Novel heterocyclic compounds as inhibitors of vanin-1 enzyme

Abstract

as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

1 . A method of treating a disease or disorder mediated by, or otherwise associated with, inhibition of the vanin-1 enzyme, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         A 1  is C(R 3 ), A 2  is N and A 3  is C(R 3 ); 
         R 1  is selected from the group consisting of:
 (i) 6 to 10 membered aryl optionally substituted with one, two, three or four E; and 
 (ii) 5 to 11 membered heteroaryl optionally substituted with one, two, three or four E, wherein said 5 to 11 membered heteroaryl (a) comprises one, two or three heteroatoms independently selected for each occurrence from the group consisting of —N═, —N(J)-, —O—, and —S— and (b) is not bound to the carbonyl of Formula (I) through a nitrogen; 
 
         W is selected from the group consisting of:
 (i) —NHCG 2 -R 2 ; 
 (ii) —NHCG 2 CG 2 -R 2 ; 
 (iii) —OCG 2 -R 2 ; 
 (iv) —OCG 2 CG 2 -R 2 ; 
 
         R 2  is selected from the group consisting of:
 (i) phenyl optionally substituted with one, two, three or four E; and 
 (ii) 5 to 6 membered heteroaryl optionally substituted with one, two, three or four E, wherein said 5 to 6 membered heteroaryl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N═, —N(J)-, —O—, and —S—; 
 (iii) —C 3 -C 7  carbocyclyl optionally substituted with one, two, three, four, five or six E; 
 (iv) 4 to 7 membered heterocyclyl optionally substituted with one, two, three, four, five or six E, wherein said 4 to 7 membered heterocyclyl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N(J)-, —O— and —S—; and 
 (v) 4 to 7 membered heterocyclyl optionally substituted with one, two, three, four, five or six E, wherein said 4 to 7 membered heterocyclyl is (i) bound to W through a first heterocyclyl ring heteroatom —N— and (ii) which optionally comprises a second ring heteroatom independently selected from the group consisting of —N(J)-, —O—, and —S—; 
 
         R 3  is independently selected for each occurrence from the group consisting of —H, —F, —Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CF 2 CF 3 , —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —SCH 3 , —SCH 2 F, —SCHF 2 , and —SCF 3 ; 
         E is independently selected for each occurrence from the group consisting of:
 (i) —H; 
 (ii) -halo; 
 (iii) —CN; 
 (iv) —OH; 
 (v) —CO 2 H; 
 (vi) —C 1 -C 6 alkyl optionally substituted with one, two, three, four, five or six K; 
 (vii) —OC 1 -C 6 alkyl optionally substituted with one, two, three, four, five or six K; 
 (viii) —SC 1 -C 6 alkyl optionally substituted with one, two, three, four, five or six K; 
 (ix) —C 3 -C 5 cycloalkyl optionally substituted with one, two, three, four, five or six K; 
 (x) —OC 3 -C 5 cycloalkyl optionally substituted with one, two, three, four, five or six K; 
 (xi) —SC 3 -C 5 cycloalkyl optionally substituted with one, two, three, four, five or six K; 
 (xii) —C 1 -C 6 alkyl(C 3 -C 5 cycloalkyl) optionally substituted with one, two, three, four, five or six K; 
 (xiii) 4 to 7 membered heterocyclyl optionally substituted with one, two, three, four, five or six K, wherein said 4 to 7 membered heterocyclyl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N(J)-, —O— or —S—; 
 (xiv) —NH 2 ; 
 (xv) —NH(C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; 
 (xvi) —N(C 1 -C 6 alkyl) 2 , which C 1 -C 6 alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K; 
 (xvii) —C(O)NH 2 ; 
 (xviii) —C(O)NH(C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; 
 (xix) —C(O)N(C 1 -C 6 alkyl) 2 , which C 1 -C 6 alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K; 
 (xx) —NHC(O)(C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; 
 (xxi) —N(C 1 -C 6 alkyl)C(O)(C 1 -C 6 alkyl), which C 1 -C 6 alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K; 
 (xxii) —SO 2 (C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; 
 (xxiii) —SO 2 NH 2 ; 
 (xxiv) —SO 2 NH(C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; 
 (xxv) —SO 2 N(C 1 -C 6 alkyl) 2 , which C 1 -C 6 alkyl is, independently for each occurrence optionally substituted with one, two, three, four, five or six K; 
 (xxvi) —NHSO 2 (C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; and 
 (xxvii) —N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), which C 1 -C 6 alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K; 
 
