N-tert-Butyl-4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1405] ##STR00211##

[1406] A solution of 2-(5-fluoro-2-methoxy-phenyl)acetic acid (57 mg, 0.31 mmol) in thionyl chloride (246 μL, 2.79 mmol) was heated at 70° C. for 1 hr. Excess thionyl chloride was removed in vacuo, azeotroping with DCM. The residue was added to a mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (60 mg, 0.31 mmol) and DIPEA (65 μL, 0.37 mmol) in DCM (30 mL) and the mixture was stirred at room temperature. After 1 hour, the mixture was partitioned between water (25 mL) and DCM (25 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with EtOAc in heptane followed by freeze drying of the product fractions afforded the titled compound as a white solid.

[1407] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.12 (dd, J=9.2, 3.2 Hz, 1H), 7.08 (td, J=8.6, 3.2 Hz, 1H), 6.98 (dd, J=9.0, 4.6 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 2H), 1.40 (s, 9H).

[1408] LC-MS (Method E): Rt 1.16 mins; MS m/z 360.1=[M+H]+ (98% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1409] To a solution of N-tert-butyl-4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (54.1 mg, 0.15 mmol) in DCM (1.3 mL) was added 1M BBr.sub.3 in DCM (452 μL, 0.45 mmol) slowly at room temperature. The reaction was stirred at room temperature for 2.5 hours and then concentrated in vacuo. The residue was partitioned between H.sub.2O (10 mL) and EtOAc (10 mL) and the organic portion separated and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as a white solid.

[1410] 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.52 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9.4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H), 1.40 (s, 9H).

[1411] LC-MS (Method A): Rt 3.01 mins; MS m/z 346.1=[M+H]+ (98% @ 215 nm)

Example 21

Racemic N-tert-butyl-4-[[-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1412] ##STR00212##

[1413] A mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (100 mg, 0.52 mmol) and indane-1-carboxylic acid (84 mg, 0.52 mmol) in 1,4-dioxane (1 mL) was treated with 50% T3P® solution in EtOAc (616 μL, 1.03 mmol) and TEA (181 μL, 1.03 mmol) and stirred at room temperature for 1.5 hours. The resulting mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic portion was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc in heptane to afford racemic N-tert-butyl-4-[[-indane-1-carbonyl]amino]pyridine-2-carboxamide.

Example 21a: N-tert-Butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 21b: N-tert-Butyl-4-[[(1R) or (1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1414] ##STR00213##

[1415] Chiral separation of racemic N-tert-butyl-4-[[-indane-1-carbonyl]amino]pyridine-2-carboxamide using Supercritical Fluid Chromatography [chiral phase column (25% IPA: 75% CO2 with Chiralcel OD-H 25 cm column at 15 ml/min)] afforded the individual enantiomers:

[1416] Example 21a: First eluted peak: N-tert-Butyl-4-[[(1R)-indane-1-carbonyl]amino]pyridine-2-carboxamide or N-tert-Butyl-4-[[(1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1417] SFC Retention time: 5.46 min, MS m/z 338.3=[M+H]+ (100% @ 215 nm)

[1418] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.20 (m, 1H), 7.16 (m, 1H), 4.16 (m, 1H), 3.11-3.03 (m, 1H), 2.95-2.87 (m, 1H), 2.40-2.27 (m, 2H), 1.40 (s, 9H).

[1419] e.e 100%

[1420] Example 21b: Second eluted peak: N-tert-Butyl-4-[[(1R)-indane-1-carbonyl]amino]pyridine-2-carboxamide or N-tert-Butyl-4-[[(1S)-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1421] SFC Retention time: 8.00 min, MS m/z 338.3=[M+H]+ (91% @ 215 nm)

[1422] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 7.20 (m, 1H), 7.16 (m, 1H), 4.16 (m, 1H), 3.11-3.03 (m, 1H), 2.95-2.87 (m, 1H), 2.39-2.27 (m, 2H), 1.40 (s, 9H).

[1423] e.e 88%

Example 22

N-tert-Butyl-4-[(2-phenylacetyl)amino]pyridine-2-carboxamide

[1424] ##STR00214##

[1425] To a mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (50 mg, 0.26 mmol) in DCM (2.59 mL) was added TEA (113 μL, 0.65 mmol) and 2-phenylacetyl chloride (41 μL, 0.31 mmol) and the mixture was stirred for 16 hours. The resulting mixture was diluted with DCM (10 mL) and washed with water (2×10 mL) followed by saturated aqueous NaHCO.sub.3 (10 mL). The organic layer was separated and dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was dissolved in a mixture of DMSO:MeCN (800 μl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method). The product fractions were combined, the pH of the mixture adjusted to pH 7 using saturated aqueous NaHCO.sub.3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the titled compound as an off-white solid.

[1426] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.33 (d, J=4.4 Hz, 4H), 7.29-7.23 (m, 1H), 3.71 (s, 2H), 1.39 (s, 9H).

[1427] LC-MS (Method A): Rt 3.23 mins; MS m/z 312.2=[M+H]+ (100% @ 215 nm)

Example 22.1

4-(3,3-Dimethylbutanoylamino)-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1428] ##STR00215##

[1429] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 3,3-dimethylbutanoyl chloride analogously to Example 22.

[1430] 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 3.21 (s, 1H), 2.25 (s, 2H), 1.64 (s, 6H), 1.02 (s, 9H).

[1431] LC-MS (Method A): Rt 3.22 mins; MS m/z 302.2=[M+H]+ (100% @ 215 nm)

Example 22.2

4-[(2-Cyclopentylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1432] ##STR00216##

[1433] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-cyclopentylacetyl chloride analogously to Example 22.

[1434] 1H NMR (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 3.21 (s, 1H), 2.39-2.35 (m, 2H), 2.28-2.19 (m, 1H), 1.80-1.72 (m, 2H), 1.64 (s, 6H), 1.63-1.56 (m, 2H), 1.56-1.47 (m, 2H), 1.23-1.13 (m, 2H).

[1435] LC-MS (Method A): Rt 3.33 mins; MS m/z 314.2=[M+H]+ (97% @ 215 nm)

Example 22.3

4-[[2-(3-Chloro-4-pyridyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1436] ##STR00217##

[1437] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78 step 1) and 2-(3-chloro-4-pyridyl)acetic acid hydrochloride analogously to Example 22.

[1438] 1H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.63 (s, 1H), 8.49 (t, J=5.3 Hz, 2H), 8.32 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (d, J=4.9 Hz, 1H), 3.99 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1439] LC-MS (Method A): Rt 2.53 mins; MS m/z 357.1/359.1=[M+H]+ (100% @ 215 nm)

Example 23

4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1440] ##STR00218##

Step 1: 4-Amino-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1441] ##STR00219##

[1442] To a mixture of 4-aminopyridine-2-carboxylic acid (1 g, 7.24 mmol), TBTU (2.79 g, 8.69 mmol) and TEA (1.21 mL, 8.69 mmol) in DMF (8 mL) was added 1-aminocyclopropanecarbonitrile (22.82 mL, 8.69 mmol) and the mixture was stirred at 40° C. for 2 days. The resulting mixture was concentrated in vacuo and the crude residue dissolved in EtOAc (15 mL). The mixture was washed with water (20 mL), NaHCO.sub.3 (15 mL) dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as an orange solid.

[1443] 1H NMR (500 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.22 (d, J=2.3 Hz, 1H), 6.62 (dd, J=5.6, 2.4 Hz, 1H), 6.37 (s, 2H), 1.51-1.47 (m, 2H), 1.31-1.27 (m, 2H).

[1444] LC-MS (Method E): Rt 0.25 mins; MS m/z 203.1=[M+H]+

Step 2: 4-[[2-(4-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1445] To a solution of 4-amino-N-(1-cyanocyclopropyl)pyridine-2-carboxamide (step 1) (100 mg, 0.45 mmol), 2-(4-chlorophenyl)acetic acid (83.52 mg, 0.49 mmol) and TEA (155 μL, 0.89 mmol) in 1,4-dioxane (2 mL) was slowly added 50% T3P® solution in EtOAc (529.41 μL, 0.89 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The crude residue was dissolved in EtOAc (10 mL) washed with NaHCO.sub.3 (15 mL), brine (15 mL) dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) afforded the titled compound as an off-white solid.

[1446] 1H NMR (500 MHz, DMSO-d6) δ=10.80 (s, 1H), 9.65 (s, 1H), 8.49 (d, J=5.5, 1H), 8.21 (d, J=1.9, 1H), 7.86 (dd, J=5.5, 2.2, 1H), 7.41-7.34 (m, 4H), 3.74 (s, 2H), 1.55-1.51 (m, 2H), 1.34-1.30 (m, 2H).

[1447] LC-MS (Method A): Rt 2.92 mins; MS m/z 355.3=[M+H]+ (98% @ 215 nm)

[1448] The compounds of the following tabulated Examples (Table 8) were prepared analogously to Example 23 by replacing 1-aminocyclopropanecarbonitrile (step 1) with the appropriate amine and by replacing 2-(4-chlorophenyl)acetic acid (step 2) with the appropriate commercially available acid.

TABLE-US-00009 TABLE 8 Ex. Structure and Name 1H NMR; LCMS Retention Time, [M + H]+, 23.1 [00220] 1H NMR (500 MHz, DMSO-d6) δ =10.81 (s, 1H), 9.66 (s, 1H), 8.50 (d, J = 5.5, 1H), 8.21 (d, J = 2.0, 1H), 7.86 (dd, J = 5.5, 2.2, 1H), 7.42 − 7.41 (m, 1H), 7.39 − 7.28 (m, 3H), 3.76 (s, 2H), 1.55 − 1.51 (m, 2H), 1.34 − 1.31 (m, 2H). LC-MS (Method A): Rt 2.92 mins; MS m/z 355.3/357.3 = [M + H]+ (96% @ 215 nm) 4-[[2-(3-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclo propyl)pyridine-2-carboxamide 23.2 [00221] 1H NMR (500 MHz, DMSO-d6) δ = 10.89 (s, 1H), 9.66 (s, 1H), 8.50 (d, J = 5.5, 1H), 8.21 (d, J = 2.0, 1H), 7.85 (dd, J = 5.5, 2.2, 1H), 7.51 (dd, J = 8.8, 5.3, 1H), 7.37 (dd, J = 9.4, 3.1, 1H), 7.21 (td, J = 8.5, 3.1, 1H), 3.94 LC-MS (Method A): Rt 2.86 mins; MS m/z 373.3/375.3 = [M + H]+ (99% @ 215 nm) 4-[[2-(2-Chloro-5-fluoro-phenyl)acetyl]amino]-N-(1- cyanocyclo propyl)pyridine-2-carboxamide 23.3 [00222] 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.25 − 7.20 (m, 2H), 7.17 − 7.13 (m, 2H), 3.45 (p, J = 8.4 Hz, 1H), 3.25 − 3.13 (m, 4H), 1.40 (s, 9H). LC-MS (MethodA): Rt 3.62 mins; MS m/z 338.2 = [M + H]+ (3.62% @ 215 nm) N-tert-Butyl-4-(indane-2-carbonyl amino)pyridine-2- carboxamide 23.4 [00223] 1H NMR (500 MHz, Methanol-d4) δ 8.44 (d, J = 5.5 Hz, 1H), 8.17 − 8.14 (m, 1H), 7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.39 (dd, J = 7.5, 1.5 Hz, 1H), 7.36 (td, J = 7.9, 1.7 Hz, 1H), 7.24 (td, J = 7.5, 1.1 Hz, 1H), 7.20 − 7.18 (m, 1H), 6.78 (t, J = 74.2 Hz, 1H), 3.85 (s, 2H). LC-MS (Method A): Rt 3.42 mins; MS m/z 378.3 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-4-[[2-[2-(difluoromethoxy) phenyl]acetyl]amino]pyridine-2-carboxamide 23.5 [00224] 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 − 7.50 (m, 1H), 7.46 − 7.42 (m, 2H), 7.20 (t, J = 54.8 Hz, 1H), 3.96 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.41 mins; MS m/z 362.2 = [M + H]+ N-tert-Butyl-4-[[2-[2-(difluoromethyl) phenyl]acetyl]amino]pyridine-2-carboxamide 23.6 [00225] 1H NMR (500 MHz, Methanol-d4) δ 8.45 (dd, J = 5.5, 0.5 Hz, 1H), 8.15 (dd, J = 2.2, 0.5 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.32 − 7.20 (m, 2H), 7.18 − 7.13 (m, 1H), 3.75 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.43 mins; MS m/z 348.3 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-4-[[2-(3,4-difluorophenyl) acetyl]amino]pyridine-2-carboxamide 23.7 [00226] 1H NMR (500 MHz, Methanol-d4) δ 8.45 (dd, J = 5.7, 0.5 Hz, 1H), 8.15 (dd, J = 2.2, 0.5 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.03 − 6.95 (m, 2H), 6.88 (tt, J = 9.2, 2.3 Hz, 1H), 3.78 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.46 mins; MS m/z 348.3 = [M + H]+ (97% @ 215 nm) N-tert-Butyl-4-[[2-(3,5-difluorophenyl) acetyl]amino]pyridine-2-carboxamide 23.8 [00227] 1H NMR (500 MHz, Methanol-d4) δ 8.45 (dd, J = 5.5, 0.4 Hz, 1H), 8.15 (dd, J = 2.2, 0.5 Hz, 1H), 7.92 (dd, J = 5.5, 2.2 Hz, 1H), 7.25 − 7.12 (m, 3H), 3.89 (d, J = 1.4 Hz, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.36 mins; MS m/z 348.2 = [M + H]+ (98% @ 215 nm) N-tert-Butyl-4-[[2-(2,3-difluorophenyl) acetyl]amino]pyridine-2-carboxamide 23.9 [00228] 1H NMR (500 MHz, Methanol-d6) δ 10.83 (s, 1H), 8.59 (d, J = 8.5 Hz, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.48 − 7.42 (m, 2H), 7.35 − 7.31 (m, 2H), 4.06 − 3.97 (m, 1H), 3.92 (s, 2H), 3.89 − 3.84 (m, 2H), 3.43 − 3.36 (m, 2H), 1.72-1.63 (m, 4H). LC-MS (Method A): Rt 2.64 mins; MS m/z 374.2/376.2 = [M + H]+ (100% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-tetrahydropyran-4- yl-pyridine-2-carboxamide 23.11 [00229]   N-(1-Cyanocyclobutyl)-4-[[2-(6-quinolyl) acetyl]amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.59 (s, 1H), 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.39 − 8.32 (m, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.93 − 7.84 (m, 2H), 7.75 (dd, J = 8.7, 2.0 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 3.96 (s, 2H), 2.73 − 2.61 (m, 2H), 2.59 − 2.51 (m, 2H), 2.09 − 1.94 (m, 2H). LC-MS (Method A): Rt 1.65 mins; MS m/z 386.3 = [M + H]+ (98% @ 215 nm) 23.12 [00230] 1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.78 (dd, J = 5.5, 2.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.69 − 7.63 (m, 1H), 7.57 − 7.47 (m, 2H), 4.00 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.58 mins; MS m/z 380.2 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-[2-(trifluoromethyl) phenyl]acetyl]amino]pyridine-2-carboxamide 23.13 [00231] 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.62 (dd, J = 8.0, 1.1 Hz, 1H), 7.43 (dd, J = 7.6, 1.7 Hz, 1H), 7.41 − 7.30 (m, 1H), 7.27 − 7.20 (m, 1H), 3.92 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.49 mins; MS m/z 390.2/392.2 = [M + H]+ (99% @ 215 nm) 4-[[2-(2-Bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2- carboxamide 23.14 [00232] 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.85 (dd, J = 7.7, 1.1 Hz, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.72 − 7.66 (m, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.53 − 7.44 (m, 1H), 4.03 (s, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 3.06 mins; MS m/z 337.3 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-(2-cyanophenyl)acetyl]amino]pyridine-2- carboxamide 23.15 [00233] 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.01 (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 − 7.42 (m, 2H), 7.36 − 7.28 (m, 2H), 3.93 (s, 2H), 3.87 (dt, J = 12.2, 3.8 Hz, 2H), 3.62 − 3.54 (m, 2H), 2.39-2.34 (m, 2H), 2.12-2.03 (m, 2H). LC-MS (Method A): Rt 2.83 mins; MS m/z 399.2/401.3 = [M + H]+ (100% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4- cyanotetrahydropyran-4-yl)pyridine-2-carboxamide 23.16 [00234]   N-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(6- 1H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.01 (s, 1H), 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.36 − 8.33 (m, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 5.5, 2.2 Hz, 1H), 7.75 (dd, J = 8.7, 2.0 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 3.97 (s, 2H), 3.86 (dt, J = 12.2, 3.8 Hz, 2H), 3.61 − 3.56 (m, 2H), 2.37 (d, J = 13.5 Hz, 2H), 2.07 (td, J = 10.1, 5.2 Hz, 2H) LC-MS (Method A): Rt 1.52 mins; MS m/z 416.3 = [M + H]+ (100% @ 215 nm) quinolyl)acetyl]amino]pyridine-2-carboxamide

Example 24

4-[[2-(2-Chloro-5-methoxy-phenyl)acetyl] amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1449] ##STR00235##

Steps 1 and 2: N-(1-Cyanocyclopropyl)-4-[[2-(3-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide

[1450] The titled compound was prepared analogously to Example 23 by replacing 2-(4-chlorophenyl)acetic acid (step 2) with 2-(3-methoxyphenyl)acetic acid.

[1451] 1H NMR (500 MHz, DMSO-d6) δ=10.77 (s, 1H), 9.65 (s, 1H), 8.49 (d, J=5.5, 1H), 8.21 (d, J=2.1, 1H), 7.86 (dd, J=5.5, 2.2, 1H), 7.24 (t, J=7.8, 1H), 6.92-6.88 (m, 2H), 6.83 (dd, J=8.0, 2.1, 1H), 3.74 (s, 3H), 3.68, (s, 2H), 1.55-1.51 (m, 2H), 1.34-1.30 (m, 2H).

[1452] LC-MS (Method E): Rt 1.03 mins; MS m/z 351.0=[M+H]+ (97% @ 215 nm)

Step 2: 4-[[2-(2-Chloro-5-methoxy-phenyl)acetyl] amino]-N-(1-cyanocyclopropyl)pyridine-2-carboxamide

[1453] To a solution of N-(1-cyanocyclopropyl)-4-[[2-(3-methoxyphenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (81 mg, 0.23 mmol) in MeCN (33.7 mL) was added NCS (77 mg, 0.58 mmol) and the mixture was stirred at 60° C. for 16 hours. The resulting mixture was concentrated in vacuo to yield a crude dry residue. The dry residue was dissolved in EtOAc (10 mL), washed with water (10 mL), NaHCO.sub.3 (10 ml) and concentrated in vacuo. Purification by preparative HPLC (acidic pH, standard elution method) afforded the titled compound as an off-white solid.

[1454] 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.66 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 6.90 (dd, J=8.8, 3.1) Hz, 1H), 3.87 (s, 2H), 3.76 (s, 3H), 1.55-1.51 (m, 2H), 1.35-1.30 (m, 2H).

[1455] LC-MS (Method A): Rt 2.84 mins; MS m/z 385.2/387.2=[M+H]+ (100% @ 215 nm)

Example 25

N-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1456] ##STR00236##

Step 1: Methyl 4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate

[1457] ##STR00237##

[1458] 2-(5-tert-Butyl-2-methoxy-phenyl)acetic acid (700 mg, 3.15 mmol) was dissolved in thionyl chloride (2.5 mL, 28.37 mmol) and stirred at 70° C. for 30 mins. The resulting mixture was concentrated in vacuo and azeotroped with toluene (3×5 mL). The residue was dissolved in DCM (15 mL) to form a solution of acid chloride and added to a stirred solution of methyl 4-aminopyridine-2-carboxylate (527 mg, 3.46 mmol) in DCM (15 mL). After stirring for 10 mins, the mixture was concentrated in vacuo to yield a brown gum. The gum was purified by chromatography on silica eluting with 25-100% EtOAc in heptane to afford the titled compound as a dark yellow glass.

[1459] 1H NMR (250 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.77 (dd, J=5.5, 2.1 Hz, 1H), 7.29-7.20 (m, 2H), 6.89 (d, J=9.3 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.68 (s, 2H), 1.26 (s, 9H).

[1460] LC-MS (Method E): Rt 1.17 mins; MS m/z 357=[M+H]+

Step 2: 4-[[2-(5-tert-Butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1461] ##STR00238##

[1462] To a solution of methyl 4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 1) (594 mg, 1.55 mmol) in THF (12 mL) was added 1M sodium hydroxide solution (1.86 mL, 1.86 mmol) and the mixture stirred for 30 mins. The pH of resulting mixture was adjusted to pH 4 by addition of hydrochloric acid. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) at which point a precipitate formed in the organic layer. The organic suspension was washed with water (20 mL), brine (20 mL), filtered through a phase separator and dried to afford the titled compound as a fine powder.

[1463] 1H NMR (250 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.28 (d, J=1.9 Hz, 1H), 7.80 (dd, J=5.6, 2.2 Hz, 1H), 7.29-7.20 (m, 2H), 6.89 (d, J=9.4 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 2H), 1.26 (s, 9H).

[1464] LC-MS (Method E): Rt 0.98 mins; MS m/z 343=[M+H]+

Step 3: 4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1465] ##STR00239##

[1466] An ice-cooled suspension of 4-[[2-(5-tert-butyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (330 mg, 0.93 mmol) in DCM (9 mL) was treated with 1M BBr.sub.3 in DCM (1.85 mL, 1.85 mmol) and stirred for 70 mins. The reaction was quenched with methanol (1 mL) and the mixture was partitioned between EtOAc (20 mL) and water (20 mL) resulting in the formation of a fine white precipitate. The precipitate was filtered and dried to afford the titled compound as a solid.

[1467] 1H NMR (250 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.65 (d, J=6.4 Hz, 1H), 8.51 (d, J=2.2 Hz, 1H), 8.14 (dd, J=6.4, 2.3 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.4, 2.5 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 3.75 (s, 2H), 1.23 (s, 9H).

[1468] LC-MS (Method E): Rt 0.97 mins; MS m/z 329=[M+H]+ (91% @ 215 nm)

Step 4: N-(3-Bicyclo[1.1.1]pentanyl)-4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1469] To a suspension of 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3) (25 mg, 0.08 mmol) in DMF (0.5 mL) was added bicyclo[1.1.1]pentan-3-amine hydrochloride (11 mg, 0.09 mmol), DIPEA (0.05 mL, 0.3 mmol) and HATU (43 mg, 0.11 mmol). After stirring at room temperature for 18 hours, the mixture was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous portion extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by C18 reverse phase chromatography eluting with 45-65% MeCN in water with 0.1% formic acid to afford the titled compound as a white powder.

[1470] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.28 (s, 1H), 9.07 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.08 (dd, J=8.4, 2.5 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 3.65 (s, 2H), 2.44 (s, 1H), 2.09 (s, 6H), 1.23 (s, 9H).

[1471] LC-MS (Method A): Rt 3.71 mins; MS m/z 394=[M+H]+

Example 25.1

4-[[2-(5-tert-Butyl-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1472] ##STR00240##

[1473] The titled compound was prepared from 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 25, step 3) and 4-aminotetrahydropyran-4-carbonitrile analogously to Example 25 step 4.

[1474] 1H NMR (500 MHz, Methanol-d4) δ 8.47 (d, J=5.5 Hz, 1H), 8.17 (d, J=1.8 Hz, 1H), 7.94 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.4, 2.5 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 3.96 (dt, J=12.5, 4.0 Hz, 2H), 3.80-3.74 (m, 2H), 3.72 (s, 2H), 2.49-2.43 (m, 2H), 2.14-2.07 (m, 2H), 1.28 (s, 9H).

[1475] LC-MS (Method A): Rt 3.22 mins; MS m/z 437=[M+H]+ (100% @ 215 nm)

Example 26

N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1476] ##STR00241##

Step 1: N-tert-butyl-4-[[2-(2-methoxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1477] ##STR00242##

[1478] A pressure tube was charged with 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6, step 1) (250 mg, 0.59 mmol), tripotassium phosphate (379 mg, 1.78 mmol), phenylboronic acid (80 mg, 0.65 mmol) in 1,4-dioxane (4 mL) and the suspension was degassed with nitrogen. Bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (24 mg, 0.03 mmol) was added under an atmosphere of nitrogen and the sealed tube was heated to 80° C. for 23 hours. The reaction mixture was concentrated in vacuo and the crude residue re-dissolved in EtOAc. The mixture was filtered through Celite® (filter material) and the filtrate concentrated in vacuo to afford a brown oil. The oil was purified by chromatography on silica eluting 25-100% EtOAc in heptane to afford the titled compound as a white solid.

[1479] 1H NMR (250 MHz, Chloroform-d) δ 8.38 (d, J=5.6 Hz, 1H), 8.26-8.14 (m, 2H), 7.97 (s, 1H), 7.59-7.50 (m, 5H), 7.46-7.37 (m, 2H), 7.37-7.28 (m, 1H), 7.05 (d, J=8.3 Hz, 1H), 4.01 (s, 3H), 3.80 (s, 2H), 1.47 (s, 9H).

[1480] LC-MS (Method E): Rt 1.29 mins; MS m/z 418=[M+H]+

Step 2: N-tert-Butyl-4-[[2-(2-hydroxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1481] To an ice-cooled solution of N-tert-butyl-4-[[2-(2-methoxy-5-phenyl-phenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (160 mg, 0.38 mmol) in DCM (2.5 mL) was added dropwise 1M BBr.sub.3 in DCM (1.92 mL, 1.92 mmol). After stirring for 10 mins, the reaction was quenched by addition of methanol (1 mL). The resulting mixture was concentrated in vacuo and the residue partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated and the aqueous portion re-extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as an amber-coloured glass.

[1482] .sup.1H NMR (500 MHz, Chloroform-d) δ 10.14-9.39 (m, 2H), 8.32 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 8.04 (dd, J=5.6, 1.9 Hz, 1H), 7.94 (s, 1H), 7.42 (d, J=7.3 Hz, 2H), 7.39 (d, J=2.1 Hz, 1H), 7.36-7.29 (m, 3H), 7.25 (t, J=7.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 3.83 (s, 2H), 1.49 (s, 9H).

[1483] LC-MS (Method A): Rt 3.64 mins; MS m/z 404=[M+H]+

Example 27

N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1484] ##STR00243##

Step 1: 2-(4-Bromo-5-chloro-2-methoxy-phenyl)acetic acid

[1485] ##STR00244##

[1486] 2-(4-Bromo-2-methoxy-phenyl)acetic acid (2 g, 8.16 mmol) and NCS (1.14 g, 8.57 mmol) were dissolved in MeCN (40.8 mL) and stirred at 50° C. for 22 hours. The resulting mixture was concentrated in vacuo and the residue purified by chromatography on silica eluting with 20-100% EtOAc in heptane. The product was further purified by dissolving in EtOAc (100 mL) and extracting into saturated aqueous NaHCO.sub.3 (3×100 mL). The combined aqueous extracts were acidified with 1M HCl and extracted with EtOAc (3×150 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the titled compound as a colourless solid.

[1487] 1H NMR (250 MHz, DMSO-d6) δ 11.97 (s, 1H), 7.46 (s, 1H), 7.34 (s, 1H), 3.79 (s, 3H), 3.50 (s, 2H).

[1488] LC-MS (Method E): Rt 1.07 mins; MS m/z not observed=[M+H]+

Step 2: 4-[[2-(4-Bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1489] ##STR00245##

[1490] The titled compound was prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide and 2-(4-bromo-5-chloro-2-methoxy-phenyl)acetic acid (step 1) analogously to Example 3.5b step 1

[1491] 1H NMR (250 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (s, 1H), 7.36 (s, 1H), 3.78 (s, 3H), 3.71 (s, 2H), 1.40 (s, 9H).

[1492] LC-MS (Method E): Rt 1.28 mins; MS m/z 454=[M+H]+ 97% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-[5-chloro-2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1493] ##STR00246##

[1494] A vessel was charged with 4-[[2-(4-bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 2)(100 mg, 0.21 mmol), potassium trifluoropyrrolin-1-ylmethyl)boranuide (45 mg, 0.23 mmol), Xphos (6 mg, 0.01 mmol), Pd(Oac).sub.2 (1.4 mg, 0.01 mmol) and Cs.sub.2CO.sub.3 (209 mg, 0.64 mmol) and placed under an atmosphere of nitrogen. THF:water (1 mL of a 10:1 mixture) was added and the mixture was heated at 80° C. for 20 hours. The resulting mixture was diluted with water (2 mL) and extracted with DCM (3×10 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the titled compound as a colourless solid.

[1495] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.16 (dd, J=6.4, 2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.29 (s, 1H), 7.07 (s, 1H), 3.75 (s, 3H), 3.69 (s, 2H), 3.65 (s, 2H), 2.51-2.49 (obscured m, 4H), 1.73-1.71 (m, 4H), 1.40 (s, 9H).

[1496] LC-MS (Method E): Rt 1.04 mins; MS m/z 459/461=[M+H]+ (78% @ 215 nm)

Step 4: N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1497] The titled compound was prepared from N-tert-Butyl-4-[[2-[5-chloro-2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetyl] amino]pyridine-2-carboxamide N-tert-butyl-4-[[2-[5-(step 3) analogously to Example 26 step 2.

[1498] 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.70 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.18 (s, 1H), 6.97 (s, 1H), 3.64 (s, 2H), 3.57 (s, 2H), 2.51-2.49 (obscured m, 4H), 1.72-1.70 (m, 4H), 1.40 (s, 9H).

[1499] LC-MS (Method A): Rt 2.08 mins; MS m/z 445.3/447.3=[M+H]+ (99% @ 215 nm)

[1500] The compounds of the following tabulated Examples (Table 9) were prepared analogously to Example 27 by replacing potassium trifluoropyrrolin-1-ylmethyl)boranuide (step 3) with the appropriate boranuide

TABLE-US-00010 TABLE 9 1H NMR Ex. Structure and Name LCMS Retention Time, [M + H]+, 27.1 [00247] 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.66 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.16 (s, 1H), 7.06 (s, 1H), 3.63-3.61 (m, 4H), 1.40 (s, 9H), 1.09 (s, 9H). LC-MS (Method A): Rt 2.08 mins; MS m/z 445.4/447.4 = [M + H]+ (99% @ 215 nm) N-tert-Butyl-4-[[2-[4-[(tert-butylamino)methyl]-5-chloro-2- hydroxy-phenyl]acetyl]amino]pyridine-2-carboxamide 27.2 [00248]   1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.74 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (s, 1H), 6.98 (s, 1H), 3.65 (s, 2H), 3.62 − 3.56 (m, 4H), 3.46 (s, 2H), 2.42-2.40 (m, 4H), 1.40 (s, 9H). LC-MS (Method A): Rt 1.91 mins; MS m/z 459.3/460.3 = [M + H]+ (100% @ 215 nm) N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-4- (morpholinomethyl)phenyl]acetyl]amino]pyridine-2- carboxamide 27.3 [00249]   N-tert-Butyl-4-[[2-[5-chloro-4-[(3,3-difluoropyrrolidin-1- 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.78 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (s, 1H), 6.95 (s, 1H), 3.64 (s, 2H), 2.93 (t, J = 13.3 Hz, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.31-2.22 (m, 2H), 1.40 (s, 9H). LC-MS (Method A): Rt 2.6 mins; MS m/z 481.3/483.3 = [M + H]+ (98% @ 215 nm) yl)methyl]-2-hydroxy-phenyl]acetyl]amino]pyridine-2- carboxamide

Example 28

N-tert-butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide

[1501] ##STR00250##

Step 1: N-(2-Chloro-5-fluoro-4-pyridyl)-2-(5-chloro-2-methoxy-phenyl)acetamide

[1502] ##STR00251##

[1503] A solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (753 mg, 3.75 mmol) in thionyl chloride (6.01 mL, 68.24 mmol) was stirred at 70° C. for 1 hour. The resulting mixture was concentrated to dryness and azeotroped with toluene (2×10 mL). The crude residue was dissolved in DMF (10 mL) and treated dropwise with a solution of 2-chloro-5-fluoro-pyridin-4-amine (500 mg, 3.41 mmol) in DMF (3 mL) followed by DIPEA (1.49 mL, 8.53 mmol). After stirring at room temperature under an inert atmosphere for 16 hours, the mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL) and brine (2×50 mL). The organic portion was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography eluting with 0-100% MeCN in water with 0.1% formic acid modifier to afford the titled compound as a light yellow solid.

[1504] 1H NMR (250 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.41 (d, J=2.7 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.33-7.28 (m, 2H), 7.01 (d, J=9.5 Hz, 1H), 3.83 (s, 2H), 3.75 (s, 3H).

