Phosphorus derivatives as histone deacetylase inhibitors
View Patent ↗The present invention relates to a novel class of phosphorus derivatives. The phosphorus compounds can be used to treat cancer. The phosphorus compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the phosphorus derivatives and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the phosphorus derivatives in vivo.
1. A compound represented by Formula I:
Wherein
Ring A is a 5- to 6- membered heteroaryl or 6-membered aryl;
With the proviso that Ring A is not tetrahydro-dioxo-pyrimidinyl;
Ring B is heteroaryl or aryl;
M is selected from:
D is a P(O) containing heterocyclyl, wherein the heterocyclyl is optionally substituted with at least one R 11 ;
R 1 and R 2 are independently selected from —OR, —NR 7 R 8 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 alkenyl, substituted or unsubstituted C 1 -C 10 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, —(CR a 2 ) r R 9 ,
—ORC(O)OR, —O(CR a 2 ) r R 9 , —O(CR a 2 ) r C(O)NR 7 R 8 , —O(CR a 2 ) r NR 7 R 8 , and —O(CR a 2 ) r OR;
or R 1 and R 2 together with the phosphorous atom to which they are attached form a phosphorous-containing heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R 11 ;
or R 2 and R 6 together with the phosphorous and C atom to which they are respectively attached, form a heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R 11 ;
or R 1 and R 4 together with the phosphorous and C atom to which they are respectively attached, form a heterocyclic ring, wherein the heterocyclic ring is optionally substituted with at least one R 11 ;
R 3 is independently selected from hydrogen, —OR, —NR 7 R 8 , —NO 2 , —CN, —C(O)NR 7 R 8 , —NR 7 R 8 C(O)R, C(O), C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl-C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl-NHSO 2 -, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 ) alkylamino;
R 4 and R 6 are independently of each other hydrogen, —OR, —NR 7 R 8 , halo, —CN, —C(O)NR 7 R 8 , —NR 7 R 8 C(O)R, —C(O)OR, —P(O)(OR) 2 , oxo, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 4 alkenyl, substituted or unsubstituted C 1 -C 4 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic or substituted or unsubstituted aryl;
or R 4 and R 6 together with the C atom to which they are attached form a heterocyclic or carbocyclic ring, which can be optionally substituted with at least one R 11 ;
R 5 is independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino and L 2 -R 9 ,
R 7 and R 8 are independently selected from hydrogen, C 1 -C 7 alkyl, —C(O)O—C 1 —C 7 alkyl, —P(O)CR a 2 , —P(O)(OR) 2 , —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, —(CR a 2 ) r C 3 -C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 9 is independently selected from hydrogen, C 1 -C 7 alkyl, heteroaryl, heterocyclic, aryl, and C 3 -C 8 cycloalkyl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 11 is independently selected from OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl-C(═O)O—, C 1 -C 7 alkyl-C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R is independently H, C 1 -C 7 alkyl, or C 3 -C 10 cycloalkyl, where alkyl or cycloalkyl is optionally substituted with at least one R 11 ;
R a is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
L l is (CH 2 ) r , ethenyl or cyclopropyl;
L 2 is independently selected from a bond, C 1 -C 4 alkylene, C 1 -C 4 alkynyl, C 1 -C 4 alkenyl, —O—, —S—, —N—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)NH—, —SO 2 NH—, —NHSO 2 —, —SO 2 —, —C(═O)—and —C(═O)O—;
L 3 is a bond, —(CR a 2 ) r C(O)(CR a 2 ) r —, —(CR a 2 ) r O(CR a 2 ) r —, —(CR a 2 ) r C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)(CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r OC(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)O(CR a 2 ) r —, —(CR a 2 ) r NR 7 (CR a 2 ) r —, or —(CR 4 R 6 ) n —;
L 4 is a bond, —(CR a 2 ) r C(O)(CR a 2 ) r —, —(CR a 2 ) r O(CR a 2 ) r —, —(CR a 2 ) r C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)(CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r OC(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)O(CR a 2 ) r —, —(CR a 2 ) r NR 7 (CR a 2 ) r —, or —(CR 4 R 6 ) n —;
X is NH 2 ;
Z is a bond, heteroaryl, heterocyclic, aryl, or C 3 -C 8 cycloalkyl, where heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
n is 0, 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
r is independently 0, 1, 2 or 3;
t is 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 ,
Wherein
Ring A is a 5- to 6- membered heteroaryl or 6-membered aryl;
With the proviso that Ring A is not tetrahydro-dioxo-pyrimidinyl;
Ring B is heteroaryl or aryl;
M is selected from:
R 1 and R 2 are independently selected from —OR, —NR 7 R 8 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 alkenyl, substituted or unsubstituted C 1 -C 10 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, —(CR a 2 ) r R 9 , —ORC(O)OR, —O(CR a 2 ) r R 9 , —O(CR a 2 ) r C(O)NR 7 R 8 , —O(CR a 2 ) r NR 7 R 8 , and —O(CR a 2 ) r OR;
or R 1 and R 2 together with the phosphorous atom to which they are attached form a phosphorous-containing heterocyclic ring, optionally substituted with at least one R 11 ;
or R 2 and R 6 together with the phosphorous and C atom to which they are respectively attached, form a heterocyclic ring, optionally substituted with at least one R 11 ;
or R 1 and R 4 together with the phosphorous and C atom to which they are respectively attached, form a heterocyclic ring, optionally substituted with at least one R 11 ;
R 3 is independently selected from hydrogen, —OR, —NR 7 R 8 , —NO 2 , —CN, —C(O)NR 7 R 8 , —NR 7 R 8 C(O)R, C(O), C 1 —C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R 4 and R 6 are independently of each other hydrogen, —OR, —NR 7 R 8 , halo, —CN, —C(O)NR 7 R 8 , —NR 7 R 8 C(O)R, C(O)OR, —P(O)(OR) 2 , oxo, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 4 alkenyl, substituted or unsubstituted C 1 -C 4 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic or substituted or unsubstituted aryl;