         G is independently selected for each occurrence from the group consisting of:
 (i) —H; 
 (ii) -halo; 
 (iii) —OH; 
 (iv) —C 1 -C 6 alkyl optionally substituted optionally substituted with one, two, three, four, five or six K; 
 (v) —OC 1 -C 6 alkyl optionally substituted with one, two, three, four, five or six K; 
 (vi) —SC 1 -C 6 alkyl optionally substituted with one, two, three, four, five or six K; 
 (vii) —NH(C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; 
 (viii) —N(C 1 -C 6 alkyl) 2 , which C 1 -C 6 alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K; 
 (ix) —C 3 -C 5 cycloalkyl optionally substituted with one, two, three, four, five or six K; and 
 (x) 4 to 5 membered heterocyclyl optionally substituted with one, two, three, four, five or six K, which said 4 to 5 membered heterocyclyl comprises one or two heteroatoms independently selected for each occurrence from the group consisting of —N(J)-, —O— or —S—;
 or two geminal G may, together with the carbon to which they are bound, form a —C 3 -C 5 cycloalkylene optionally substituted with one, two, three, four, five or six K or a 4 to 5 membered heterocyclylene optionally substituted with one, two, three, four, five or six K, wherein said 4 to 5 membered heterocyclylene comprises one heteroatom independently selected from the group consisting of —N(J)-, —O—, or —S—; 
 
 
         J is independently selected, for each occurrence, from the group consisting of:
 (i) —H; 
 (ii) —C 1 -C 6 alkyl optionally substituted with one, two, three, four, five or six K; 
 (iii) —C(O)NH 2 ; 
 (iv) —C(O)NH(C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six K; 
 (v) —C(O)N(C 1 -C 6 alkyl) 2 , which C 1 -C 6 alkyl is, independently for each occurrence, optionally substituted with one, two, three, four, five or six K; and 
 (vi) —SO 2 (C 1 -C 6 alkyl), which C 1 -C 6 alkyl is optionally substituted with one, two, three, four, five or six halo; and 
 
         K is independently selected, for each occurrence, from the group consisting of —H, —F, —Cl, —OH, —CN, —CO 2 H, —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CF 2 CF 3 , —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —SCH 3 , —SCH 2 F, —SCHF 2 , —SCF 3 —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , and —CONH 2 . 
       
     
     
         2 . The method according to  claim 1  wherein R 3  is selected from the group consisting of —H, —F, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , —OCH 2 F, —OCHF 2 , and —OCF 3 . 
     
     
         3 . The method according to  claim 2  wherein R 1  is selected from the group consisting of phenyl, thiophenyl, 1,4-dioxochromanyl, quinolinyl, pyrazolyl, indazolyl, pyridinyl, N-methyl-indazolyl and N-methyl-pyrazolyl. 
     
     
         4 . The method according to  claim 3  wherein W is selected from the group consisting of
 —NHCG 2 -R 2  and —OCG 2 -R 2 . 
 
     
     
         5 . The method according to  claim 4  wherein G is selected from the group consisting of —H; —C 1 -C 6 alkyl; methyl; —OC 1 -C 6 alkyl; —C 3 -C 5 cycloalkyl; or two geminal G may, together with the carbon to which they are bound, form a —C 3 -C 5 cycloalkylene, for example cyclopropylene or cyclobutylene. 
     