[1505] LC-MS (Method E): Rt 1.25 mins; MS m/z 328.9, 330.9=[M+H]+

Step 2: N-tert-Butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide

[1506] ##STR00252##

[1507] All reagents charged to Coware equipment (carbon monoxide generating system) according to the following procedure; To chamber A was added N-(2-chloro-5-fluoro-4-pyridyl)-2-(5-chloro-2-methoxy-phenyl)acetamide (step 1) (170 mg, 0.52 mmol), sodium carbonate (164 mg, 1.55 mmol), XantPhos Pd-G3 (third generation (G3) Buchwald precatalyst) (49 mg, 0.05 mmol) and toluene (5 mL) followed by 2-methylpropan-2-amine (64 mg, 0.88 mmol). The resulting solution was de-gassed with nitrogen for 5 minutes. To chamber B was added formic acid (49 μL, 1.29 mmol) in toluene (5 mL) followed by mesyl chloride (100 μL, 1.29 mmol). The vessel was sealed and TEA (288 μL, 2.07 mmol) added to chamber B to generate carbon monoxide. The Coware equipment was heated at 100° C. overnight and allowed to cool to room temperature. The resulting mixture was concentrated in vacuo, dissolved in EtOAc (30 mL) and washed with water (2×25 mL). The organic portion was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude residue by preparative HPLC (acidic pH, early elution method) afforded the titled compound as a beige solid.

[1508] 1H NMR (250 MHz, Methanol-d4) δ 8.91 (d, J=6.5 Hz, 1H), 8.41 (d, J=2.6 Hz, 1H), 7.29-7.23 (m, 2H), 7.00-6.94 (m, 1H), 3.84 (s, 3H), 3.79 (s, 2H), 1.45 (s, 9H).

[1509] LC-MS (Method E): Rt 1.25 mins; MS m/z 394.1, 396.1=[M+H]+ (97% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide

[1510] To a cooled (0° C.) solution of N-tert-butyl-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-5-fluoro-pyridine-2-carboxamide (step 2) (30 mg, 0.08 mmol) in DCM (2 mL) was added 1M BBr.sub.3 in DCM (190 μL, 0.19 mmol). The reaction mixture was allowed to warm to room temperature and stirring continued for a further 1 hour. The reaction was quenched by addition of water (0.5 mL) and concentrated in vacuo. The crude material was re-dissolved in EtOAc (2 mL) and washed with sat. NaHCO.sub.3 (2 mL). The organic portion was concentrated in vacuo and purification of the crude residue was carried out by C18 reverse phase chromatography (0-100% MeCN in water with 0.1% formic acid modifier). The product fractions were concentrated in vacuo and freeze-dried to afford the titled compound as a white solid.

[1511] 1H NMR (500 MHz, DMSO-d6) δ 10.02 (br. S, 1H), 8.82 (d, J=6.6 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 7.91 (s, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.79-3.74 (m, 2H), 1.38 (s, 9H).

[1512] LC-MS (Method A): Rt 3.37 mins; MS m/z 380.3/381.3/382.3=[M+H]+ (99% @ 215 nm)

Example 28.1

N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-3-fluoro-pyridine-2-carboxamide

[1513] ##STR00253##

[1514] The titled compound was prepared from 2-chloro-3-fluoro-pyridin-4-amine and 2-(5-chloro-2-methoxy-phenyl)acetic acid analogously to Example 28 steps 1-3.

[1515] 1H NMR (500 MHz, DMSO-d6) δ 8.29-8.25 (m, 2H), 8.02 (s, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.78 (s, 2H), 1.38 (s, 9H).

[1516] LC-MS (Method A): Rt 3.30 mins; MS m/z 380.2/382.2=[M+H]+

Example 30

4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide

[1517] ##STR00254##

Step 1: Methyl 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylate

[1518] ##STR00255##

[1519] To a stirred solution of 2-(2-chlorophenyl)acetic acid (3.08 g, 18.07 mmol), methyl 4-aminopyridine-2-carboxylate (2.5 g, 16.43 mmol) and TEA (4.3 mL, 24.65 mmol) in 1,4-dioxane (40 mL) was added 50% T3P® solution in EtOAc (14.68 mL, 24.65 mmol). The resulting mixture was stirred at room temperature for 2 hour and then diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 10-100% EtOAc in heptane to afford the titled compound as a pale orange solid.

[1520] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.31 (d, J=1.9 Hz, 1H), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.48-7.40 (m, 2H), 7.36-7.28 (m, 2H), 3.91 (s, 2H), 3.86 (s, 3H).

[1521] LC-MS (Method E): Rt 1.00 mins; MS m/z 305.0/307.0=[M+H]+ (96% @ 215 nm)

Step 2: 4-[[2-(2-Chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid

[1522] ##STR00256##

[1523] 2M LiOH (16.07 mL, 32.13 mmol) was added to a stirred solution of methyl 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylate (step 2) (3.4 g, 10.71 mmol) in THF (40 mL) and stirred at room temperature for 20 minutes. The resulting mixture was partially concentrated in vacuo to remove the volatile solvent and acidified to pH 2 with 2M aq HCl. The resulting suspension was filtered and dried in a vacuum oven at 40° C. to afford the titled compound as an off-white solid.

[1524] 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.49-7.41 (m, 2H), 7.35-7.29 (m, 2H), 3.92 (s, 2H).

[1525] LC-MS (Method E): Rt 0.89 mins; MS m/z 290.9/292.9=[M+H]+ (100% @ 215 nm)

Step 3: 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyanocyclobutyl)pyridine-2-carboxamide

[1526] A solution of 1-aminocyclobutanecarbonitrile (33 mg, 0.34 mmol), DIPEA (0.07 mL, 0.41 mmol), HATU (131 mg, 0.34 mmol) and 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (100 mg, 0.34 mmol) in DMF (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions lyophilised overnight to afford the titled compound as an off-white powder.

[1527] 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.60 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.52-7.38 (m, 2H), 7.38-7.24 (m, 2H), 3.92 (s, 2H), 2.70-2.62 (m, 2H), 2.59-2.52 (m, 2H), 2.09-1.93 (m, 2H).

[1528] LC-MS (Method A): Rt 3.02 mins; MS m/z 369.2=[M+H]+ (100% @ 215 nm)

Example 30.1

4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1529] ##STR00257##

[1530] A solution of 2-methylbut-3-yn-2-amine (14 mg, 0.17 mmol), DIPEA (0.08 mL, 0.43 mmol), HATU (65 mg, 0.17 mmol) and 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 30, step 2)(50 mg, 0.17 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo then the residue partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were combined and lyophilised overnight to afford the titled compound as an off-white powder.

[1531] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.49-7.39 (m, 2H), 7.37-7.29 (m, 2H), 3.92 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1532] LC-MS (Method A): Rt 3.25 mins; MS m/z 356.3/358.2=[M+H]+ (100% @ 215 nm)

Example 30.2

4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide

[1533] ##STR00258##

[1534] A solution of 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride (26 mg, 0.17 mmol), DIPEA (0.08 mL, 0.43 mmol), HATU (65 mg, 0.17 mmol) and 4-[[2-(2-chlorophenyl) acetyl]amino]pyridine-2-carboxylic acid (Example 30, step 2) (50 mg, 0.17 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were combined and lyophilised overnight to afford the titled compound as an off-white powder.

[1535] 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.05 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.54-7.40 (m, 2H), 7.40-7.25 (m, 2H), 3.91 (s, 2H), 2.14-2.08 (m, 2H), 2.08-2.04 (m, 2H), 2.00-1.94 (m, 2H), 1.87-1.81 (m, 2H).

[1536] LC-MS (Method A): Rt 3.39 mins; MS m/z 388.3/390.3=[M+H]+ (99% @ 215 nm)

Example 30.3

4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyclopropyl-1-methyl-ethyl)pyridine-2-carboxamide

[1537] ##STR00259##

[1538] The titled compound was prepared from 4-[[2-(2-chlorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 30 step 2) and 2-cyclopropylpropan-2-amine analogously to Example 30 step 3.

[1539] 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.49-7.42 (m, 2H), 7.35-7.31 (m, 2H), 3.92 (s, 2H), 1.41-1.34 (m, 1H), 1.31 (s, 6H), 0.43-0.36 (m, 4H).

[1540] LC-MS (Method A): Rt 3.73 mins; MS m/z 372.2/374.2=[M+H]+ (100% @ 215 nm)

[1541] The compounds of the following tabulated Examples (Table 9a) were prepared analogously to Example 30 by replacing 1-aminocyclobutanecarbonitrile (step 3) with the appropriate commercially available amine.

TABLE-US-00011 TABLE 9a 1H NMR Ex. Structure and Name LCMS Retention Time, [M + H]+, 30.3a [00260] 1H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.84 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.50 − 7.42 (m, 2H), 7.38 − 7.29 (m, 2H), 3.93 (s, 2H), 1.73 (s, 6H). LC-MS (Method A): Rt 2.96 mins; MS m/z 357.2/359.3 = [M + H]+ (99% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-1- methyl-ethyl)pyridine-2-carboxamide 30.4 [00261] 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.99 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 − 7.40 (m, 2H), 7.36 − 7.29 (m, 2H), 3.91 (s, 2H), 1.96 (s, 6H), 1.22 (s, 3H). LC-MS (Method A): Rt 3.65 mins; MS m/z 370.3/372.3 = [M + H]+ (97% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-methyl-3- bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide 30.5 [00262] 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.49 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 − 7.38 (m, 2H), 7.36 − 7.28 (m, 2H), 3.91 (s, 2H), 2.57 (s, 6H). LC-MS (Method A): Rt 3.08 mins; MS m/z 381.2/383.2 = [M + H]+ (100% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1-cyano-3- bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide 30.6 [00263] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.07 (t, J = 3.3 Hz, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.56 − 7.40 (m, 2H), 7.40 − 7.25 (m, 2H), 3.92 (s, 2H), 3.57 − 3.42 (m, 1H), 2.03 − 1.80 (m, 2H). LC-MS (Method A): Rt 3.04 mins; MS m/z 366.1/368.2 = [M + H]+ (99% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2- difluorocyclopropyl)pyridine-2-carboxamide 30.7 [00264] 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.66 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.50 − 7.40 (m, 2H), 7.36 − 7.27 (m, 2H), 3.92 (s, 2H), 1.59 − 1.46 (m 2H), 1.37 − 1.28 (m, 2H). LC-MS (Method A): Rt 2.77 mins; MS m/z 355.2/357.2 = [M + H]+ (98% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1- cyanocyclopropyl)pyridine-2-carboxamide 30.8 [00265] 1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.76 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.44 (m, 2H), 7.36 − 7.17 (m, 2H), 3.91 (s, 2H), 1.36 (s, 3H), 0.91 − 0.72 (m, 2H), 0.72 − 0.57 (m, 2H). LC-MS (Method A): Rt 3.02 mins; MS m/z 344.2/346.2 = [M + H]+ (100% @ 215 nm) 4-[[2-(2-Clorophenyl)acetyl]amino]-N-(1- methylcyclopropyl)pyridine-2-carboxamide 30.9 [00266] 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.37 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H),7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.48 − 7.40 (m, 2H), 7.35 − 7.30 (m, 2H), 3.91 (s, 2H), 2.41 (d, J = 2.2 Hz, 6H). LC-MS (Method A): Rt 3.30 mins; MS m/z 374.3/376.2 = [M + H]+ (100% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(3-fluoro-1- bicyclo[1.1.1]pentanyl)pyridine-2-carboxamide 30.10 [00267] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.44 (d, J = 11.9 Hz, 2H), 7.35 − 7.31 (m, 2H), 4.58 (d, J = 47.5 Hz, 2H), 3.92 (s, 2H), 1.39 (d, J = 1.9 Hz, 6H). LC-MS (Method A): Rt 3.32 mins; MS m/z 364.2/366.2 = [M + H]+ (100% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2-fluoro-1,1- dimethyl-ethyl)pyridine-2-carboxamide 30.11* [00268] 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.45 (s, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.48 − 7.41 (m, 2H), 7.35 − 7.30 (m, 2H), 3.92 (s, 2H), 3.76 (dt, J = 11.7, 3.9 Hz, 2H), 3.67 − 3.59 (m, 2H), 3.38 (s, 1H), 2.19-2.13 (m, 2H), 2.09-2.01 (m, 2H). LC-MS (Method A): Rt 2.95 mins; MS m/z 398.2/400.2 = [M + H]+ (100% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(4- ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide. 30.12 [00269] 1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.05 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.48 − 7.42 (m, 2H), 7.35 − 7.30 (m, 2H), 3.92 (s, 2H), 2.33 − 2.27 (m, 4H), 1.79 − 1.72 (m, 4H). LC-MS (Method A): Rt 3.24 mins; MS m/z 383.2/385.2 = [M + H]+ (99% @ 215 nm) 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(1- cyanocyclopentyl)pyridine-2-carboxamide 30.13 [00270] 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.29 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.47 − 7.41 (m, 2H), 7.34 − 7.30 (m, 2H), 6.46 (t, J = 57.0 Hz, 1H), 3.92 (s, 2H), 1.44 (s, 6H) LC-MS (Method A): Rt 3.53 mins; MS m/z 382.2/384.2 = [M + H]+ 4-[[2-(2-Chlorophenyl)acetyl]amino]-N-(2,2-difluoro- 1,1-dimethyl-ethyl)pyridine-2-carboxamide *Example 30.11: the amine, 4-ethynyltetrahydropyran-4-amine hydrochloride was prepared according to the procedure described in Journal of Organic Chemistry, 71(18), 7110-7112; 2006

Example 31

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1542] ##STR00271##

Step 1: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1543] ##STR00272##

[1544] 1M BBr.sub.3 in DCM (308.67 mL, 308.67 mmol) was added slowly over 1 hour to a suspension of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1, step 2) (25.0 g, 77.17 mmol, 99%) in DCM (500 mL) at 0-5° C. under an inert atmosphere of N.sub.2. The mixture was allowed to warm to room temperature and stirred for a further hour. The reaction mixture was concentrated in vacuo and the residue was suspended in EtOAc (500 mL) and water (500 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and the aqueous layer adjusted to pH 4 by portion-wise addition of sat. aq. NaHCO.sub.3 (350 mL). The precipitate was collected by filtration, washed with water (2×100 mL), EtOAc (2×100 mL), diethyl ether (2×150 mL) and dried in a high vacuum oven at 40° C. to afford the titled compound as a beige solid.

[1545] 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.82 (br. s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.6, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H).

[1546] LC-MS (Method E): Rt 0.86 mins; MS m/z 306.9/308.9=[M+H]+ (97% @ 215 nm)

Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1547] ##STR00273##

[1548] HATU (19.34 g, 50.86 mmol) was added to a stirred solution of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) (13 g, 42.39 mmol), 4-aminotetrahydropyran-4-carbonitrile (8.02 g, 63.58 mmol) and DIPEA (18.51 mL, 105.97 mmol) in DMF (150 mL) and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with 0.5 M aq. NaOH (100 mL) and stirred at room temperature for 30 mins. Water (500 mL) and EtOAc (500 mL) were added and the resulting precipitate was removed by filtration. The aqueous portion was extracted with EtOAc (250 mL) and the combined organics were washed with water (2×750 mL), sat. NaHCO.sub.3 (500 mL), brine (700 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford a yellow oil. The material was purified on chromatography on silica eluting with 0-100% EtOAc in heptane then 0-15% MeOH in EtOAc. The product fractions were combined and concentrated in vacuo. The residue was subsequently purified on KP-NH silica eluting with 50-100% EtOAc in heptane then 0-15% MeOH in EtOAc. The clean product fractions were combined and concentrated in vacuo and azeotroped with MeCN (3×500 mL) to afford the titled compound.

[1549] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (br s, 1H), 9.83 (s, 1H), 9.00 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.86 (td, J=12.5 Hz, 3.9 Hz, 2H), 3.68 (s, 2H), 3.64-3.53 (m, 2H), 2.41-2.32 (m, 2H), 2.12-2.00 (m, 2H).

[1550] LC-MS (Method A): Rt 2.67 mins; MS m/z 415.2/417.2=[M+H]+

Step 3: Recrystallisation 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[1551] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl) pyridine-2-carboxamide (step 2) (1881 mg, 4.44 mmol) was suspended in MeCN (16 mL) and heated at reflux for 10 min. Additional MeCN (2 mL) was added and the mixture was heated at reflux for 30 mins at which point it was observed that all the material had gone into solution. The heat was reduced to 55° C. and the mixture was seeded with a crystal of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl) pyridine-2-carboxamide. The temperature of the mixture was maintained at 55° C. for 1 hour and then allowed to cool slowly to room temperature overnight. The resulting crystals were collected by filtration, washed with minimum volume of ice cold MeCN (˜5 mL) and dried in a vacuum oven at 40° C. for 2 hours to afford the titled compound as an off-white crystalline solid.

[1552] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (br s, 1H), 9.82 (br s, 1H), 9.00 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.86 (td, J=12.5 Hz, 3.9 Hz, 2H), 3.68 (s, 2H), 3.63-3.54 (m, 2H), 2.40-2.34 (m, 2H), 2.12-2.03 (m, 2H).

[1553] LC-MS (Method A): Rt 2.68 mins; MS m/z 415.3/417.2=[M+H]+ (99% @ 215 nm)

Example 31.2

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-ethynylcyclopentyl)pyridine-2-carboxamide

[1554] ##STR00274##

[1555] The titled compound was prepared from 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) and 1-ethynylcyclopentanamine hydrochloride analogously to Example 31 step 2.

[1556] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.82 (br. s, 1H), 8.48-8.45 (m, 2H), 8.17 (d, J=1.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 3.16 (s, 1H), 2.30-2.22 (m, 2H), 2.14-2.05 (m, 2H), 1.77-1.66 (m, 4H).

[1557] LC-MS (Method A): Rt 3.34 mins; MS m/z 398.2/400.2=[M+H]+ (100% @ 215 nm)

Example 31.3

4-[2-(5-Chloro-2-hydroxyphenyl)acetamido]-N-[(1s,2s)-2-hydroxycyclohexyl]pyridine-2-carboxamide

[1558] ##STR00275##

[1559] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2-hydroxycyclohexyl)pyridine-2-carboxamide was prepared from 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) and trans-2-aminocyclohexanol analogously to Example 31 step 2.

[1560] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s (br), 1H), 9.82 (s (br), 1H), 8.47 (d, J=5.5 Hz, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 4.68 (d, J=5.5 Hz, 1H), 3.66 (s, 2H), 3.60-3.53 (m, 1H), 3.45-3.41 (m, 1H), 1.94-1.85 (m, 2H), 1.67-1.57 (m, 2H), 1.30-1.18 (m, 4H).

[1561] LC-MS (Method A): Rt 2.64 mins; MS m/z 404.3/406.3=[M+H]+ (97% @ 215 nm)

Example 31.3a

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S,2S)-2-hydroxycyclo hexyl]pyridine-2-carboxamide or 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclohexyl]pyridine-2-carboxamide

[1562] ##STR00276##

[1563] Chiral separation of 4-[2-(5-chloro-2-hydroxyphenyl)acetamido]-N-[(1s,2s)-2-hydroxycyclohexyl]pyridine-2-carboxamide (Example 31.3) using Supercritical Fluid Chromatography SFC (15% Methanol+0.2% DEA: 85% CO.sub.2 with Chiralcel OJ-H 25 cm column at 4 ml/min) afforded the titled compound.

[1564] SFC Retention Time (second eluted peak)=23.32 mins MS (ESIPos): m/z=404.1 (M+H)+.

[1565] 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=5.5 Hz, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 4.69 (d, J=5.5 Hz, 1H), 3.66 (s, 2H), 3.61-3.53 (m, 1H), 3.47-3.41 (m, 1H), 1.95-1.86 (m, 2H), 1.68-1.58 (m, 2H), 1.28-1.23 (m, 4H).

[1566] LC-MS (Method A): Rt 2.64 mins; MS m/z 404.2/406.2=[M+H]+ (100% @ 215 nm)

Example 31.4

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-ethynyltetrahydropyran-4-yl)pyridine-2-carboxamide

[1567] ##STR00277##

Step 1: 2-Methyl-N-tetrahydropyran-4-ylidene-propane-2-sulfinamide

[1568] ##STR00278##

[1569] A solution of tetrahydropyran-4-one (2.4 g, 23.97 mmol) in THF (50 mL) under an inert atmosphere was treated with tetraethoxytitanium (9.57 g, 41.95 mmol) followed by 2-methylpropane-2-sulfinamide (2.91 g, 23.97 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was poured into sat. aq. NaHCO.sub.3 (100 mL) and stirred for 5 minutes. A resulting suspension was filtered and the solid washed further with water (50 mL) and EtOAc (100 mL). The filtrate was separated and the aqueous layer washed once more with EtOAc (50 mL). The combined organic portions were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford a crude oil. The oil was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the titled compound as a colourless oil.

[1570] LC-MS (Method E): Rt 0.74 mins; MS m/z 204.0=[M+H]+ (100% @ 215 nm)

Step 2: 4-Ethynyltetrahydropyran-4-amine hydrochloride

[1571] ##STR00279##

[1572] A cooled (−78° C.) solution of ethynyl(trimethyl)silane (725 mg, 7.38 mmol) in toluene (10 mL) under nitrogen was treated dropwise with n-BuLi (1.6M in hexanes) (3.38 mL, 5.41 mmol). After stirring at −78° C. for 15 mins, the mixture was treated with a cooled (−78° C.) solution of 2-methyl-N-tetrahydropyran-4-ylidene-propane-2-sulfinamide (500 mg, 2.46 mmol) in toluene (5 mL) and trimethylalumane (1.48 mL, 2.95 mmol) via cannula. Stirring was continued at −78° C. for 2 hours and then the solution was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled to 0° C. and quenched with sat. aq. Na.sub.2SO.sub.4 (˜20 mL). The mixture was filtered and washed with EtOAc (˜50 mL). The biphasic filtrate was separated and organic portion washed further with water (25 mL). The aqueous layer was back-extracted with EtOAc (50 mL) and the combined organic extracts were washed with brine (25 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford an off-white solid. The solid was dissolved in anhydrous dioxane (2 mL) and treated with 4M HCl (2 mL). After stirring at room temperature for 4 hours, the resulting precipitate was filtered and washed with cold dioxane to afford the titled compound as a beige solid.

[1573] 1H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 3H), 3.91 (s, 1H), 3.91-3.86 (m, 2H), 3.48 (td, J=11.9, 2.0 Hz, 2H), 1.95 (td, J=12.4, 4.5 Hz, 2H), 1.89-1.84 (m, 2H).

[1574] LC-MS (Method E): Rt 0.2 mins; MS m/z 126.0=[M+H]+

Step 3: 4-[[2-(5-Chloro-2-hydroxy-phenyl) acetyl]amino]-N-(4-ethynyltetrahydro pyran-4-yl)pyridine-2-carboxamide

[1575] The titled compound was prepared from 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Ex 31 step 1) and 4-ethynyltetrahydropyran-4-amine hydrochloride (step 2) analogously to Example 31 step 2.

[1576] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.81 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.45 (s, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.76 (dt, J=7.7, 4.0 Hz, 2H), 3.68 (s, 2H), 3.66-3.60 (m, 2H), 3.38 (s, 1H), 2.18-2.13 (m, 2H), 2.09-2.01 (m, 2H).

[1577] LC-MS (Method A): Rt 2.80 mins; MS m/z 414.2/416.2=[M+H]+ (99% @ 215 nm)

Example 32

N-[(6-Amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1578] ##STR00280##

Step 1: tert-butyl N-[6-[[[4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]methyl]-2-pyridyl]carbamate

[1579] ##STR00281##

[1580] To a solution of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1 step 2)(100 mg, 0.3 mmol) in DMF (1 mL) was added tert-butyl N-[6-(aminomethyl)-2-pyridyl]carbamate (68 mg, 0.3 mmol) followed by DIPEA (63 μL, 0.36 mmol) and the mixture stirred at room temperature for 15 mins. HATU (126 mg, 0.33 mmol) was added and the stirring continued at room temperature for 1 hour. The resulting mixture was diluted with H.sub.2O (2 mL) and the pH adjusted to pH 6 by addition of sat. aq. NH.sub.4Cl. The mixture was extracted with EtOAc (2×5 mL) and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was triturated with MeCN and water to afford the titled compound as white solid.

[1581] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.70 (s, 1H), 9.23 (t, J=6.1 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.69-7.63 (m, 2H), 7.32-7.29 (m, 2H), 7.03-7.00 (m, 1H), 6.91 (dd, J=6.9, 1.2 Hz, 1H), 4.49 (d, J=6.1 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 2H), 1.46 (s, 9H).

[1582] LC-MS (Method A): Rt 3.78 mins; MS m/z 526.3/528.2=[M+H]+ (100% @ 215 nm)

Step 2: N-[(6-Amino-2-pyridyl)methyl]-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl] amino]pyridine-2-carboxamide

[1583] tert-Butyl N-[6-[[[4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]methyl]-2-pyridyl]carbamate (step 1)(107 mg, 0.2 mmol) was added to a cooled (0-5° C.) suspension of 1M BBr.sub.3 in DCM (895 μL, 0.9 mmol) in DCM (1.1 mL). The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue partitioned between EtOAc (5 mL) and water (4 mL). The pH of the aqueous layer to pH7 by addition of sat. aq. NaHCO.sub.3 and the organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was triturated in MeCN:H.sub.2O (4:1), filtered, washed with MeCN and dried in a high vacuum oven to afford the titled compound as a light tan solid.

[1584] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.81 (s, 1H), 9.05 (t, J=5.9 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.1 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 6.32 (d, J=8.2 Hz, 1H), 5.93 (br. S, 2H), 4.36 (d, J=5.9 Hz, 2H), 3.67 (s, 2H).

[1585] LC-MS (Method A): Rt 1.70 mins; MS m/z 412.2/414.4=[M+H]+ (97% @ 215 nm)

[1586] The compounds of the following tabulated Examples (Table 10) were prepared analogously to Example 32 by replacing tert-butyl N-[6-(aminomethyl)-2-pyridyl]carbamate (step 1) with the appropriate commercially available amine.

TABLE-US-00012 TABLE 10 1H NMR Ex. Structure and Name LCMS Retention Time, [M + H]+, 32.1 [00282] 1H NMR (500 MHz, Methanol-d4) δ 8.47 (d, J = 5.6 Hz, 1H), 8.24 − 8.17 (m, 1H), 7.93 − 7.89 (m, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 8.6, 2.2 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 3.72 (s, 2H), 3.40 (t, J = 7.1 Hz, 2H), 2.27 (t, J = 7.4 Hz, 2H), 1.67-1.55 (m, 4H), 1.42-1.26 (m, 14H). LC-MS (Method A): Rt 3.71 mins; MS m/z 504.4/506.4 = [M + H]+ 12-[[4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine- 2-carbonyl]amino]dodecanoic acid 32.2 [00283]   4-[[2-(5-Chloro-2-hydroxy-phenyl) 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.89 (s, 1H), 9.40 (t, J = 6.4 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.73 (dt, J = 7.8, 1.9 Hz, 1H), 7.34 (dd, J = 7.8, 4.8 Hz, 1H), 7.21 (d, J = 2.9 Hz, 1H),7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.51 (d, J = 6.4 Hz, 2H), 3.67 (s, 2H). LC-MS (Method A): Rt 1.80 mins; MS m/z 397.2/399.2 = [M + H]+ (96% @ 215 nm) acetyl]amino]-N-(3-pyridylmethyl)pyridine-2-carboxamide 32.3 [00284]   1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.82 (s, 1H), 9.33 (t, J = 5.7 Hz, 1H), 8.56-8.50 (m, 2H), 8.24 (s, 1H), 7.86 (d, J = 3.7 Hz, 1H), 7.76 (t, J = 7.2 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.31 − 7.25 (m, 1H), 7.25 − 7.20 (m, 1H), 7.13 (dd, J = 8.5, 2.2 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H), 3.68 (s, 2H). LC-MS (Method A): Rt 1.98 mins; MS m/z 397.2/399.2 = [M + H]+ (97% @ 215 nm) 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2- pyridylmethyl)pyridine-2-carboxamide 32.4 [00285]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4- 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.82 (s, 1H), 9.43 (t, J = 6.4 Hz, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.52 − 8.46 (m, 2H), 8.22 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.29 (d, J = 6.0 Hz, 2H), 7.22 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.51 (d, J = 6.4 Hz, 2H), 3.68 (s, 2H). LC-MS (Method A): Rt 1.63 mins; MS m/z 397.2/399.2 = [M + H]+ (96% @ 215 nm) pyridylmethyl)pyridine-2-carboxamide 32.5 [00286] 1H NMR (500 MHz, Methanol-d4) δ 8.35 dd, J = 5.01, 0.52 Hz, 1H), 8.06 (dd, J = 1.71, 0.49, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.11 (dd, J = 7.5, 1.5 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 7.04 − 6.96 (m, 2H), 6.74 − 6.70 (m, 1H), 6.69 − 6.65 (m, 2H), 4.47 (s, 2H), 3.60 (s, 2H). LC-MS (Method A): Rt 3.01 mins; MS m/z 412.2/414.2 = [M + H]+ (97% @ 215 nm) 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(2- hydroxyphenyl) methyl]pyridine-2-carboxamide 32.6 [00287]   1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.80 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.33 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 3.58 − 3.54 (m, 4H), 2.57 (s, 2H), 1.37 (s, 6H), 1.24 (s, 2H). LC-MS (Method A): Rt 1.80 mins; MS m/z 447.3/449.3 = [M + H]+ (100% @ 215 nm) 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1- dimethyl-2-morpholino-ethyl)pyridine-2-carboxamide 32.7 [00288]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(2- 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.81 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.24 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.12 (t, J = 5.5 Hz, 1H), 3.67 (s, 2H), 3.44 (d, J = 5.5 Hz, 2H), 1.33 (s, 6H). LC-MS (Method A): Rt 2.56 mins; MS m/z 378.2/380.2 = [M + H]+ (100% @ 215 nm) hydroxy-1,1-dimethyl-ethyl)pyridine-2-carboxamide 32.8 [00289]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3,3- 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.82 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 9.6 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 4.60 − 4.32 (m, 1H), 3.68 (s, 2H), 3.18 − 3.07 (m, 1H), 2.97 − 2.79 (m, 2H), 2.69 − 2.62 (m, 1H), 1.90 − 1.79 (m, 1H), 1.78 − 1.63 (m, 1H). LC-MS (Method A): Rt 1.95 mins; MS m/z 425.2/427.2 = [M + H]+ (99% @ 215 nm) difluoro-4-piperidyl)pyridine-2-carboxamide 32.9 [00290]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1H- 1H NMR (500 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.89 − 10.63 (m, 2H), 9.86 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.91 (m, 3H), 3.69 (s, 2H). LC-MS (Method A): Rt 1.65 mins; MS m/z 372.2/374.2 = [M + H]+ (97% @ 215 nm) imidazol-2-yl)pyridine-2-carboxamide

Example 33

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R,2R)-2-hydroxycyclopentyl]pyridine-2-carboxamide

[1587] ##STR00291##

[1588] To a solution of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1)(100 mg, 0.33 mmol), (1R,2R)-2-aminocyclopentanol hydrochloride (45 mg, 0.33 mmol) and DIPEA (228 μL, 1.3 mmol) in DMF (2 mL) was added HATU (149 mg, 0.39 mmol) and the mixture was stirred at room temperature for 1 hour. The resulting mixture was partitioned between EtOAc (10 mL) and water (15 mL) then washed with sat. aq NaHCO.sub.3 (10 mL). The combined aqueous washes were extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude residue by chromatography on silica using a Biotage Isolera 11 g KP-NH system eluting with 0-15% MeOH in EtOAc afforded the titled compound as an off-white solid.

[1589] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.83 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 4.80 (s, 1H), 4.03-3.94 (m, 2H), 3.66 (s, 2H), 2.03-1.96 (m, 1H), 1.89-1.81 (m, 1H), 1.71-1.58 (m, 2H), 1.54-1.42 (m, 2H).

[1590] LC-MS (Method A): Rt 2.50 mins; MS m/z 390.3/392.3=[M+H]+ (99% @ 215 nm)

Example 34

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide

[1591] ##STR00292##

[1592] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1)(4.0 g, 13.04 mmol) and 2-amino-2-methyl-propanenitrile hydrochloride (3.15 g, 26.08 mmol) were suspended in DMF (40 mL) and treated with DIPEA (9.11 mL, 52.17 mmol) and stirred to form a solution. HATU (5.95 g, 15.65 mmol) was added the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (60 mL) and 4:1 EtOAc/heptane (100 ml). The biphasic suspension was filtered using minimal EtOAc and the organic portion was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the residue by chromatography on silica eluting with 0-100% EtOAc in heptane followed by 0-100% MeOH in EtOAc afforded a yellow glassy solid. TBME (10 mL) was added to the solid and the mixture was heated to reflux (90° C.) and further TBME (90 mL) was added gradually. MeCN was added in 0.5 mL aliquots until full dissolution occurred (9 mL). The mixture was cooled to 60° C. then to 0° C. for 3 hours. The resulting mixture was allowed to stand at room temperature for 4 days and then filtered and dried in a vacuum oven to afford the titled compound as a white crystalline solid.

[1593] 1H NMR (500 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.87 (s, 1H), 8.82 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.72 (s, 6H).

[1594] LC-MS (Method A): Rt 2.81 mins; MS m/z 373.2/375.2=[M+H]+ (98% @ 215 nm)

Example 35

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl) tetrahydrofuran-3-yl]pyridine-2-carboxamide

[1595] ##STR00293##

[1596] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) (150 mg, 0.49 mmol) and DIPEA (256.27 μL, 1.47 mmol) were suspended in DMF (2 mL) and treated with (3-aminotetrahydrofuran-3-yl)methanol (69 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for 30 min and then partitioned between EtOAc (15 mL) and water (15 mL). The organic portion was washed with sat. aq. NaHCO.sub.3 (10 mL). The combined aqueous washes were extracted with EtOAc (2×10 mL) and the combined organic extracts dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by chromatography on silica using a Biotage Isolera 11 g KP-NH system, eluting with 0-15% DCM/MeOH afforded the titled compound as an off-white solid.