or R 4 and R 6 together with the C atom to which they are attached form a heterocyclic or carbocyclic ring, optionally substituted with at least one R 11 ;
R 5 is independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 —C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino and L 2 -R 9 , R 7 and R 8 are independently selected from hydrogen, C 1 -C 7 alkyl, —C(O)O—C 1 -C 7 alkyl, —P(O)CR a 2 , —P(O)(OR) 2 , —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, —(CR a 2 ) r C 3 -C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 9 is independently selected from hydrogen, C 1 -C 7 alkyl, heteroaryl and aryl, where alkyl, heteroaryl or aryl is optionally substituted with at least one R 11 ;
R 10 is independently selected from hydrogen, C 1 -C 7 alkyl, —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, -(CR a 2 ) r C 3 -C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 11 is independently selected from OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R is independently H, C 1 -C 7 alkyl, or C 3 -C 10 cycloalkyl, where alkyl or cycloalkyl is optionally substituted with at least one R 11 ;
R a is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
R b is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
L 1 is (CH 2 ) r , ethenyl or cyclopropyl;
L 2 is independently selected from a bond, C 1 -C 4 alkylene, C 1 -C 4 alkynyl, C 1 -C 4 alkenyl, —O—, —S—, —N—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)NH—, —SO 2 NH—, —NHSO 2 —, —SO 2 —, —C(═O)— and —C(═O)O—;
L 3 is a bond, —(CR a 2 ) r C(O)(CR a 2 ) r —, —(CR a 2 ) r O(CR a 2 ) r , —(CR a 2 ) r C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)(CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r OC(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)O(CR a 2 ) r —, —(CR a 2 ) r NR 7 (CR a 2 ) r —, or —(CR 4 R 6 ) n —;
L 4 is a bond, —(CR a 2 ) r C(O)(CR a 2 ) r —, —(CR a 2 ) r O(CR a 2 ) r , —(CR a 2 ) r C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)(CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r OC(O)NR 7 (CR a 2 ) r —, —(CR a 2 ) r NR 7 C(O)O(CR a 2 ) r —, —(CR a 2 ) r NR 7 (CR a 2 ) r —, or —(CR 4 R 6 ) n —;
X is NH 2 ;
Z is a bond, heteroaryl, heterocyclic, aryl, or C 3 -C 8 cycloalkyl, where heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
n is 0, 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
q is 1 or 2;
r is independently 0, 1, 2 or 3;
t is 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
3. The compound of claim 2 ,
Wherein
Ring A is a 5- to 6- membered heteroaryl or 6-membered aryl;
With the proviso that Ring A is not tetrahydro-dioxo-pyrimidinyl;
Ring B is heteroaryl or aryl;
M is selected from:
R l and R 2 are independently selected from —OR, —NR 7 R 8 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 alkenyl, substituted or unsubstituted C 1 -C 10 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, —(CR a 2 ) r R 9 , —ORC(O)OR, —O(CR a 2 ) r R 9 , —O(CR a 2 ) r C(O)NR 7 R 8 , —O(CR a 2 ) r NR 7 R 8 , and —O(CR a 2 ) r OR;
or R 1 and R 2 together with the phosphorous atom to which they are attached form a phosphorous-containing heterocyclic ring;
or R 2 and R 6 together with the phosphorous and C atom to which they are respectively attached, form a heterocyclic ring;
or R 1 and R 4 together with the phosphorous and C atom to which they are respectively attached, form a heterocyclic ring;
R 3 is independently selected from hydrogen, —OR, —NR 7 R 8 , —NO 2 , —CN, —C(O)NR 7 R 8 , —NR 7 R 8 C(O)R, C(O), C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R 4 and R 6 are independently of each other hydrogen, —OR, —NR 7 R 8 , halo, —CN, —C(O)NR 7 R 8 , —NR 7 R 8 C(O)R, —C(O)OR, —P(O)(OR) 2 , oxo, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 4 alkenyl, substituted or unsubstituted C 1 -C 4 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic or substituted or unsubstituted aryl;
or R 4 and R 6 together with the C atom to which they are attached form a heterocyclic or carbocyclic ring;
R 5 is independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino and L 2 -R 9 ,
R 7 and R 8 are independently selected from hydrogen, C 1 -C 7 alkyl, —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, —(CR a 2 ) r C 3 -C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 9 is independently selected from hydrogen, C 1 -C 7 alkyl, heteroaryl, heterocyclic, aryl, and C 3 -C 8 cycloalkyl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 10 is independently selected from hydrogen, C 1 -C 7 alkyl, —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, —(CR a 2 ) r C 3 -C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 11 is independently selected from OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R is independently H, C 1 -C 7 alkyl, or C 3 -C 10 cycloalkyl, where alkyl or cycloalkyl is optionally substituted with at least one R 11 ;
R a is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
R b is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
L 1 is (CH 2 ) r , ethenyl or cyclopropyl;
L 2 is independently selected from a bond, C 1 -C 4 alkylene, C 1 -C 4 alkynyl, C 1 -C 4 alkenyl, —O—, —S—, —N—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)NH—, —SO 2 NH—, —NHSO 2 —, —SO 2 —, —C(═O)—and —C(═O)O—;
L 3 is a bond, —(CR a 2 ) r C(O)—, —(CR a 2 ) r O—, —(CR a 2 ) r C(O)NR 7 —, —(CR a 2 ) r NR 7 C(O)—, —(CR a 2 ) r NR 7 C(O)NR 7 —, —(CR a 2 ) r OC(O)NR 7 —, —(CR a 2 ) r NR 7 C(O)O—, —(CR a 2 ) r NR 7 —, or —(CR 4 R 6 ) n —;
L 4 is a bond, —(CR a 2 ) r C(O)—, —(CR a 2 ) r O—, —(CR a 2 ) r C(O)NR 7 —, —(CR a 2 ) r NR 7 C(O)—, —(CR a 2 ) r NR 7 C(O)NR 7 —, —(CR a 2 ) r OC(O)NR 7 —, —(CR a 2 ) r NR 7 C(O)O—, —(CR a 2 ) r NR 7 —, or —(CR 4 R 6 ) n —;
X is NH 2 ;
Z is a bond, heteroaryl, heterocyclic, aryl, or C 3 -C 8 cycloalkyl, where heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
