COMPOUNDS AND THERAPEUTIC USES THEREOF
The invention relates to compounds, pharmaceutical compositions and methods useful for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, ischemia, and other complications associated with these diseases and disorders.
1 . A compound having a structure according to Formula IIIb
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y 2 is —OCH 2 —, —SCH 2 —, —N(R)CH 2 —, —N(R)C(═O)—, —C(═O)N(R)—, —S(═O) 2 CH 2 —, —S(═O)CH 2 —, —CH 2 O—, —CH 2 CH 2 O—, —CH 2 S—, —CH 2 N(R)—, —CH 2 S(═O) 2 —, —CH 2 S(═O)—, —C(═O)O—, —OC(═O)—, —SO 2 N(R)—, —N(R)SO 2 —, ethylene, propylene, n-butylene, —O—C 1-4 alkylene-N(R)C(═O)—, —O—C 1-4 alkylene-C(═O)N(R)—, —N(R)C(═O)—C 1-4 alkylene-O—, —C(═O)N(R)—C 1-4 alkylene-O—, —C 1-4 alkylene-S(═O) 2 —, —C 1-4 alkylene-S(═O)—, —S(═O) 2 —C 1-4 alkylene-, —S(═O)—C 1-4 alkylene-, —C 1-4 alkylene-SO 2 N(R)—, —C 1-4 alkylene-N(R)SO 2 —, —SO 2 N(R)—C 1-4 alkylene-, —N(R)SO 2 —C 1-4 alkylene-, —C 1-4 alkylene-O—C 1-4 alkylene-, —O—C 1-4 alkylene-, —C 1-4 alkylene-O—, —S—C 1-4 alkylene-, —C 1-4 alkylene-S—, —C 1-4 alkylene-S—C 1-4 alkylene-, —N(R)—C 1-4 alkylene-, —C 1-4 alkylene-N(R)—, —C 1-4 alkylene-N(R)—C 1-4 alkylene-, —C 1-4 alkylene-C(═O)—O—C 1-4 alkylene-, —C 1-4 alkylene-O—C(═O)—C 1-4 alkylene-, —C 1-4 alkylene-C(═O)—N(R)—C 1-4 alkylene-, —C 1-4 alkylene-N(R)—C(═O)—C 1-4 alkylene-, —C(═O)—N(R)—C 1-4 alkylene-SO 2 N(R)—, or —N(R)—C(═O)—C 1-4 alkylene-SO 2 N(R)—;
wherein for the purpose of Y 2 , R is H, C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl, or is methylene or ethylene that forms a 5- or 6-membered heterocycle with a carbon atom of Y 3 ;
Y 3 is aryl or heteroaryl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Y 4 is optionally present, and when present is aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
any methylene group of the o, p, and q regions and Y 2 is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl;
R 6 is absent;
wherein S, T, U, and V are carbon;
with the proviso that when p is 0, Y 2 is —C(═O)N(H)— or —OC(H) 2 C(═O)N(H)—, and Y 3 is phenyl or pyridinyl, then either Y 4 is present or any substituent on Y 3 is not —C(═O)NH 2 ; and
with the proviso that the compound is NOT
1-(6-methoxy-3-pyridyl)-3-[[4-(3-pyridylmethoxy)phenyl]methyl]urea,
ethyl 3-(pyridin-3-yl)-4-({4-[(3-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzyl)oxy]phenyl}sulfonyl)butanoate;
4-({4-(3-[(3-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzyl)oxy]phenyl}sulfonyl)-3-[4-(trifluoromethyl)phenyl]butanoic acid;
3-phenyl-4-({4-[(3-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzyl)oxy]phenyl}sulfonyl)butanoic acid;
3-(4-chloro-3-fluorophenyl)-4-[(4-{[3-{[(pyridin-3-ylmethyl)carbamoyl]amino}-5-(trifluoromethyl)benzyl]oxy}phenyl)sulfonyl]butanoic acid;