[1597] 1H NMR (500 MHz, DMSO-d6) δ=10.73 (s, 1H), 9.82 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.17 (s, 1H), 3.88-3.77 (m, 4H), 3.67 (s, 2H), 3.62-3.59 (m, 2H), 2.34-2.28 (m, 1H), 2.00-1.94 (m, 1H).

[1598] LC-MS (Method A): Rt 2.36 mins; MS m/z 406.3/408.3=[M+H]+ (97% @ 215 nm)

Example 35a and 35b

Enantiomers of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-3-(hydroxymethyl)tetrahydrofuran-3-ylpyridine-2-carboxamide

[1599] Chiral separation of racemic 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-3-(hydroxymethyl)tetrahydrofuran-3-ylpyridine-2-carboxamide (Example 35) using Supercritical Fluid Chromatography [chiral phase column (5 μL at 1 mg/mL MeOH+95/5% CO2/(IPOH)+0.5% IPAm with Chiralpak IG (300 mm×4.6) 20 μm column at 2.4 mL/min)] afforded the individual enantiomers:

Example 35a: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide

[1600] ##STR00294##

[1601] First eluted peak: SFC Retention Time=6.10 mins

[1602] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.76 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.16 (t, J=5.3 Hz, 1H), 3.88-3.77 (m, 4H), 3.67 (s, 2H), 3.61 (m, 2H), 2.34-2.29 (m, 1H), 2.00-1.94 (m, 1H).

[1603] LC-MS (Method A): Rt 2.23 mins; MS m/z 406.2/408.2=[M+H]+ (97% @ 215 nm)

Example 35b: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3R)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(3S)-3-(hydroxymethyl)tetrahydrofuran-3-yl]pyridine-2-carboxamide

[1604] ##STR00295##

[1605] Second eluted peak: SFC Retention Time=7.70 mins

[1606] 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.77 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.17 (s, 1H), 3.89-3.76 (m, 4H), 3.67 (s, 2H), 3.61 (d, J=3.0 Hz, 2H), 2.35-2.28 (m, 1H), 2.01-1.93 (m, 1H).

[1607] LC-MS (Method A): Rt 2.23 mins; MS m/z 406.2/408.2=[M+H]+ (97% @ 215 nm)

[1608] The compounds of the following tabulated Examples (Table 11) were prepared analogously to Example 35 from either 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) or 3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzoic acid (Example 41 step 3) and the appropriate commercially available amine.

TABLE-US-00013 TABLE 11 1H NMR Ex. Structure and Name LCMS Retention Time, [M + H]+, 35.1 [00296]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-hydroxy-4- methyl-cyclohexyl)pyridine-2-carboxamide as a 6:4 mixture of stereoisomers 1H NMR (500 MHz, DMSO-d6) δ = 8.46 (dd, J = 5.6, 2.1 Hz, 1H), 8.43 − 8.23 (m, 1H), 8.18 (t, J = 2.5 Hz, 1H), 7.83 − 7.80 (m, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.35 − 4.00 (m, 1H), 3.84 − 3.67 (m, 1H), 3.66 (s, 2H), 1.77 − 1.67 (m, 2H), 1.61 − 1.50 (m, 4H), 1.49 − 1.34 (m, 2H), 1.17 − 1.10 (m, 3H). LC-MS (Method A): Rt 2.52 mins; MS m/z 418.3/420.3 = [M + H]+ (96% @ 215 nm) 35.2 [00297]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [(1s,2r)-2-(hydroxy methyl)cyclohexyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ = 10.78 (s, 1H), 9.31 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 5.5 Hz, 2.2, 1H), 7.21 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.63 (t, J = 4.3 Hz, 1H), 4.19 − 4.13 (m, 1H), 3.66 (s, 2H), 3.51 − 3.45 (m, 2H), 1.84 (s, 1H), 1.76 − 1.69 (m, 1H), 1.61 − 1.53 (m, 3H), 1.51 − 1.44 (m, 2H), 1.36- 1.28 (m, 2H). LC-MS (Method A): Rt 3.03 mins; MS m/z 418.3/420.3 = [M + H]+ (99% @ 215 nm) 35.3 [00298]   1H NMR (500 MHz, DMSO-d6) δ = 10.70 (s, 1H), 9.80 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6 Hz, 2.7, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.81 (d, J = 2.6 Hz, 1H), 4.40 − 4.33 (m, 1H), 4.23 − 4.17 (m, 1H), 3.67 (s, 2H), 2.01 − 1.93 (m, 2H), 1.75-1.65 (m, 3H), 1.61 − 1.55 (m, 1H). LC-MS (Method A): Rt 2.36 mins; MS m/z 390.3/ 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- 392.3 = [M + H]+ (98% @ 215 nm) [(1s,3r)-3-hydroxycyclopentyl]pyridine-2- carboxamide 35.4 [00299]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[2-hydroxy-1- (hydroxymethyl)-1-methyl-ethyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ = 8.43 (d, J = 5.6, 1H), 8.36 (s, 1H), 8.17 (d , J = 2.1 Hz, 1H), 7.78 (dd, J = 5.4, 2.1 Hz, 1H), 7.17 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.96 (t, J = 5.6 Hz, 2H), 3.64 (s, 2H), 3.59 − 3.62 (m, 2H), 3.48 − 3.51 (m, 2H), 1.29 (s, 3H), LC-MS (Method A): Rt 2.21 mins; MS m/z 394.3/337.3 = [M + H]+ (95% @ 215 nm) 35.6 [00300]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-hydroxycyclohexyl) pyridine-2-carboxamide as a mixture of stereoisomers 1H NMR (500 MHz, DMSO-d6) δ 8.52 (d, J = 5.5 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 5.5, 2.2 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 7.18 (dd, J = 8.6, 2.7 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 4.54 (d, J = 3.2 Hz, 1H), 4.31 − 4.21 (m, 1H), 3.99 (s, 1H), 3.72 (s, 2H), 1.82 − 1.74 (m, 3H), 1.75 − 1.64 (m, 1H), 1.62 − 1.55 (m, 1H), 1.55 − 1.49 (m, 1H), 1.49 − 1.39 (m, 2H). LC-MS (Method A): Rt 2.56 mins; MS m/z 404.2/406.2 = [M + H]+ (100% @ 215 nm) 35.7 [00301]   1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.82 (s, 1H), 8.87 (t, J = 6.0 Hz, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.82 (dd, 1H), 7.30 − 7.25 (m, 2H), 7.21 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 8.6, 2.7 Hz, 1H), 6.96 − 6.89 (m, 3H), 6.79 (d, J = 8.6 Hz, 1H), 4.02 (t, J = 6.2 Hz, 2H), 3.66 (s, 2H), 3.46 (q, J = 6.7 Hz, 2H), 2.02 − 1.94 (m, 2H). 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- LC-MS (Method A): Rt 3.45 mins; MS m/z (3-phenoxypropyl)pyridine-2-carboxamide 440.3/442.3 = [M + H]+ (98% @ 215 nm) 35.8 [00302]   1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.80 (s, 1H), 8.76 (s, 1H), 8.43 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 1.36 (s, 3H), 0.80 − 0.75 (m, 2H), 0.64 − 0.57 (m, 2H). LC-MS (Method A): Rt 2.85 mins; MS m/z 360.1/362.1 = [M + H]+ 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- (1-methylcyclo propyl)pyridine-2-carboxamide 35.9 [00303]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [1-methyl-1-(2-pyridyl)ethyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.81 (s, 1H), 9.63 (s, 1H), 8.60 (m, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.90 − 7.80 (m, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.39 − 7.27 (m, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 1.76 (s, 6H). LC-MS (Method A): Rt 2.34 mins; MS m/z 425.3/ 427.2 = [M + H]+ (98% @ 215 nm) 35.10 [00304]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- (3-phenylpropyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.83 (s, 1H), 8.78 (t, J = 6.1 Hz, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.31 − 7.25 (m, 2H), 7.25 − 7.20 (m, 3H), 7.20 − 7.15 (m, 1H), 7.14-7.09 (m, 1H), 6.80 (d, 1H), 3.66 (s, 2H), 2.61 (t, J = 7.8 Hz, 2H), 1.85 (p, J = 7.6 Hz, 2H). LC-MS (Method A): Rt 3.53 mins; MS m/z 424.3/ 426.3 = [M + H]+ (98% @ 215 nm) 35.11 [00305]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [2-hydroxy-1-(2-pyridyl)ethyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.72 (br. S, 1H), 9.80 (br. s, 1H), 9.08(d, J = 8.2 Hz, 1H), 8.60 − 8.55 (m, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.41 − 7.38 (m, 1H), 7.31 − 7.28 (m, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.10 (dt, J = 8.2, 5.5 Hz, 1H), 5.03 (t, J = 5.6 Hz, 1H), 3.87 − 3.80 (m, 1H), 3.76 − 3.70 (m, 1H), 3.67 (s, 2H). LC-MS (Method A): Rt 2.09 mins; MS m/z 427.2/ 429.2 = [M + H]+ (98% @ 215 nm) 35.12 [00306]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [(5-methoxy-2-pyridyl)methyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.74 (br. S, 1H), 9.82 (br. S, 1H), 9.23 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.23 (dd, J = 9.5, 2.5 Hz, 2H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.36 (dd, J = 8.6, 3.0 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H), 3.67 (s, 2H). LC-MS (Method A): Rt 2.39 mins; MS m/z 427.2/429.2 = [M + H]+ (100% @ 215 nm) 35.13 [00307]   Ethyl 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butanoate 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.80 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.67 (s, 2H), 2.81 (s, 2H), 1.47 (s, 6H), 1.11 (t, J = 7.1 Hz, 3H). LC-MS (Method A): Rt 3.39 mins; MS m/z 434.3/436.3 = [M + H]+ (92% @ 215 nm) 35.14 [00308]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- (3-hydroxy-1,1-dimethyl-propyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.82 (s, 1H), 8.53 (s, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.63 (t, J = 4.7 Hz, 1H), 3.67 (s, 2H), 3.56 (q, J = 6.4 Hz, 2H), 1.86 (t, J = 6.5 Hz, 2H), 1.41 (s, 6H). LC-MS (Method A): Rt 2.56 mins; MS m/z 392.2/394.2 = [M + H]+ (100% @ 215 nm) 35.15 [00309]   N-Benzyl-4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.81 (s, 1H), 9.25 (t, J = 6.4 Hz, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.32 (s, 2H), 7.31 (d, J = 1.2 Hz, 2H), 7.26 − 7.21 (m, 1H), 7.20 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 8.6, 2.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 4.48 (d, J = 6.4 Hz, 2H), 3.66 (s, 2H). LC-MS (Method A): Rt 3.23 mins; MS m/z 396.4/398.4 = [M + H]+ (100% @ 215 nm) 35.16 [00310]   1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.56 (s, 1H), 9.83 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 7.92 − 7.86 (m, 3H), 7.39 − 7.33 (m, 2H), 7.23 (d, J = 2.7 Hz, 1H), 7.16 − 7.08 (m, 2H), 6.81 (d, J = 8.6 Hz, 1H), 3.69 (s, 2H). LC-MS (Method A): Rt 3.41 mins; MS m/z 382.3/384.3 = [M + H]+ (100% @ 215 nm) 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl] amino]-N-phenyl-pyridine-2-carboxamide 35.17 [00311]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [(1S,2S)-2-hydroxycyclopentyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.82 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 4.4 Hz, 1H), 4.02 − 3.94 (m, 2H), 3.67 (s, 2H), 2.03 − 1.95 (m, 1H), 1.90 − 1.81 (m, 1H), 1.71 − 1.59 (m,2H), 1.54 − 1.42 (m, 2H). LC-MS (Method A): Rt 2.50 mins; MS m/z 390.2/ 392.2 = [M + H]+ (99% @ 215 nm) 35.18 [00312]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [(1R,2S)-2-hydroxy cyclopentyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.81 (s, 1H), 8.46 (d. 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.09 (s, 1H), 4.05 − 3.98 (m, 2H), 3.66 (s, 2H), 1.99 − 1.88 (m, 1H), 1.88 − 1.79 (m, 1H), 1.79 − 1.71 (m, 1H), 1.64 − 1.57 (m, 1H), 1.56 − 1.46 (m, 2H). LC-MS (Method A): Rt 2.58 mins; MS m/z 390.3/ 392.3 = [M + H]+ (100% @ 215 nm) 35.19 [00313]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [(1S,2R)-2-hydroxy cyclopentyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.83 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.09 (s, 1H), 4.06 − 3.97 (m, 2H), 3.67 (s, 2H), 2.01 − 1.90 (m, 1H), 1.89 − 1.79 (m, 1H), 1.80 − 1.71 (m, 1H), 1.65 − 1.58 (m, 1H), 1.57 − 1.46 (m, 2H). LC-MS (Method A): Rt 2.63 mins; MS m/z 390.3/ 392.3 = [M + H]+ (99% @ 215 nm) 35.20 [00314]   3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N- (1-methylcyclohexyl)benzamide 1H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.49 (s, 1H), 7.90 (t, J = 1.7 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.43 − 7.40 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.00 (dd, J = 9.4, 3.2 Hz, 1H), 6.89 (td, J = 8.6, 3.2 Hz, 1H), 6.77 (dd, J = 8.8, 4.9 Hz, 1H), 3.61 (s, 2H), 2.21 (d, J = 13.3 Hz, 2H), 1.54 − 1.41 (m, 5H), 1.38 − 1.29 (m, 2H), 1.32 (s, 3H), 1.28 − 1.22 (m, 1H). LC-MS (Method A): Rt 3.36 mins; MS m/z 385.3 = [M + H]+ (98% @ 215 nm) 35.21 [00315]   N-(1,1-Dimethylprop-2-ynyl)-3-[[2-(5-fluoro-2- hydroxy-phenyl)acetyl]amino]benzamide 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.48 (s, 1H), 8.20 (S. 1H), 7.94 (t, J = 1.8 Hz, 1H), 7.79 − 7.75 (m, 1H), 7.44 (dt, J = 7.8, 1.29 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.00 (dd, J = 9.4, 3.2 Hz, 1H), 6.89 (td, J = 8.6, 3.2 Hz, 1H), 6.77 (dd, J = 8.8, 4.9 Hz, 1H), 3.62 (s, 2H), 3.08 (s, 1H), 1.59 (s, 6H). LC-MS (Method A): Rt 2.67 mins; MS m/z 355.3 = [M + H]+ (97% @ 215 nm) 35.22 [00316]   N-Cyclohexyl-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.46 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.96 (t, J = 1.8 Hz, 1H), 7.79-7.75 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.00 (dd, J = 9.4, 3.2 Hz, 1H), 6.89 (td, J = 8.6, 3.2 Hz, 1H), 6.79 − 6.75 (m, 1H), 3.78 − 3.68 (m, 1H), 3.61 (s, 2H), 1.85 − 1.68 (m, 4H), 1.60 (d, J = 12.6 Hz, 1H), 1.31 (q, J = 10.7, 8.8 Hz, 4H), 1.18 − 1.06 (m, 1H). LC-MS (Method A): Rt 3.03 mins; MS m/z 371.3 = [M + H]+ (98% @ 215 nm) 35.23 [00317]   3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3- (hydroxymethyl)tetrahydro furan-3-yl]benzamide 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.48 (s, 1H), 8.12 (s, 1H), 7.95 (t, J = 1.8 Hz, 1H), 7.81 − 7.75 (m, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.00 (dd, J = 9.4, 3.2 Hz, 1H), 6.89 (td, J = 8.6, 3.2 Hz, 1H), 6.77 (dd, J = 8.8, 4.9 Hz, 1H), 4.97 (s, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.81 − 3.73 (m, 3H), 3.69 − 3.61 (m, 4H), 2.22 (dt, J = 12.8, 6.4 Hz, 1H), 2.05 (dt, J = 12.9, 7.7 Hz, 1H). LC-MS (Method A): Rt 1.98 mins; MS m/z 389.2 = [M + H]+ (98% @ 215 nm) 35.24 [00318]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1- ethynylcyclohexyl)pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.82 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.24 (s, 1H), 8.19 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 3.68 (s, 2H), 3.27 (s, 1H), 2.15 − 2.08 (m, 2H), 1.95 − 1.86 (m, 2H), 1.62 − 1.50 (m, 5H), 1.34 − 1.23 (m, 1H). LC-MS (Method A): Rt 3.62 mins; MS m/z 412.1/414.1 = [M + H]+ (98% @ 215 nm) 35.25 [00319]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1- (hydroxymethyl)cyclobutyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.82 (brs, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.40 (s, 1H), 8.21 − 8.14 (m, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.00 (t, J = 5.3 Hz, 1H), 3.67 (s, 2H), 3.61 (d, J = 4.7 Hz, 2H), 2.07 − 2.01 (m, 2H), 1.89 − 1.78 (m, 1H), 1.78 − 1.66 (m, 1H). LC-MS (Method A): Rt 2.53 mins; MS m/z 390.2/ 392.2 = [M + H]+ (98% @ 215 nm) 35.26 [00320]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3- (hydroxymethyl)oxetan-3-yl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.82 (s, 1H), 9.00 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.18 (t, J = 5.9 Hz, 1H), 4.73 (d, J = 6.5 Hz, 2H), 4.53 (d, J = 6.6 Hz, 2H), 3.70 (d, J = 5.9 Hz, 2H), 3.67 (s, 2H). LC-MS (Method A): Rt 2.11 mins; MS m/z 392.2/394.2 = [M + H]+ (98% @ 215 nm) 35.27 [00321]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1- cyano-2-methoxy-1-methyl-ethyl)pyridine-2- carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.77 (s, 1H), 8.77 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.23 (d, J = 2.7 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 3.86 (d, J = 9.5 Hz, 1H), 3.69 (s, 2H), 3.67 (d, J = 9.5 Hz, 1H), 3.42 (s, 3H), 1.71 (s, 3H). LC-MS (Method A): Rt 3.02 mins; MS m/z 403.2/405.2 = [M + H]+ (98% @ 215 nm) 35.28 [00322]   4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- [(1-hydroxycyclobutyl)methyl]pyridine-2-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.81 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.42 (t, J = 5.9 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 5.38 (s, 1H), 3.67 (s, 2H), 3.43 (d, J = 5.9 Hz, 2H), 2.00 − 1.86 (m, 4H), 1.70 − 1.57 (m, 1H), 1.57 − 1.41 (m, 1H). LC-MS (Method A): Rt 2.59 mins; MS m/z 390.1/392.1 = [M + H]+ (95% @ 215 nm)

Example 36

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1609] ##STR00323##

[1610] To a solution of 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) (20 g, 63.25 mmol, 97%), 2-methylbut-3-yn-2-amine (7.99 mL, 75.9 mmol) and DIPEA (16.57 mL, 94.88 mmol) in DMF (315 mL) was added HATU (28.86 g, 75.9 mmol) and the mixture stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed sequentially with 1M HCl, 1M NaOH and brine. The acid washing was re-extracted with EtOAc and the combined organic extracts were washed with 1M NaOH, brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford a yellow foam. The foam was absorbed onto silica and purified by chromatography eluting with 0-100% EtOAc in heptanes. The isolated material was suspended in MeCN (50 mL) and heated to reflux until all solids had dissolved. The resulting solution was allowed to cool to room temperature and stand for 8 hours to yield crystals. The crystals were filtered, washed with ice cooled MeCN and dried in a vacuum oven overnight to afford crop 1 of the titled compound. The filtrate from was combined with the impure fractions from chromatography and repurified by chromatography on silica eluting with 0-100% EtOAc in heptanes. The isolated material was combined with crop 1 and recrystallised again by heating at reflux in MeCN. The solution was allowed to cool and stand at room temperature to afford crystals which were filtered, washed with ice-cooled MeCN and dried in a vacuum oven to afford the titled compound as a crystalline solid. 1H NMR (500 MHz, DMSO-d6) δ 10.71 (br s, 1H), 9.82 (br s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J=1.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.68 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

[1611] LC-MS (Method A): Rt 3.07 mins; MS m/z 372.1/374.1=[M+H]+ (99% @ 215 nm)

Example 37

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl)pyridine-2-carboxamide

[1612] ##STR00324##

Step 1: 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl)pyridine-2-carboxamide

[1613] ##STR00325##

[1614] To a solution of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1 step 2)(100 mg, 0.31 mmol) in DMF (2 mL) was added DIPEA (0.06 mL, 0.33 mmol) and HATU (124 mg, 0.33 mmol) and the mixture stirred for 15 mins. The resulting mixture was treated with 2-amino-2,3-dimethyl-butanenitrile (37 mg, 0.33 mmol) and stirring continued for 55 minutes. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford a crude oil. The crude oil was adsorbed onto silica and purified by chromatography on silica eluting with 10-100% EtOAc in heptane to yield an oil. The oil was triturated with ether to afford the titled compound as a white solid.

[1615] 1H NMR (250 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.69 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.37-7.25 (m, 2H), 7.07-6.95 (m, 1H), 3.75 (s, 3H), 3.73 (s, 2H), 2.63-2.53 (m, 1H), 1.61 (s, 3H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).

[1616] LC-MS (Method E): Rt 1.21 mins; MS m/z 415.1/417.1=[M+H]+ (95%®215 nm)

Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl) pyridine-2-carboxamide

[1617] A cooled (0° C.) solution 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-N-(1-cyano-1,2-dimethyl-propyl) pyridine-2-carboxamide (step 1) (84 mg, 0.19 mmol) in DCM (2 mL) was treated with 1M BBr.sub.3 in DCM (962 μL, 0.96 mmol) and stirred at room temperature for 15 mins. The reaction was quenched with methanol (1 mL) the resulting mixture was reduced in vacuo. The residue was redissolved in EtOAc and washed with saturated NaHCO.sub.3 and brine. The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in DMSO:MeOH (800 μl, 1:1), filtered and purified via preparative HPLC (acidic pH, standard elution method). The product fractions were combined, concentrated in vacuo and the residue re-dissolved in MeCN:H2O (5 mL, 1:2) and freeze dried to afford the titled compound as a white powder.

[1618] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.83 (s, 1H), 8.68 (s, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.68 (s, 2H), 2.56 (hept, J=6.8 Hz, 1H), 1.61 (s, 3H), 1.08 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).

[1619] LC-MS (Method A): Rt 3.25 mins; MS m/z 401.2/403.2=[M+H]+ (100%®215 nm)

Example 38

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclopentyl)pyridine-2-carboxamide

[1620] ##STR00326##

[1621] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) (100 mg, 0.33 mmol) and DIPEA (0.23 mL, 1.3 mmol) were suspended in DMF (2.1 mL) and treated with 1-methylcyclopentanamine hydrochloride (66 mg, 0.49 mmol) followed by HATU (149 mg, 0.39 mmol) and the mixture stirred at room temperature for 24 hours. The resulting mixture was diluted with EtOAc (10 mL) and washed with sat. aq NaHCO.sub.3 (10 mL), water (10 ml), brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in MeOH (800 μl), filtered and purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as a white solid.

[1622] 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.82 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.10 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 2.14-2.05 (m, 2H), 1.70-1.60 (m, 6H), 1.43 (s, 3H).

[1623] LC-MS (Method A): Rt 3.54 mins; MS m/z 388.2/390.2=[M+H]+ (100% @ 215 nm)

Example 39

N-(4-tert-Butylcyclohexyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (1:1 mixture cis/trans)

[1624] ##STR00327##

[1625] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) (150 mg, 0.49 mmol) and DIPEA (0.26 mL, 1.47 mmol) were suspended in DMF (1.95 mL) and treated with 4-tert-butylcyclohexanamine (1:1 mixture cis/trans) (91 mg, 0.59 mmol) and HATU (223 mg, 0.59 mmol) and the mixture was stirred for 3 hours. The mixture was diluted with EtOAc (10 mL) and the organics were washed with saturated aqueous NaHCO.sub.3 (2×10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was dissolved in DMSO:MeCN (800 μl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method). The product fractions were combined, neutralised with saturated sodium bicarbonate and extracted with EtOAc (3×20 mL). The combined organic extracts where concentrated in vacuo to afford the titled compound as a pale yellow solid.

[1626] 1H NMR (500 MHz, DMSO-d6) δ 10.95-10.61 (m, 2H), 9.93-9.68 (m, 2H), 8.49 (d, J=5.6 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.36 (d, J=8.7 Hz, 1H), 8.28 (d, J=7.6 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.81 (d, J=2.2 Hz, 1H), 7.24-7.19 (m, 2H), 7.13 (d, J=2.6 Hz, 1H), 7.12 (d, J=2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 2H), 4.13-4.07 (m, 1H), 3.68-3.65 (m, 4H), 1.93-1.83 (m, 4H), 1.81-1.73 (m, 2H), 1.69-1.60 (m, 2H), 1.60-1.51 (m, 2H), 1.42-1.33 (m, 2H), 1.24 (s, 1H), 1.17-1.03 (m, 5H), 1.03-0.97 (m, 1H), 0.89-0.83 (m, 18H). Contains a 1:1 mixture of the cis and trans products.

[1627] LC-MS (Method A): Rt 4.34 mins; MS m/z 444.4/446.4=[M+H]+ (42% @ 215 nm)

[1628] LC-MS (Method A): Rt 4.36 mins; MS m/z 444.4/446.4=[M+H]+ (52% @ 215 nm)

Example 40

N-tert-Butyl-4-[[2-(2-chloro-3-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide

[1629] ##STR00328##

[1630] To a solution of 2-(2-chloro-3-fluoro-phenyl)acetic acid (146 mg, 0.78 mmol) in THF (3 mL) was added DIPEA (271 μL, 1.55 mmol), 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (100 mg, 0.52 mmol) and HATU (236 mg, 0.62 mmol) and the mixture was stirred at room temperature for 90 mins. The resulting mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the aqueous portion extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with EtOAc in heptane to afford the titled compound as white amorphous solid.

[1631] 1H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J=5.5 Hz, 1H), 8.18 (dd, J=5.5, 2.1 Hz, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.30-7.23 (m, 1H), 7.21-7.10 (m, 2H), 3.94 (s, 2H), 1.47 (s, 9H).

[1632] LC-MS (Method A): Rt 3.49 mins; MS m/z 364.2/366.2=[M+H]+ (100%®215)

Example 40.1

N-tert-Butyl-4-[[2-(2-chloro-5-fluoro-phenyl)acetyl]amino]pyridine-2-carboxamide

[1633] ##STR00329##

[1634] The titled compound was prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and 2-(2-chloro-5-fluoro-phenyl)acetic acid analogously to Example 40.

[1635] 1H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.51 (dd, J=8.8, 5.3 Hz, 1H), 7.36 (dd, J=9.4, 3.1 Hz, 1H), 7.20 (td, J=8.5, 3.1 Hz, 1H), 3.93 (s, 2H), 1.40 (s, 9H).

[1636] LC-MS (Method A): Rt 3.51 mins; MS m/z 364=[M+H]+

Example 41

N-(4-Cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide

[1637] ##STR00330##

Step 1: Ethyl 3-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]benzoate

[1638] ##STR00331##

[1639] A mixture of ethyl 3-aminobenzoate (300 mg, 1.82 mmol) and 2-(5-fluoro-2-methoxy-phenyl)acetic acid (334 mg, 1.82 mmol) in 1,4-dioxane (5 mL) was treated with 50% T3P® solution in EtOAc (2.31 mL, 1.82 mmol) and TEA (634 μL, 3.63 mmol). After stirring at room temperature for 2 hours, the mixture was partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with EtOAc in heptane afforded the titled compound as a white solid.

[1640] 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.26 (t, J=1.8 Hz, 1H), 7.86-7.82 (m, 1H), 7.63 (dt, J=7.79, 1.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.11 (dd, J=9.2, 3.1 Hz, 1H), 7.07 (td, J=8.6, 3.2 Hz, 1H), 6.98 (dd, J=9.0, 4.6 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.75 (s, 3H), 3.66 (s, 2H), 1.31 (t, J=7.1 Hz, 3H).

[1641] LC-MS (Method E): Rt 1.20 mins; MS m/z 332.1=[M+H]+ (100% @ 215 nm)

Step 2: 3-[[2-(5-Fluoro-2-methoxy-phenyl)acetyl]amino]benzoic acid

[1642] ##STR00332##

[1643] Ethyl 3-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]benzoate (step 1) (470 mg, 1.42 mmol) in THF (3 mL) and MeOH (1 mL) was treated with 2M aqueous LiOH solution (2.84 mL, 5.67 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The volatile solvents were removed in vacuo and the aqueous portion was diluted with water (100 mL) and acidified with 2M HCl solution to pH 2. The resulting precipitate was collected by filtration, washed with water (30 mL) and under vacuum to afford the titled compound as a white solid.

[1644] 1H NMR (500 MHz, DMSO-d6) δ 12.92 (s, 1H), 10.26 (s, 1H), 8.23 (t, J=1.7 Hz, 1H), 7.84-7.78 (m, 1H), 7.63-7.58 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.11 (dd, J=9.2, 3.1 Hz, 1H), 7.07 (td, J=8.6, 3.2 Hz, 1H), 6.98 (dd, J=9.0, 4.7 Hz, 1H), 3.75 (s, 3H), 3.66 (s, 2H).

[1645] LC-MS (Method E): Rt 1.02 mins; MS m/z 304.0=[M+H]+ (98% @ 215 nm)

Step 3: 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]benzoic acid

[1646] ##STR00333##

[1647] To a solution of 3-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]benzoic acid (step 2)(400 mg, 1.29 mmol) in DCM (5 mL) was added 1M BBr.sub.3 in DCM (5.17 mL, 5.17 mmol) the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated in vacuo and the crude residue was partitioned between water (60 mL) and EtOAc (60 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as a grey-purple solid.

[1648] 1H NMR (500 MHz, DMSO-d6) δ 12.91 (s, 1H), 10.25 (s, 1H), 9.47 (s, 1H), 8.24 (t, 1.7 Hz, 1H), 7.87-7.79 (m, 1H), 7.62-7.59 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.00 (dd, J=9.4, 3.1 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.62 (s, 2H).

[1649] LC-MS (Method E): Rt 0.98 mins; MS m/z 290.0=[M+H]+ (89% @ 215 nm)

Step 4: N-(4-Cyanotetrahydropyran-4-yl)-3-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]benzamide

[1650] The titled compound was prepared from 3-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]benzoic acid (step 3) and 4-aminotetrahydropyran-4-carbonitrile analogously to Example 1.1 step 3.

[1651] 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.58 (s, 1H), 8.83 (s, 1H), 8.05 (t, J=1.8 Hz, 1H), 7.86-7.79 (m, 1H), 7.52 (d, J=7.8, 1.3 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.00 (dd, J=9.4, 3.2 Hz, 1H), 6.89 (td, J=8.6, 3.2 Hz, 1H), 6.78 (dd, J=8.8, 4.9 Hz, 1H), 3.87 (dt, J=12.2, 4.0 Hz, 2H), 3.63 (s, 2H), 3.62-3.56 (m, 2H), 2.35-2.28 (m, 2H), 2.04-1.97 (m, 2H).

[1652] LC-MS (Method A): Rt 2.41 mins; MS m/z 398.2=[M+H]+ (97% @ 215 nm)

Example 42

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(2-hydroxyethyl) tetrahydropyran-4-yl]pyridine-2-carboxamide

[1653] ##STR00334##

Step 1: Methyl 2-[4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-yl]acetate

[1654] ##STR00335##

[1655] The titled compound was prepared from methyl 2-(4-aminotetrahydropyran-4-yl)acetate and 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) analogously to Example 33.

[1656] 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=5.6 Hz, 1H), 8.19-8.17 (m, 2H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.10 (dd, J=8.6, 2.7 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 3.71-3.66 (m, 2H), 3.66 (s, 2H), 3.53-3.45 (m, 5H), 2.91 (s, 2H), 2.33-2.27 (m, 2H), 1.79-1.72 (m, 2H).

[1657] LC-MS (Method E): Rt 1.06 mins; MS m/z 462.1=[M+H]+ (87% @ 215 nm)

Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(2-hydroxyethyl) tetrahydropyran-4-yl]pyridine-2-carboxamide

[1658] A cooled (−78° C.) solution of methyl 2-[4-[[4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-yl]acetate (step 1) (50 mg, 0.11 mmol) in anhydrous THF (2 mL) was treated with 2.4M lithium aluminium hydride in THF (90 μL, 0.22 mmol) and stirred at −78° C. for 10 mins. A further portion of 2.4 M lithium aluminium hydride in THF (45 μL, 0.11 mmol) was added and stirring continued at −78° C. for 5 minutes. The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. 2M NaOH (3 mL) was added and the mixture was extracted with EtOAc (10 mL). The organic phase was washed with Rochelle Salt solution (2×10 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by preparative HPLC (acidic pH, standard elution method) afforded the titled compound as an off-white solid.

[1659] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.87 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.15 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.38 (s, 1H), 3.68-3.62 (m, 4H), 3.51-3.45 (m, 4H), 2.31-2.24 (m, 2H), 1.99 (t, J=7.0 Hz, 2H), 1.68-1.61 (m, 2H).