n is 0,1,2,3or 4;
p is 1, 2, 3 or 4;
q is 1 or 2;
r is independently 0, 1, 2 or 3;
t is 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
4. The compound of claim 3 ,
Wherein
Ring A is a 5- to 6- membered heteroaryl or 6-membered aryl;
With the proviso that Ring A is not tetrahydro-dioxo-pyrimidinyl;
Ring B is heteroaryl or aryl;
M is selected from:
R 1 and R 2 are independently selected from —OR, —NR 7 R 8 , unsubstituted C 1 -C 10 alkyl, unsubstituted C 3 -C 10 cycloalkyl, —(CR a 2 ) r R 9 , —ORC(O)OR, —O(CR a 2 ) r R 9 , —O(CR a 2 ) r C(O)NR 7 R 8 , —O(CR a 2 ) r NR 7 R 8 , and —O(CR a 2 ) r OR;
or R 1 and R 2 together with the phosphorous atom to which they are attached form a phosphorous-containing heterocyclic ring;
R 3 is hydrogen;
R 4 and R 6 are independently of each other hydrogen, —OR, —NH 2 , halo, —CN, —C(O)NH 2 , —NH 2 C(O)R, —C(O)OR, —P(O)(OR) 2 , oxo, or unsubstituted C 1 -C 6 alkyl;
R 5 is L 2 -R 9 ;
R 7 and R 8 are independently selected from hydrogen, C 1 -C 7 alkyl —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, —(CR a 2 ) r C 3 —C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 9 is independently selected from hydrogen, C 1 -C 7 alkyl, heteroaryl and aryl, where heteroaryl, aryl or alkyl is optionally substituted with at least one R 11 ;
R 10 is independently selected from unsubstituted C 1 -C 7 alkyl and unsubstituted aryl;
R 11 is independently selected from C 1 -C 7 alkyl, halo, CF 3 , OH and C 1 -C 7 alkoxy;
R is independently H, C 1 -C 7 alkyl, or C 3 -C 10 cycloalkyl, where alkyl or cycloalkyl is optionally substituted with at least one R 11 ;
R a is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
R b is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
L 1 is (CH 2 ) r or ethenyl;
L 2 is a bond;
L 3 is a bond, —(CR a 2 ) r O—, —(CR a 2 ) r C(O)—, —(CR a 2 ) r NR 7 —, —(CR 4 R 6 ) n —;
L 4 is a bond or —(CR 4 R 6 ) n —;
X is NH 2 ;
Z is a bond, heteroaryl, heterocyclic, aryl, or C 3 -C 8 cycloalkyl, where heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
n is 0, 1 or 2;
p is 1, 2, 3 or 4;
q is 1 or 2;
r is independently 0, 1, 2 or 3;
t is 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
5. A compound represented by Formula II:
wherein R 1 and R 2 are independently selected from OH, NR 7 R 8 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 alkenyl, substituted or unsubstituted C 1 -C 10 alkynyl, substituted or unsubstituted C 1 -C 10 alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic and substituted or unsubstituted aryl;
or R 1 and R 2 together with the phosphorous atom to which they are attached form a phosphorous-containing heterocyclic ring;
or R 2 and R 6 together with the phosphorous and Y atom to which they are respectively attached, form a heterocyclic ring;
or R 1 and R 4 together with the phosphorous and Y atom to which they are respectively attached, form a heterocyclic ring;
R 3 is independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R 4 and R 6 are independently of each other hydrogen, OH, NR 7 R 8 , halo or substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkenyl, substituted or unsubstituted C 1 -C 4 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic or substituted or unsubstituted aryl;
or R 4 and R 6 together with the Y atom to which they are attached form a heterocyclic or carbocyclic ring;
R 5 is independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino and L 2 -R 9 , wherein R 9 is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted C 3 -C 8 cycloalkyl, L 2 is selected from a bond, C 1 -C 4 alkylene, C 1 -C 4 alkynyl, C 1 -C 4 alkenyl, —O—, —S—, —N—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)NH—, —SO 2 NH—, —NHSO 2 —, —SO 2 —, —C(═O)— and —C(═O)O—;
R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic and substituted or unsubstituted aryl;
Ring A is a 5- to 6- membered heteroaryl or 6-membered aryl;
Ring B is heteroaryl or aryl;
n is 0, 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
t is 1, 2, 3 or 4;
L 1 is (CH 2 ) r , ethenyl or cyclopropyl, wherein r is 0, 1 or 2;
X is NH 2 ;
Y is C or N;
With the proviso that Ring A is not tetrahydro-dioxo-pyrimidinyl;
or a stereoisomer or pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , wherein R 1 and R 2 are independently selected from OH, NR 7 R 8 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted heteroaryl and substituted or unsubstituted aryl;
or R 1 and R 2 together with the phosphorous atom to which they are attached form a phosphorous-containing heterocyclic ring;
R 3 is independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R 4 and R 6 are independently of each other hydrogen, OH, NH 2 , halo or unsubstituted C 1 -C 4 alkyl;
or R 4 and R 6 together with the Y atom to which they are attached form a heterocyclic or carbocyclic ring;
R 5 is independently selected from hydrogen, OH, NH 2 , nitro, CN, amide, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl—C(═O)O—, C 1 -C 7 alkyl—C(═O)—, C 1 -C 7 alkynyl, halo, hydroxyalkoxy, C 1 -C 7 alkyl—NHSO 2 —, C 1 -C 7 alkyl—SO 2 NH—, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino, di(C 1 -C 7 )alkylamino and L 2 -R 9 , wherein R 9 is substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl, L 2 is selected from a bond, C 1 -C 4 alkylene, C 1 -C 4 alkynyl, C 1 -C 4 alkenyl, —O—, —S—, —N—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)NH—, —SO 2 NH—, —NHSO 2 —, —SO 2 —, —C(═O)—and —C(═O)O—;
R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted aryl;
Ring A is a 5- to 6- membered monocyclic heteroaryl or 6-membered monocyclic aryl;
Ring B is heteroaryl or aryl;
n is 0, 1, 2, 3 or 4;
p is 1, 2, 3 or 4;
t is 1, 2, 3 or 4;
L 1 is (CH 2 ), , ethenyl or cyclopropyl, wherein r is 0, 1 or 2;
X is NH 2 ;
Y is C or N;
With the proviso that Ring A is not tetrahydro-dioxo-pyrimidinyl;
or a stereoisomer or pharmaceutically acceptable salt thereof.