3-phenyl-4-[(4-{[3-{[(pyridin-3-ylmethyl)carbamoyl]amino}-5-(trifluoromethyl)benzyl]oxy}phenyl) sulfonyl]butanoic acid;
3-(pyridin-3-yl)-4-({4-[(3-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzyl)oxy]phenyl}sulfonyl)butanoic acid;
4-({4-[(4-fluoro-3-{[(pyridin-3-ylmethyl)carbamoyl]amino}benzyl)oxy]phenyl}sulfonyl)-3-(pyridin-3-yl)butanoic acid;
Benzoic acid, 2-hydroxy-4-[[(3-pyridinylamino)carbonyl]amino]-, phenyl ester,
Benzamide, N-(3-amino-4-pyridinyl)-4-[[[[(3-pyridinylmethyl)amino]carbonyl]amino]methyl]-,
Benzamide, N-(2-amino-3-pyridinyl)-4-[[[[(3-pyridinylmethyl)amino]carbonyl]amino]methyl]-,
Benzamide, N-(2-amino-5-fluorophenyl)-4-[[[[(3-pyridinylmethyl)amino]carbonyl]amino]methyl]-,
Benzamide, N-(2-hydroxyphenyl)-4-[[[[(3-pyridinylmethyl)amino]carbonyl]amino]methyl]-,
Benzamide, N-(2-amino-5-chlorophenyl)-4-[[[[(3-pyridinylmethyl)amino]carbonyl]amino]methyl]-,
Benzamide, 2-chloro-5-nitro-N-[4-[[(4-pyridinylamino)carbonyl]amino]phenyl]-,
Benzamide, N-[4-[[[3-(diethylamino)propyl]amino]carbonyl]phenyl]-4-[[(3-pyridinylamino)carbonyl]amino]-,
Benzamide, N-(2-aminophenyl)-4-[[[(3-pyridinylamino)carbonyl]amino]methyl]-,
Benzamide, N-(2-aminophenyl)-4-[2-[[[(3-pyridinylmethyl)amino]carbonyl]amino]ethyl]-,
Benzamide, N-(2-aminophenyl)-4-[[[[(3-pyridinylmethyl)amino]carbonyl]amino]methyl]-,
Benzoic acid, 2-hydroxy-4-[[(3-pyridinylamino)carbonyl]amino]-, phenyl ester,
1,3-Benzenedicarboxamide, N,N′-bis[3-(diethylamino)propyl]-5-[[4-[[(4-pyridinylamino)carbonyl]amino]benzoyl]amino]-,
Urea, N-[4-(phenylmethoxy)phenyl]-N′-[2-(3-pyridinyl)ethyl]-,
Urea, N-[4-(phenylmethoxy)phenyl]-N′-3-pyridinyl-,
Urea, N-(6-methyl-3-pyridinyl)-N′-[2-[2-(phenylmethoxy)phenyl]ethyl]-,
Urea, N-(6-methoxy-3-pyridinyl)-N′-[4-(phenylmethoxy)phenyl]-,
N4-[[4-[[[(2,6-dichloro-4-pyridinyl)amino]carbonyl]amino]phenyl]methyl]-N6-[(3-methoxyphenyl)methyl]-4,6-pyrimidinedicarboxamide,
Benzenesulfonamide, 4-fluoro-N-[4-[[(3-pyridinylamino)carbonyl]amino]phenyl]-, or
Hexanamide, 2-[2,4-bis(1,1-dimethylpropyl)phenoxy]-N-[2-chloro-4-[[[(2-chloro-3-pyridinyl)amino]carbonyl]amino]-5-hydroxyphenyl]-.
2 . The compound of claim 1 , wherein the structure is according to Formula IIIb1
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
Y 3 is aryl or heteroaryl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Y 4 is optionally present, and when present is aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
any methylene group of the o, p, and q regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl; and
R 3 and R 4 are each independently H, halo, or C 1-4 alkyl, or R 3 and R 4 , taken together with the carbon to which they are attached, form a cyclopropyl or cyclobutyl ring.