[1660] LC-MS (Method A): Rt 2.32 mins; MS m/z 434.2/434.6=[M+H]+ (100% @ 215 nm)

Example 43

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2-trifluoro ethylamino)propyl]pyridine-2-carboxamide

[1661] ##STR00336##

Step 1: tert-Butyl N-[3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyl]carbamate

[1662] ##STR00337##

[1663] The titled compound was prepared from tert-butyl N-(3-amino-3-methyl-butyl)carbamate and 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) analogously to Example 33.

[1664] 1H NMR (500 MHz, DMSO-d6) δ=1.33 (s, 9H), 1.37 (s, 6H), 1.85-1.93 (m, 2H), 2.91-2.98 (m, 2H), 3.66 (s, 2H), 6.73 (s, 1H), 6.79 (d, J=8.6, 1H), 7.11 (dd, J=8.6, 2.7, 1H), 7.20 (d, J=2.7, 1H), 7.81 (dd, J=5.5, 2.2, 1H), 8.00 (s, 1H), 8.17 (d, J=2.0, 1H), 8.44 (d, J=5.5, 1H), 10.84 (s, 1H).

[1665] LC-MS (Method E): Rt 1.18 mins; MS m/z 491/493=[M+H]+ (92% @ 215 nm)

Step 2: N-(3-Amino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1666] ##STR00338##

[1667] tert-Butyl N-[3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butyl]carbamate (step 1) (302 mg, 0.62 mmol) was dissolved in 20% TFA in DCM (2.0 mL) and the mixture was agitated at room temperature for 18 hours. The resulting mixture was loaded under gravity onto a 2 g Isolute® SCX-2 cartridge washing the column with 1:1 DCM/MeOH (100 mL). The product was eluted with 1:1 DCM/1M NH.sub.3 in MeOH (100 mL) to afford the titled compound as a white crystalline solid

[1668] 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.59 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7.09 (dd, J=8.6, 2.7 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.65 (s, 2H), 2.65-2.63 (m, 2H), 1.83-1.77 (m, 2H), 1.39 (s, 6H).

[1669] LC-MS (Method E): Rt 0.86 mins; MS m/z 391.1/393.1=[M+H]+ (99% @ 215 nm)

Step 3: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1,1-dimethyl-3-(2,2,2-trifluoro ethylamino)propyl]pyridine-2-carboxamide

[1670] ##STR00339##

[1671] A solution of N-(3-amino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 2) (39 mg, 0.1 mmol) in THF (1 mL) was treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.015 mL, 0.10 mmol) and stirred at room temperature for 16 hours. A further portion of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.015 mL, 0.10 mmol) was added and the mixture was stirred for a further 2 hours. The reaction mixture was concentrated in vacuo and purification of the crude product by chromatography on silica eluting with 75% EtOAc in heptane (isocratic gradient) afforded the titled compound as a white solid.

[1672] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.83 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.66 (s, 2H), 3.22-3.15 (m, 2H), 2.67-2.64 (m, 2H), 2.35-2.31 (m, 1H), 1.90-1.85 (m, 2H), 1.38 (s, 6H).

[1673] LC-MS (Method A): Rt 2.10 mins; MS m/z 473.2/475.2=[M+H]+ (100% @ 215 nm)

Example 44

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexanyl)pyridine-2-carboxamide

[1674] ##STR00340##

[1675] To a solution of 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride (21 mg, 0.14 mmol), DIPEA (0.09 mL, 0.52 mmol) and 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino] pyridine-2-carboxylic acid (Example 31 step 1) (40 mg, 0.13 mmol) in DMF (1 mL) was added HATU (55 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 2 hours. The resulting mixture was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in DMSO:MeCN:H2O (1.4 mL, 3:3:1), filtered and purified by preparative HPLC (basic pH, early elution method) to afford the titled compound as an off-white solid.

[1676] 1H NMR (500 MHz, Methanol-d4) δ 8.47 (dd, J=5.5, 0.5 Hz, 1H), 8.14 (dd, J=1.7, 0.5 Hz, 1H), 7.91 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.6 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.73 (s, 2H), 2.22-2.11 (m, 4H), 2.09-2.05 (dd, 2H), 1.96-1.89 (m, 2H).

[1677] LC-MS (Method A): Rt 3.21 mins; MS m/z 404.3/406.3=[M+H]+ (100% @ 215 nm)

Example 45

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(2,2-dimethylpropanoyl amino)-1,1-dimethyl-propyl]pyridine-2-carboxamide

[1678] ##STR00341##

[1679] The titled compound was prepared from N-(3-amino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Example 43 step 2) and 2,2-dimethylpropanoic acid analogously to Example 33.

[1680] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.80 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.40 (t, J=5.5 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 3.12-3.02 (m, 2H), 1.95-1.87 (m, 2H), 1.39 (s, 6H), 1.04 (s, 9H).

[1681] LC-MS (Method A): Rt 3.0 mins; MS m/z 475.4/477.4=[M+H]+ (100% @ 215 nm)

Example 46

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide

[1682] ##STR00342##

[1683] 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) (120 mg, 0.39 mmol) and DIPEA (273 μL, 1.57 mmol) were suspended in THF (2 mL) and treated with 2-amino-3-hydroxy-2-methyl-propanenitrile hydrochloride (64 mg, 0.47 mmol) followed by HATU (179 mg, 0.47 mmol). After stirring at room temperature for 18 hours, the resulting mixture was partitioned between DCM (10 ml) and water (10 ml). The organic portion was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-100% TBME in heptane 0-100% TBME in MeOH. The resulting residue was dissolved in DMSO:MeOH (1200 μl, 1:1) and purified by preparative HPLC (acidic pH, early elution method) and the product fractions were concentrated in vacuo to remove the volatile organics. The resulting aqueous mixture was treated with sat. aq. NaHCO.sub.3 (3 mL) and DCM (5 ml) and agitated until clear. The organic portion was separated by filtration through a hydrophobic PTFE fritted tube and concentrated in vacuo to afford the titled compound as a white crystalline solid.

[1684] 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.80 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.90 (t, J=5.8 Hz, 1H), 3.81 (dd, J=10.9, 5.4 Hz, 1H), 3.73 (dd, J=10.9, 5.2 Hz, 1H), 3.68 (s, 2H), 1.66 (s, 3H).

[1685] LC-MS (Method A): Rt 2.47 mins; MS m/z 389.3/391.2=[M+H]+ (99% @ 215 nm)

[1686] Chiral separation of racemic 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-cyano-2-hydroxy-1-methyl-ethyl)pyridine-2-carboxamide using Supercritical Fluid Chromatography [chiral phase column: 25% Ethanol: 75% CO.sub.2 with Chiralpak IC 25 cm column at 4 ml/min] afforded the individual enantiomers:

Example 46a: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide

[1687] ##STR00343##

[1688] First eluted peak: SFC Retention Time=8.89 mins; MS m/z 389.0/391.0

[1689] 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.78 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 5.90 (t, J=5.1 Hz, 1H), 3.81 (dd, J=11.0, 4.6 Hz, 1H), 3.73 (dd, J=11.3, 4.7 Hz, 1H), 3.67 (s, 2H), 1.66 (s, 3H).

[1690] 100% e.e

Example 46b: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1S)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide or 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-[(1R)-1-cyano-2-hydroxy-1-methyl-ethyl]pyridine-2-carboxamide

[1691] ##STR00344##

[1692] Second eluted peak: SFC Retention Time=10.84 mins; MS m/z 389.0/391.0

[1693] 1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.82 (s, 1H), 8.72 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.1 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 7.10 (dd, J=8.5, 2.7 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 5.90 (s, 1H), 3.82 (dd, J=10.7, 3.3 Hz, 1H), 3.73 (dd, J=10.4, 2.9 Hz, 1H), 3.67 (s, 2H), 1.66 (s, 3H).

[1694] 88% e.e.

Example 47

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)pyridine-2-carboxamide

[1695] ##STR00345##

[1696] To a mixture comprising 3-aminotetrahydrofuran-3-carbonitrile hydrochloride (31 mg, 0.21 mmol) and 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31 step 1) (60 mg, 0.18 mmol, 90%) in DMF (2 mL) was added EDCI (74 mg, 0.39 mmol), HOAt (53 mg, 0.39 mmol) and DIPEA (123 μL, 0.7 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with water (10 mL) then acidified with 10% citric acid aqueous solution to pH 4 and extracted with DCM (10 mL). The organic layer was separated using a PTFE fritted tube and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were freeze-dried to afford the titled compound as a white solid.

[1697] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.85 (s, 1H), 9.51 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.27 (d, J=9.5 Hz, 1H), 4.04 (d, J=9.5 Hz, 1H), 3.97-3.91 (m, 1H), 3.90-3.84 (m, 1H), 3.68 (s, 2H), 2.74-2.67 (m, 1H), 2.65-2.58 (m, 1H).

[1698] LC-MS (Method A): Rt 2.68 mins; MS m/z 401.1/403.1=[M+H]+ (98% @ 215 nm)

[1699] The compounds of the following tabulated Examples (Table 12) were prepared analogously to Example 47 by replacing 3-aminotetrahydrofuran-3-carbonitrile hydrochloride with the appropriate commercially available amine.

TABLE-US-00014 TABLE 12 1H NMR Ex. Structure and Name LCMS Retention Time, [M + H]+, 47.1 [00346] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.84 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.19 (m, 2H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 8.6, 2.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 3.72-3.67 (m, 4H), 3.54-3.48 (m, 5H), 2.92 (s, 2H), 2.35-2.28 (m, 2H), 1.80-1.72 (m, 2H). LC-MS (Method A): Rt 2.80 mins; MS m/z 462.2/ 464.1 = [M + H]+ (98% @ 215 nm) 47.2 [00347] 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.81 (s, 1H), 8.77 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.1 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 3.71 (dt, J = 11.7, 4.1 Hz, 2H), 3.67 (s, 2H), 3.61 (s, 3H), 3.60-3.55 (m, 2H), 2.13-2.08 (m, 2H), 2.06-1.99 (m, 2H). LC-MS (Method A): Rt 2.72 mins; MS m/z 448.2/ 450.2 = [M + H]+ (100% @ 215 nm) 47.3 [00348] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (br. s, 1H), 10.07 (s, 1H), 9.84 (br. s, 1H), 8.54 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.89 (dd, J = 5.5, 2.2 Hz, 1H), 7.22 (d, J = 2.7 Hz, 1H), 7.12 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.94 (d, J = 7.6 Hz, 2H), 4.84 (d, J = 7.6 Hz, 2H), 3.68 (s, 2H). LC-MS (Method A): Rt 2.59 mins; MS m/z 387.1/ 389.1 = [M + H]+ (98% @ 215 nm)

Example 48

4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide

[1700] ##STR00349##

Steps 1-3: 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1701] ##STR00350##

[1702] The titled compound was prepared from methyl 4-aminopyridine-2-carboxylate and 2-(5-fluoro-2-methoxy-phenyl)acetic acid analogously to Example 41 steps 1-3.

[1703] 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.51 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.28 (d, J=1.7 Hz, 1H), 7.81 (dd, J=5.5, 1.7 Hz, 1H), 7.02 (dd, J=9.2, 3.0 Hz, 1H), 6.91 (td, J=8.6, 3.1 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H).

[1704] LC-MS (Method E): Rt 0.76 mins; MS m/z 291.0=[M+H]+ (84% @ 215 nm)

Step 4: 4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide

[1705] The titled compound was prepared from 4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (steps 1-3) and 1-methylcyclobutanamine hydrochloride analogously to Example 47.

[1706] 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 9.50 (s, 1H), 8.48 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9.4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H), 2.43-2.35 (m, 2H), 2.03-1.96 (m, 2H), 1.84-1.77 (m, 2H), 1.47 (s, 3H).

[1707] LC-MS (Method A): Rt 3.00 mins; MS m/z 358.2/359.2=[M+H]+ (95% @ 215 nm)

Example 48.1

N-(4-Cyanotetrahydropyran-4-yl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1708] ##STR00351##

[1709] The titled compound was prepared from 4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 48, steps 1-3) and 4-aminotetrahydropyran-4-carbonitrile analogously to Example 47.

[1710] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.50 (s, 1H), 9.01 (s, 1H), 8.53 (d, J=5.8 Hz, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1H), 7.03 (dd, J=9.4, 3.2 Hz, 1H), 6.92 (td, J=8.6, 3.2 Hz, 1H), 6.78 (dd, J=8.8, 4.9 Hz, 1H), 3.87 (dt, J=12.2, 3.8 Hz, 2H), 3.69 (s, 2H), 3.63-3.56 (m, 2H), 2.41-2.35 (m, 2H), 2.12-2.04 (m, 2H).

[1711] LC-MS (Method A): Rt 2.45 mins; MS m/z 399.2/400.2=[M+H]+ (99% @ 215 nm)

Example 49

N-[3-(tert-Butylamino)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide

[1712] ##STR00352##

Step 1: 3-[[4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butanoic acid

[1713] ##STR00353##

[1714] A solution of ethyl 3-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butanoate (Example 35.13)(688 mg, 1.57 mmol) in THF (7.5 mL) was treated with 2M aqueous sodium hydroxide (1.57 mL, 3.14 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was partitioned between DCM (25 ml) and water (10 mL) and 2M aqueous KHSO.sub.4 (10 mL) was added. The biphasic solution agitated until clarification of the solution. The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford titled compound as a yellow viscous gel.

[1715] 1H NMR (500 MHz, DMSO-d6) δ=12.21 (s, 1H), 10.67 (s, 1H), 9.80 (s, 1H), 8.44 (d, J=5.5, 1H), 8.39 (s, 1H), 8.17 (d, J=2.0, 1H), 7.81 (dd, J=5.5, 2.2, 1H), 7.22 (d, J=2.7, 1H), 7.12 (dd, J=8.6, 2.7, 1H), 6.79 (t, J=8.6, 1H), 3.67 (s, 2H), 2.73 (s, 2H), 1.48 (s, 6H).

[1716] LC-MS (Method E): Rt 1.04 mins; MS m/z 406.2/408.1=[M+H]+ (83% @ 215 nm)

Step 2: N-[3-(tert-Butylamino)-1,1-dimethyl-3-oxo-propyl]-4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide

[1717] 3-[[4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]-3-methyl-butanoic acid (step 1)(120 mg, 0.39 mmol) and DIPEA (205 μL, 1.17 mmol) were suspended in THF (2 mL) and treated with 2-methylpropan-2-amine (62 μL, 0.59 mmol) followed by HATU (179 mg, 0.47 mmol). The resulting mixture was stirred at room temperature for 42 hours and then partitioned between DCM (10 ml) and water (10 ml). The organic portion was separated by filtration through a hydrophobic PTFE fritted tube and concentrated in vacuo. Purification of the residue by preparative HPLC (acidic pH, early elution method) afforded the titled compound as a white crystalline solid.

[1718] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.05 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.28 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.59 (s, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.13 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.68 (s, 2H), 2.38 (s, 2H), 1.45 (s, 6H),

[1719] LC-MS (Method A): Rt 3.16 mins; MS m/z 461.3/463.3=[M+H]+ (99% @ 215 nm)

Example 50

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(methanesulfonamido)-1,1-dimethyl-propyl]pyridine-2-carboxamide

[1720] ##STR00354##

[1721] A solution of N-(3-amino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Example 43, step 2)(76 mg, 0.19 mmol) in THF (0.5 mL) was treated with K.sub.2CO.sub.3 (54 mg, 0.39 mmol) and the reaction mixture was stirred at room temperature. A solution of methane sulfonyl chloride (63.2 μL in 1000 μL in THF) was prepared and a 250 μL aliquot was added dropwise to the reaction mixture and stirred for 1 hour at room temperature. The resulting mixture was partitioned between DCM and water (8 mL 1:1) and the organic portion was separated by filtration through a hydrophobic PTFE fritted tube and concentrated in vacuo. The residue was dissolved in DMSO:MeOH (1200 μl, 1:1) and purified by (acidic pH, early elution method) and the first major product peak fractions were concentrated in vacuo. The resulting turbid aqueous mixture was treated with saturated aqueous NaHCO.sub.3 (3 mL) and DCM (5 mL) and the biphasic solution was agitated until a clear biphasic solution was obtained. The organic portion was separated by filtration through a hydrophobic PTFE fritted tube and concentrated in vacuo to afford the titled compound as a white crystalline solid

[1722] 1H NMR (500 MHz, DMSO-d6) δ=10.79 (s, 1H), 9.82 (s, 1H), 8.45 (d, J=5.5, 1H), 8.18 (d, J=1.9, 1H), 8.04 (s, 1H), 7.81 (dd, J=5.5, 2.2, 1H), 7.21 (d, J=2.7, 1H), 7.12 (dd, J=8.6, 2.7, 1H), 6.92 (t, J=5.8, 1H), 6.79 (d, J=8.6, 1H), 3.66 (s, 2H), 2.95 (dt, J=10.9, 5.9, 2H), 2.86 (s, 3H), 1.97-2.06 (m, 2H), 1.38 (s, 6H).

[1723] LC-MS (Method A): Rt 2.73 mins; MS m/z 469.2/471.2=[M+H]+ (99% @ 215 nm)

Example 51

N-(3-Acetamido-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1724] ##STR00355##

[1725] A solution of N-(3-amino-1,1-dimethyl-propyl)-4-[[2-(5-chloro-2-hydroxy-phenyl) acetyl]amino]pyridine-2-carboxamide; 2,2,2-trifluoroacetic acid (TFA salt of Example 43, step 2) (100 mg, 0.16 mmol) in THF (2.5 mL) was treated with DIPEA (113 μL, 0.65 mmol) followed by acetic anhydride (17 μL, 0.18 mmol) and the mixture was stirred at room temperature for 6 hours. 1M aqueous NaOH (0.5 mL) was added and stirring continued at room temperature for 1 hour. Further 1M aqueous NaOH (0.5 mL) was added followed by MeOH (˜0.25 mL) and the mixture was stirred overnight. The resulting mixture was partitioned between DCM (5 mL) and water (3 mL) and the organic portion was separated. The aqueous layer was concentrated in vacuo and the crude residue was dissolved in 1:1 DCM/MeOH and purified by chromatography on silica eluting with 0-100% TBME in heptane followed by MeOH in TBME to afford the titled compound as a clear white crystalline solid.

[1726] 1H NMR (500 MHz, DMSO-d6) δ=8.40 (d, J=5.5, 1H), 8.11 (d, J=1.8, 1H), 8.02 (s, 1H), 7.81-7.79 (m, 1H), 7.75 (dd, J=5.5, 2.1, 1H), 7.08 (s, 1H), 7.00 (d, J=8.2, 1H), 6.64 (d, J=8.1, 1H), 4.09 (s, 1H), 3.58 (s, 2H), 3.00-3.09 (m, 2H), 1.88-1.95 (m, 2H), 1.73 (s, 3H), 1.38 (s, 6H).

[1727] LC-MS (Method A): Rt 2.51 mins; MS m/z 433.3/435.3=[M+H]+ (97% @ 215 nm)

Example 53

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[4-(hydroxymethyl)tetrahydro pyran-4-yl]pyridine-2-carboxamide

[1728] ##STR00356##

[1729] To a cooled (−78° C.) solution of methyl 4-[[4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carbonyl]amino]tetrahydropyran-4-carboxylate (Example 47.2) (52 mg, 0.1161 mmol) in THF (1.5 mL) under a nitrogen atmosphere was added dropwise a solution of 2.4M lithium aluminium hydride in THF (97 μL, 0.23 mmol). After stirring at −78° C. for 45 minutes, the mixture was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed in vacuo and purification by preparative HPLC (acidic pH, early elution method) afforded the titled compound as a white solid.

[1730] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.87 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.06 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.89 (s, 1H), 3.71-3.65 (m, 4H), 3.62 (s, 2H), 3.54-3.47 (m, 2H), 2.23-2.16 (m, 2H), 1.66 (ddd, J=14.0, 10.2, 4.2 Hz, 2H).

[1731] LC-MS (Method A): Rt 2.33 mins; MS m/z 420.1/422.1=[M+H]+ (98% @ 215 nm)

Example 54

N-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1732] ##STR00357##

Step 1: 4-[[2-(3-Bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1733] ##STR00358##

[1734] The titled compound was prepared from 2-(3-bromophenyl)acetic acid and 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) analogously to Example 21.

[1735] 1H NMR (250 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.02 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.57-7.54 (m, 1H), 7.47 (dt, J=6.9, 2.1 Hz, 1H), 7.36-7.27 (m, 2H), 3.75 (s, 2H), 1.39 (s, 9H).

[1736] LC-MS (Method E): Rt 1.23 mins; MS m/z 390.1/392.1=[M+H]+ (98% @ 215 nm)

Step 2: 4-[[2-(3-Acetylphenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1737] ##STR00359##

[1738] A solution of 4-[[2-(3-bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 1)(200 mg, 0.51 mmol), 1-vinyloxybutane (332 μL, 2.56 mmol), triphenylphosphine (27 mg, 0.1 mmol) and TEA (107 μL, 0.61 mmol) in MeCN (1 mL) was degassed with nitrogen and treated with Pd(OAc).sub.2 (12 mg, 0.05 mmol). The mixture was sealed and heated at 100° C. overnight. Further portions of 1-vinyloxybutane (332 μL, 2.56 mmol), TEA (107 μL, 0.61 mmol), triphenylphosphine (27 mg, 0.1 mmol) and Pd(OAc).sub.2 (12 mg, 0.05 mmol) were added and heating continued at 100° C. for a further 8 hours. The resulting mixture was filtered through Celite® and washed with EtOAc. The filtrate was absorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in heptane afforded the titled compound as an orange glassy solid.

[1739] 1H NMR (250 MHz, Chloroform-d) δ 8.34 (d, J=5.6 Hz, 1H), 8.11 (dd, J=5.5, 2.3 Hz, 1H), 7.90-7.84 (m, 2H), 7.59 (s, 1H), 7.50-7.43 (m, 2H), 3.77 (s, 2H), 2.56 (s, 3H), 1.39 (s, 9H).

[1740] LC-MS (Method E): Rt 1.13 mins; MS m/z 354.1=[M+H]+ (93% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-[3-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1741] To a solution of 4-[[2-(3-acetylphenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 2) (45 mg, 0.12 mmol) in methanol (1 mL) at 0° C. was added NaBH.sub.4 (4.5 mg, 0.12 mmol) and the mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction was quenched by addition of 3 drops of sat. NaHCO.sub.3 solution and purification by preparative HPLC (acidic pH, standard elution method) afforded the titled compound as a colourless powder.

[1742] 1H NMR (500 MHz, Methanol-d4) δ 8.42 (d, J=5.5 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.89 (dd, J=5.5, 2.2 Hz, 1H), 7.37 (s, 1H), 7.33-7.22 (m, 3H), 4.85-4.79 (m, 1H), 3.74 (s, 2H), 1.47 (s, 9H), 1.43 (d, J=6.5 Hz, 3H).

[1743] LC-MS (Method A): Rt 2.77 mins; MS m/z 356.3=[M+H]+

Example 55

N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1744] ##STR00360##

Step 1: Methyl 4-amino-5-chloro-pyridine-2-carboxylate

[1745] ##STR00361##

[1746] NCS (483 mg, 3.61 mmol) was added to a solution of methyl 4-aminopyridine-2-carboxylate (500 mg, 3.29 mmol) in DMF (10 mL) and the reaction mixture was stirred at 60° C. overnight. The resulting mixture was diluted with EtOAc (50 mL) and washed with water (2×50 mL), brine (2×50 mL), dried over sodium sulfate and concentrated in vacuo. The resulting crude residue was purified by chromatography on KP-NH silica eluting 0-10% MeOH in DCM. The mixed fractions were combined and concentrated in vacuo. The resulting crude residue was further purified by chromatography on KP-NH silica eluting 0-100% EtOAc in heptane to afford the titled compound as a light pink solid.

[1747] 1H NMR (250 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.42 (s, 1H), 6.68 (s, 2H), 3.82 (s, 3H).

[1748] LC-MS (Method C): Rt 1.61 mins; MS m/z 186.8/188.8=[M+H]+ (90% @ 215 nm)

Step 2: Methyl 5-chloro-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate

[1749] ##STR00362##

[1750] To a solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (106 mg, 0.53 mmol) and methyl 4-amino-5-chloro-pyridine-2-carboxylate (step 1) (100. mg, 0.48 mmol) in 1,4-dioxane (5 mL) was added TEA (0.17 mL, 0.96 mmol) followed by 50% T3P® solution in EtOAc (0.57 mL, 0.96 mmol). The resulting mixture was stirred at room temperature under an inert atmosphere overnight. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2×10 mL) and brine (10 mL). The organic portion was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the titled compound as a white solid.

[1751] 1H NMR (250 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.77 (s, 1H), 8.72 (s, 1H), 7.36-7.29 (m, 2H), 7.06-6.99 (m, 1H), 3.88 (s, 2H), 3.86 (s, 3H), 3.78 (s, 3H).

[1752] LC-MS (Method E): Rt 1.15 mins; MS m/z 369.0/371.0=[M+H]+ (91% @ 215 nm)

Step 3: 5-Chloro-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[1753] ##STR00363##

[1754] A solution of methyl 5-chloro-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 2)(106 mg, 0.26 mmol) in THF (3 mL) was treated with 1M NaOH (392 μL, 0.39 mmol) and stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo and the residue dissolved in water (15 mL). The pH of was adjusted to pH 5 by addition of 1M HCl and the resulting precipitate filtered and dried in a vacuum oven at 40° C. to afford the titled compound as a white solid.

[1755] 1H NMR (250 MHz, DMSO-d6) δ 13.33 (br. s, 1H), 9.90 (s, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 7.36-7.30 (m, 2H), 7.07-7.01 (m, 1H), 3.88 (s, 2H), 3.79 (s, 3H).

[1756] LC-MS (Method E): Rt 1.05 mins; MS m/z 355.0/357.0=[M+H]+ (79% @ 215 nm)

Step 4-5: N-tert-Butyl-5-chloro-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1757] The titled compound was prepared from 5-chloro-4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3) and 2-methylpropan-2-amine analogously to Example 32, steps 1 and 2.

[1758] 1H NMR (500 MHz, DMSO-d6) δ 10.30-9.70 (m, 2H), 8.74 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.15 (dd, J=8.6, 2.7 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 3.81 (s, 2H), 1.39 (s, 9H).

[1759] LC-MS (Method A): Rt 3.64 mins; MS m/z 396.2/398.2=[M+H]+ (97% @ 215 nm)

Example 56

N-tert-Butyl-4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxamide

[1760] ##STR00364##

[1761] N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Example 3)(164 mg, 0.45 mmol) was suspended in anhydrous acetone (10 mL) and treated with K.sub.2CO.sub.3 (94 mg, 0.68 mmol) followed by 1-(bromomethyl)-4-methoxy-benzene (100 mg, 0.5 mmol). The reaction mixture was heated in a pressure tube at 50° C. overnight. The resulting mixture was concentrated in vacuo and then re-dissolved in EtOAc (25 mL). The mixture was washed with water (25 mL) and brine (25 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The solid was dissolved in EtOAc/MeOH (2:1 ˜15 mL) and the suspension was filtered and washed with EtOAc (20 mL) to afford the titled compound as a white solid.

[1762] 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.34 (d, J=2.7 Hz, 1H), 7.30 (dd, J=8.7, 2.7 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.8 Hz, 1H), 6.67-6.63 (m, 2H), 4.97 (s, 2H), 3.71 (s, 2H), 3.65 (s, 3H), 1.41 (s, 9H).

[1763] LC-MS (Method A): Rt 4.13 mins; MS m/z 482.3/484.3=[M+H]+ (91% @ 215 nm)

Example 57a: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1764] ##STR00365##

Step 1: N-tert-Butyl-4-[(7-methoxyindane-1-carbonyl)amino]pyridine-2-carboxamide

[1765] ##STR00366##

[1766] To a mixture of 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (200 mg, 1.03 mmol) and 7-methoxyindane-1-carboxylic acid (199 mg, 1.03 mmol) in 1,4-dioxane (5 mL) was added 50% T3P® solution in EtOAc (1231 μL, 2.07 mmol) and TEA (362 μL, 2.07 mmol). The reaction mixture was stirred at room temperature under an inert atmosphere for 16 hours. The resulting mixture was diluted with EtOAc (20 mL) and the organic mixture was washed with water (20 mL), sat. NaHCO.sub.3 (20 mL) and brine (20 mL). The organic portion was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by chromatography on KP-NH silica eluting with 0-80% heptane in EtOAc to afford the titled compound as a light pink foam.

[1767] 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.4 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 4.12 (dd, J=8.8, 5.4 Hz, 1H), 3.68 (s, 3H), 3.09-2.99 (m, 1H), 2.92-2.85 (m, 1H), 2.41-2.34 (m, 1H), 2.24-2.15 (m, 1H), 1.40 (s, 9H).

[1768] LC-MS (Method E): Rt 1.21 mins; MS m/z 368.1=[M+H]+ (100% @ 215 nm)

Step 2: N-tert-Butyl-4-[(4-chloro-7-methoxy-indane-1-carbonyl)amino]pyridine-2-carboxamide

[1769] ##STR00367##

[1770] The titled compound was prepared from N-tert-butyl-4-[(7-methoxyindane-1-carbonyl)amino]pyridine-2-carboxamide (step 1) analogously to Example 24, step 2.

[1771] 1H NMR (250 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.20 (dd, J=5.6, 2.2 Hz, 1H), 8.01 (s, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 4.22 (d, J=7.5 Hz, 1H), 4.02 (s, 3H), 3.23-2.77 (m, 3H), 2.32-2.15 (m, 1H), 1.47 (s, 9H).

[1772] LC-MS (Method E): Rt 1.27 mins; MS m/z 402.1/404.1=[M+H]+

Step 3: Example 57a: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide and Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1773] To a solution of N-tert-butyl-4-[(4-chloro-7-methoxy-indane-1-carbonyl)amino]pyridine-2-carboxamide (step 2) (50 mg, 0.12 mmol) in DCM (2 mL) was added 1M BBr.sub.3 in DCM (249 μL, 0.25 mmol). The resulting mixture was stirred at room temperature under an inert atmosphere for 1 hour. Further 1M BBr.sub.3 in DCM (249 μL, 0.25 mmol) was added and the mixture stirred for a further 24 hours. The reaction was quenched with water (1 mL) and concentrated in vacuo. The crude material was dissolved in EtOAc (20 mL) and the organic mixture was washed with sat. NaHCO.sub.3 (20 mL), water (20 mL) and brine (20 mL). The organic portion was concentrated in vacuo to afford a racemic mixture

[1774] Chiral separation of racemic N-tert-butyl-4-[[4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide using Supercritical Fluid Chromatography [chiral phase column (15% Ethanol: 95% CO2 with Chiralpak IC 25 cm column at 15 ml/min)] afforded the individual enantiomers:

Example 57a: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1775] SFC retention Time: 6.00 mins

[1776] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (br. s, 1H), 9.76 (br. s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.18 (dd, J=8.9, 5.2 Hz, 1H), 3.05-2.96 (m, 1H), 2.93-2.84 (m, 1H), 2.43-2.36 (m, 1H), 2.27-2.19 (m, 1H), 1.40 (s, 9H).

[1777] LC-MS (Method A): Rt 3.58 mins; MS m/z 388.2/390.2=[M+H]+ (96% @ 215 nm)

Example 57b: N-tert-butyl-4-[[(1S) or (1R)-4-chloro-7-hydroxy-indane-1-carbonyl]amino]pyridine-2-carboxamide

[1778] SFC retention Time: 7.84 mins

[1779] 1H NMR (500 MHz, DMSO-d6) δ 10.89 (br. s, 1H), 9.76 (br. s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 8.02 (s, 1H), 7.82 (dd, J=5.5, 2.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 4.18 (dd, J=8.9, 5.1 Hz, 1H), 3.04-2.95 (m, 1H), 2.94-2.84 (m, 1H), 2.42-2.36 (m, 1H), 2.29-2.21 (m, 1H), 1.40 (s, 9H).

[1780] LC-MS (Method A): Rt 3.58 mins; MS m/z 388.2/390.2=[M+H]+ (95% @ 215 nm)

Example 58

N-tert-Butyl-4-[[2-(2-cyclopropylphenyl)acetyl]amino]pyridine-2-carboxamide

[1781] ##STR00368##

[1782] A mixture comprising 4-[[2-(2-bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide ((Example 23.13)(100 mg, 0.25 mmol), cyclopropylboronic acid (44 mg, 0.51 mmol), tripotassium phosphate (215 mg, 1.01 mmol) in toluene (5 mL) and water (0.5 mL) was degassed with nitrogen for 10 mins and treated with Pd(OAc).sub.2 (11 mg, 0.05 mmol) and P(Cy).sub.3 (28 mg, 0.1 mmol). The reaction mixture was sealed and heated at 100° C. for 5 hours. After cooling to room temperature, the mixture was filtered through Celite® and the filtrate diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by preparative HPLC (basic pH, early elution method) followed by preparative HPLC (acidic pH, early elution method). Further purification using chromatography on silica eluting with 0-100% EtOAc in heptane afforded the titled compound as an off-white solid.