7. The compound of claim 3 , represented by the Formula IA:
Ring A is phenyl, pyridyl or pyrimidinyl;
Ring B is heteroaryl or aryl;
R 1 and R 2 are independently selected from —OR, unsubstituted C 1 -C 10 alkyl, unsubstituted C 3 -C 10 cycloalkyl, —(CR a 2 ) r R 9 and —O(CR a 2 ) r R 9 ;
R 3 is hydrogen;
R 4 and R 6 are independently of each other hydrogen, —OR, —NH 2 , halo, —CN, —C(O)NH 2 , —NH 2 C(O)R, —C(O)OR, —P(O)(OR) 2 , oxo, unsubstituted C 1 -C 6 alkyl;
R 5 is L2-R9;
R 7 is selected from hydrogen, C 1 -C 7 alkyl, —C(O)O—C 1 -C 7 alkyl, —P(O)CR a 2 , —P(O)(OR) 2 , —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, —(CR a 2 ) r C 3 -C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 9 is independently selected from hydrogen, C 1 -C 7 alkyl, heteroaryl and aryl, where heteroaryl, aryl or alkyl is optionally substituted with at least one R 11 ;
R 11 is independently selected from C 1 -C 7 alkyl, halo, haloalkyl, OH and C 1 -C 7 alkoxy;
R is independently H, C 1 -C 7 alkyl, or C 3 -C 10 cycloalkyl, where alkyl or cycloalkyl is optionally substituted with at least one R 11 ;
R a is independently selected from H and C 1 -C 7 alkyl, where C 1 -C 7 alkyl is optionally substituted with at least one R 11 ;
L 1 is (CH 2 ) r or ethenyl;
L 2 is a bond;
L 3 is a bond, —(CR a 2 ) r C(O)NR 7 —, —(CR a 2 ) r NR 7 C(O)—, —(CR a 2 ) r NR 7 C(O)NR 7 —, —(CR a 2 ) r OC(O)NR 7 —, —(CR a 2 ) r NR 7 C(O)O—, —(CR a 2 ) r NR 7 —or —(CR 4 R 6 ) n —;
L 4 is a bond or —(CR 4 R 6 ) n —;
X is NH 2 ;
Z is a bond;
n is 0, 1 or 2;
p is 1;
r is independently 0, 1, 2 or 3;
t is 1, 2, 3, or 4;
or a stereoisomer or pharmaceutically acceptable salt thereof.
8. The compound of claim 7 , represented by Formula IB,
R 1 and R 2 are independently selected from —OR and unsubstituted C 1 -C 4 alkyl;
R 4 and R 6 are hydrogen;
R 5 is L 2 -R 9 ;
R 7 is selected from hydrogen, C 1 -C 7 alkyl, —C(O)O—C 1 -C 7 alkyl, —P(O)CR a 2 , —P(O)(OR) 2 , —(CR a 2 ) r heteroaryl, —(CR a 2 ) r heterocyclic, —(CR a 2 ) r C 3 -C 8 cycloalkyl and —(CR a 2 ) r aryl, where alkyl, heteroaryl, heterocyclic, aryl or cycloalkyl is optionally substituted with at least one R 11 ;
R 9 is independently selected from hydrogen, heteroaryl and aryl, where heteroaryl or aryl is optionally substituted with at least one R 11 ;
R a is independently selected from H and unsubstituted C 1 -C 4 alkyl;
R is unsubstituted C 1 -C 4 alkyl;
L 3 is —(CR a 2 ) r C(O)NR 7 —, —(CR a 2 ) r OC(O)NR 7 —, or —(CR a 2 ) r NR 7 —;
L 4 is a bond or —(CR 4 R 6 ) n —;
n is 0, 1 or 2;
r is independently 0, 1, 2 or 3;
or a stereoisomer or pharmaceutically acceptable salt thereof.
9. The compound of claim 7 , wherein
R 10 , R 11 , and R 13 are independently of each other hydrogen or fluoro;
R 12 is hydrogen, substituted or unsubstituted phenyl or substituted or unsubstituted thienyl and X is amino.
10. The compound of claim 7 , wherein the
R 10 and R 11 are independently of each other hydrogen or fluoro;
R 12 is hydrogen, substituted or unsubstituted phenyl or substituted or unsubstituted thienyl and X is amino.