3 . The compound of claim 1 , wherein the structure is according to Formula IIIb4
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
Y 4 is optionally present, and when present is aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
R 1 , if present one or more times, is independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R 3 and R 4 are each independently H, halo, or C 1-4 alkyl, or R 3 and R 4 , taken together with the carbon to which they are attached, form a cyclopropyl or cyclobutyl ring; and
any methylene group of the o, p, and q regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
4 . The compound of claim 1 , wherein the structure is according to Formula IIIb7
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
o, p, and q are each independently 0, 1, or 2;
R 1 and R 5 , if one or both are present one or more times, are each independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R 3 and R 4 are each independently H, halo, or C 1-4 alkyl, or R 3 and R 4 , taken together with the carbon to which they are attached, form a cyclopropyl or cyclobutyl ring; and
any methylene group of the o, p, and q regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
5 . The compound of claim 1 , wherein the structure is according to Formula IIIb2
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
Y 3 is aryl or heteroaryl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Y 4 is optionally present, and when present is aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
any methylene group of the o, p, and q regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl; and
R 2 is H, halo, C 1-5 alkyl, C 1-5 alkenyl, or C 1-5 alkynyl.
6 . The compound of claim 1 , wherein the structure is according to Formula IIIb5
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
Y 4 is optionally present, and when present is aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
R 1 , if present one or more times, is independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R 2 is H, halo, C 1-5 alkyl, C 1-5 alkenyl, or C 1-5 alkynyl; and
any methylene group of the o, p, and q regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
7 . The compound of claim 1 , wherein the structure is according to Formula IIIb8
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
o, p, and q are each independently 0, 1, or 2;
R 1 and R 5 , if one or both are present one or more times, are each independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R 2 is H, halo, C 1-5 alkyl, C 1-5 alkenyl, or C 1-5 alkynyl; and
any methylene group of the o, p, and q regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
8 . The compound of claim 1 , wherein the structure is according to Formula IIIb3
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
Y 3 is aryl or heteroaryl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
Y 4 is optionally present, and when present is aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
u is 0 or 1; and
any methylene group of the o, p, q, and u regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
9 . The compound of claim 1 , wherein the structure is according to Formula IIIb6
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
Y 4 is optionally present, and when present is aryl, heteroaryl, carbocycle, or heterocycle, wherein any ring atom is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, trihalomethyl, C 1-5 alkoxy, C-amido, N-amido, sulfonamide, amino, aminosulfonyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
o, p, and q are each independently 0, 1, or 2;
u is 0 or 1;
R 1 , if present one or more times, is independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
any methylene group of the o, p, q, and u regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
10 . The compound of claim 1 , wherein the structure is according to Formula IIIb9
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
o, p, and q are each independently 0, 1, or 2;
u is 0 or 1;
R 1 and R 5 , if one or both are present one or more times, are each independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
any methylene group of the o, p, q, and u regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
11 . The compound of claim 1 , wherein the structure is according to Formula IIIb10
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
o, p, and q are each independently 0, 1, or 2;
R 1 and R 5 , if one or both are present one or more times, are each independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R 3 and R 4 are each independently H, halo, or C 1-4 alkyl, or R3 and R4, taken together with the carbon to which they are attached, form a cyclopropyl or cyclobutyl ring; and
S, T, U, and V are carbon.
12 . The compound of claim 1 , wherein the structure is according to Formula IIIb11
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
R 6 is absent;
o, p, and q are each independently 0, 1, or 2;
R 1 , if one or both are present one or more times, is independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino;
R 2 is H, halo, C 1-5 alkyl, C 1-5 alkenyl, or C 1-5 alkynyl;
any methylene group of the o, p, and q regions is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl; and
S, T, U, and V are carbon.