[1783] 1H NMR (500 MHz, Methanol-d4) δ 8.43 (dd, J=5.6, 0.4 Hz, 1H), 8.13 (dd, J=2.2, 0.4 Hz, 1H), 7.92 (dd, J=5.5, 2.2 Hz, 1H), 7.23 (dd, J=7.3, 1.5 Hz, 1H), 7.21-7.13 (m, 2H), 7.07 (dd, J=7.3, 1.2 Hz, 1H), 3.98 (s, 2H), 2.01-1.91 (m, 1H), 1.47 (s, 9H), 0.95-0.82 (m, 2H), 0.67-0.58 (m, 2H).

[1784] LC-MS (Method A): Rt 3.69 mins; MS m/z 352.3=[M+H]+ (99% @ 215 nm)

Example 59

4-[[2-(3-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1785] ##STR00369##

Step 1: 2-(3-Bromo-5-chloro-2-methoxy-phenyl)acetic acid

[1786] ##STR00370##

[1787] Bromine (8 mL, 139.34 mmol) was added to a stirred solution of 2-(5-chloro-2-methoxy-phenyl)acetic acid (1 g, 4.98 mmol) in acetic acid (8 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and treated with EtOAc (50 mL) followed by saturated aqueous Na.sub.2S2O.sub.3 (ca. 30 mL). The organic layer was separated and concentrated in vacuo to obtain a yellow gummy solid. The solid was purified by C18 reverse phase chromatography eluting with 10-100% (0.1% formic acid in water: 0.1% formic acid in MeCN) to afford the titled compound as an off-white solid.

[1788] 1H NMR (500 MHz, DMSO-d6) δ 12.53 (s, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 3.73 (s, 3H), 3.65 (s, 2H).

[1789] LC-MS (Method E): Rt 1.08 mins; MS m/z not observed=[M+H]+ (100% @ 215 nm)

Step 2: 4-[[2-(3-Bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1790] ##STR00371##

[1791] To a stirred solution of 2-(3-bromo-5-chloro-2-methoxy-phenyl)acetic acid (step 1)(755 mg, 2.7 mmol), 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) (475. mg, 2.46 mmol) and TEA (644 μL, 3.69 mmol) in 1,4-dioxane (10 mL) was added 50% T3P® solution in EtOAc (2.19 mL, 3.69 mmol). The resulting mixture was stirred at room temperature for 2 hours and then diluted with water (40 mL) and EtOAc (50 mL). The organic layer was separated, washed with water (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the titled compound as an off-white solid.

[1792] 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.04 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.71 (d, J=2.6 Hz, 1H), 7.48 (d, J=2.6 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 1.41 (s, 9H).

[1793] LC-MS (Method E): Rt 1.29 mins; MS m/z 454.0/456.0/458.0=[M+H]+ (99% @ 215 nm)

Step 3: 4-[[2-(3-Bromo-5-chloro-2-hydroxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1794] 1M BBr.sub.3 in DCM (0.2 mL, 0.2 mmol) was added to a stirred suspension of 4-[[2-(3-bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 2) (30 mg, 0.07 mmol) in DCM (1 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by dropwise addition of sat. NaHCO.sub.3 (20 mL) then diluted with EtOAc (20 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by preparative HPLC (acidic pH, early elution method) and the product containing fractions were combined and lyophilised overnight to afford the titled compound as an off-white powder.

[1795] 1H NMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.62 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.52 (d, J=2.6 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 3.78 (s, 2H), 1.40 (s, 9H).

[1796] LC-MS (Method A): Rt 3.81 mins; MS m/z 440.1/442.1=[M+H]+ (99% @ 215 nm)

Example 60

N-(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

[1797] ##STR00372##

Step 1-2: 4-[[2-(2-Fluorophenyl)acetyl]amino]pyridine-2-carboxylic acid

[1798] ##STR00373##

[1799] The titled compound was prepared from 2-(2-fluorophenyl)acetic acid and methyl 4-aminopyridine-2-carboxylate analogously to Example 30 steps 1-2.

[1800] 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.78 (dd, J=5.5, 2.1 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.21-7.15 (m, 2H), 3.81 (s, 2H).

[1801] LC-MS (Method E): Rt 0.81 mins; MS m/z 275.0=[M+H]+ (100% @ 215 nm)

Step 3: N-(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

[1802] The titled compound was prepared from 4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxylic acid (step 1-2) and 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride analogously to Example 30 step 3.

[1803] 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.05 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.40 (td, J=7.6, 1.6 Hz, 1H), 7.36-7.31 (m, 1H), 7.21-7.15 (m, 2H), 3.81 (s, 2H), 2.13-2.05 (m, 4H), 1.99-1.95 (m, 2H), 1.87-1.82 (m, 2H).

[1804] LC-MS (Method A): Rt 3.22 mins; MS m/z 372.3=[M+H]+ (98% @ 215 nm)

Example 60.1

N-(1-Cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

[1805] ##STR00374##

[1806] The titled compound was prepared from 4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxylic acid (step 1-2) and 2-amino-3-hydroxy-2-methyl-propanenitrile hydrochloride analogously to Example 30 step 3.

[1807] 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.72 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.37-7.28 (m, 1H), 7.22-7.14 (m, 2H), 5.99-5.79 (m, 1H), 3.86-3.78 (m, 3H), 3.72 (dd, J=10.9, 4.7 Hz, 1H), 1.65 (s, 3H).

[1808] LC-MS (Method A): Rt 2.41 mins; MS m/z 357.2=[M+H]+ (99% @ 215 nm)

Example 60.2

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxamide

[1809] ##STR00375##

[1810] The titled compound was prepared from 4-[[2-(2-fluorophenyl)acetyl]amino]pyridine-2-carboxylic acid (step 1-2) and 2-methylbut-3-yn-2-amine analogously to Example 30 step 3.

[1811] 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.43-7.37 (m, 1H), 7.37-7.30 (m, 1H), 7.22-7.15 (m, 2H), 3.82 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1812] LC-MS (Method A): Rt 3.08 mins; MS m/z 340.2=[M+H]+ (99% @ 215 nm)

Example 61

N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1813] ##STR00376##

Step 1: N-tert-Butyl-4-[[2-(5-chloro-3-isopropenyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1814] ##STR00377##

[1815] The titled compound was prepared from 4-[[2-(3-bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 59 step 2) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane analogously to Example 58.

[1816] 1H NMR (500 MHz, DMSO-d6) δ 10.84-10.75 (m, 1H), 8.48-8.42 (m, 1H), 8.23-8.17 (m, 1H), 8.03 (s, 1H), 7.84-7.79 (m, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.17 (d, J=2.7 Hz, 1H), 5.25-5.22 (m, 1H), 5.17-5.15 (m, 1H), 3.77 (d, J=2.8 Hz, 2H), 3.58 (s, 3H), 2.14-2.04 (m, 3H), 1.40 (s, 9H).

[1817] LC-MS (Method E): Rt 1.33 mins; MS m/z 416.1=[M+H]+ (86% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-(5-chloro-3-isopropyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[1818] ##STR00378##

[1819] 10% Pd/C (9 mg, 0.01 mmol) was added to a stirred solution of N-tert-butyl-4-[[2-(5-chloro-3-isopropenyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 1) (120 mg, 0.17 mmol) in EtOH (10 mL). The resulting mixture was placed under an atmosphere of hydrogen and after stirring for 16 hours the mixture was filtered through Celite® and washed through with EtOH (15 mL). The filtrate was concentrated in vacuo and purification by preparative HPLC (acidic pH, early elution method) afforded the titled compound as a pale yellow solid.

[1820] 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 3.77 (s, 2H), 3.66 (s, 3H), 3.21 (hept, J=6.9 Hz, 1H), 1.40 (s, 9H), 1.18 (d, J=6.9 Hz, 6H).

[1821] LC-MS (Method E): Rt 1.34 mins; MS m/z 418.2=[M+H]+ (99% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-(5-chloro-2-hydroxy-3-isopropyl-phenyl)acetyl]amino]pyridine-2-carboxamide

[1822] 1M BBr.sub.3 in DCM (0.34 mL, 0.34 mmol) was added to a stirred suspension of N-tert-butyl-4-[[2-(5-chloro-3-isopropyl-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide (step 2)(48 mg, 0.11 mmol) in DCM (2 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAc (5 mL), washed with sat. NaHCO.sub.3 (5 mL) and the organic portion was dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were combined, lyophilised overnight to afford the titled compound as an off-white powder.

[1823] 1H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.75 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.10-7.01 (m, 2H), 3.74 (s, 2H), 3.29-3.22 (m, 1H), 1.40 (s, 9H), 1.14 (d, J=6.8 Hz, 6H).

[1824] LC-MS (Method A): Rt 3.25 mins; MS m/z 356.3=[M+H]+ (100% @ 215 nm)

Example 62

N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1825] ##STR00379##

Step 1: N-tert-Butyl-4-[[2-[5-chloro-3-(1-hydroxyethyl)-2-methoxy-phenyl]acetyl]amino]pyridine-2-carboxamide

[1826] ##STR00380##

[1827] The titled compound was prepared from 4-[[2-(3-bromo-5-chloro-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 59, step 2) and 1-vinyloxybutane analogously to Example 54 steps 2-3.

[1828] 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 5.23 (d, J=4.5 Hz, 1H), 5.06-4.87 (m, 1H), 3.77 (d, J=2.6 Hz, 2H), 3.68 (s, 3H), 1.40 (s, 9H), 1.31 (d, J=6.4 Hz, 3H).

[1829] LC-MS (Method E): Rt 1.18 mins; MS m/z 420.2/422.2=[M+H]+ (100% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-[5-chloro-2-hydroxy-3-(1-methoxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1830] 1M BBr.sub.3 in DCM (0.5 mL, 0.5 mmol) was added to a cooled (0° C.) suspension of N-tert-butyl-4-[[2-[5-chloro-3-(1-hydroxyethyl)-2-methoxy-phenyl]acetyl]amino]pyridine-2-carboxamide (70 mg, 0.17 mmol) in DCM (2 mL) and stirred at room temperature for 1 hour. The reaction was quenched by addition of sat NaHCO.sub.3 (1 mL) then diluted with DCM (7 mL). The organic layer was separated, concentrated in vacuo and purification of the crude residue by preparative HPLC (acidic pH, early elution method) afforded the titled compound as an off-white powder.

[1831] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.87 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H), 4.68 (q, J=6.3 Hz, 1H), 3.76 (s, 2H), 3.17 (s, 3H), 1.40 (s, 9H), 1.29 (d, J=6.4 Hz, 3H).

[1832] LC-MS (Method A): Rt 3.80 mins; MS m/z 420.3=[M+H]+ (100% @ 215 nm)

Example 63

4-[[2-(6-Quinolyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide

[1833] ##STR00381##

Step 1: 4-Nitro-N-tetrahydropyran-4-yl-pyridine-2-carboxamide

[1834] ##STR00382##

[1835] To a stirred solution of HATU (724 mg, 1.9 mmol) in DMF (1 mL) was added DIPEA (363 μL, 2.08 mmol) and 4-nitropyridine-2-carboxylic acid (320 mg, 1.9 mmol) and the mixture was stirred for 15 mins. Tetrahydropyran-4-amine (0.18 mL, 1.73 mmol) was added in one portion and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with water (10 mL), NaHCO.sub.3 (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as a pale orange solid.

[1836] 1H NMR (500 MHz, DMSO-d6) δ=1.70-1.75 (m, 4H), 3.37-3.44 (m, 2H), 3.88 (dt, J=11.2, 3.2, 2H), 4.05 (s, 1H), 8.33 (dd, J=5.3, 2.3, 1H), 8.53 (dd, J=2.3, 0.5, 1H), 8.92 (d, J=8.2, 1H), 9.02 (dd, J=5.3, 0.5, 1H).

Step 2: 4-Amino-N-tetrahydropyran-4-yl-pyridine-2-carboxamide

[1837] ##STR00383##

[1838] A mixture comprising 4-nitro-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (step 1) (338 mg, 1.35 mmol) and 10% Pd—C (29 mg, 0.13 mmol) in EtOH (4 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was filtered and the filtrate washed with EtOAc (2×10 mL). The combined organic extracts were concentrated in vacuo and purification of the crude residue by chromatography on silica eluting with 0-100% EtOAc in heptane afforded the titled compound as a pale orange solid.

[1839] 1H NMR (500 MHz, DMSO-d6) δ=1.57-1.67 (m, 2H), 1.67-1.73 (m, 2H), 3.38 (td, J=11.6, 2.3, 2H), 3.81-3.88 (m, 2H), 3.90-3.99 (m, 1H), 6.30 (s, 2H), 6.58 (dd, J=5.6, 2.4, 1H), 7.21 (d, J=2.3, 1H), 8.01 (d, J=5.5, 1H), 8.37 (d, J=8.4, 1H).

[1840] LC-MS (Method C): Rt 0.32 mins; MS m/z 222.0=[M+H]+ (98% @ 215 nm)

Step 3: 4-[[2-(6-Quinolyl)acetyl]amino]-N-tetrahydropyran-4-yl-pyridine-2-carboxamide

[1841] A mixture of 4-amino-N-tetrahydropyran-4-yl-pyridine-2-carboxamide (step 2) (104 mg, 0.47 mmol) and 2-(6-quinolyl)acetic acid (87.99 mg, 0.47 mmol) in 1,4-dioxane (2 mL) was treated with 50% T3P® solution in EtOAc (1118 μL, 0.94 mmol) and TEA (164 μL, 0.94 mmol). After stirring at room temperature for 1.5 hours, the mixture was concentrated in vacuo. The crude residue was washed with water (15 mL), NaHCO.sub.3 (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by chromatography on silica eluting with 0-20% EtOAc/MeOH afforded the titled compound an off-white solid.

[1842] 1H NMR (500 MHz, DMSO-d6) δ=1.64-1.73 (m, 4H), 3.38 (td, J=11.4, 3.2, 2H), 3.83-3.89 (m, 2H), 3.95 (s, 2H), 3.97-4.05 (m, 1H), 7.50-7.55 (m, 1H), 7.74 (dd, J=8.7, 2.0, 1H), 7.84 (dd, J=5.5, 2.2, 1H), 7.90 (d, J=1.7, 1H), 7.99 (d, J=8.6, 1H), 8.22 (d, J=2.0, 1H), 8.35 (d, J=7.4, 1H), 8.49 (d, J=5.5, 1H), 8.58 (d, J=8.4, 1H), 8.88 (dd, J=4.2, 1.7, 1H), 10.86 (s, 1H).

[1843] LC-MS (Method A): Rt 1.51 mins; MS m/z 391.0=[M+H]+ (99% @ 215 nm)

Example 64

4-(Benzylcarbamoylamino)-N-tert-butyl-pyridine-2-carboxamide

[1844] ##STR00384##

[1845] A mixture of isocyanatomethylbenzene (72 μL, 0.52 mmol) and 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1)(100 mg, 0.52 mmol) in anhydrous DMF (1 mL) was stirred at 80° C. overnight. The resulting mixture was concentrated in vacuo and the residue partitioned between EtOAc (2 mL) and brine (2 mL). The organic portion was separated and the aqueous layer was re-extracted with EtOAc (2 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was dissolved in DMSO:MeCN:H.sub.2O (1.1 mL, 5:4:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as an off-white solid.

[1846] 1H NMR (250 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.05-7.97 (m, 2H), 7.62 (dd, J=5.6, 2.3 Hz, 1H), 7.38-7.20 (m, 5H), 6.97 (t, J=5.9 Hz, 1H), 4.32 (d, J=5.9 Hz, 2H), 1.39 (s, 9H).

[1847] LC-MS (Method A): Rt 2.74 mins; MS m/z 327.3=[M+H]+ (98% @ 215 nm)

[1848] The compounds of the following tabulated Examples (Table 13) were prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and the appropriate isocyanate analogously to Example 64

TABLE-US-00015 TABLE 13 1H NMR Ex. Sructure and Name LCMS Retention Time, [M + H]+, 64.1 [00385] 1H NMR (250 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.30 (d, J = 5.5 Hz, 1H), 8.01 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 5.6, 2.3 Hz, 1H), 6.43 (t, J = 5.8 Hz, 1H), 2.96 (t, J = 6.3 Hz, 2H), 1.75-1.55 (m, 5H), 1.48-1.31 (m, 10H), 1.29-1.08 (m, 3H), 0.99-0.80 (m, 2H). LC-MS (Method A): Rt 3.21 mins; MS m/z 333.3 = [M + H]+ (98% @ 215 nm) 64.2 [00386] 1H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 8.01 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.60 (dd, J = 5.6, 2.2 Hz, 1H), 7.33-7.29 (m, 2H), 7.26- 7.17 (m, 3H), 6.42 (t, J = 5.6 Hz, 1H), 3.39-3.34 (m, 2H), 2.77 (t, J = 7.2 Hz, 2H), 1.39 (s, 9H). LC-MS (Method A): Rt 2.91 mins; MS m/z 341.3 = [M + H]+ (95% @ 215 nm) 64.3 [00387] 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.57 (dd, J = 5.6, 2.3 Hz, 1H), 7.37-7.33 (m, 4H), 7.26- 7.22 (m, 1H), 6.93 (d, J = 7.8 Hz, 1H), 4.84 (p, J = 7.0 Hz, 1H), 1.41 (d, J = 7.0 Hz, 3H), 1.38 (s, 9H). LC-MS (Method A): Rt 2.92 mins; MS m/z 341.4 = [M + H]+ (98% @ 215 nm) 64.4 [00388] 1H NMR (500 MHz, Methanol-d4) δ 8.34 (d, J = 5.7 Hz, 1H), 7.94-7.89 (m, 1H), 7.75 (dd, J = 5.7, 2.1 Hz, 1H), 7.41-7.31 (m, 4H), 7.30-7.22 (m, 1H), 4.95 (q, J = 7.0 Hz, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.48 (s, 9H). LC-MS (Method A): Rt 2.91 mins; MS m/z 341.3 = [M + H]+ (99% @ 215 nm) 64.5 [00389] 1H NMR (500 MHz, Methanol-d4) δ 8.34 (d, J = 5.3 Hz, 1H), 7.92 (s, 1H), 7.79-7.73 (m, 1H), 7.45 (dd, J = 7.4, 1.8 Hz, 1H), 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.35-7.24 (m, 2H), 4.52 (s, 2H), 1.48 (s, 9H). LC-MS (Method A): Rt 3.07 mins; MS m/z 361.2/ 363.2 = [M + H]+ (100% @ 215 nm) 64.6 [00390] 1H NMR (500 MHz, Methanol-d4) δ 8.38 (d, J = 5.6 Hz, 1H), 8.29 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 5.6, 2.2 Hz, 1H), 7.55 (dt, J = 8.1, 0.9 Hz, 1H), 7.50 (s, 1H), 7.40-7.35 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.03 (m, 1H), 1.50 (s, 9H). LC-MS (Method A): Rt 2.68 mins; MS m/z 352.3 = [M + H]+ (99% @ 215 nm) 64.7 [00391] 1H NMR (500 MHz, Methanol-d4) δ 8.38-8.33 (m, 1H), 7.96-7.91 (m, 1H), 7.77 (dd, J = 5.6, 2.3 Hz, 1H), 7.38 (s, 1H), 7.38 (t, J = 1.5 Hz, 1H), 7.31-7.25 (m, 2H), 4.42 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.12 mins; MS m/z 361.3/ 363.3 = [M + H]+ (100% @ 215 nm) 64.8 [00392] 1H NMR (500 MHz, Methanol-d4) δ 8.37-8.32 (m, 1H), 7.95-7.91 (m, 1H), 7.77 (dd, J = 5.6, 2.3 Hz, 1H), 7.35 (s, 4H), 4.41 (s, 2H), 1.49 (s, 9H). LC-MS (Method A): Rt 3.12 mins; MS m/z 361.3/ 363.2 = [M + H]+ (100% @ 215 nm)

Example 65

N-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide

[1849] ##STR00393##

Step 1: N-tert-Butyl-4-[(2-methoxyphenyl)carbamoylamino]pyridine-2-carboxamide

[1850] ##STR00394##

[1851] The titled compound was prepared from 1-isocyanato-2-methoxy-benzene and 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) analogously to Example 64.

[1852] 1H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.43-8.37 (m, 2H), 8.11 (dd, J=8.0, 1.6 Hz, 1H), 8.06-8.03 (m, 2H), 7.63 (dd, J=5.5, 2.3 Hz, 1H), 7.06-6.98 (m, 2H), 6.92 (td, J=7.8, 1.5 Hz, 1H), 3.89 (s, 3H), 1.41 (s, 9H).

[1853] LC-MS (Method A): Rt 3.21 mins; MS m/z 343.2=[M+H]+ (100% @ 215 nm)

Step 2: N-tert-Butyl-4-[(2-hydroxyphenyl)carbamoylamino]pyridine-2-carboxamide

[1854] N-tert-Butyl-4-[(2-methoxyphenyl)carbamoylamino]pyridine-2-carboxamide (step 1) (41 mg, 0.12 mmol) was added to a suspension of 1M BBr.sub.3 in DCM (532 μL, 0.53 mmol) in DCM (1 mL) at 0° C.-5° C. After stirring at room temperature for 2.5 hours, the mixture was concentrated in vacuo and the residue partitioned between EtOAc (4 mL) and water (4 mL). The pH of the aqueous layer was adjusted to pH 5-6 with sat. aq. NaHCO.sub.3 and the organic layer separated, washed with brine (2 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in MeCN:H.sub.2O (1.1 mL, 4:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as a beige solid.

[1855] 1H NMR (250 MHz, DMSO-d6) δ 10.38-9.64 (m, 2H), 8.50-8.26 (m, 2H), 8.07-7.99 (m, 3H), 7.63 (dd, J=5.6, 2.3 Hz, 1H), 6.89-6.72 (m, 3H), 1.40 (s, 9H).

[1856] LC-MS (Method A): Rt 2.72 mins; MS m/z 329.3=[M+H]+ (100% @ 215 nm)

Example 65.1

N-tert-Butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

[1857] ##STR00395##

[1858] The titled compound was prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and 1-(isocyanatomethyl)-2-methoxy-benzene analogously to Example 65 step 1.

[1859] 1H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.02 (s, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.60 (dd, J=5.6, 2.3 Hz, 1H), 7.29-7.21 (m, 2H), 7.03-6.99 (m, 1H), 6.94-6.88 (m, 1H), 6.75 (t, J=5.9 Hz, 1H), 4.28 (d, J=5.9 Hz, 2H), 3.84 (s, 3H), 1.40 (s, 9H).

[1860] LC-MS (Method A): Rt 2.86 mins; MS m/z 357.3=[M+H]+ (99% @ 215 nm)

Example 65.2

N-tert-Butyl-4-[(2-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

[1861] ##STR00396##

[1862] The titled compound was prepared from N-tert-butyl-4-[(2-methoxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide (Example 65.1) analogously to Example 65 step 2

[1863] 1H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.31 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.01 (s, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.60 (dd, J=5.6, 2.3 Hz, 1H), 7.16 (dd, J=7.5, 1.5 Hz, 1H), 7.08 (td, J=7.8, 1.7 Hz, 1H), 6.82 (dd, J=8.0, 1.0 Hz, 1H), 6.76 (td, J=7.4, 1.1 Hz, 1H), 6.72 (t, J=5.9 Hz, 1H), 4.24 (d, J=5.8 Hz, 2H), 1.39 (s, 9H).

[1864] LC-MS (Method A): Rt 2.56 mins; MS m/z 343.2=[M+H]+ (97% @ 215 nm)

Example 65.3

N-tert-Butyl-4-[(3-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

[1865] ##STR00397##

[1866] The titled compound was prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and 1-(isocyanatomethyl)-3-methoxy-benzene analogously to Example 65 steps 1 and 2.

[1867] 1H NMR (500 MHz, Methanol-d4) δ 8.34 (d, J=5.6 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.77 (dd, J=5.6, 2.2 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.83-6.77 (m, 2H), 6.72-6.65 (m, 1H), 4.35 (s, 2H), 1.48 (s, 9H).

[1868] LC-MS (Method A): Rt 2.24 mins; MS m/z 343.3=[M+H]+ (96% @ 215 nm)

Example 65.4

N-tert-Butyl-4-[(4-hydroxyphenyl)methylcarbamoylamino]pyridine-2-carboxamide

[1869] ##STR00398##

[1870] The titled compound was prepared from 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) and 1-(isocyanatomethyl)-4-methoxy-benzene analogously to Example 65 steps 1 and 2.

[1871] 1H NMR (500 MHz, Methanol-d4) δ 8.34 (d, J=5.6 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H), 7.77 (dd, J=5.6, 2.3 Hz, 1H), 7.21-7.14 (m, 2H), 6.80-6.73 (m, 2H), 4.31 (s, 2H), 1.48 (s, 9H).

[1872] LC-MS (Method A): Rt 2.16 mins; MS m/z 343.3=[M+H]+ (98% @ 215 nm)

Example 66

N-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1873] ##STR00399##

Step 1: 4-[[2-(5-Acetyl-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1874] ##STR00400##

[1875] 4-[[2-(5-Bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6, step 1) (985 mg, 2.34 mmol), ZnF.sub.2 (218 mg, 1.87 mmol) and Pd(dba).sub.2 (135 mg, 0.23 mmol) were dissolved in anhydrous DMF (10 mL) at room temperature and degassed with N2 in a sealed pressure vial. To the mixture was added tri-tert-butylphosphine (1M in toluene, 0.47 mL, 0.47 mmol) followed by trim ethyl (vinyloxy)silane (0.42 mL, 2.81 mmol) and the vial heated at 70° C. overnight. Additional trimethyl(vinyloxy)silane (105 μL, 0.70 mmol) was added and the mixture heated at 70° C. for a further 4 hours. After cooling to room temperature, the mixture was diluted with TBME (40 mL) and filtered through a pad of kieselguhr. The filtrate was concentrated in vacuo and purification of the residue by chromatography on silica eluting with 0-100% TBME in heptane afforded the titled compound as a yellow solid.

[1876] 1H NMR (500 MHz, Chloroform-d) δ 8.40-8.37 (m, 1H), 8.21 (dd, J=5.6, 2.2 Hz, 1H), 7.99-7.92 (m, 3H), 7.83 (s, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 4.02 (s, 3H), 3.78 (s, 2H), 2.58 (s, 3H), 1.47 (s, 9H).

[1877] LC-MS (Method E): Rt 1.11 mins, MS m/z 384.1=[M+H]+ (78% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-[5-(1-hydroxyethyl)-2-methoxyphenyl]acetyl]amino]pyridine-2-carboxamide

[1878] ##STR00401##

[1879] A solution of 4-[[2-(5-acetyl-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (step 1) (45 mg, 0.09 mmol) in MeOH (1 mL) was treated with NaBH.sub.4 (4 mg, 0.1 mmol) and stirred at room temperature for 2 hours. The reaction was quenched by addition to 10% aq. H.sub.3PO.sub.4 (1 mL) and the mixture extracted with EtOAc (2×2 mL). The combined organic extracts were washed with water (2 mL) and brine (2 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as an off-white solid.

[1880] 1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.04 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.23-7.17 (m, 2H), 6.94-6.89 (m, 1H), 4.65 (q, J=6.4 Hz, 1H), 3.73 (s, 3H), 3.68 (s, 2H), 1.40 (s, 9H), 1.29 (d, J=6.4 Hz, 3H)

[1881] LC-MS (Method E): Rt 1.06 mins; MS m/z 386.1=[M+H]+ (97% @ 215 nm)

Step 3: N-tert-Butyl-4-[[2-[2-hydroxy-5-(1-hydroxyethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1882] N-tert-butyl-4-[[2-[5-(1-hydroxyethyl)-2-methoxy-phenyl]acetyl]amino]pyridine-2-carboxamide (step 2) (39 mg, 0.09 mmol) was added to a suspension of 1M BBr.sub.3 in DCM (303 μL, 0.3 mmol) in DCM (1 mL) in DCM (1 mL) at 0-5° C. After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo and the residue partitioned between EtOAc (4 mL) and water (4 mL). The pH of the aqueous layer was adjusted to pH 5-6 with sat. aq. NaHCO.sub.3 and the organic layer separated, washed with brine (2 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in MeCN:H.sub.2O (1.1 mL, 4:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as a beige powder.

[1883] 1H NMR (500 MHz, DMSO-d6) δ 10.64 (br. s, 1H), 9.34 (br. s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.12 (d, J=2.1 Hz, 1H), 7.03 (dd, J=8.2, 2.2 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 4.93 (d, J=4.1 Hz, 1H), 4.63-4.57 (m, 1H), 3.64 (s, 2H), 1.40 (s, 9H), 1.27 (d, J=6.4 Hz, 3H).

[1884] LC-MS (Method A): Rt 2.45 mins; MS m/z 372.3=[M+H]+ (99% @ 215 nm)

Example 67

N-tert-Butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide

[1885] ##STR00402##

Step 1: N-tert-Butyl-4-[[2-[2-methoxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide

[1886] ##STR00403##

[1887] To a solution of 4-[[2-(5-acetyl-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 66 step 1)(73 mg, 0.15 mmol) in dichloroethane (1.5 mL) was added the 2,2,2-trifluoroethanamine (14 μL, 0.18 mmol) and acetic acid (17 μL, 0.3 mmol) and the mixture was stirred at room temperature for 30 mins. Sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added and the reaction mixture stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue dissolved in EtOAc (4 mL). The mixture was washed with sat. aq. NaHCO.sub.3 (4 mL), brine (4 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (acidic pH, early elution method) and the product fractions were combined and the pH was adjusted to pH8 using sat. aq. NaHCO.sub.3. The mixture was extracted with DCM using a hydrophobic phase separator and the filtrate was concentrated in vacuo to afford the titled compound as an off-white solid.

[1888] LC-MS (Method E): Rt 1.07 mins; MS m/z 467.2=[M+H]+ (99% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-[2-hydroxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl]amino]pyridine-2-carboxamide

[1889] The titled compound was prepared from N-tert-Butyl-4-[[2-[2-methoxy-5-[1-(2,2,2-trifluoroethylamino)ethyl]phenyl]acetyl] amino]pyridine-2-carboxamide (step 1) analogously to Example 66 step 3.

[1890] 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.39 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.04 (dd, J=8.2, 2.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 3.71-3.62 (m, 3H), 3.03-2.91 (m, 2H), 2.67 (q, J=8.7, 8.1 Hz, 1H), 1.40 (s, 9H), 1.23 (d, J=6.6 Hz, 3H).

[1891] LC-MS (Method A): Rt 2.22 mins; MS m/z 453.3=[M+H]+ (97% @ 215 nm)

Example 68

N-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1892] ##STR00404##

Step 1: 4-[[2-[3-(Bromomethyl)phenyl]acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[1893] ##STR00405##

[1894] The titled compound was prepared from 2-[3-(bromomethyl)phenyl]acetic acid and 4-amino-N-tert-butyl-pyridine-2-carboxamide (Example 3 step 1) analogously to Example 3.5b step 1.

[1895] LC-MS (Method E): Rt 1.20 mins; MS m/z 404.0/406.0=[M+H]+ (44% @ 215 nm)

Step 2: N-tert-Butyl-4-[[2-[3-(cyanomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1896] 4-[[2-[3-(Bromomethyl)phenyl]acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Step 1) (50 mg, 0.05 mmol) was treated with sodium cyanide (5 mg, 0.11 mmol) and tetrabutylammonium bromide (2 mg, 0.01 mmol) in a 1:1 mixture of DCM:water (2 mL) and stirred at room temperature for 18 hours. The resulting mixture was diluted with sat. aq. NaHCO.sub.3 (5 mL) and extracted into DCM (3×5 mL). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DMSO:MeCN (800 μl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as a colourless glassy solid.

[1897] 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.33-7.28 (m, 2H), 7.24 (d, J=7.7 Hz, 1H), 4.04 (s, 2H), 3.74 (s, 2H), 1.39 (s, 9H).

[1898] LC-MS (Method A): Rt 3.04 mins; MS m/z 351.2=[M+H]+ (96% @ 215 nm)

Example 69

N-tert-Butyl-4-[[2-[3-(methoxymethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1899] ##STR00406##

[1900] A vessel was charged with 4-[[2-(3-bromophenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 54 step 1)(50 mg, 0.13 mmol) PdCl.sub.2dppf (3 mg), potassium trifluoro(methoxymethyl)boranuide (0.45 mL, 0.26 mmol) 2M aq. sodium carbonate (0.26 mL, 0.51 mmol) and heated at 80° C. for 16 hours. The mixture was allowed to cool to room temperature, poured onto water (20 mL) and extracted into EtOAc (3×20 mL). The combined organic extracts were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was dissolved in DMSO:MeCN (800 μl, 1:1), filtered and purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as an off-white solid.

[1901] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.02 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.34-7.27 (m, 2H), 7.25 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 4.40 (s, 2H), 3.71 (s, 2H), 3.29 (s, 3H), 1.39 (s, 9H).

[1902] LC-MS (Method C): Rt 3.18 mins; MS m/z 356.3=[M+H]+ (94% @ 215 nm)

Example 70

N-tert-Butyl-4-[[2-[2-hydroxy-5-(morpholinomethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1903] ##STR00407##

[1904] The titled compound was prepared from 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6 step 1) and potassium trifluoro(morpholinomethyl)boranuide analogously to Example 27 steps 3 and 4.