11. The compound of claim 9 or 10 , wherein R 12 is
R 17 and R 21 are independently selected from hydrogen and fluoro;
R 18 , R 19 or R 20 are independently selected from hydrogen, halo, methyl, methoxy and halomethyl.
12. The compound of claim 9 or 10 , wherein R 12 is
R 22 , R 23 and R 24 are independently selected from hydrogen, methyl, amino, hydroxyl, and halo.
13. The compound of claim 9 or 10 , wherein R 12 is
R 22 , R 23 and R 24 are independently selected from hydrogen, methyl, amino, hydroxyl and halo.
14. The compound of claim 12 , wherein Ring B is selected from phenyl, benzothiophenyl, benzofuranyl, thiazolyl, benzothiazolyl, furanyl, pyridyl, pyrimidyl, quinolinyl, thiophenyl, benzodioxyl, benzooxadiazolyl, quinoxalinyl, benzotriazolyl, benzoimidazolyl and benzooxazolyl.
15. The compound of claim 1 selected from:
Diethyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]phosphonate;
Diethyl [4 -({[2 -amino-5 -(3 -thienyl)phenyl]amino}carbonyl)phenyl]phosphonate;
Diethyl (4- {[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)phosphonate;
Diethyl(4- {[(4-amino- 1 -phenyl-1H-pyrazol-3 -yl)amino]carbonyl}phenyl)phosphonate;
Ethyl hydrogen [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]phosphonate;
Ethyl hydrogen (4- {[(4-amino-l-phenyl-1H-pyrazol-3 -yl)amino]carbonyl}phenyl) phosphonate;
Methyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]phenylphosphinate;
Methyl [4-({[2-amino-5 -(3 -thienyl)phenyl]amino }carbonyl)phenyl]phenylphosphinate;
Methyl (4- {[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)phenylphosphinate;
Ethyl [4 -({[2 -amino-5 -(2 -thienyl)phenyl]amino}carbonyl)phenyl]methylphosphinate;
Ethyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]phenylphosphinate;
Ethyl (4- {[(4-aminobiphenyl-3-yl)amino]carbonyl}phenyl)methylphosphinate;
Methyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)phenyl]methylphosphinate;
2-(ethylsulfonyl)ethyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methylphosphinate;
3-hydroxy-3-methylbutyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methylphosphinate;
Cyclobutyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methylphosphinate;
Ethyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyllethylphosphinate;
Ethyl [5-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)pyridin-2-yl]methylphosphinate;
N-(2-Amino-5-thiophen-2-yl-phenyl)-4-(diisopropyl-phosphinoyl)-benzamide;
N42-Amino-5-(2-thienyl)phenyl]-4-[(1-methyl-4-oxido-1,4-azaphosphinan-4-yl)methyl]benzamide;
N-(2-Amino-5-thiophen-2-yl-phenyl)-4-(dimethyl-phosphinoyl)-benzamide;
N-(2-Amino-5-phen-2-yl-phenyl)-4-(dimethyl-phosphinoyl)-benzamide;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phosphonic acid dimethyl ester;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phosphonic acid monomethyl ester;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phosphonic acid monoethyl ester;
[4-(4-Amino-1-phenyl-1H-pyrazol-3-ylcarbamoyl)-benzyl]-phosphonic acid diethyl ester;
[4-(2-Amino-5-thiophen-3-yl-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester;
N2-amino-5-(2-thienyl)phenyl]-4-[(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)methyl]benzamide;
Diisopropyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]phosphonate;
Diethyl [3-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]phosphonate;
Methyl tetrahydro-2H-pyran-4-ylmethyl[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl) benzyl]phosphonate;
Methyl P-[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]-N -1,3-thiazo 1-2-ylphosphonamidoate;
Ethyl {[[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl](methoxy)phosphoryl]oxy}acetate;
Diethyl (4- {[(4-aminobiphenyl-3-yl)amino]carbonyl}benzyl)phosphonate;
Methyl pyridin-3-ylmethyl[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]phosphonate;
Methyl P-[4-({[2-amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)benzyl]- N-benzylphosphonamidoate;
Methyl P-[4-({[2-amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)benzyl]-N-(pyridin-3-ylmethyl) phosphonamidoate;
Dib enzyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyl]phosphonate;
2-amino-2-oxoethyl methyl[4-({[2-amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)benzyl]phosphonate;
2-amino-2-methylpropyl methyl[4-({[2-amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)benzyl]phosphonate;
3 -hydroxy-3 -methylbutyl methyl[4-({[2-amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)benzyl]phosphonate;
Tetraethyl {[4-({[2-amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)phenyl]methylene}bis (phosphonate);
Diethyl [[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyll(cyano)methyl]phosphonate;
Methyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl](diethoxyphosphoryl)acetate;
Methyl 3-[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]-2-(dimethoxyphosphoryl) propanoate;