13 . The compound of claim 1 , wherein the structure is according to Formula IIIc
and pharmaceutically acceptable salts and solvates thereof;
wherein:
Y is 3-pyridinyl or 4-pyridinyl, wherein any ring carbon is optionally independently substituted with halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamide, amino, hydroxyl, mercapto, alkylthio, sulfonyl, or sulfinyl;
Y 2 is —OCH 2 —, —SCH 2 —, —N(R)CH 2 —, —N(R)C(═O)—, —C(═O)N(R)—, —S(═O) 2 CH 2 —, —S(═O)CH 2 —, —CH 2 O—, —CH 2 CH 2 O—, —CH 2 S—, —CH 2 N(R)—, —CH 2 S(═O) 2 —, —CH 2 S(═O)—, —C(═O)O—, —OC(═O)—, —SO 2 N(R)—, —N(R)SO 2 —, ethylene, propylene, n-butylene, —O—C 1-4 alkylene-N(R)C(═O)—, —O—C 1-4 alkylene-C(═O)N(R)—, —N(R)C(═O)—C 1-4 alkylene-O—, —C(═O)N(R)—C 1-4 alkylene-O—, —C 1-4 alkylene-S(═O) 2 —, —C 1-4 alkylene-S(═O)—, —S(═O) 2 —C 1-4 alkylene-, —S(═O)—C 1-4 alkylene-, —C 1-4 alkylene-SO 2 N(R)—, —C 1-4 alkylene-N(R)SO 2 —, —SO 2 N(R)—C 1-4 alkylene-, —N(R)SO 2 —C 1-4 alkylene-, —C 1-4 alkylene-O—C 1-4 alkylene-, —O—C 1-4 alkylene-, —C 1-4 alkylene-O—, —S—C 1-4 alkylene-, —C 1-4 alkylene-S—, —C 1-4 alkylene-S—C 1-4 alkylene-, —N(R)—C 1-4 alkylene-, —C 1-4 alkylene-N(R)—, —C 1-4 alkylene-N(R)—C 1-4 alkylene-, —C 1-4 alkylene-C(═O)—O—C 1-4 alkylene-, —C 1-4 alkylene-O—C(═O)—C 1-4 alkylene-, —C 1-4 alkylene-C(═O)—N(R)—C 1-4 alkylene-, —C 1-4 alkylene-N(R)—C(═O)—C 1-4 alkylene-, —C(═O)—N(R)—C 1-4 alkylene-SO 2 N(R)—, or —N(R)—C(═O)—C 1-4 alkylene-SO 2 N(R)—;
wherein for the purpose of Y 2 , R is H, C 1-5 alkyl, C 1-5 alkenyl, or C 1-5 alkynyl;
R 6 is absent;
o, p, and q are each independently 0, 1, or 2;
R 1 and R 5 , if one or both are present one or more times, are each independently selected from halo, C 1-5 alkyl, nitro, cyano, C 1-5 alkoxy, C-amido, N-amido, trihalomethyl, C-carboxy, O-carboxy, sulfonamide, amino, aminoalkyl, hydroxyl, mercapto, alkylthio, sulfonyl, and sulfinyl, wherein C 1-5 alkyl, C 1-5 alkoxy, C-amido, N-amido, amino, aminoalkyl, and alkylthio are each optionally substituted with heterocyclo, cycloalkyl, or amino; and
any methylene group of the o, p, and q regions, or Y 2 , is optionally independently substituted with C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3 or C 4 cycloalkyl.
14 . A compound selected from Tables 1, 2, 3, or 4, or a pharmaceutically-acceptable salt thereof.
15 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
16 . A method of treating cancer, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient.
17 . A method of treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, ischemia, and other complications associated with these diseases and disorders, in a human patient, comprising identifying a patient in need of such treatment and administering a therapeutically effective amount of a compound of claim 1 .
18 . A method of delaying the onset, or reducing the severity of, one or more symptoms of cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, ischemia, and other complications associated with these diseases and disorders, in a human patient, comprising identifying a patient in need of such treatment and administering a therapeutically effective amount of a compound of claim 1 .
19 . A method of inhibiting the activity of Nampt in human cells comprising, contacting said cells with a compound of claim 1 .