[1905] 1H NMR (500 MHz, DMSO-d6) δ 10.64 (br s, 1H), 9.43 (br s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.1, 2.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 3.64 (s, 2H), 3.55-3.51 (m, 4H), 2.34-2.25 (m, 4H), 1.40 (s, 9H).

[1906] LC-MS (Method A): Rt 1.66 mins; MS m/z 427.4=[M+H]+ (98% @ 215 nm)

Example 71

3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)benzamide

[1907] ##STR00408##

Step 1: Methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoate

[1908] ##STR00409##

[1909] A solution comprising methyl 3-aminobenzoate (1 g, 6.62 mmol) and 2-(5-chloro-2-methoxy-phenyl)acetic acid (1.39 g, 6.95 mmol) in DMF (10 mL) was treated with DIPEA (1.73 mL, 9.92 mmol) followed by HATU (3019 mg, 7.94 mmol) and stirred at room temperature for 1 hour. The resulting mixture was diluted with water (50 mL) and EtOAc (60 mL) to form a biphasic solution. Heptane (15 ml) was added and the organic portion was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was treated with TBME (50 ml) and the resultant suspension filtered, washing with through with TBME and dried in vacuo to afford the titled compound as an off-white powdery solid.

[1910] 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.28 (t, J=1.8 Hz, 1H), 7.84-7.80 (m, 1H), 7.63 (dt, J=7.7, 1.2 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.29 (dd, J=6.5, 2.9 Hz, 2H), 7.03-6.98 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.66 (s, 2H).

[1911] LC-MS (Method E): Rt 1.17 mins; MS m/z 334.0/336.0=[M+H]+ (98% @ 215 nm)

Step 2: 3-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]benzoic acid

[1912] ##STR00410##

[1913] The titled compound was prepared from methyl 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoate (step 1) analogously to Example 41 step 2.

[1914] 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.26 (s, 1H), 8.22 (s, 1H), 7.81 (dd, J=8.1, 1.1 Hz, 1H), 7.61 (dt, J=7.7, 1.2 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.29 (dd, J=6.9, 2.7 Hz, 2H), 7.03-6.98 (m, 1H), 3.76 (s, 3H), 3.66 (s, 2H).

[1915] LC-MS (Method E): Rt 1.06 mins; MS m/z 319.9/321.7=[M+H]+ (99% @ 215 nm)

Step 3: 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]benzoic acid

[1916] ##STR00411##

[1917] The titled compound was prepared from 3-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]benzoic acid (step 2) analogously to Example 41 step 3.

[1918] 1H NMR (500 MHz, DMSO-d6) δ 12.91 (br s, 1H), 10.25 (s, 1H), 9.78 (s, 1H), 8.23 (t, J=1.8 Hz, 1H), 7.82 (dd, J=8.1, 1.1 Hz, 1H), 7.61 (dt, J=7.7, 1.2 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.62 (s, 2H).

[1919] LC-MS (Method E): Rt 1.01 mins; MS m/z 305.9/308.0=[M+H]+ (99% @ 215 nm)

Step 4: 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(3-cyanotetrahydrofuran-3-yl)benzamide

[1920] To a solution of 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoic acid (step 3) (150 mg, 0.49 mmol), 3-aminotetrahydrofuran-3-carbonitrile hydrochloride (73 mg, 0.49 mmol) and DIPEA (343 μL, 1.96 mmol) in DMF (1.5 mL) was added HATU (224 mg, 0.59 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with EtOAc and washed with 1M NaOH (3×20 mL). The aqueous layer was extracted into EtOAc (2×10 mL), then acidified with 1M HCl and the remaining product extracted into EtOAc (3×30 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) afforded the titled compound as an off-white solid.

[1921] 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.82 (br s, 1H), 9.21 (s, 1H), 8.08 (t, J=1.8 Hz, 1H), 7.81 (dd, J=8.1, 1.1 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.26 (d, J=9.5 Hz, 1H), 3.96 (d, J=9.5 Hz, 1H), 3.94-3.86 (m, 2H), 3.62 (s, 2H), 2.62-2.55 (m, 2H).

[1922] LC-MS (Method A): Rt 2.64 mins; MS m/z 400.3/402.2=[M+H]+ (99% @ 215 nm)

Example 71.1

3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclohexyl)benzamide

[1923] ##STR00412##

[1924] The titled compound was prepared from 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoic acid (Example 71 step 3) and 1-methylcyclohexanamine analogously to Example 71.

[1925] 1H NMR (500 MHz, Methanol-d4) δ 7.94 (t, J=1.8 Hz, 1H), 7.75-7.72 (m, 1H), 7.51-7.47 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.12 (dd, J=8.6, 2.6 Hz, 1H), 6.83 (s, 1H), 3.72 (s, 2H), 2.27 (d, J=13.1 Hz, 2H), 1.68-1.56 (m, 5H), 1.54-1.47 (m, 2H), 1.46 (s, 3H), 1.45-1.36 (m, 1H).

[1926] LC-MS (Method A): Rt 3.58 mins; MS m/z 401.2/403.2=[M+H]+ (96% @ 215 nm)

Example 72

4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetrahydro furan-3-yl]pyridine-2-carboxamide

[1927] ##STR00413##

[1928] The titled compound was prepared from 4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 49 steps 1-3) and (3-aminotetrahydrofuran-3-yl)methanol analogously to Example 35.

[1929] 1H NMR (500 MHz, DMSO-d6) δ 9.52 (br s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.42 (s, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.02 (dd, J=9.4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.79-6.75 (m, 1H), 5.17 (s, 1H), 3.90-3.77 (m, 4H), 3.67 (s, 2H), 3.62 (s, 2H), 2.35-2.29 (m, 1H), 2.01-1.95 (m, 1H).

[1930] LC-MS (Method A): Rt 1.99 mins; MS m/z 390.2/392.3=[M+H]+ (100% @ 215 nm)

Example 73

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)-2-methoxy-1-methyl-ethyl]pyridine-2-carboxamide

[1931] ##STR00414##

[1932] The titled compound was prepared from 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, step 1) and 2-amino-3-methoxy-2-methyl-propan-1-ol hydrochloride (prepared according to Tetrahedron, Volume 56, Issue 23, 2 Jun. 2000, Pages 3799-3816) analogously to Example 35.

[1933] 1H NMR (500 MHz, Methanol-d4) δ 8.45 (dd, J=5.5, 0.5 Hz, 1H), 8.19-8.14 (m, 1H), 7.91 (dd, J=5.5, 2.2 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.83 (d, J=11.1 Hz, 1H), 3.76-3.69 (m, 3H), 3.65 (d, J=9.1 Hz, 1H), 3.59 (d, J=9.1 Hz, 1H), 3.42 (s, 3H), 1.44 (s, 3H).

[1934] LC-MS (Method A): Rt 2.63 mins; MS m/z 408.2=[M+H]+ (99% @ 215 nm)

Example 73.1

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylbut-2-ynyl) pyridine-2-carboxamide

[1935] ##STR00415##

[1936] The titled compound was prepared from 4-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 31, step 1) and 2-methylpent-3-yn-2-amine hydrochloride (prepared according to WO 03048128 A1 page 55) analogously to Example 73.

[1937] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (br s, 1H), 9.81 (br s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.12 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.67 (s, 2H), 1.78 (s, 3H), 1.63 (s, 6H).

[1938] LC-MS (Method A): Rt 3.31 mins; MS m/z 386.3/388.2=[M+H]+ (97% @ 215 nm)

Example 74

3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)benzamide

[1939] ##STR00416##

[1940] 2-Methylbut-3-yn-2-amine (49 mg, 0.59 mmol) and 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoic acid (Example 71, step 3)(150 mg, 0.49 mmol) were dissolved in DMF (1 mL) and treated with TEA (0.26 mL, 1.47 mmol) followed by HATU (224 mg, 0.59 mmol) and stirred for 2 hours. The resulting mixture was diluted with EtOAc and washed with sat. aq. Na.sub.2CO.sub.3 (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with 1M NaOH (3×20 mL). The aqueous layer was acidified with 1M HCl and the remaining product extracted into EtOAc (3×30 mL). The combined organic extracts were neutralised with a saturated aqueous sodium bicarbonate wash, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic pH, early elution method) to afford the titled compound as an off-white foamy solid.

[1941] 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.79 (s, 1H), 8.20 (s, 1H), 7.94 (t, J=1.8 Hz, 1H), 7.80-7.74 (m, 1H), 7.47-7.42 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.61 (s, 2H), 3.08 (s, 1H), 1.59 (s, 6H).

[1942] LC-MS (Method A): Rt 2.92 mins; MS m/z 371.2/373.2=[M+H]+ (97% @ 215 nm)

Example 74.1

3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl)tetra hydrofuran-3-yl]benzamide

[1943] ##STR00417##

[1944] The titled compound was prepared from 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoic acid (Example 71, step 3) and (3-aminotetrahydrofuran-3-yl)methanol analogously to Example 74.

[1945] 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.80 (s, 1H), 8.12 (s, 1H), 7.95 (t, J=1.8 Hz, 1H), 7.81-7.74 (m, 1H), 7.53-7.47 (m, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.97 (t, J=5.8 Hz, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.81-3.73 (m, 3H), 3.67 (dd, J=10.8, 5.7 Hz, 1H), 3.64-3.59 (m, 3H), 2.23 (dt, J=12.8, 6.4 Hz, 1H), 2.05 (dt, J=12.9, 7.7 Hz, 1H).

[1946] LC-MS (Method A): Rt 2.24 mins; MS m/z 405.2/407.2=[M+H]+ (100% @ 215 nm)

Example 75

N-tert-Butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1947] ##STR00418##

Step 1: Ethyl (E)-3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-methoxy-phenyl]prop-2-enoate

[1948] ##STR00419##

[1949] A mixture comprising 4-[[2-(5-bromo-2-methoxy-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 6 step 1)(500 mg, 1.19 mmol), ethyl prop-2-enoate (0.52 mL, 4.76 mmol), Pd.sub.2(dba).sub.3 (109 mg, 0.12 mmol), tri-o-tolyl phosphine (109 mg, 0.36 mmol), TEA (1.04 mL, 5.95 mmol) in DMF (10 mL) under a nitrogen atmosphere was stirred at 90° C. for 18 hours. The resulting mixture was filtered, diluted with EtOAc (10 mL) and washed with brine (1×10 mL). The brine was re-extracted with EtOAc (2×10 mL) and the combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the titled compound as an orange/brown solid.

[1950] 1H NMR (250 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.44 (d, J=5.6 Hz, 1H), 8.19-8.16 (m, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.67-7.60 (m, 2H), 7.56 (s, 1H), 7.04 (d, J=9.2 Hz, 1H), 6.46 (d, J=16.0 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 2H), 1.40 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).

[1951] LC-MS (Method E): Rt 1.23 mins; MS m/z 440.0=[M+H]+ (65% @ 215 nm)

Step 2: Ethyl 3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-methoxy-phenyl]propanoate

[1952] ##STR00420##

[1953] Ethyl (E)-3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-methoxy-phenyl]prop-2-enoate (step 1)(625 mg, 0.92 mmol) in EtOH (9.24 mL) under nitrogen, was treated with 10% Pd—C (50% w/w, 20 mg, 0.09 mmol) and placed under hydrogen. After stirring at room temperature for 19 hours, the mixture was filtered through kieselguhr (diatomaceous earth) and washed with through with EtOAc. The filtrate was concentrated in vacuo to afford the titled compound as an off-white solid.

[1954] 1H NMR (250 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.13-7.04 (m, 2H), 6.89 (d, J=8.3 Hz, 1H), 4.02 (qd, J=7.1, 1.1 Hz, 2H), 3.72 (s, 3H), 3.65 (s, 2H), 2.78 (t, J=7.4 Hz, 2H), 2.60-2.52 (m, 2H), 1.40 (s, 9H), 1.14 (t, J=7.2 Hz, 3H).

[1955] LC-MS (Method E): Rt 1.23 mins; MS m/z 442.3=[M+H]+ (61% @ 215 nm)

Step 3: 3-[3-[2-[[2-(tert-Butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-methoxy-phenyl]propanoic acid

[1956] ##STR00421##

[1957] To a solution of ethyl 3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-methoxy-phenyl]propanoate (step 2) (332 mg, 0.75 mmol) in THF (4.3 mL)/water (1 mL), 1M LiOH (631 mg, 15.04 mmol) was added and the reaction mixture was stirred at room temperature for 5.5 hours. The resulting mixture was extracted with EtOAc and the aqueous layer was diluted with water and acidified to pH 3-4 with 6M HCl. The resulting mixture was extracted with EtOAc (3×25 ml) and the combined organic extracts were filtered, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as a yellow oil.

[1958] 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.11-7.06 (m, 2H), 6.89 (d, J=8.3 Hz, 1H), 3.72 (s, 3H), 3.66 (s, 2H), 2.75 (t, J=7.7 Hz, 2H), 1.40 (s, 9H).

[1959] LC-MS (Method E): Rt 1.08 mins; MS m/z 414.2=[M+H]+ (79% @ 215 nm)

Step 4: N-tert-Butyl-4-[[2-[5-(3-hydroxypropyl)-2-methoxy-phenyl]acetyl]amino]pyridine-2-carboxamide

[1960] ##STR00422##

[1961] To a cooled (0° C.) solution of 3-[3-[2-[[2-(tert-butylcarbamoyl)-4-pyridyl]amino]-2-oxo-ethyl]-4-methoxy-phenyl]propanoic acid (step 3)(196 mg, 0.47 mmol) in THF (3.96 mL) was added TEA (0.17 mL, 1.19 mmol) followed by the dropwise addition of methyl carbonochloridate (0.09 mL, 1.19 mmol). The reaction mixture was stirred for 30 minutes at 0° C. then treated with NaBH.sub.4 (90 mg, 2.37 mmol) followed by dropwise addition of MeOH (0.5 mL). After stirring at 0° C. for a further 90 minutes, the mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaHCO.sub.3 (10 mL), brine (20 mL) then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the titled compound as an off-white solid.

[1962] 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.08-7.03 (m, 2H), 6.88 (d, J=8.3 Hz, 1H), 4.42 (t, J=5.1 Hz, 1H), 3.72 (s, 3H), 3.66 (s, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.71-1.64 (m, 2H), 1.40 (s, 9H).

[1963] LC-MS (Method E): Rt 1.09 mins; MS m/z 400.1=[M+H]+ (100% @ 215 nm)

Step 5: N-tert-Butyl-4-[[2-[2-hydroxy-5-(3-hydroxypropyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[1964] The titled compound was prepared from N-tert-butyl-4-[[2-[5-(3-hydroxypropyl)-2-methoxy-phenyl]acetyl]amino]pyridine-2-carboxamide (step 4) analogously to Example 41 step 3.

[1965] 1H NMR (500 MHz, Methanol-d4) δ 8.41 (d, J=5.5 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.96 (dd, J=8.2, 2.2 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 3.70 (s, 2H), 3.55 (t, J=6.5 Hz, 2H), 2.63-2.54 (m, 2H), 1.84-1.75 (m, 2H), 1.47 (s, 9H).

[1966] LC-MS (Method A): Rt 2.57 mins; MS m/z 386.3=[M+H]+ (97% @ 215 nm)

Example 76

4-[[2-(5-Chloro-4-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclo butyl)pyridine-2-carboxamide

[1967] ##STR00423##

Step 1: 4-Amino-N-(1-methylcyclobutyl)pyridine-2-carboxamide

[1968] ##STR00424##

[1969] 4-Aminopyridine-2-carboxylic acid (700 mg, 5.07 mmol) and DIPEA (3.54 mL, 20.27 mmol) were suspended in DMF (39 mL) and treated with 1-methylcyclobutanamine hydrochloride (924 mg, 7.6 mmol) and HATU (2312 mg, 6.08 mmol). After stirring at room temperature for 4 days the reaction mixture was filtered and the solid washed with DMF (2×2 mL). The filtrate was concentrated in vacuo and the crude residue dissolved in EtOAc (20 mL) and washed with sat. NaHCO.sub.3 solution (20 mL). The aqueous layer was re-extracted with EtOAc (20 mL) and the combined organic layers were washed with brine (2×20 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude residue by C18 reverse phase chromatography eluting with 5-100% MeCN in water afforded the titled compound as a white solid

[1970] 1H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.99 (d, J=5.7 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H), 6.60 (dd, J=5.7, 2.3 Hz, 1H), 6.53 (br s, 2H), 2.40-2.32 (m, 2H), 2.00-1.94 (m, 2H), 1.83-1.76 (m, 2H), 1.45 (s, 3H).

[1971] LC-MS (Method E): Rt 0.62 mins; MS m/z 206.0=[M+H]+ (99% @ 215 nm)

Step 2: 4-[[2-(5-Chloro-4-fluoro-2-methoxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide

[1972] ##STR00425##

[1973] A solution of 4-amino-N-(1-methylcyclobutyl)pyridine-2-carboxamide (step 1)(81 mg, 0.4 mmol) and 2-(5-chloro-4-fluoro-2-methoxy-phenyl)acetic acid (100 mg, 0.36 mmol) in DMF (1.9 mL) was treated with TEA (0.16 mL, 0.9 mmol) and T3P® (50% solution in EtOAc) (0.21 mL, 0.72 mmol) and stirred at room temperature for 17 hours. The reaction was quenched with sat NaHCO.sub.3 (2 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-100% EtOAc in heptane to afford the titled compound as an off-white solid.

[1974] 1H NMR (500 MHz, Methanol-d4) δ 8.49-8.47 (m, 1H), 8.15 (dd, J=2.2, 0.4 Hz, 1H), 7.92 (dd, J=5.5, 2.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.97 (d, J=11.2 Hz, 1H), 3.86 (s, 3H), 3.74 (s, 2H), 2.49 (dd, J=9.7, 2.4 Hz, 2H), 2.19-2.13 (m, 2H), 1.99-1.93 (m, 2H), 1.59 (s, 3H).

[1975] LC-MS (Method E): Rt 1.22 mins; MS m/z 406.1/408.2=[M+H]+ (79% @ 215 nm)

Step 3: 4-[[2-(5-Chloro-4-fluoro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methylcyclo butyl)pyridine-2-carboxamide

[1976] The titled compound was prepared from 4-[[2-(5-chloro-4-fluoro-2-methoxy-phenyl)acetyl]amino]-N-(1-methylcyclobutyl)pyridine-2-carboxamide (step 2) analogously to Example 41 step 3.

[1977] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (br s, 1H), 10.32 (br s, 1H), 8.48-8.43 (m, 2H), 8.13 (d, J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.75 (d, J=11.0 Hz, 1H), 3.65 (s, 2H), 2.43-2.38 (m, 2H), 2.03-1.96 (m, 2H), 1.85-1.77 (m, 2H), 1.47 (s, 3H).

[1978] LC-MS (Method A): Rt 3.34 mins; MS m/z 392.2/394.2=[M+H]+ (100% @ 215 nm)

Example 77

4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1979] ##STR00426##

Step 1: Methyl 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2-carboxylate

[1980] ##STR00427##

[1981] 2-(2,5-Difluorophenyl)acetic acid (407 mg, 2.37 mmol) was dissolved in thionyl chloride (1.8 mL, 20.43 mmol) and the mixture heated at 70° C. for 1 h. The resulting mixture was concentrated in vacuo and the residue azeotropically dried with toluene. The crude acid chloride was dissolved in DCM (4 mL) and added dropwise to a cooled (0° C.) solution of methyl 4-aminopyridine-2-carboxylate (300 mg, 1.97 mmol) and DIPEA (0.69 mL, 3.94 mmol) in DCM (6 mL). The mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was transferred to a separating funnel and washed sequentially with water (10 mL) and sat. NaHCO.sub.3 solution (10 mL). The organic portion was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with 50-100% EtOAc in heptane afforded the titled compound as a colourless glass.

[1982] 1H NMR (500 MHz, Chloroform-d) δ 8.56 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.89-7.81 (m, 2H), 7.12-7.06 (m, 2H), 7.04-6.99 (m, 1H), 3.98 (s, 3H), 3.76-3.74 (m, 2H)

[1983] LC-MS (Method E): Rt 0.99 mins; MS m/z 307.0=[M+H]+

Step 2: 4-[[2-(2,5-Difluorophenyl)acetyl]amino]pyridine-2-carboxylic acid

[1984] ##STR00428##

[1985] To a solution of methyl 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2-carboxylate (step 1)(364 mg, 1.07 mmol) in THF (2 mL)/MeOH (2 mL)/water (2 mL) was added 1M LiOH (31 mg, 1.28 mmol) and the mixture stirred at room temperature overnight. A further 0.5 equivalent of 1M LiOH was added and stirring continued for 2 hours. The resulting mixture was acidified to pH 2 using 1M HCl solution (2 mL) resulting in the formation of a precipitate. Water (5 mL) was added to the mixture, stirred for 5 mins and the solid was filtered and dried in a vacuum oven to afford the titled compound as a colourless powder.

[1986] 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.79 (dd, J=5.6, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.22 (m, 1H), 7.20-7.15 (m, 1H), 3.83 (s, 2H).

[1987] LC-MS (Method E): Rt 0.83 mins; MS m/z 293.0=[M+H]+

Step 3: 4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1988] To a solution of 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (50 mg, 0.16 mmol) and DIPEA (60 μL, 0.34 mmol) in DMF (1 mL) was added HATU (68 mg, 0.18 mmol) and the mixture stirred for 5 mins then treated with 2-methylbut-3-yn-2-amine (19 μL, 0.18 mmol). The resulting mixture was stirred at room temperature for 1 hour and then diluted with EtOAc. The mixture was washed with 1M HCl solution, brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the titled compound as a colourless powder.

[1989] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.24 (dt, J=9.1, 4.6 Hz, 1H), 7.21-7.14 (m, 1H), 3.83 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[1990] LC-MS (Method A): Rt 3.16 mins; MS m/z 358.2=[M+H]+

Example 77.1

4-[[2-(2,5-Difluorophenyl)acetyl]amino]-N-(4-fluoro-1-bicyclo[2.1.1]hexanyl) pyridine-2-carboxamide

[1991] ##STR00429##

[1992] The titled compound was prepared from 4-[[2-(2,5-difluorophenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 77 step 2) and 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride analogously to Example 77 step 3.

[1993] 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.05 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.27-7.22 (m, 1H), 7.20-7.15 (m, 1H), 3.83 (s, 2H), 2.13-2.09 (m, 2H), 2.08-2.04 (m, 2H), 1.99-1.95 (m, 2H), 1.86-1.82 (m, 2H).

[1994] LC-MS (Method A): Rt 3.28 mins; MS m/z 390.2=[M+H]+

Example 78

4-[[2-(4-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1995] ##STR00430##

Step 1: 4-Amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[1996] ##STR00431##

[1997] To a mixture of 4-aminopyridine-2-carboxylic acid (2 g, 14.48 mmol), TBTU (5.58 g, 17.38 mmol) and TEA (2.42 mL, 17.38 mmol) in DMF (36 mL) was added 2-methylbut-3-yn-2-amine (22.82 mL, 17.38 mmol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude residue was dissolved in EtOAc (40 mL) and washed with sat. NaHCO.sub.3 solution (40 mL). The aqueous was further extracted with EtOAc (40 mL) and the combined organic portions were washed with brine (2×40 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was triturated with the minimum amount of ether at 0° C. to afford the titled compound as an off-white crystalline solid.

[1998] 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 6.59 (dd, J=5.6, 2.4 Hz, 1H), 6.36 (s, 2H), 3.19 (s, 1H), 1.62 (s, 6H).

[1999] LC-MS (Method F): Rt 1.28 mins; MS m/z 204.3=[M+H]+

Step 2: 4-[[2-(4-Chloro-2-methoxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[2000] ##STR00432##

[2001] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (step 1) and 2-(4-chloro-2-methoxy-phenyl)acetic acid analogously to Example 3.5b.

[2002] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=2.1 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.0, 2.0 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 2H), 3.21 (s, 1H), 1.65 (s, 6H).

[2003] LC-MS (Method A): Rt 3.44 mins; MS m/z 386.2/388.2=[M+H]+ (96% @ 215 nm)

Step 3: 4-[[2-(4-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[2004] The titled compound was prepared from 4-[[2-(4-chloro-2-methoxy-phenyl)acetyl]amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide(step 2) analogously to Example 3 step 3.

[2005] 1H NMR (500 MHz, DMSO-d6) δ 10.71 (br s, 1H), 10.04 (br s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.83-6.79 (m, 2H), 3.65 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

[2006] LC-MS (Method A): Rt 3.09 mins; MS m/z 372.2/374.2=[M+H]+ (99% @ 215 nm)

Example 78.1

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-4-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[2007] ##STR00433##

[2008] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, step 1) and 2-[2-methoxy-4-(trifluoromethyl)phenyl]acetic acid analogously to Example 78 steps 2 and 3.

[2009] 1H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.30 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.07 (s, 1H), 3.76 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H).

[2010] LC-MS (Method A): Rt 3.27 mins; MS m/z 406.2=[M+H]+ (98% @ 215 nm)

Example 78.2

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-[2-hydroxy-5-(trifluoromethyl)phenyl]acetyl]amino]pyridine-2-carboxamide

[2011] ##STR00434##

[2012] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, step 1) and 2-[2-methoxy-5-(trifluoromethyl)phenyl]acetic acid analogously to Example 78 steps 2 and 3.

[2013] 1H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.48 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.45 (dd, J=8.5, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 3.77 (s, 2H), 3.21 (s, 1H), 1.65 (s, 6H).

[2014] LC-MS (Method A): Rt 3.25 mins; MS m/z 406.2=[M+H]+ (98% @ 215 nm)

Example 79

4-[(2-Chroman-4-ylacetyl)amino]-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide

[2015] ##STR00435##

[2016] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, step 1) and 2-chroman-4-ylacetic acid analogously to Example 3.5b

[2017] 1H NMR (500 MHz, Methanol-d4) δ 8.46 (d, J=5.5 Hz, 1H), 8.19 (d, J=1.7 Hz, 1H), 7.92 (dd, J=5.5, 2.2 Hz, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.09-7.04 (m, 1H), 6.81 (td, J=7.5, 1.2 Hz, 1H), 6.75 (dd, J=8.2, 1.1 Hz, 1H), 4.22-4.18 (m, 2H), 3.44 (dq, J=10.4, 5.1 Hz, 1H), 2.92 (dd, J=14.7, 5.7 Hz, 1H), 2.73 (s, 1H), 2.62 (dd, J=14.7, 9.3 Hz, 1H), 2.20-2.11 (m, 1H), 1.94-1.84 (m, 1H), 1.73 (s, 6H).

[2018] LC-MS (Method A): Rt 3.38 mins; MS m/z 378.3=[M+H]+ (98% @ 215 nm)

Example 79.1

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1-isopropyl-3,5-dimethyl-pyrazol-4-yl)acetyl]amino]pyridine-2-carboxamide

[2019] ##STR00436##

[2020] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, step 1) and 2-(1-isopropyl-3,5-dimethyl-pyrazol-4-yl)acetic acid analogously to Example 3.5b.

[2021] 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.46 (d, 1H), 8.31 (s, 1H), 8.19 (d, J=1.9 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 4.43-4.34 (m, 1H), 3.43 (s, 2H), 3.21 (s, 1H), 2.18 (s, 3H), 2.08 (s, 3H), 1.64 (s, 6H), 1.31 (d, J=6.6 Hz, 6H).

[2022] LC-MS (Method A): Rt 2.54 mins; MS m/z 382.3=[M+H]+ (100% @ 215 nm)

Example 79.2

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indazol-4-yl)acetyl]amino]pyridine-2-carboxamide

[2023] ##STR00437##

[2024] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, step 1) and 2-(1H-indazol-4-yl)acetic acid analogously to Example 3.5b.

[2025] 1H NMR (500 MHz, Methanol-d4) δ 8.44 (dd, J=5.4, 0.5 Hz, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.17 (dd, J=2.3, 0.5 Hz, 2H), 7.93 (dd, J=5.6, 2.2 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.36 (dd, J=8.4, 7.0 Hz, 1H), 7.13-7.10 (m, 1H), 4.56 (br s, 1H), 4.08 (s, 2H), 2.72 (s, 1H), 1.72 (s, 6H).

[2026] LC-MS (Method A): Rt 2.51 mins; MS m/z 362.2=[M+H]+

Example 79.3

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(1H-indol-7-yl)acetyl]amino]pyridine-2-carboxamide

[2027] ##STR00438##

[2028] The titled compound was prepared from 4-amino-N-(1,1-dimethylprop-2-ynyl)pyridine-2-carboxamide (Example 78, step 1) and 2-(1H-indol-7-yl)acetic acid analogously to Example 3.5b.

[2029] 1H NMR (500 MHz, DMSO-d6) δ 11.05 (br s, 1H), 10.82 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.5, 2.1 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.36 (t, J=2.7 Hz, 1H), 7.02-6.94 (m, 2H), 6.48-6.42 (m, 1H), 4.01 (s, 2H), 3.21 (s, 1H), 1.65 (s, 6H).

[2030] LC-MS (Method A): Rt 3.19 mins; MS m/z 361.2=[M+H]+

Example 80

3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl) benzamide

[2031] ##STR00439##

Step 1: 3-[[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]benzoic acid

[2032] ##STR00440##

[2033] To a solution of 3-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]benzoic acid (Example 71 step 3)(464 mg, 1.046 mmol) in DMF (5 mL) was added K.sub.2CO.sub.3 (619 mg, 4.48 mmol) and 1-(bromomethyl)-4-methoxy-benzene (751 mg, 3.73 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL) to form a precipitate which was filtered and washed with water. The solid was dissolved in THF (7 mL) and treated with aq. 1M LiOH (8.96 mL, 8.96 mmol) and stirred at room temperature for 20 hours. The volatile solvents were removed in vacuo causing the formation of a precipitate. The mixture was diluted with water (50 mL) and neutralised with aq. 3M HCl solution. The precipitate was filtered and washed with water to afford the titled compound as an off-white solid.

[2034] 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.20 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.62 (dt, J=7.7, 1.1 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.30-7.24 (m, 3H), 7.08 (d, J=8.8 Hz, 1H), 6.70-6.66 (m, 2H), 5.00 (s, 2H), 3.67 (s, 2H), 3.66 (s, 3H).

[2035] LC-MS (Method E): Rt 1.18 mins; MS m/z 448.0/450.1=[M+Na]+ (96% @ 215 nm)

Step 2: 3-[[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)benzamide

[2036] ##STR00441##

[2037] The titled compound was prepared from 3-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]benzoic acid (step 1) and 4-aminotetrahydropyran-4-carbonitrile analogously to Example 31 step 2.

[2038] 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.82 (s, 1H), 8.04 (t, J=1.7 Hz, 1H), 7.83 (d, J=9.4 Hz, 1H), 7.56 (dt, J=7.6, 1.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.30-7.26 (m, 3H), 7.08 (d, J=8.8 Hz, 1H), 6.73-6.70 (m, 2H, 5.00 (s, 2H), 3.90-3.84 (m, 2H), 3.68 (s, 2H), 3.67 (s, 3H), 3.63-3.57 (m, 2H), 2.33 (d, J=13.5 Hz, 2H), 2.04-1.97 (m, 2H).

[2039] LC-MS (Method E): Rt 1.20 mins; MS m/z 556.1/558.0=[M+H]+ (95% @ 215 nm)

Step 3: 3-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl) benzamide

[2040] 3-[[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]-N-(4-cyanotetra hydropyran-4-yl)benzamide (step 2)(70 mg, 0.13 mmol) was dissolved in 1M HCl in dioxane (1.97 mL, 1.97 mmol) and stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (5 mL) and water (5 mL). The organic portion was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude material by preparative HPLC (acidic pH, standard elution method) afforded the titled compound as an off-white solid.

[2041] 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.66 (br s, 1H), 8.82 (s, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.84-7.79 (m, 1H), 7.52 (dt, J=7.6, 1.0 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.91-3.83 (m, 2H), 3.62 (s, 2H), 3.62-3.57 (m, 2H), 2.35-2.29 (m, 2H), 2.04-1.97 (m, 2H).

[2042] LC-MS (Method A): Rt 2.66 mins; MS m/z 414.2/416.2=[M+H]+ (100% @ 215 nm)

Example 81

N-(1-Cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2043] ##STR00442##

Step 1: Methyl 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate

[2044] ##STR00443##

[2045] The titled compound was prepared from methyl 4-aminopyridine-2-carboxylate and 2-(5-fluoro-2-methoxy-phenyl)acetic acid analogously to Example 8 step 1.

[2046] 1H NMR (250 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.15-7.03 (m, 2H), 7.02-6.93 (m, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.71 (s, 2H).

[2047] LC-MS (Method E): Rt 0.99 mins; MS m/z 319.0 (83% @ 215 nm)

Step 2: 4-[[2-(5-Fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[2048] ##STR00444##

[2049] The titled compound was prepared from methyl 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 1) analogously to Example 7 step 2.

[2050] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.6, 2.2 Hz, 1H), 7.14-7.05 (m, 2H), 6.98 (dd, J=9.0, 4.6 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 2H).

[2051] LC-MS (Method A): Rt 0.87 mins; MS m/z 305.0=[M+H]+

Step 3: N-(1-Cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2052] ##STR00445##

[2053] The titled compound was prepared from 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) and 2-amino-2-methyl-propanenitrile hydrochloride acid analogously to Example 77 step 3.