Diethyl {2-[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]-1-cyanoethyl}phosphonate;
Tetraethyl {2- [4-({[2 -amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)phenyl]ethane-1 , 1 -diyl }bis(phosphonate);
Diethyl {2-amino- 1 - [4-({[2-amino-5 -(2-thienyl)phenyl]amino 1 carbonyl)b enzyl]-2-oxoethyl }phosphonate;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phenyl-phosphinic acid methyl ester;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-phenyl-phosphinic acid;
[4-(2-Amino-5-thiophen-3-yl-phenylcarbamoyl)-benzyl]-phenyl-phosphinic acid methyl ester;
[4-(4-Amino-l-phenyl-1H-pyrazol-3-ylcarbamoyl)-benzyl]-phenyl-phosphinic acid methyl ester;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-methyl-phosphinic acid ethyl ester;
[4-(4-Amino-biphenyl-3-ylcarbamoyl)-benzyl]-methyl-phosphinic acid ethyl ester;
[4-(4-Amino-biphenyl-3-ylcarbamoyl)-benzyl]-methyl-phosphinic acid ethyl ester;
[4-(4-Amino-biphenyl-3-ylcarbamoyl)-benzyl]-methyl-phosphinic acid ethyl ester;
[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-benzyl]-methyl-phosphinic acid cyclobutyl ester;
Methyl [4-({[2-amino-5-(2-thienyl)-phenyl]amino}-carbonyl)benzyl]-methylphosphinate;
Isopropyl [4-({[2-amino-5 -(2-thienyl)-p henyl]amino }-c arbonyl)b enzyl]-methylpho sphinate;
N-[2-Amino-5 -(2-thienyl)phenyl]-4-({methyl [(pyridin-3 -ylmethyl)amino]-phosphoryl}methyl)-benzamide;
Pyridin-3 -ylmethyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino }-carbonyl)benzyl]methyl-phosphinate;
Methyl [4-({[2-amino-5 -(2-thienyl)-phenyl]amino }-carbonyl)benzyl]-ethylphosphinate;
Ethyl [4-({[2-amino-5 -(2-thienyl)-phenyl]amino}-carbonyl)benzyl]-ethylphosphinate;
Isopropyl [4-({[2-amino-5 -(2-thienyl)-phenyl]amino }-carbonyl)benzyl]-ethylphosphinate;
Cyclobutyl [4-({[2-amino-5 -(2-thienyl)-phenyl]amino }-carbonyl)benzyl]-ethylphosphinate;
N-[2-Amino-5 -(2-thienyl)phenyl]-4-({ethyl [(pyridin-3 -ylmethyl)amino]-phosphoryl}methyl)-benzamide;
Pyridin-3 -ylmethyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino }-carbonyl)benzyllethyl-phosphinate;
Cyclobutyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]phenylphosphinate;
Methyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl](4-fluorophenyl)phosphinate;
Methyl [3 -({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]phenylphosphinate;
Isopropyl [3 -({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]methylphosphinate;
Methyl [3 -({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]ethylphosphinate;
Ethyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyl]phenylphosphinate;
Isopropyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]phenylphosphinate;
2,2,2-trifluoroethyl[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]phenylphosphinate;
Ethyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyl]isopropylphosphinate;
Ethyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyl]cyclopropylphosphinate;
3 -hydroxy-3 -methylbutyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyl]phenylphosphinate;
2-amino-2-methylpropyl[4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyl]phenylphosphinate;
2-amino-2-oxoethyl[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]phenylphosphinate;
Methyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]cyclopropylphosphinate;
Methyl (5)- [4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]methylphosphinate;
Methyl (R)-[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]methylphosphinate;
Methyl (4- {[(4-aminobiphenyl-3 -yl)amino]carbonyl}benzyl)methylphosphinate;
3 -hydroxy-3 -methylbutyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]ethylphosphinate;
3-hydroxy-3-methylbutyl [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]methylphosphinate;
2-(ethylsulfonyl)ethyl[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]methylphosphinate;
Diethyl {[5 -({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)pyridin-2-yl]methyl}phosphonate;
Diethyl {[5 -({[2-amino-5 -(3 -thienyl)phenyl]amino}carbonyl)pyridin-2-yl]methyl}phosphonate;
Methyl {[5 -({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)pyridin-2-yl]methyl}phenylphosphinate;
Methyl {[5-({[2-amino-5-(3 -thienyl)phenyl]amino}carbonyl)pyridin-2-yl]methyl}phenylphosphinate;
{[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl]-hydroxy-methyl}-phosphonic acid dimethyl ester;
{1[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl]-1-fluoro-ethyl}-phosphonic acid dimethyl ester;
{1-[4-(2-Amino-5-thiophen-3-yl-phenylcarbamoyl)-phenyl]-1-fluoro-ethyl}-phosphonic acid dimethyl ester;
{1-[4-(4-Amino-biphenyl-3-ylcarbamoyl)-phenyl]-1-fluoro-ethyl}-phosphonic acid dimethyl ester;
{[4-(2-Amino-5-thiophen-3-yl-phenylcarbamoyl)-phenyl]-hydroxy-methyl}-phosphonic acid dimethyl ester;
{[4-(4-Amino-biphenyl-3-ylcarbamoyl)-phenyl]-hydroxy-methyl}-phosphonic acid dimethyl ester;