     
         6 . The method according to  claim 1  wherein the compound of Formula I is selected from the group consisting of:
 3-[(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[1-(pyridin-3-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-({2-[(2-phenylpropan-2-yl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-[(2-{[(2-aminopyrimidin-5-yl)methyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[1-(pyrazin-2-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[(6-aminopyridin-3-yl)methyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[1-(pyridin-3-yl)ethyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 4-(1-{[5-(3-cyanobenzoyl)pyrimidin-2-yl]amino}ethyl)benzamide; 
 (−)-4-(1-{[5-(3-cyanobenzoyl)pyrimidin-2-yl]amino}ethyl)benzamide; 
 (+)-4-(1-{[5-(3-cyanobenzoyl)pyrimidin-2-yl]amino}ethyl)benzamide; 
 {2-[(pyrazin-2-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 {2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 [3-(methylsulfonyl)phenyl]{2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (3-methylphenyl){2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (2-fluorophenyl){2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 [3-(methylsulfonyl)phenyl](2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)methanone; 
 (3-methoxyphenyl)(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)methanone; 
 [3-(methylsulfonyl)phenyl]{2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 [3-(methylsulfonyl)phenyl]{2-[(pyridazin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (3,4-difluorophenyl){2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 4-({[5-(3-methylbenzoyl)pyrimidin-2-yl]amino}methyl)benzamide; 
 [2-(benzylamino)pyrimidin-5-yl](3-chlorophenyl)methanone; 
 (3-chiorophenyl){2-[(2-phenylpropan-2-yl)amino]pyrimidin-5-yl}methanone; 
 3-({[5-(3-chlorobenzoyl)pyrimidin-2-yl]amino}methyl)benzonitrile; 
 3-{[2-(benzylamino)pyrimidin-5-yl]carbonyl}benzonitrile; 
 3-({2-[(4-chlorobenzyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-({2-[(4-methoxybenzyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-({2-[(2,4-difluorobenzyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-({2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-({2-[(2-chlorobenzyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 4-[({5-[3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzamide; 
 phenyl{2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 [2-(benzylamino)pyrimidin-5-yl][3-(trifluoromethyl)phenyl]methanone; 
 (3-chlorophenyl){2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}methanone; 
 {2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}(3-methoxyphenyl)methanone; 
 (3-methylphenyl){2-[(pyridin-2-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (3-methylphenyl){2-[(pyridin-4-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 [2-(benzylamino)pyrimidin-5-yl](3-methylphenyl)methanone; 
 (3,4-difluorophenyl){2-[(4-methoxybenzyl)amino]pyrimidin-5-yl}methanone; 
 4-({[5-(3-methylbenzoyl)pyrimidin-2-yl]amino}methyl)benzonitrile; 
 4-({[5-(3,4-difluorobenzoyl)pyrimidin-2-yl]amino}methyl)benzamide; 
 (3,4-difluorophenyl){2-[(2-phenylpropan-2-yl)amino]pyrimidin-5-yl}methanone; 
 [2-(benzylamino)pyrimidin-5-yl](3-methoxyphenyl)methanone; 
 {2-[(4-fluorobenzyl)oxy]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 {2-[(4-chlorobenzyl)oxy]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 3-({[5-(3-chlorobenzoyl)pyrimidin-2-yl]amino}methyl)benzamide; 
 4-({[5-(3,4-difluorobenzoyl)pyrimidin-2-yl]amino}methyl)benzoic acid; 
 4-[({5-[4-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzonitrile; 
 {2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}[4-(trifluoromethyl)phenyl]methanone; 
 (4-chlorophenyl){2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}methanone; 
 {2-[(4-methoxybenzyl)amino]pyrimidin-5-yl}(4-methoxyphenyl)methanone; 
 {2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}[4-(trifluoromethyl)phenyl]methanone; 
 {2-[(4-methoxybenzyl)amino]pyrimidin-5-yl}[4-(trifluoromethyl)phenyl]methanone; 
 {2-[(pyridin-4-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 {2-[(4-chlorobenzyl)amino]pyrimidin-5-yl}(4-chlorophenyl)methanone; 
 (2-{[4-(trifluoromethoxy)benzyl]amino}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 4-({[5-(4-methoxybenzoyl)pyrimidin-2-yl]amino}methyl)benzamide; 
 (4-methoxyphenyl){2-[(pyridin-2-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 {2-[(4-chloro-2-fluorobenzyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 3-[({5-[3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzonitrile; 