[2054] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.82 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.17-7.05 (m, 2H), 6.99 (dd, J=9.0, 4.6 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 2H), 1.72 (s, 6H).

[2055] LC-MS (Method E): Rt 1.09 mins; MS m/z 371.1=[M+H]+ (87% @ 215 nm)

Step 4: N-(1-Cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2056] The titled compound was prepared from N-(1-cyano-1-methyl-ethyl)-4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino] pyridine-2-carboxamide (step 3) analogously to Example 3 step 3.

[2057] 1H NMR (500 MHz, DMSO-d6) δ 10.72 (br s, 1H), 9.52 (br s, 1H), 8.82 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.87 (dd, J=5.5, 2.1 Hz, 1H), 7.02 (dd, J=9.4, 3.1 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.68 (s, 2H), 1.72 (s, 6H).

[2058] LC-MS (Method A): Rt 2.53 mins; MS m/z 357.2=[M+H]+ (99% @ 215 nm)

Example 81.1

N-(1-Cyano-2-hydroxy-1-methyl-ethyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino] pyridine-2-carboxamide

[2059] ##STR00446##

[2060] The titled compound was prepared from 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81 step 2) and 2-amino-3-hydroxy-2-methyl-propanenitrile analogously to Example 81 step 3 and 4.

[2061] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (br s, 1H), 9.53 (br s, 1H), 8.73 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.02 (dd, J=9.3, 3.2 Hz, 1H), 6.95-6.87 (m, 1H), 6.78 (dd, J=8.8, 4.9 Hz, 1H), 5.91 (t, J=5.8 Hz, 1H), 3.82 (dd, J=11.1, 5.2 Hz, 1H), 3.73 (dd, J=10.9, 4.9 Hz, 1H), 3.68 (s, 2H), 1.66 (s, 3H).

[2062] LC-MS (Method A): Rt 2.20 mins; MS m/z 373.3=[M+H]+ (100% @ 215 nm)

Example 81.2

4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-isopropyl-pyridine-2-carboxamide

[2063] ##STR00447##

[2064] The titled compound was prepared from 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81 step 2) and analogously to Example 81 steps 3 and 4.

[2065] 1H NMR (500 MHz, DMSO-d6) δ 10.65 (br s, 1H), 9.50 (br s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.00 (dd, J=9.4, 3.2 Hz, 1H), 6.95-6.86 (m, 1H), 6.76 (dd, J=8.8, 4.9 Hz, 1H), 4.16-4.02 (m, 1H), 3.66 (s, 2H), 1.17 (d, J=6.6 Hz, 6H).

[2066] LC-MS (Method A): Rt 2.56 mins; MS m/z 322.2=[M+H]+ (100% @ 215 nm)

Example 81.3

N-(1,1-Dimethylprop-2-ynyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2067] ##STR00448##

[2068] The titled compound was prepared from 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81 step 2) and 2-methylbut-3-yn-2-amine analogously to Example 81 steps 3 and 4.

[2069] 1H NMR (500 MHz, DMSO-d6) δ 10.70 (br s, 1H), 9.52 (br s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9.4, 3.2 Hz, 1H), 6.90 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H), 3.20 (s, 1H), 1.64 (s, 6H).

[2070] LC-MS (Method A): Rt 2.84 mins; MS m/z 356.2=[M+H]+ (97% @ 215 nm)

Example 81.4

N-(4-Fluoro-1-bicyclo[2.1.1]hexanyl)-4-[[2-(5-fluoro-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2071] ##STR00449##

[2072] The titled compound was prepared from 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81 step 2) and 4-fluorobicyclo[2.1.1]hexan-1-amine hydrochloride analogously to Example 81 steps 3 and 4.

[2073] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.51 (br s, 1H), 9.04 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.84 (dd, J=5.5, 2.1 Hz, 1H), 7.01 (dd, J=9.3, 3.1 Hz, 1H), 6.91 (td, J=8.6, 3.1 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 3.67 (s, 2H), 2.16-2.02 (m, 4H), 2.00-1.91 (m, 2H), 1.89-1.79 (m, 2H).

[2074] LC-MS (Method A): Rt 2.97 mins; MS m/z 388.2=[M+H]+ (98% @ 215 nm)

Example 81.5

4-[[2-(5-Fluoro-2-hydroxy-phenyl)acetyl]amino]-N-[1-(hydroxymethyl)cyclobutyl]pyridine-2-carboxamide

[2075] ##STR00450##

[2076] The titled compound was prepared from 4-[[2-(5-fluoro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 81 step 2) and (1-aminocyclobutyl)methanol hydrochloride analogously to Example 81 steps 3 and 4.

[2077] 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.52 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.40 (s, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.01 (dd, J=9.4, 3.2 Hz, 1H), 6.91 (td, J=8.6, 3.2 Hz, 1H), 6.77 (dd, J=8.8, 4.9 Hz, 1H), 5.00 (s, 1H), 3.67 (s, 2H), 3.61 (s, 2H), 2.09-2.01 (m, 2H), 1.88-1.79 (m, 1H), 1.78-1.67 (m, 1H).

[2078] LC-MS (Method A): Rt 2.33 mins; MS m/z 374.2=[M+H]+ (96% @ 215 nm)

Example 82

N-tert-Butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide

[2079] ##STR00451##

Step 1: 2-(5-Chloro-2-methoxy-phenyl)-N-(6-chloropyrimidin-4-yl)acetamide

[2080] ##STR00452##

[2081] A suspension of 6-chloropyrimidin-4-amine (250 mg, 1.93 mmol) and 2-(5-chloro-2-methoxy-phenyl)acetic acid (0.14 mL, 2.03 mmol) in 1,4-dioxane (2.5 mL) was treated with DIPEA (1.01 mL, 5.79 mmol) followed by T3P® (50% in EtOAc) (2754 μL, 2.32 mmol) and the mixture was stirred at room temperature for 2 hours. The resulting mixture was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO.sub.3 (10 mL) and the organic portion was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane followed by 0 to 100% MeOH in EtOAc to afford the titled compound as an orange powdery solid.

[2082] 1H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.77 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.33-7.29 (m, 2H), 7.03-6.98 (m, 1H), 3.79 (s, 2H), 3.74 (s, 3H).

[2083] LC-MS (Method E): Rt 1.14 mins; MS m/z 311.9/313.9=[M+H]+ (100% @ 215 nm)

Step 2: N-tert-Butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide

[2084] The following procedure was based on the literature reference: CA 2915356 Page 131.

[2085] All reagents charged to COware equipment (carbon monoxide generating system):

Chamber A: Aryl chloride, 2-methylpropan-2-amine, BINAP, Pd(OAc).sub.2, TEA 1,4-dioxane
Chamber B: formic acid, MsCl, TEA, 1,4-dioxane

[2086] To chamber A was added 2-(5-chloro-2-methoxy-phenyl)-N-(6-chloropyrimidin-4-yl)acetamide (step 1) (202 mg, 0.65 mmol), Pd(OAc).sub.2 (15 mg, 0.06 mmol), 2-methylpropan-2-amine (95 mg, 1.29 mmol) and BINAP (81 mg, 0.13 mmol). The reaction vessel was flushed with nitrogen then 1,4-dioxane (2.5 mL) was added. To chamber B was added 1,4-dioxane (2.5 mL) followed by mesyl chloride (125 μL, 1.62 mmol) and formic acid (61 μL, 1.62 mmol) and the mixtures were stirred. To chamber A was added triethylamine (283 μL, 1.94 mmol) and to chamber B was added triethylamine (361 μL, 2.59 mmol) which quickly evolved CO gas. The COware equipment was heated at 80° C. for 22 hours and allowed to cool to room temperature. The mixture from chamber A was partitioned between DCM (5 mL) and water (5 mL) and the organic portion separated via filtration through a hydrophobic PTFE fritted tube. The filtrate was and concentrated in vacuo and the residue purified by preparative HPLC (acidic pH, standard elution method). The product fractions were combined and concentrated in vacuo to remove the volatile solvents. The aqueous residue was treated with DCM (10 mL) and saturated aqueous NaHCO.sub.3 (10 mL) and the organic portion was separated by filtration through a hydrophobic PTFE fritted tube. The filtrate was concentrated in vacuo to afford the titled compound as a peach crystalline solid.

[2087] 1H NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.95 (d, J=1.2 Hz, 1H), 8.53 (d, J=1.2 Hz, 1H), 8.04 (s, 1H),), 7.33-7.29 (m, 2H), 7.03-6.99 (m, 1H), 3.80 (s, 2H), 3.74 (s, 3H), 1.39 (s, 9H).

[2088] LC-MS (Method A): Rt 3.56 mins; MS m/z 377.2/379.2=[M+H]+ (97% @ 215 nm)

Example 83

N-(1-Cyano-1-methyl-ethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide

[2089] ##STR00453##

Step 1: 4-Amino-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide

[2090] ##STR00454##

[2091] To a mixture of 4-aminopyridine-2-carboxylic acid (15 g, 108.6 mmol), TBTU (41.84 g, 130.32 mmol) and triethylamine (37.84 mL, 271.5 mmol) in DMF (271.52 mL) was added 2-amino-2-methyl-propanenitrile hydrochloride (14.4 g, 119.46 mmol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the solid washed with DMF (2×30 mL). The combined filtrate was concentrated in vacuo and the crude residue dissolved in EtOAc (300 mL) and washed with sat. NaHCO.sub.3 solution (2×300 mL). The aqueous portion was re-extracted with EtOAc (30 mL) and the organic layers were combined, washed with brine (160 mL×2), dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the resulting solid by chromatography on silica eluting with 0-100% EtOAc in heptane yielded a solid which was triturated with ice cold TBME:heptane (3:1 mixture) to afford the titled compound as a colourless crystalline solid.

[2092] 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.03 (d, J=5.6 Hz, 1H), 7.21 (d, J=2.3 Hz, 1H), 6.62 (dd, J=5.6, 2.4 Hz, 1H), 6.40 (s, 2H), 1.70 (s, 6H).

[2093] LCMS (Method E) Rt 0.35 mins; MS m/z 205.0=[M+H]+

Step 2: N-(1-Cyano-1-methyl-ethyl)-4-(thiophene-3-carbonylamino)pyridine-2-carboxamide

[2094] Oxalyl chloride (29 μL, 0.331 mmol) was added to a stirred solution of thiophene-3-carboxylic acid (47 mg, 0.368 mmol) dissolved in DMF (1 drop, ˜5 μL) in 1,4-dioxane (1 mL). The mixture was sealed and stirred at room temperature for 1 hour. The resulting acid chloride mixture was treated with a stock solution (1.6 mL) of 4-amino-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (step 1) (45 mg, 0.22 mmol) and TEA (100 μL, 0.72 mmol) in 1,4-dioxane (1.5 mL). The mixture was re-sealed and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and purification of the crude residue by preparative HPLC (acidic pH, standard elution method) afforded the titled compound as an off-white powder.

[2095] 1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.85 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.49-8.46 (m, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.09 (dd, J=5.5, 2.2 Hz, 1H), 7.71-7.69 (m, 1H), 7.68-7.66 (m, 1H), 1.74 (s, 6H).

[2096] LCMS (Method A) Rt 2.60 mins; MS m/z 315.2=[M+H]+ (99% @ 215 nm)

[2097] The compounds of the following tabulated Examples (Table 14) were prepared from 4-amino-N-(1-cyano-1-methyl-ethyl)pyridine-2-carboxamide (Example 83 step 1) analogously to Example 83 step 2 by replacing thiophene-3-carboxylic acid with the appropriate commercially available acid.

TABLE-US-00016 TABLE 14 1H NMR, Ex. Structure and Name LCMS Retention Time, [M + H]+, 83.1 [00455] 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.81 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 2.26 (d, J = 7.1 Hz, 2H), 1.83-1.75 (m, 1H), 1.72 (s, 6H), 1.71-1.64 (m, 4H), 1.63-1.58 (m, 1H), 1.28-1.09 (m, 3H), 1.03-0.93 (m, 2H). 83.2 [00456] 1H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.81 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 2.41-2.34 (m, 1H), 1.87-1.80 (m, 2H), 1.79-1.74 (m, 2H), 1.72 (s, 6H), 1.68-1.62 (m, 1H), 1.41 (qd, J = 12.4, 2.8 Hz, 2H), 1.33-1.14 (m, 3H). 83.3 [00457] 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.83 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.26-8.21 (m, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 3.16 (p, J = 8.6 Hz, 1H), 2.43-2.31 (m, 2H), 2.27-2.05 (m, 3H), 1.98-1.90 (m, 1H), 1.73 (s, 6H). LCMS (Method A) Rt 2.74 mins; MS m/z 337.3 = [M + H]+ (97% @ 215 nm) 83.4 [00458] 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.81 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 5.5, 2.2 Hz, 1H), 2.18-2.07 (m, 2H), 1.73 (s, 6H), 1.70-1.56 (m, 4H), 1.55-1.49 (m, 2H), 1.32 (s, 3H). LCMS (Method A) Rt 3.08 mins; MS m/z 315.3 = [M + H]+ (100% @ 215 nm) 83.5 [00459] 1H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.81 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 2.41-2.36 (m, 2H), 1.75-1.64 (m, 10H), 1.63-1.57 (m, 1H), 1.54-1.47 (m, 2H), 1.28-1.07 (m, 4H), 0.94-0.85 (m, 2H). LCMS (Method A) Rt 3.64 mins; MS m/z 343.3 = [M + H]+ (100% @ 215 nm) 83.6 [00460] 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.81 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 2.38-2.32 (m, 1H), 2.24-2.18 (m, 2H), 2.00-1.97 (m, 1H), 1.94-1.87 (m, 1H), 1.72 (s, 6H), 1.52-1.40 (m, 3H), 1.38-1.33 (m, 1H), 1.21-1.06 (m, 4H). LCMS (Method A) Rt 3.39 mins; MS m/z 341.3 = [M + H]+ (99% @ 215 nm) 83.7 [00461] 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.82 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 2.29 (s, 2H), 1.72 (s, 6H), 1.52-1.36 (m, 7H), 1.36-1.27 (m, 3H), 1.02 (s, 3H). LCMS (Method A) Rt 3.56 mins; MS m/z 343.3 = [M + H]+ (100% @ 215 nm) 83.8 [00462] 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.13 (s, 2H), 8.88 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 5.5, 2.2 Hz, 1H), 2.35- 2.29 (m, 1H), 1.74 (s, 6H), 1.20-1.15 (m, 2H), 1.13- 1.09 (m, 2H). LCMS (Method A) Rt 2.56 mins; MS m/z 351.3 = [M + H]+ (99% @ 215 nm) 83.9 [00463] 1H NMR (500 MHz, DMSO-d6) δ 11.28 (br. s, 1H), 8.88 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.03 (dd, J = 5.5, 2.2 Hz, 1H), 7.25 (s, 1H), 2.61 (d, J = 7.1 Hz, 2H), 2.05-1.96 (m, 1H), 1.74 (s, 6H), 0.94 (d, J = 6.7 Hz, 6H). LCMS (Method A) Rt 3.23 mins; MS m/z 356.3 = [M + H]+ (100% @ 215 nm) 83.10 [00464] 1H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.82 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 2.35 (d, J = 7.1 Hz, 2H), 2.03-1.92 (m, 3H), 1.90-1.83 (m, 1H), 1.82-1.75 (m, 3H), 1.72 (s, 6H), 1.31-1.21 (m, 2H). LCMS (Method A) Rt 2.99 mins; MS m/z 365.3 = [M + H]+ (100% @ 215 nm) 83.11 [00465] 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.80 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 5.6, 2.2 Hz, 1H), 7.28-7.23 (m, 4H), 7.20- 7.14 (m, 1H), 3.12 (s, 2H), 1.72 (s, 6H), 1.24 (q, J = 4.2 Hz, 2H), 0.87 (q, J = 4.4 Hz, 2H). LCMS (Method A) Rt 3.26 mins; MS m/z 363.3 = [M + H]+ (100% @ 215 nm) 83.13 [00466] 1H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.83 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 5.3 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 6.90 (dd, J = 5.3, 1.3 Hz, 1H), 6.70 (s, 1H), 3.82 (s, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.73 (s, 6H). LCMS (Method A) Rt 2.29 mins; MS m/z 368.3 = [M + H]+ (97% @ 215 nm) 83.14 [00467] 1H NMR (500 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.86 (s, 1H), 8.58-8.55 (m, 1H), 8.45-8.41 (m, 1H), 8.05 (dd, J = 5.5, 2.2 Hz, 1H), 7.06 (s, 1H), 4.05 (s, 3H), 1.74 (s, 6H), 1.29 (s, 9H). LCMS (Method A) Rt 3.32 mins; MS m/z 369.3 = [M + H]+ (100% @ 215 nm) 83.15 [00468] 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.83 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.82-7.79 (m, 1H), 7.71-7.65 (m, 3H), 7.59 (d, J = 1.6 Hz, 1H), 7.55-7.51 (m, 1H), 6.47- 6.45 (m, 1H), 1.73 (s, 6H). LCMS (Method A) Rt 2.50 mins; MS m/z 375.30 = [M + H]+ (98% @ 215 nm) 83.16 [00469] 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.88 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.43 (d, J = 7.5 Hz, 1H), 8.38 (t, J = 7.8 Hz, 1H), 8.22 (d, 1H), 8.18 (dd, J = 5.5, 2.2 Hz, 1H), 1.75 (s, 6H). LCMS (Method A) Rt 3.23 mins; MS m/z 378.20 = [M + H]+ (100% @ 215 nm) 83.17 [00470] 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.68 (s, 1H), 8.85 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.09 (dd, J = 5.5, 2.2 Hz, 1H), 7.67- 7.64 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 4.68 (s, 2H), 1.74 (s, 6H). LCMS (Method A) Rt 2.32 mins; MS m/z 380.20 = [M + H]+ (94% @ 215 nm) 83.18 [00471] 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.86 (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.07 (dd, J = 5.5, 2.2 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.37-7.33 (m, 1H), 7.18-7.14 (m, 1H), 4.61 (q, J = 7.0 Hz, 2H), 1.75 (s, 6H), 1.34 (t, J = 7.0 Hz, 3H). LCMS (Method A) Rt 3.64 mins; MS m/z 376.3 = [M + H]+ (94% @ 215 nm) 83.19 [00472] 1H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.88 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 5.5, 2.2 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 5.53 (q, J = 8.9 Hz, 2H), 1.74 (s, 6H). LCMS (Method A) Rt 2.85 mins; MS m/z 381.3 = [M + H]+ (100% @ 215 nm) 83.20 [00473] 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.64 (s, 1H), 8.87 (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.75- 7.71 (m, 2H), 7.54-7.49 (m, 3H), 1.73 (s, 6H). LCMS (Method A) Rt 3.02 mins; MS m/z 376.3 = [M + H]+ (99% @ 215 nm) 83.21 [00474] 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.84 (s, 1H), 8.53 (d, J = 5.6 Hz, 2H), 8.36 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H), 8.03 (dd, J = 5.6, 2.2 Hz, 1H), 7.40- 7.36 (m, 2H), 7.34-7.28 (m, 3H), 5.41 (s, 2H), 1.73 (s, 6H). LCMS (Method A) Rt 2.89 mins; MS m/z 389.3 = [M + H]+ (100% @ 215 nm) 83.22 [00475] 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.88 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.06 (dd, J = 5.5, 2.2 Hz, 1H), 7.85-7.80 (m, 2H), 7.58 (s, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 4.16 (s, 3H), 1.75 (s, 6H). LCMS (Method A) Rt 3.44 mins; MS m/z 389.3 = [M + H]+ (100% @ 215 nm) 83.23 [00476] 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.87 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.11-8.07 (m, 1H), 7.89 (dd, J = 5.5, 2.0 Hz, 1H), 7.85-7.76 (m, 3H), 2.32 (s, 3H), 1.74 (s, 6H). LCMS (Method A) Rt 2.61 mins; MS m/z 391.3 = [M + H]+ (96% @ 215 nm) 83.24 [00477] 1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.15 (s, 1H), 8.86 (s, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.06 (dd, J = 5.5, 2.2 Hz, 1H), 7.83- 7.79 (m, 2H), 7.59-7.54 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 1.74 (s, 6H). Pyrazole CH3 behind DMSO peak at 2.50. LCMS (Method A) Rt 3.32 mins; MS m/z 389.3 = [M + H]+ (99% @ 215 nm) 83.25 [00478] 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.87 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 4.9, 1.9 Hz, 1H), 8.15 (dd, J = 7.4, 1.9 Hz, 1H), 7.99 (dd, J = 5.5, 2.1 Hz, 1H), 7.45-7.40 (m, 2H), 7.29 (dd, J = 7.4, 4.9 Hz, 1H), 7.25-7.20 (m, 3H), 1.73 (s, 6H). LCMS (Method A) Rt 3.24 mins; MS m/z 402.3 = [M + H]+ (100% @ 215 nm) 83.26 [00479] 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.80 (s, 1H), 8.47 (d, J = 5.6 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 5.6, 2.2 Hz, 1H), 7.45 (dd, J = 5.1, 1.2 Hz, 1H), 6.99 (dd, J = 5.1, 3.5 Hz, 1H), 6.92 (dd, J = 3.4, 1.0 Hz, 1H), 6.56 (s, 1H), 5.30 (s, 2H), 2.53 (s, 3H), 2.24 (s, 3H), 1.73 (s, 6H). LCMS (Method A) Rt 3.47 mins; MS m/z 422.3 = [M + H]+ (100% @ 215 nm) 83.27 [00480] 1H NMR (500 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.88 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.08 (dd, J = 5.5, 2.2 Hz, 1H), 7.95 (dd, J = 7.8, 1.7 Hz, 1H), 7.59-7.55 (m, 1H), 7.30-7.28 (m, 2H), 7.19-7.14 (m, 1H), 4.00 (s, 3H), 1.75 (s, 6H). LCMS (Method A) Rt 3.58 mins; MS m/z 406.2 = [M + H]+ (77% @ 215 nm) 83.28 [00481] 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.87 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.02-7.97 (m, 3H), 7.58-7.54 (m, 3H), 2.69 (s, 3H), 1.74 (s, 6H). LCMS (Method A) Rt 3.52 mins; MS m/z 406.2 = [M + H]+ (100% @ 215 nm) 83.29 [00482] LCMS (Method A) Rt 2.29 mins; MS m/z 366.2 = [M + H]+ (94% @ 215 nm) 83.30 [00483] 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.54 (s, 1H), 8.90 (s, 1H), 8.62 (d, J = 5.5 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 7.5 Hz, 1H), 8.41-8.38 (m, 1H), 8.15 (dd, J = 5.5, 2.2 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 1.75 (s, 6H). LCMS (Method A) Rt 2.71 mins; MS m/z 366.2 = [M + H]+ (94% @ 215 nm) 83.31 [00484] 1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.81 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 5.5, 2.2 Hz, 1H), 7.34-7.28 (m, 2H), 7.15-7.07 (m, 2H), 3.30-3.26 (m, 1H), 2.68-2.62 (m, 2H), 1.72 (s, 6H), 1.25 (d, J = 7.0 Hz, 3H). LCMS (Method A) Rt 3.21 mins; MS m/z 369.3 = [M + H]+ (97% @ 215 nm) 83.32 [00485] 1H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H), 8.60 (d, J = 5.4 Hz, 1H), 8.47 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 3.7 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 3.82 (s, 3H), 1.75 (s, 6H). LCMS (Method A) Rt 3.33 mins; MS m/z 390.2 = [M + H]+ (99% @ 215 nm)

Example 84

N-tert-Butyl-3-[[2-(2-hydroxycyclohexyl)acetyl]amino]benzamide

[2098] ##STR00486##

[2099] HATU (268 mg, 0.7 mmol) was added to a stirred solution of 2-(2-oxocyclohexyl)acetic acid (100 mg, 0.64 mmol), 3-amino-N-tert-butyl-benzamide hydrochloride (146 mg, 0.64 mmol) and DIPEA (0.28 mL, 1.6 mmol) in DMF (2 mL) the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (10 mL) and the combined organic extracts were washed with water (2×20 mL), brine (15 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude material was then dissolved in MeOH (2 mL) and treated with NaBH.sub.4 (36 mg, 0.96 mmol). The resulting mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. The crude residue was partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) afforded the titled compound as an off white powder as a 7:3 mixture of diastereoisomers.

[2100] 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.93-7.81 (m, 1H), 7.82-7.73 (m, 1H), 7.71-7.63 (m, 1H), 7.43-7.36 (m, 1H), 7.31 (t, J=7.8 Hz, 1H), 4.70-4.18 (m, 1H), 3.74-2.93 (m, 1H), 2.87-2.35 (m, 1H), 2.27-1.97 (m, 1H), 1.96-1.77 (m, 1H), 1.76-0.88 (m, 17H).

[2101] LCMS (Method A) Rt 2.63 mins; MS m/z 333.3=[M+H]+ (61% @ 215 nm); Rt 2.65 mins; MS m/z 333.3=[M+H]+ (38%®215 nm)

Example 85

N-tert-Butyl-6-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide

[2102] ##STR00487##

[2103] The titled compound was prepared from N-tert-butyl-6-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyrimidine-4-carboxamide (Example 82) and analogously to Example 1 step 2.

[2104] 1H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.84 (s, 1H), 8.94 (d, J=1.2 Hz, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.04 (s, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.75 (s, 2H), 1.39 (s, 9H).

[2105] LCMS (Method A) Rt 3.16 mins; MS m/z 363.2=[M+H]+ (98% @ 215 nm)

Example 86

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1-(methoxy methyl)ethyl]pyridine-2-carboxamide

[2106] ##STR00488##

Step 1: Methyl 2-(5-chloro-2-hydroxy-phenyl)acetate

[2107] ##STR00489##

[2108] Methyl 2-(2-hydroxyphenyl)acetate (1.68 g, 10.11 mmol), NCS (1.35 g, 10.11 mmol) and triphenylphosphine sulfide (298 mg, 1.01 mmol) were dissolved in chloroform (40 mL) and stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue dissolved in EtOAc (50 mL). The mixture was washed with water (2×50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-50% EtOAc in heptane to afford the titled compound as a colourless viscous oil that solidified upon standing at room temperature.

[2109] 1H NMR (500 MHz, DMSO-d6) δ 9.81 (br. s, 1H), 7.18 (d, J=2.7 Hz, 1H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.59 (s, 3H), 3.56 (s, 2H).

[2110] LC-MS (Method E): Rt 1.02 mins; MS m/z no ionisaton observed

Step 2: Methyl 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate

[2111] ##STR00490##

[2112] Methyl 2-(5-chloro-2-hydroxy-phenyl)acetate (step 1)(1.83 mL, 7.76 mmol) was suspended in anhydrous acetone (50 mL) and treated with K.sub.2CO.sub.3 (1.61 g, 11.64 mmol) followed by 1-(bromomethyl)-4-methoxy-benzene (1.2 mL, 8.55 mmol). After heating at reflux (60° C.) for 2 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting crude residue was purified by chromatography on silica eluting with 0-25% EtOAc in heptane to afford the titled compound as a viscous yellow oil.

[2113] 1H NMR (500 MHz, DMSO-d6) δ 7.32-7.27 (m, 4H), 7.07 (d, J=8.6 Hz, 1H), 6.96-6.92 (m, 2H), 5.01 (s, 2H), 3.75 (s, 3H), 3.62 (s, 2H), 3.55 (s, 3H).

[2114] LC-MS (Method E): Rt 1.23 mins; MS m/z no ionization observed=[M+H]+

Step 3: Lithium 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate

[2115] ##STR00491##

[2116] Methyl 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate (step 2) (2.4 g, 6.57 mmol) was dissolved in THF (5 mL) and treated with 2M aqueous lithium hydroxide hydrate solution (3.45 mL, 6.9 mmol). After stirring at room temperature for 1 hour, MeOH (5 mL) was added to the bi-phasic mixture and stirring continued at room temperature for 1 hour. Additional lithium hydroxide hydrate (13.8 mg, 0.33 mmol, 0.05 eq.) was added and the solution was stirred for another hour. A further portion of lithium hydroxide hydrate (13.8 mg, 0.33 mmol, 0.05 eq.) was added and stirring continued for 1 hour. The resulting mixture was concentrated in vacuo and azeotroped with MeCN (3×50 mL). The solid was suspended in diethyl ether (50 mL), filtered, washed with diethyl ether (2×25 mL) and dried under suction to afford the titled compound as a white powdery solid.

[2117] 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.36 (m, 2H), 7.22 (d, J=2.7 Hz, 1H), 7.07 (dd, J=8.7, 2.8 Hz, 1H), 6.94-6.89 (m, 3H), 4.97 (s, 2H), 3.75 (s, 3H), 3.17 (s, 2H).

[2118] LC-MS (Method E): Rt 1.17 mins; MS m/z 260.9=[M−H]− (95% @ 215 nm) [major mass ion observed for the decarboxylated ion fragment]

Step 4: Methyl 4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxylate

[2119] ##STR00492##

[2120] To a mixture of lithium 2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetate (step 3) (1.5 g, 4.8 mmol) and methyl 4-aminopyridine-2-carboxylate (0.8 g, 5.28 mmol) in anhydrous 1,4-dioxane (50 mL) was added simultaneously 50% T3P® solution in EtOAc (5.71 mL, 9.59 mmol) and TEA (3.35 mL, 19.19 mmol). The reaction mixture was stirred at room temperature, for 1 hour and then quenched by careful addition of NaHCO.sub.3 (50 mL). H.sub.2O (10 mL) was added to dissolve excess salts and the mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by chromatography on NH-silica eluting with a gradient of 0-100% EtOAc in heptane afforded the titled compound as an off-white solid.

[2121] 1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.75 (dd, J=5.5, 2.1 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.30 (dd, J=8.7, 2.7 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 1H), 6.65-6.61 (m, 2H), 4.97 (s, 2H), 3.87 (s, 3H), 3.70 (s, 2H), 3.64 (s, 3H).

[2122] LC-MS (Method F): Rt 1.63 mins; MS m/z 441.2/443.2=[M+H]+ (100% @ 215 nm)

Step 5: 4-[[2-[5-Chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxylic acid

[2123] ##STR00493##

[2124] Methyl 4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxylate (step 4) (1.98 g, 4.49 mmol) was dissolved in THF (2.5 mL) and MeOH (2.5 mL) and treated with a 2M aqueous lithium hydroxide hydrate solution (2.47 mL, 4.94 mmol) and stirred at room temperature for 1 hour. Additional THF (2.5 mL), MeOH (2.5 mL) and water (2.5 mL) were added and stirring continued at room temperature overnight. The resulting mixture was diluted with EtOAc (50 mL) and water (50 mL). The pH was adjusted to pH 5 using 2M KHSO.sub.4 (2 mL) and the precipitate was filtered. The filter cake was washed with water (20 mL), EtOAc (20 mL), diethyl ether (20 mL) and dried under vacuum to afford the titled compound as a white solid.

[2125] 1H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.11 (d, J=1.7 Hz, 1H), 7.75 (dd, J=5.6, 2.1 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.7, 2.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.68-6.64 (m, 2H), 4.98 (s, 2H), 3.71 (s, 2H), 3.65 (s, 3H) [OH not observed].

[2126] LC-MS (Method E): Rt 1.04 mins; MS m/z 427.0/429.0=[M+H]+ (98% @ 215 nm)

Step 6: 2-Amino-3-methoxy-2-(methoxymethyl)propanenitrile

[2127] ##STR00494##

[2128] To a suspension of 1,3-dimethoxypropan-2-one (400 mg, 3.39 mmol) in 7M ammonia in MeOH (4.84 mL, 33.86 mmol) was added ammonium chloride (226 mg, 4.23 mmol) followed by sodium cyanide (207 mg, 4.23 mmol). After stirring at room temperature for 15 minutes, water (2.4 mL) was added and stirring continued for 3 hours. The mixture was diluted with EtOAc (30 mL) and washed with sat. sodium carbonate solution (3×20 mL) and brine (2×20 mL). The organic portion was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compound as a colorless oil.

[2129] 1H NMR (500 MHz, Methanol-d4) δ 3.55 (d, J=9.5 Hz, 2H), 3.45 (d, J=9.5 Hz, 2H), 3.45 (s, 6H)

[2130] LC-MS (Method E): Rt 0.66 mins; MS m/z 145.1=[M+H]+ (67% @ 215 nm)

Step 7: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-[1-cyano-2-methoxy-1-(methoxymethyl)ethyl]pyridine-2-carboxamide

[2131] To a solution of DIPEA (0.25 mL, 1.41 mmol), 4-[[2-[5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]acetyl]amino]pyridine-2-carboxylic acid (step 5) (200 mg, 0.47 mmol) and 50% T3P® solution in EtOAc (0.6 mL, 0.94 mmol) in DMF (2 mL) was added 2-amino-3-methoxy-2-(methoxymethyl)propanenitrile (step 6)(101 mg, 0.7 mmol) and the reaction mixture was stirred at room temperature for 6 hours. The resulting mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous layer was re-extracted with EtOAc (10 mL) and the combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue was dissolved in dioxane (2 mL) and treated with 4N HCl in dioxane (2 mL, 8.0 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo and purification of the crude product by preparative HPLC (acidic pH, early elution method) afforded the titled compound as an off white solid.