{[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl]-fluoro-methyl}-phosphonic acid dimethyl ester;
{Amino-[4-(2-amino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl]-methyl}-phosphonic acid dimethyl ester;
{[4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl]-hydroxy-methyl}-phenyl-phosphinic acid ethyl ester;
{1- [4-(2-Amino-5-thiophen-2-yl-phenylcarbamoyl)-phenyl]-1-fluoro-ethyl}-phenyl-phosphinic acid methyl ester;
{1-[4-(2-Amino-5-thiophen-3-yl-phenylcarbamoyl)-phenyl]-1-fluoro-ethyl}-phenyl-phosphinic acid methyl ester;
{1-[4-(4-Amino-biphenyl-3 -ylcarbamoyl)-phenyl]- 1 -fluoro-ethyl}-phenyl-phosphinic acid methyl ester;
{[4-(2-Amino-5-thiophen-3-yl-phenylcarbamoyl)-phenyl]-hydroxy-methyl}-phenyl-phosphinic acid ethyl ester;
{[4-(4-Amino-biphenyl-3-ylcarbamoyl)-phenyl]-hydroxy-methyl}-phenyl-phosphinic acid ethyl ester;
N-(2-Amino-5-thiophen-2-yl-phenyl)-4-(diisopropyl-phosphinoylmethyl)-benzamide;
N-(2-Amino-5-thiophen-2-yl-phenyl)-4-(diethyl-phosphinoylmethyl)-benzamide;
N-(2-Amino-5-thiophen-2-yl-phenyl)-4-(dimethyl-phosphinoylmethyl)-benzamide;
N-[2-Amino-5-(2-thienyl)phenyl]-3-[(diethylphosphoryl)methyl]benzamide;
N2-amino-5-(2-thienyl)phenyl]-4-[2-(dimethylphosphoryl)ethyl]benzamide;
Ethyl- {2-[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]ethyl}methyl phosphinate;
N-[2-Amino-5-(2-thienyl)phenyl]-4-[(3-methyl-3-oxido-2,4-dioxa-9-aza-3-phosphaspiro[5.5 ]undec-9-yl)methyl]benzamide;
N-[2-Amino-5-(2-thienyl)phenyl]-4-[(3-methyl-3-oxido-2,4-dioxa-9-aza-3-phosphaspiro[5.5 ]undec-9-yl)carbonyl]benzamide;
N-[2-Amino-5-(2-thienyl)phenyl]-6-(3-methyl-3-oxido-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undec-9-yl) nicotinamide;
N-[2-amino-5-(2-thienyl)phenyl]-6- {2-[bis(dimethylamino)phosphoryl]-2,8 -diazaspiro[4.5]dec-8-yl }nicotinamide;
N-[2-Amino-5-(2-thienyl)phenyl]-4-[(4-oxido-4-phenyl-1,4-azaphosphinan-l-yl)methyl]benzamide;
N-[2-Amino-5-(2-thienyl)phenyl]-4-[(4-oxido-4-phenyl-1,4-azaphosphinan-l-yl)carbonyl]benzamide;
N-[2-Amino-5-(2-thienyl)phenyl]-6-(4-oxido-4-phenyl-1,4-azaphosphinan-l-yl)nicotinamide;
N-[2-Amino-5-(2-thienyl)phenyl]-4-[(4-ethyl-4-oxido-1,4-azaphosphinan-1-yl)methyl]benzamide;
N-[2-Amino-5-(2-thienyl)phenyl]-4-[(4-ethyl-4-oxido-1,4-azaphosphinan-l-yl)carbonyl]benzamide;
N-[2-Amino-5-(2-thienyl)phenyl]-6-(4-ethyl-4-oxido-1,4-azaphosphinan-l-yl)nicotinamide;
N-(4-aminobiphenyl-3-yl)-4-[(4-oxido-4-phenyl-1,4-azaphosphinan-l-yl)methyl]benzamide;
N42-amino-5-(2-thienyl)phenyl]-4-[2-(4-oxido-4-phenyl-1,4-azaphosphinan-l-yl)ethyl]benzamide;
N42-amino-5-(2-thienyl)phenyl]-4-[2-(4-ethyl-4-oxido-1,4-azaphosphinan-l-yl)ethyl]benzamide;
N42-amino-5-(2-thienyl)phenyl]-4-2-(4-oxido-4-phenyl-1,4-azaphosphinan-l-yl)-2-oxoethyl]benzamide;
N42-amino-5-(2-thienyl)phenyl]-4-2-(4-ethyl-4-oxido-1,4-azaphosphinan-l-yl)-2-oxoethyl]benzamide;
N-[2-amino-5-(2-thienyl)phenyl]-4- {[[2-(dimethylphosphoryl)ethyl](methyl)amino]methyl}benzamide;
N-[2-amino-5-(2-thienyl)phenyl]-4- {[[2-(diisopropylphosphoryl) ethyl](methyl) amino]methyl}benzamide;
N-[2-amino-5-(2-thienyl)phenyl]-4- {[[2-(diphenylphosphoryl) ethyl](methyl)amino]ethyl}benzamide;
N42-amino-5-(2-thienyl)phenyl]-6-[[2-(dimethylphosphoryl) ethyl](methyl)amino]nicotinamide;
N42-amino-5-(2-thienyl)phenyl]-6-[[2-(diisopropylphosphoryl) ethyl](methyl)amino]nicotinamide;
N42-amino-5-(2-thienyl)phenyl]-6-[[2-(diphenylphosphoryl) ethyl](methyl)amino]nicotinamide;
N-[2-amino-5-(2-thienyl)phenyl]-N- [2-(dimethylphosphoryl)ethyl]-N-methylterephthalamide;
N-[2-amino-5-(2-thienyl)phenyl]-N-[2-(diisopropylphosphoryl) ethyl]-N-methylterephthalamide;
N-[2-amino-5-(2-thienyl)phenyl]-N- [2-(diphenylphosphoryl)ethyl]-N-methylterephthalamide;
N-[2-amino-5-(2-thienyl)phenyl]-6- {[2-(diisopropylphosphoryl) ethyl]amino]nicotinamide;
N42-amino-5-(2-thienyl)phenyl]-N-[2-(diisopropylphosphoryl) ethyl]terephthalamide;
N42-amino-5-(2-thienyl)phenyl]-4-({[2-(diisopropylphosphoryl) ethyl]amino}methyl) benzamide;
N-[2-amino-5-(2-thienyl)phenyl]-N-[2-(dimethylphosphoryl)ethyl]terephthalamide;
N42-amino-5-(2-thienyl)phenyl]-4-({[2-(dimethylphosphoryl) ethyl]amino}methyl) benzamide;
Methyl (4- {[(4-aminobiphenyl-3-yl)amino]carbonyl}benzyl)[2-(dimethylphosphoryl)ethyl]carbamate;
Diethyl {1 - [5 -({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)pyridin-2-yl]piperidin-4-yl}phosphonate;
Diethyl (1- {[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]methyl}pip eridin-4-yl) phosphonate;
Diethyl (1- {[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]carbonyl}piperidin-4-yl) phosphonate;
[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl dimethylphosphinate;
2-[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]ethyl ethyl methylphosphonate;
[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl ethylmethylphosphonate;