 (4-chiorophenyl){2-[(4-methoxybenzyl)amino]pyrimidin-5-yl}methanone; 
 3-({[5-(3-cyanobenzoyl)pyrimidin-2-yl]amino}methyl)benzonitrile; 
 3-({2-[(1-phenylcyclopropyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 {2-[(1I-phenylcyclopropyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 {2-[(pyridazin-3-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 4-({[5-(3-cyanobenzoyl)pyrimidin-2-yl]amino}methyl)benzamide; 
 5-[({5-[3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]pyridine-2-carboxamide; 
 5-[({5-[4-fluoro-3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]pyridine-2-carboxamide; 
 (2-{[1-(pyridin-3-yl)cyclopropyl]amino}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 3-[(2-{[(2-oxo-1,2-dihydropyridin-4-yl)methyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 (2-{[(6-methylpyridin-3-yl)methyl]amino}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 [2-(benzylamino)pyrimidin-5-yl](4-methoxyphenyl)methanone; 
 (4-methoxyphenyl)(2-{[4-(trifluoromethoxy)benzyl]amino}pyrimidin-5-yl)methanone; 
 4-[({5-[3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzonitrile; 
 3-({[5-(4-methoxybenzoyl)pyrimidin-2-yl]amino}methyl)benzonitrile; 
 4-({2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 4-({2-[(4-methoxybenzyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 [4-fluoro-3-(trifluoromethyl)phenyl]{2-[(pyridin-2-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 [4-fluoro-3-(trifluoromethyl)phenyl]{2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 [4-fluoro-3-(trifluoromethyl)phenyl]{2-[(pyridin-4-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 [2-(benzylamino)pyrimidin-5-yl][4-fluoro-3-(trifluoromethyl)phenyl]methanone; 
 4-[({5-[4-fluoro-3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzonitrile; 
 {2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}[4-fluoro-3-(trifluoromethyl)phenyl]methanone; 
 4-[({5-[4-fluoro-3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzamide; 
 4-[({5-[4-fluoro-3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzoic acid; 
 [2-(benzylamino)pyrimidin-5-yl][3-fluoro-5-(trifluoromethyl)phenyl]methanone; 
 4-[({5-[3-fluoro-5-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzonitrile; 
 4-[({5-[3-fluoro-5-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzamide; 
 {2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}[3-(methylsulfonyl)phenyl]methanone; 
 [2-(benzylamino)pyrimidin-5-yl](2,3-dihydro-1,4-benzodioxin-6-yl)methanone; 
 2,3-dihydro-1,4-benzodioxin-6-yl{2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 [2-(benzylamino)pyrimidin-5-yl](phenyl)methanone; 
 {2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}(thiophen-2-yl)methanone; 
 {2-[(2-fluorobenzyl)amino]pyrimidin-5-yl}(phenyl)methanone; 
 (2-chlorophenyl){2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (1-methyl-1H-pyrazol-4-yl){2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (2-methylquinolin-6-yl){2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 5-({[5-(3-cyanobenzoyl)pyrimidin-2-yl]amino}methyl)pyridine-2-carboxamide; 
 4-{[(5-benzoylpyrimidin-2-yl)amino]methyl}benzamide; 
 5-{[(5-benzoylpyrimidin-2-yl)amino]methyl}pyridine-2-carboxamide; 
 3-({2-[(pyridazin-3-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 phenyl{2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 phenyl{2-[(2-phenylpropan-2-yl)amino]pyrimidin-5-yl}methanone; 
 phenyl{2-[(1-phenylcyclopropyl)amino]pyrimidin-5-yl}methanone; 
 3-({2-[(pyridazin-4-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-{[(5-benzoylpyrimidin-2-yl)amino]methyl}benzonitrile; 
 phenyl{2-[1-(pyridin-3-yl)cyclopropyl]amino}pyrimidin-5-yl)methanone; 
 phenyl{2-[(pyridazin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 phenyl{2-[(pyrazin-2-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 3-({2-[(pyrazin-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-({2-[(pyridin-3-ylmethyl)amino]pyri m id in-5-yl}carbonyl)benzonitrile; 
 {2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 3-({2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 {2-[(2-phenylpropan-2-yl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 {2-[(pyridazin-4-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 3-({[5-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)pyrimidin-2-yl]amino}methyl)benzonitrile; 
 2,3-dihydro-1,4-benzodioxin-6-yl{2-[(2-phenylpropan-2-yl)amino]pyrimidin-5-yl}methanone; 
 4-[({5-[3-(methylsulfonyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzamide; 
 4-[({5-[3-(methylsulfonyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzonitrile; 