[2132] 1H NMR (500 MHz, Methanol-d4) δ 8.48 (d, J=5.5 Hz, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.96 (dd, J=5.5, 2.2 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.11 (dd, J=8.6, 2.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.00 (d, J=9.5 Hz, 2H), 3.83 (d, J=9.5 Hz, 2H), 3.73 (s, 2H), 3.50 (s, 6H).

[2133] LC-MS (Method A): Rt 3.09 mins; MS m/z 433.1=[M+H]+ (98% @ 215 nm)

Example 87

4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide and

Example 88 4-[[2-(2-amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

Step 1: A mixture of 2-(4-tert-butyl-2-nitro-phenyl)acetic acid and 2-(4-tert-butyl-3-nitro-phenyl)acetic acid

[2134] ##STR00495##

[2135] A stirred solution of 2-(4-tert-butylphenyl)acetic acid (1.0 g, 5.2 mmol) in water (5 mL) was treated dropwise with nitric acid (0.65 mL, 15.6 mmol) and sulfuric acid (0.55 mL, 10.4 mmol) and the mixture was stirred at room temperature for 10 hours. The resulting mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic portion was separated, washed with brine (2 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by chromatography on silica eluting with 0-100% EtOAc in heptane afforded the titled mixture as a yellow oil.

[2136] 1H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J=2.1 Hz, 1H), 7.76 (dd, J=8.0, 2.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.48-7.42 (m, 2H), 3.95 (s, 2H), 3.66 (s, 2H), 1.34 (s, 9H), 1.33 (s, 9H).

[2137] LC-MS (Method E): Rt 1.13 mins; MS m/z=no ionisation observed

Step 2: A mixture of N-tert-butyl-4-[[2-(4-tert-butyl-2-nitro-phenyl)acetyl]amino]pyridine-2-carboxamide and N-tert-butyl-4-[[2-(4-tert-butyl-3-nitro-phenyl)acetyl]amino]pyridine-2-carboxamide

[2138] ##STR00496##

[2139] To a solution of DIPEA (1.36 mL, 7.76 mmol), 50% T3P® solution in EtOAc (0.6 mL, 5.17 mmol) and a mixture of 2-(4-tert-butyl-2-nitro-phenyl)acetic acid and 2-(4-tert-butyl-3-nitro-phenyl)acetic acid (step 1) (720 mg, 3.03 mmol) in DMF (5 mL) was added 4-amino-N-tert-butyl-pyridine-2-carboxamide (645 mg, 3.34 mmol) and the reaction mixture was stirred at room temperature for 6 hours. The resulting mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous layer was re-extracted with EtOAc (10 mL) and the combined extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford the titled compounds as a yellow oil.

[2140] 1H NMR (500 MHz, DMSO-d6) δ 10.81 (m, 2H), 8.46 (m, 2H), 8.16 (m, 2H), 8.03 (m, 3H), 7.84-7.74 (m, 3H), 7.64 (d, J=8.1 Hz, 1H), 7.55-7.47 (m, 3H), 4.15 (s, 2H), 3.81 (s, 2H), 1.40 (s, 18H), 1.34 (s, 18H).

[2141] LC-MS (Method E): Rt 1.29 mins; MS m/z 413.5=[M+H]+ (100% @ 215 nm)

Step 3: 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide and 4-[[2-(2-amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[2142] To a mixture of N-tert-butyl-4-[[2-(4-tert-butyl-2-nitro-phenyl)acetyl]amino]pyridine-2-carboxamide and N-tert-butyl-4-[[2-(4-tert-butyl-3-nitro-phenyl)acetyl]amino]pyridine-2-carboxamide (step 2)(950 mg, 2.3 mmol) in EtOH (5 mL) was added 10% Pd—C (123 mg, 1.15 mmol) and the mixture was stirred under an atmosphere of hydrogen for 18 hours. The resulting mixture was filtered through Celite® and washed through with methanol. The filtrate was concentrated in vacuo and purification of the crude by preparative HPLC (basic pH, early elution method) afforded the following compounds as white solids:

Example 87: 4-[[2-(3-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[2143] ##STR00497##

[2144] 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.59 (d, J=1.9 Hz, 1H), 6.48 (dd, J=8.0, 1.9 Hz, 1H), 4.76 (s, 2H), 3.50 (s, 2H), 1.40 (s, 9H), 1.31 (s, 9H).

[2145] LC-MS (Method A): Rt 3.56 mins; MS m/z 383.3=[M+H]+ (100% @ 215 nm)

Example 88: 4-[[2-(2-Amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide

[2146] ##STR00498##

[2147] 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.59 (dd, J=7.9, 2.0 Hz, 1H), 4.96 (s, 2H), 3.52 (s, 2H), 1.40 (s, 9H), 1.22 (s, 9H).

[2148] LC-MS (Method A): Rt 3.58 mins; MS m/z 383.3=[M+H]+ (99% @ 215 nm)

Example 89

N-tert-Butyl-4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2149] ##STR00499##

[2150] To a cooled (0° C.) solution of 4-[[2-(3-amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 87) (100 mg, 0.26 mmol) in water (0.2 mL) was added sulfuric acid (0.02 mL, 0.29 mmol) in water (0.3 mL) followed by sodium nitrite (20 mg, 0.29 mmol) in water (0.5 mL). After stirring at 5° C. for 3 hours, copper sulfate pentahydrate (326 mg, 1.31 mmol) and copper (I) oxide (112.23 mg, 0.78 mmol) in water (0.5 mL) were added and the mixture stirred at room temperature for 12 hours. The resulting mixture was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification of the crude material by preparative HPLC (acidic pH early elution method) afforded the titled compound as a white solid.

[2151] 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.30 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.20 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.76 (d, J=1.7 Hz, 1H), 6.68 (dd, J=7.9, 1.7 Hz, 1H), 3.56 (s, 2H), 1.40 (s, 9H), 1.32 (s, 9H).

[2152] LC-MS (Method A): Rt 3.76 mins; MS m/z 384.2=[M+H]+ (99% @ 215 nm)

Example 90

N-tert-Butyl-4-[[2-(4-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2153] ##STR00500##

[2154] The titled compound was prepared from 4-[[2-(2-amino-4-tert-butyl-phenyl)acetyl]amino]-N-tert-butyl-pyridine-2-carboxamide (Example 88) analogously to Example 89.

[2155] 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.36 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.79 (dd, J=7.9, 1.9 Hz, 1H), 3.61 (s, 2H), 1.40 (s, 9H), 1.25 (s, 9H).

[2156] LC-MS (Method A): Rt 3.76 mins; MS m/z 384.2=[M+H]+ (100% @ 215 nm)

Example 91

N-tert-Butyl-4-[[2-(4-tert-butyl-2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide

[2157] ##STR00501##

[2158] To a solution of N-tert-butyl-4-[[2-(2-fluoro-5-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxamide (Example 3.13b) (300 mg, 0.87 mmol) in DCM (12 mL) was added tert-butanol (332 μL, 3.47 mmol) and H.sub.2SO.sub.4 (250 μL, 0.87 mmol) and the mixture stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and partitioned between EtOAc (20 mL) and water (20 mL). The organic portion was separated, washed with brine (20 mL) and concentrated in vacuo. Purification of the residue by preparative HPLC (acidic pH, standard elution method) afforded the titled compound as a white solid.

[2159] 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.31 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 6.87 (d, J=11.9 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 3.65 (s, 2H), 1.40 (s, 9H), 1.32 (s, 9H).

[2160] LC-MS (Method A): Rt 3.89 mins; MS m/z 402.3=[M+H]+ (96% @ 215 nm)

Example 92

4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[2161] ##STR00502##

Step 1: Methyl 4-[[2-(4-chloro-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate

[2162] ##STR00503##

[2163] The titled compound was prepared from 2-(4-chloro-3-methoxy-phenyl)acetic acid and methyl 4-aminopyridine-2-carboxylate analogously to Example 41 step 1.

[2164] 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.78 (dd, J=5.5, 2.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 6.91 (dd, J=8.1, 1.7 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.73 (s, 2H).

[2165] LC-MS (Method E): Rt 1.03 mins; MS m/z 335.0/337.0=[M+H]+ (95% @ 215 nm)

Step 2: 4-[[2-(4-Chloro-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[2166] ##STR00504##

[2167] The titled compound was prepared from methyl 4-[[2-(4-chloro-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 1) analogously to Example 41 step 2.

[2168] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 6.91 (dd, J=8.1, 1.9 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 2H).

[2169] LC-MS (Method E): Rt 0.88 mins; MS m/z 321.0/322.9=[M+H]+ (100% @ 215 nm)

Step 3: 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[2170] ##STR00505##

[2171] The titled compound was prepared from 4-[[2-(4-Chloro-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) and BBr.sub.3 analogously Example 31 step 1.

[2172] LC-MS (Method E): Rt 0.80 mins; MS m/z 306.9/308.9=[M+H]+ (62% @ 215 nm)

Step 4: 4-[[2-(4-Chloro-3-hydroxy-phenyl)acetyl]amino]-N-(4-cyanotetrahydropyran-4-yl)pyridine-2-carboxamide

[2173] To a solution of 4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3)(65%, 50 mg, 0.11 mmol), 4-aminotetrahydropyran-4-carbonitrile (16 mg, 0.13 mmol) and DIPEA (0.04 mL, 0.21 mmol) in DMF (0.5 mL) was added HATU (48 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 0.5 M NaOH (aq., 0.4 mL), stirred for 5 min then acidified to pH 5 with 2M aqueous HCl. The aqueous layer was extracted with EtOAc (2×5 mL) and the combined organic extracts were washed with water (5 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification by preparative HPLC (acidic pH, early elution method) followed by lyophilisation of the clean fractions afforded the titled compound as an off white powder.

[2174] 1H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.11 (br s, 1H), 9.00 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.85 (dd, J=5.5, 2.2 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.76 (dd, J=8.2, 1.9 Hz, 1H), 3.90-3.82 (m, 2H), 3.63 (s, 2H), 3.62-3.53 (m, 2H), 2.39-2.33 (m, 2H), 2.13-2.00 (m, 2H).

[2175] LC-MS (Method A): Rt 2.50 mins; MS m/z 415.1/417.1=[M+H]+ (100% @ 215 nm)

[2176] The compounds of the following tabulated Examples (Table 15) were prepared from 4-[[2-(4-chloro-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 92, step 3) analogously to Example 92 step 4 by replacing 4-aminotetrahydropyran-4-carbonitrile with the appropriate commercially available amine.

TABLE-US-00017 TABLE 15 1H NMR Ex. Structure and Name LCMS Retention Time, [M + H]+, 92.1 [00506] 1H NMR (500 MHz, DMSO-d6) δ 10.79 (s, 1H), 10.14 (br s, 1H), 8.83 (s, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 6.76 (d, J = 7.5 Hz, 1H), 3.63 (s, 2H), 1.72 (s, 6H). LC-MS (Method A): Rt 2.63 mins; MS m/z 373.1/375.1 = [M + H]+ (95% @ 215 nm) 92.2 [00507] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.12 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.2, 2.0 Hz, 1H), 3.63 (s, 2H), 3.21 (s, 1H), 1.64 (s, 6H). LC-MS (Method A): Rt 2.90 mins; MS m/z 372.1/374.1 = [M + H]+ (97% @ 215 nm) 92.3 [00508] 1H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 10.13 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 5.5, 2.2 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 1.9 Hz, 1H), 6.76 (dd, J = 8.2, 1.9 Hz, 1H), 4.80 (d, J = 4.5 Hz, 1H), 3.98 (dq, J = 13.1, 7.2, 6.4 Hz, 2H), 3.62 (s, 2H), 2.05-1.93 (m, 1H), 1.92-1.79 (m, 1H), 1.72-1.57 (m, 2H), 1.57-1.38 (m, 2H). LC-MS (Method A): Rt 2.37 mins; MS m/z 390.1/392.1 = [M + H]+ (99% @ 215 nm)

Example 93

4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl) tetrahydrofuran-3-yl]pyridine-2-carboxamide

[2177] ##STR00509##

Step 1: (4-tert-Butyl-3-methoxy-phenyl)methanol

[2178] ##STR00510##

[2179] To a stirred solution of 4-tert-butyl-3-methoxy-benzoic acid (1.9 g, 9.12 mmol) in THF (20 mL) was added 1M borane-THF (25.55 mL, 25.55 mmol) and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, the reaction was quenched with methanol (10 mL) and the volatile solvent removed in vacuo. More methanol (10 mL) was added and the volatiles were removed in vacuo. This process was repeated once more to afford the titled compound as a pale yellow oil.

[2180] 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 6.81 (d, J=7.8 Hz, 1H), 5.09 (s, 1H), 4.45 (s, 2H), 3.80 (s, 3H), 1.32 (s, 9H).

Step 2: 1-tert-Butyl-4-(chloromethyl)-2-methoxy-benzene

[2181] ##STR00511##

[2182] A stirred solution of (4-tert-butyl-3-methoxy-phenyl)methanol (step 1)(1.56 g, 8.03 mmol) and DMF (0.59 mL, 8.03 mmol) in DCM (20 mL) was treated dropwise with thionyl chloride (1.42 mL, 16.06 mmol) and the mixture stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo and the residue diluted with EtOAc (10 mL) and washed with saturated NaHCO.sub.3 (10 mL). The organic portion was separated, washed with brine (2 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the titled compound as a yellow oil.

[2183] 1H NMR (400 MHz, DMSO-d6) δ 7.21 (d, J=7.9 Hz, 1H), 7.05 (d, J=1.4 Hz, 1H), 6.94 (dd, J=7.9, 1.6 Hz, 1H), 4.72 (s, 2H), 3.82 (s, 3H), 1.33 (s, 9H).

Step 3: 2-(4-tert-Butyl-3-methoxy-phenyl)acetonitrile

[2184] ##STR00512##

[2185] A solution of 1-tert-butyl-4-(chloromethyl)-2-methoxy-benzene (step 2)(1.7 g, 7.99 mmol) in DMF (10 mL) was treated with sodium cyanide (0.78 g, 15.98 mmol) and the resulting mixture stirred at room temperature for 8 hours. The mixture was diluted with EtOAc (30 mL) and washed with sat. sodium carbonate (3×20 mL) and brine (2×20 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford the titled compound as a yellow oil.

[2186] 1H NMR (500 MHz, DMSO-d6) δ 7.22 (d, J=7.9 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.86 (dd, J=7.9, 1.7 Hz, 1H), 3.96 (s, 2H), 3.82 (s, 3H), 1.32 (s, 9H).

Step 4: 2-(4-tert-Butyl-3-methoxy-phenyl)acetic acid

[2187] ##STR00513##

[2188] To a solution of 2-(4-tert-butyl-3-methoxy-phenyl)acetonitrile (step 3) (1.52 g, 7.48 mmol) H.sub.2O (5 mL) was added lithium hydroxide hydrate (1.76 mL, 37.39 mmol) and the reaction mixture was heated at reflux for 10 hours. After cooling to room temperature, the mixture was acidified with concentrated HCl solution. The mixture was extracted with DCM (10 mL) and the combined organic extracts were dried over sodium sulphate and concentrated in vacuo to afford the titled compound as a pale yellow solid.

[2189] 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.13 (d, J=7.9 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H), 6.76 (dd, J=7.9, 1.7 Hz, 1H), 3.79 (s, 3H), 3.51 (s, 2H), 1.32 (s, 9H).

[2190] LC-MS (Method E): Rt 1.14 mins; MS m/z 220.9=[M+H]+ (99% @ 215 nm)

Step 5: Methyl 4-[[2-(4-tert-butyl-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate

[2191] ##STR00514##

[2192] The titled compound was prepared from 2-(4-tert-butyl-3-methoxy-phenyl)acetic acid (step 4) and methyl 4-aminopyridine-2-carboxylate analogously to Example 30 step 1.

[2193] 1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.80 (dd, J=5.5, 2.1 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 6.96 (d, J=1.5 Hz, 1H), 6.84 (dd, J=7.9, 1.6 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.66 (s, 2H), 1.31 (s, 9H).

[2194] LC-MS (Method E): Rt 1.19 mins; MS m/z 357.0=[M+H]+ (97% @ 215 nm)

Step 6: 4-[[2-(4-tert-Butyl-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[2195] ##STR00515##

[2196] The titled compound was prepared from methyl 4-[[2-(4-tert-butyl-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate (step 5) and lithium hydroxide hydrate analogously to Example 30 step 2.

[2197] 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.6, 2.2 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.84 (dd, J=7.9, 1.6 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 2H), 1.31 (s, 9H)

[2198] LC-MS (Method E): Rt 1.03 mins; MS m/z 343.1=[M+H]+ (94% @ 215 nm)

Step 7: 4-[[2-(4-tert-Butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid

[2199] ##STR00516##

[2200] The titled compound was prepared from 4-[[2-(4-tert-butyl-3-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 6) and BBr.sub.3 analogously to Example 31 step 1.

[2201] 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.32 (s, 1H), 8.60 (d, J=6.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.98 (dd, J=5.9, 2.1 Hz, 1H), 7.08 (d, J=7.9 Hz, 1H), 6.76 (d, J=1.7 Hz, 1H), 6.71-6.66 (m, 1H), 3.62 (s, 2H), 1.32 (s, 9H).

[2202] LC-MS (Method E): Rt 0.97 mins; MS m/z 329=[M+H]+ (76% @ 215 nm)

Step 8: 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]-N-[3-(hydroxymethyl) tetrahydrofuran-3-yl]pyridine-2-carboxamide

[2203] The titled compound was prepared from 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 7) and (3-aminotetrahydrofuran-3-yl)methanol analogously to Example 31 step 2.

[2204] 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.30 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.1 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.76 (d, J=1.7 Hz, 1H), 6.68 (dd, J=7.9, 1.6 Hz, 1H), 5.17 (t, J=5.6 Hz, 1H), 3.90-3.76 (m, 4H), 3.61 (d, J=5.2 Hz, 2H), 3.56 (s, 2H), 2.32 (ddd, J=12.6, 7.6, 5.0 Hz, 1H), 1.98 (dt, J=12.8, 7.8 Hz, 1H), 1.32 (s, 9H).

[2205] LC-MS (Method A): Rt 2.91 mins; MS m/z 428.3=[M+H]+ (96% @ 215 nm)

[2206] The compounds of the following tabulated Examples (Table 16) were prepared from 4-[[2-(4-tert-butyl-3-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 93, step 7) analogously to Example 93 step 8 by replacing (3-aminotetrahydrofuran-3-yl)methanol with the appropriate commercially available amine.

TABLE-US-00018 TABLE 16 1H NMR Ex. Structure and Name LCMS Retention Time, [M + H]+, 93.1 [00517] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.31 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 6.69 (dd, J = 8.0, 1.6 Hz, 1H), 4.69 (d, J = 5.5 Hz, 1H), 3.61- 3.52 (m, 3H), 3.48-3.39 (m, 1H), 1.96-1.84 (m, 2H), 1.69-1.58 (m, 2H), 1.32 (s, 9H), 1.32-1.20 (m, 4H). LC-MS (Method A): Rt 3.24 mins; MS m/z 426.3 = [M + H]+ (100% @ 215 nm) 93.2 [00518] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.31 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 1.6 Hz, 1H), 6.69 (dd, J = 8.0, 1.7 Hz, 1H), 4.81 (d, J = 4.3 Hz, 1H), 4.05- 3.93 (m, 2H), 3.56 (s, 2H), 2.05-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.74-1.58 (m, 2H), 1.56-1.42 (m, 2H), 1.32 (s, 9H). LC-MS (Method A): Rt 3.12 mins; MS m/z 412.3 = [M + H]+ (100% @ 215 nm) 93.3 [00519] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.30 (s, 1H), 9.01 (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 1.7 Hz, 1H), 6.69 (dd, J = 8.0, 1.7 Hz, 1H), 3.87 (dt, J = 12.2, 3.8 Hz, 2H), 3.64-3.55 (m, 4H), 2.41-2.33 (m, 2H), 2.08 (ddd, J = 13.8, 10.3, 3.9 Hz, 2H), 1.32 (s, 9H). LC-MS (Method A): Rt 3.30 mins; MS m/z 437.2 = [M + H]+ (98% @ 215 nm) 93.4 [00520] 1H NMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.30 (s, 1H), 8.83 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 6.69 (dd, J = 7.9, 1.8 Hz, 1H), 3.57 (s, 2H), 1.73 (s, 6H), 1.33 (s, 9H). LC-MS (Method A): Rt 3.41 mins; MS m/z 395.2 = [M + H]+ (99% @ 215 nm) 93.5 [00521] 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.30 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.69 (dd, J = 8.0, 1.8 Hz, 1H), 3.56 (s, 2H), 3.21 (s, 1H), 1.65 (s, 6H), 1.32 (s, 9H). LC-MS (Method A): Rt 3.64 mins; MS m/z 394.2 = [M + H]+ (96% @ 215 nm)

Example 94

4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl) pyridine-2-carboxamide

[2207] ##STR00522##

Step 1: 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl)pyridine-2-carboxamide

[2208] ##STR00523##

[2209] The titled compound was prepared from 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (Example 8.1 step 2) and 2-phenylpropan-2-amine analogously to Example 86, step 7.

Step 2: 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl)pyridine-2-carboxamide

[2210] The titled compound was prepared from 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]-N-(1-methyl-1-phenyl-ethyl)pyridine-2-carboxamide (step 1) and BBr.sub.3 analogously to Example 3 step 3.

[2211] 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.80 (s, 1H), 8.56 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.84 (dd, J=5.6, 2.2 Hz, 1H), 7.41-7.37 (m, 2H), 7.33-7.28 (m, 2H), 7.23-7.18 (m, 2H), 7.11 (dd, J=8.6, 2.7 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 3.65 (s, 2H), 1.72 (s, 6H).

[2212] LC-MS (Method A): Rt 3.88 mins; MS m/z 424.2/426.2=[M+H]+ (99% @ 215 nm)

Biological Example 95

Automated Whole-Cell Patch Clamp Assay to Detect TMEM16A Activity in Recombinant Cells

Cell Culture and Preparation

[2213] Fisher rat thyroid (FRT) cells stably expressing human TMEM16A (TMEM16Aabc variant; Dr Luis Galietta, Insituto Giannina, Italy) were cultured in T-75 flasks in Hams F-12 media with Coon's modification (Sigma) supplemented with 10% (v/v) foetal bovine serum, penicillin-streptomycin (10,000 U/mL/10000 μg/mL), G-418 (750 μg/mL), L-glutamine (2 mM) and sodium bicarbonate solution (7.5% v/v). At ˜90% confluence cells were harvested for experiments by detachment with a 2:1 (v/v) mixture of Detachin (BMS Biotechnology) and 0.25% (w/v) trypsin-EDTA. Cells were diluted to a density of 3.5-4.5×10.sup.6 cells/mL with media consisting of CHO-S-SFM II (Sigma), 25 mM HEPES (Sigma) and Soy bean trypsin inhibitor (Sigma).

Whole-Cell Patch Clamp Recording

[2214] FRT-TMEM16A cells were whole-cell patch clamped using an automated planar patch clamp system (Qpatch, Sophion). Briefly, once high resistance (GOhm) seals were established between the cells and the planar recording array the patch was ruptured using suction pulses to establish the whole-cell recording configuration of the patch clamp technique. The assay employed the following solutions (all reagents Sigma):

Intracellular solution (mM): N-methyl-D-glucamine 130, CaCl.sub.2) 18.2, MgCl.sub.2 1, HEPES 10, EGTA 10, BAPTA 20, Mg-ATP 2, pH 7.25, 325 mOsm with sucrose.
Extracellular solution (mM): N-methyl-D-glucamine 130, CaCl.sub.2) 2, MgCl.sub.2 1, HEPES 10, pH 7.3, 320 mOsm with sucrose.

[2215] The intracellular solution buffers intracellular calcium at levels required to give ˜20% activation of the maximal TMEM16A mediated current (EC.sub.20 for calcium ions). Cells were voltage clamped at a holding potential of −70 mV and a combined voltage step (to +70 mV)/ramp (−90 my to +90 mV) was applied at 0.05 Hz. After a period of current stabilisation test compounds, solubilised in 100% (v/v) DMSO and subsequently diluted into extracellular solution, were applied to generate a cumulative concentration response curve. Each concentration of test compound was incubated for 5 minutes before addition of the next concentration. After the final concentration was tested a supramaximal concentration of either a known active positive modulator or the TMEM16A inhibitor, CaCCinhA01 (Del La Fuente et al, 2008) was added to define the upper and lower limits of the assay.

[2216] Compound activity was quantified by measuring the increase in current upon compound addition and expressing this as a percentage increase of baseline TMEM16A current level. Percentage increases in current were determined for each concentration and the data plotted as a function of concentration using either the Qpatch software or Graphpad Prism v6.05 providing the concentration which gave 50% of its maximal effect (EC.sub.50) and maximum efficacy (percentage of baseline increase).

[2217] The method of calculating the results is illustrated in FIG. 1, which shows an example trace from the Qpatch TMEM16A assay. In FIG. 1, I.sub.BL equals baseline current, I.sub.[#1] equals the peak current during test compound concentration 1 incubation period and so on.

[2218] Peak TMEM16A current at +70 mV was plotted as a function of time over the assay period. Baseline current (I.sub.BL) was measured after a period of stabilisation. The increase in current for each compound addition was determined by taking the peak current during the incubation period and subtracting the current from the previous recording period and then expressing this as a percentage of the baseline current. For test compound concentration 1 in FIG. 1 this is:

(I.sub.[#1]−I.sub.BL/I.sub.BL)×100

[2219] For each additional concentration tested the increase in current was determined by subtracting the current from the previous incubation period and normalising the baseline value—for test concentration 2 in FIG. 1 this is:

(I.sub.[#2]−I.sub.[#1}/I.sub.BL)×100

[2220] The values for each test concentration were plotted as a cumulative function of concentration eg. for test concentration two this would be the sum of the peak changes measured during concentration one plus concentration two.

[2221] The results obtained for the example compounds are shown in Table 8, from which it can be seen that the compounds of the present invention are capable of significantly increasing the TMEM16A current level.

TABLE-US-00019 TABLE 17 % Potentiation shown by 3.33 μM solution of Test Compounds and Calculated EC.sub.50 Values % Potentiation EC.sub.50 Avg Example @ 3.33 μM Avg (μM)  1 203 0.21  1.1 182 0.56  1.2 170 0.54  1.3 233 0.24  1.4 195 0.40  1.5 149 0.34  1.6 255 0.06  1.7 239 0.15  1.8 300 0.41  1.9 79 4.20  1.10 200 0.08  2 262 0.27  2.1 216 0.49  2.2 158 1.61  2.3 203 0.59  2.4 53  2.5 51 1.34  2.6 140 2.91  2.7 51 8.19  2.8 74 4.55  2.9 148 0.99  2.10 133 0.46  2.11 126 0.43  2.12 111 0.31  2.13 126 0.46  2.14 100 1.78  2.15 163 0.49  2.16 60 4.27  2.17 172 0.27  2.18 118 1.41  2.19 249 0.46  3 287 0.11  3.1a 128 0.18  3.2a 116 0.16  3.3a 91 0.07  3.4a 206 0.14  3.5a 311 0.50  3.6a 546 0.37  3.7a 135 0.28  3.5b 150 0.20  3.6b 205 0.12  3.7b 160 0.18  3.8b 203 0.30  3.9b 144 0.96  3.10b 159 0.46  3.11b 168 0.41  3.12b 143 0.34  3.13b 179 0.25  3.14b 251 0.04  3.15b 127  3.16b 167 0.17  3.17b 227 0.12  4 96 1.50  4.1 79 2.17  4.2 116 0.66  4.3 151 1.53  4.4 61 4.19  4.5 138 0.70  4.6 53 3.86  4.7 68  4.8 55 2.07  4.9 60 4.66  5 78 0.80  5.1 140 0.87  5.2 63  5.3 152 0.88  5.4 57  5.5 132 0.72  5.6 101 0.15  5.7 131 1.23  5.8 116 0.46  5.9 126 1.13  5.10 78 3.77  5.11 89 0.17  5.12 100 0.76  5.13 94 1.14  5.14 128 0.76  5.15 87  5.16 110  5.17 94 0.65  5.18 79 0.46  5.19 75 1.85  5.20 221 0.57  5.21 172 0.51  5.22 94  5.23 144 1.20  5.24 189 0.14  5.25 67  5.26 110 1.20  5.27 84  5.29 190 0.86  5.31 145  5.32 285  5.33 49  5.34 185 0.64  5.35 106 0.18  5.36 44 0.06  5.37 117 0.15  5.38 231 0.15  5.39 147  6 162 1.14  7 153 0.65  7.1 241 0.34  7.2 203 0.26  7.3 125 0.20  7.4 52 0.65  7.5 239 0.28  7.6 285 0.10  7.7 234 0.13  7.8 231 0.92  7.9 288 0.23  7.10 218 0.36  7.11 167 0.32  7.12 101 2.11  7.13 212 0.09  7.14 225 0.15  7.15 230 0.05  7.16 354 0.13  8 88 3.02  8.1 155 0.59  8.2 169 1.96  8.3 238 0.23  9 149 0.23  9.1 77 4.62  9.2 196 0.19 10 250 0.22 11 76 0.90 12 112 1.76 13 245 1.00 14 58 15 200 0.13 16 63 17 173 1.49 18 405 0.45 19 57 20 111 0.22 21a 99 1.57 21b 164 1.08 22.1 114 22.2 157 0.26 22.3 132 23 93 23.1 150 23.2 87 23.3 59 0.47 23.4 115 23.5 110 23.6 108 23.7 98 23.8 122 23.9 47 23.11 101 23.12 197 0.33 23.13 169 0.57 23.14 33 23.15 147 1.19 23.16 68 1.40 24 68 25 330 0.37 25.1 393 0.14 26 108 27 90 27.1 52 27.2 300 27.3 166 0.29 28 318 0.40 28.1 68 30 113 1.22 30.1 245 0.14 30.2 221 0.18 30.3 100 0.25 30.3a 221 30.4 95 0.75 30.5 63 30.6 80 30.7 124 0.34 30.8 121 0.70 30.9 100 0.47 30.10 265 30.11 125 0.22 30.12 314 30.13 205 0.38 31 223 0.12 31.2 110 0.01 31.3 205 0.21 31.3a 238 0.55 31.4 186 0.02 32 171 32.1 246 32.2 183 0.34 32.3 288 0.29 32.4 187 0.71 32.5 177 0.59 32.6 153 0.82 32.7 111 0.20 32.8 79 32.9 31 33 245 0.24 34 245 0.09 35 180 0.19 35a 137 0.10 35b 190 0.31 35.1 51 35.2 300 0.61 35.3 144 35.4 138 35.6 53 35.7 97 35.8 250 0.18 35.9 455 0.54 35.10 223 0.28 35.11 107 35.12 158 0.42 35.13 191 0.35 35.14 172 0.27 35.15 158 0.15 35.16 85 0.33 35.17 153 0.15 35.18 147 0.43 35.19 248 0.47 35.20 240 0.42 35.21 200 0.41 35.22 104 0.22 35.24 120 0.01 35.25 126 0.10 35.26 157 35.27 496 0.33 36 199 0.02 37 352 0.12 38 307 0.05 39 262 0.06 40 153 0.70 40.1 91 0.87 41 38 42 143 0.76 43 174 0.70 44 377 0.05 45 151 46 275 0.25 46a 249 0.11 46b 215 47 237 0.18 47.1 156 1.92 47.2 212 0.23 47.3 237 0.35 48 195 0.10 48.1 185 0.42 49 226 0.68 50 65 51 54 53 184 0.39 54 62 55 114 56 76 57a 285 0.51 57b 162 0.67 58 217 59 175 60 126 0.35 60.1 60 60.2 169 0.20 61 85 62 99 63 37 64 55 64.1 78 64.2 61 64.3 70 64.4 2 64.5 143 0.45 64.6 0 64.7 83 64.8 97 65 55 65.1 75 0.47 65.2 73 0.48 65.3 33 65.4 10 66 130 67 158 1.10 68 39 69 47 70 138 71 162 71.1 256 0.25 72 53 73 196 0.31 73.1 389 0.28 74 337 0.18 74.1 49 75 34 76 366 0.22 77 139 0.41 77.1 151 0.54 78 98 0.02 78.1 238 0.05 78.2 86 0.02 79 60 79.1 45 79.2 211 79.3 64 0.24 80 130 81 151 0.37 81.1 108 81.2 103 0.42 81.3 129 0.04 81.4 122 0.04 81.5 74 82 88 0.72 83 6 83.1 159 83.2 41 83.3 16 83.4 58 83.5 185 83.6 248 83.7 147 83.8 35 83.9 18 83.10 62 83.11 13 83.13 −1 83.14 70 83.15 −10 83.16 60 83.17 8 83.18 16 83.19 28 83.20 9 83.21 70 83.22 85 83.23 −11 83.24 55 83.25 −8 83.26 95 83.27 −11 83.28 20 83.29 −9 83.30 93 83.31 78 83.32 −16 85 155 0.35 86 593 0.35 87 332 0.22 88 270 0.24 89 366 0.09 90 219 0.12 92 133 0.11 92.1 151 0.14 92.2 71 0.01 93.1 207 0.05 93.2 220 0.04 93.3 130 0.06 93.4 476 0.07 93.5 136 0.02 94 516 0.34

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