[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl methylphenylphosphonate;
N42-amino-5 -(2-thienyl)phenyl]-4 -({[(4R, 5 R)-4,5 -dimethyl-2-oxido- 1 ,3 ,2-dioxaphospholan-2-yl ]oxy}methyl)benzamide;
4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl dimethylphosphate;
1 -[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]ethyl ethyl methylphosphonate;
1 -[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]ethyl methyl methylphosphonate;
1 -[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]ethyl methyl phenylphosphonate;
4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl ethylphenylphosphonate;
2- [4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]ethyl dimethylphosphinate;
2- [4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]ethyl methyl methylphosphonate;
1 -[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]-2,2,2-trifluoro- 1 -(trifluoromethyl) ethyl dimethylphosphinate;
4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl dimethylphosphinate;
(4- {[(4-aminobiphenyl-3 -yl)amino]carbonyl}phenyl)methyldimethylphosphinate;
1 -[4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)phenyl]ethyldiethylphosphinate;
4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyldiethylphosphinate;
1 -[4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)phenyl]ethyldimethylphosphinate;
4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)benzyldiisopropylphosphinate;
1 -[4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)phenyl]ethyldiisopropylphosphinate;
Dimethyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)b enzyl]amidophosphate;
N2-amino-5 -(2-thienyl)phenyl]-4 -({[(4R, 5R)-4,5-dimethyl-2-oxido- 1,3,2 -dioxaphospholan-2-yl ]amino }methyl)benzamide;
N42-amino-5 -(2-thienyl)phenyl]-4 -({[bis(dimethylamino)pho sphoryl]amino }methyl) benzamide;
Dimethyl [4-({[2 -amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]amidophosphate;
Diethyl [4-({[2-amino-5 -(2 -thienyl)phenyl]amino }carbonyl)phenyl]amidophosphate;
Dimethyl [4-({[2 -amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]amidophosphate;
Dimethyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]methylamidophosphate;
Dimethyl (4- {[(4-aminobiphenyl-3 -yl)amino]carbonyl}phenyl)methylamidophosphate;
N42-amino -5 -(2-thienyl)phenyl]-4- [bis (dimethylpho sphoryl)amino]b enzamide ;
Dimethyl {[({[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)b enzyl]amino }carbonyl) oxy]methyl}phosphonate;
4-(dimethylphosphoryl)benzyl (4- {[(4-aminobiphenyl-3 -yl)amino]carbonyl}benzyl)carbamate;
[5 -(dimethylphosphoryl)pyridin-3 -yl]methyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)b enzyl]carbamate;
Diethyl ({[(4- {[(4-aminobiphenyl-3 -yl)amino]carbonyl}phenyl)methyl][(methyloxy)carbonyl]amino }methyl)phosphonate;
Diethyl {[({[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]amino}carbonyl) oxy]methyl}phosphonate;
Dimethyl {[({[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)b enzyl]amino }carbonyl) oxy]methyl}phosphonate;
Methyl {[({[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)b enzyl]amino }carbonyl) oxy]methyl}methylphosphinate;
Ethyl {[({[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]amino}carbonyl) oxy]methyl}methylphosphinate;
Ethyl {[({[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzyl]amino}carbonyl) oxy]methyl}ethylphosphinate;
(dimethylphosphoryl)methyl [4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)b enzyl]carbamate;
Diethyl (4- {[4-({[2-amino-5 -(2-thienyl)phenyl]amino }carbonyl)benzoyl]amino}phenyl)phosphonate;
Diethyl [({[4-({[2-amino-5 -(2-thienyl)phenyl]amino}carbonyl)phenyl]carbonyl}amino)methyl]phosphonate;
Diethyl [({[4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}amino) methyl]phosphonate;
N-[2-amino-5 -(2-thienyl)phenyl]-4- [(2s)-2-oxido-2-phenyl- 1 ,3 ,2-dioxaphosphinan-5 -yl]benzamide;
N42-amino-5 -(2-thienyl)phenyl]-4- [(2r)-2-oxido-2-phenyl- 1 ,3 ,2-dioxaphosphinan-5 -yl]benzamide;
N42-amino-5 -(2-thienyl)phenyl]-4- [(2s)-2-methyl-2-oxido- 1 ,3 ,2-dioxaphosphinan-5 -yl]benzamide;
N42-amino-5 -(2-thienyl)phenyl]-4- [(20-2-methyl-2-oxido- 1 ,3 ,2-dioxaphosphinan-5 -yl]benzamide;
Dimethyl [3 -((lE)-3 - {[2-amino-5-(2-thienyl)phenyl]amino}-3 -oxoprop- 1 -en-1 -yl)phenyl]phosphonate;
Ethyl [3 -41E)-3 - {[2-amino-5 -(2-thienyl)phenyl]amino }-3 -oxoprop- 1 -en- 1 -yl)phenyl]methylphosphinate;
Ethyl {3 -[4-({[2-({[(1 , 1 -dimethylethyl)oxy]carbonyl}amino)-5 -(2-thienyl)phenyl]amino }carbonyl)phenyl]-3 -oxopropyl}methylphosphinate; and
N42-amino-5 -(2-thienyl)phenyl]-4-(2-methyl-2-oxido- 1 ,2-oxaphospholan-5 -yl)benzamide or a pharmaceutically acceptable salt or stereoisomer thereof.
16. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.
17. A method for the treatment of cancer in a mammal comprising the step of administering to the mammal a therapeutically effective amount of the compound of claim 1 .