 {2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}[3-fluoro-5-(trifluoromethyl)phenyl]methanone; 
 [3-fluoro-5-(trifluoromethyl)phenyl]{2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 3-({2-[(1I-phenylcyclobutyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-fluoro-5-({2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 4-fluoro-3-({2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 2-methyl-5-({2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-[(2-{[1-(pyrimidin-5-yl)ethyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 2-chloro-5-({2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 2-fluoro-5-({2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-({2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzamide; 
 (1-methyl-1H-indazol-6-yl){2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 (4-methoxyphenyl)(2-{[1-(pyrimidin-5-yl)ethyl]amino}pyrimidin-5-yl)methanone; 
 {2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}[2-(trifluoromethyl)pyridin-4-yl]methanone; 
 (3-methoxyphenyl)(2-{[1-(pyrimidin-5-yl)ethyl]amino}pyrimidin-5-yl)methanone; 
 (3-methoxyphenyl){2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 2,3-dihydro-1,4-benzodioxin-6-yl{2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 3-chloro-5-[(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[1-(pyrazin-2-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzamide; 
 3-[(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzoic acid; 
 3-[(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzamide; 
 {3-[(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]phenyl}acetic acid; 
 3-[(2-{[1-(5-aminopyrazin-2-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 5-(1-{[5-(3-cyanobenzoyl)pyrimidin-2-yl]amino}cyclopropyl)pyridine-2-carboxamide; 
 3-[(2-{[1-(6-hydroxypyridin-3-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 (3-methoxyphenyl)(2-{[4-(4-methylpiperazin-1-yl)benzyl]amino}pyrimidin-5-yl)methanone; 
 [2-(benzyloxy)pyrimidin-5-yl][3-(trifluoromethyl)phenyl]methanone; 
 {2-[(2,4-difluorobenzyl)oxy]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 {2-[(4-methoxybenzyl)oxy]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 (2-{[4-(trifluoromethoxy)benzyl]oxy}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 (1-methyl-1H-indazol-5-yl){2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 4-(1-{[5-(4-methoxybenzoyl)pyrimidin-2-yl]amino}ethyl)benzamide; 
 2-methoxy-5-[(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[(4-hydroxycyclohexyl)methyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-({2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 3-[(2-{[(1-methylpiperidin-4-yl)methyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; and 
 (2-{[(1-ethylpyrrolidin-2-yl)methyl]amino}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         7 . The method according to  claim 1  wherein the compound of Formula I is selected from the group consisting of:
 3-[(2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[1-(pyridin-3-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 3-[(2-{[1-(pyrazin-2-yl)cyclopropyl]amino}pyrimidin-5-yl)carbonyl]benzonitrile; 
 {2-[(pyrazin-2-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 {2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}[3-(trifluoromethyl)phenyl]methanone; 
 (2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 [3-(methylsulfonyl)phenyl](2-{[1-(pyrimidin-5-yl)cyclopropyl]amino}pyrimidin-5-yl)methanone; 
 [3-(methylsulfonyl)phenyl]{2-[(pyrimidin-5-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 4-[({5-[3-(trifluoromethyl)benzoyl]pyrimidin-2-yl}amino)methyl]benzamide; 
 (2-{[(6-methylpyridin-3-yl)methyl]amino}pyrimidin-5-yl)[3-(trifluoromethyl)phenyl]methanone; 
 [4-fluoro-3-(trifluoromethyl)phenyl]{2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}methanone; 
 3-({2-[(pyridin-3-ylmethyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; and 
 3-({2-[(1-phenylcyclobutyl)amino]pyrimidin-5-yl}carbonyl)benzonitrile; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . The method according to  claim 1  wherein the disease or disorder is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis. 
     
     
         9 . The method according to  claim 6  wherein the disease or disorder is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis. 
     
     
         10 . The method according to  claim 7  wherein the disease or disorder is selected from the group consisting of inflammatory bowel disease, ulcerative colitis, Crohn's disease, colorectal cancer, and gastritis.