Claims for Patent: 8,293,897

Summary for Patent: 8,293,897

Title:	Compounds comprising a spiro-ring and methods of use
Abstract:	The present invention provides novel compounds useful in modulating the protein tyrosine kinase activity, and in modulating inter--and/or intra--cellular signaling. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
Inventor(s):	Xi; Ning (Thousand Oaks, CA)
Assignee:	Xi; Ning (Newbury Park, CA) Sunshine Lake Pharma Co., Ltd. (Northern Industrial Area, Songshan Lake, Dongguan, Guangdong, CN)
Application Number:	12/576,375
Patent Claims:	1. A compound of Formula (I): ##STR00084## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide or a pharmaceutically acceptable salt thereof, wherein: Q.sub.1 is formula (IIb): ##STR00085## Q.sub.2 is formula (III): ##STR00086## R.sup.1 is --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, R.sup.5S(.dbd.O)-alkyl, R.sup.5R.sup.5aN--C(.dbd.O)-alkyl, R.sup.5S(.dbd.O)-alkoxy, R.sup.5R.sup.5aN--C(.dbd.O)-alkoxy, hydroxy-substituted aminoalkoxy, amino-substituted haloalkoxy, hydroxy-substituted haloalkoxy, hydroxy-substituted cyclopropylalkoxy, R.sup.5S(.dbd.O).sub.2O-substituted cyclopropylalkoxy, heterocyclyl(aminoalkoxy), heteroaryl(hydroxyalkoxy), spiro bicyclyl, spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy, spiro bicyclylamino, spiro bicycloxoalkoxy, spiro heterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spiro bicyclyl --C(.dbd.O)N--, spiro bicyclyl-C(.dbd.O)O--, spiro heterobicyclyl-C(.dbd.O)--, spiro heterobicyclyl-C(.dbd.O)O--, spiro bicyclylamino-C(.dbd.O)N--, spiro heterobicyclylamino-C(.dbd.O)N--, spiro bicyclylN-C(.dbd.O)NR.sup.5N--, or spiro heterobicyclyl-C(.dbd.O)NR.sup.5--; or R.sup.1 is ##STR00087## ##STR00088## ##STR00089## wherein each of X.sub.4 and X.sub.4' is independently (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2; each of m and n is independently 0, 1 or 2; and t is 1, 2 or 3; R.sup.2 is H, halo, cyano, hydroxyl, R.sup.5aR.sup.5N--, --C(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)OR.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, R.sup.5aR.sup.5N-alkyl, R.sup.5(S.dbd.O)-alkyl, R.sup.5R.sup.5aN--(C.dbd.O)alkyl, R.sup.5aR.sup.5N-alkoxy, R.sup.5(S.dbd.O)-alkoxy, R.sup.5R.sup.5aN--(C.dbd.O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl, spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino, spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiro heterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spiro bicyclyl --C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)O--, spiro heterobicyclyl-C(.dbd.O)--, spiro heterobicyclyl-C(.dbd.O)O--, spiro bicyclylamino-C(.dbd.O)--, spiro heterobicyclylamino-C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)NR.sup.5--, or spiro heterobicyclyl-C(.dbd.O)NR.sup.5--, aryl, heteroaryl, arylaliphatic or heteroarylaliphatic, with the proviso that when alkoxy or alkylamino is substituted, each of alkoxy or alkylamino is independently substituted with one or more hydroxy groups, amino groups or substituted amino groups; R.sup.3 is H, F, Cl, Br, I, --CN, hydroxyl, R.sup.5aR.sup.5N--, aliphatic, alkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkyl aliphatic, cycloalkylalkoxy, or heterocyclylalkoxy; each of U.sub.1 and U.sub.2 is independently CR.sup.4 or N; V is NR.sup.5R.sup.5a, OR.sup.5, aliphatic, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic, or heteroarylaliphatic; each of W.sub.1, W.sub.2, W.sub.3 and W.sub.4 is independently CR.sup.4R.sup.4a, NR.sup.5, CR.sup.4 or N; X.sub.1 is (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2, where m is 0, 1 or 2; each of X.sub.2 and X.sub.3 is independently O, S or NR.sup.5; each of Z.sub.1 and Z.sub.2 is independently NR.sup.5 or CR.sup.4R.sup.4a; each of R.sup.4 and R.sup.4a is independently H, F, Cl, Br, I, --CN, hydroxyl, --NR.sup.5aR.sup.5, alkoxy, cycloalkoxy, heterocycloalkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl, with the proviso that where R.sup.4 and R.sup.4a are bonded to the same carbon atom, R.sup.4 and R.sup.4a, together with the carbon atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring; each of R.sup.5 and R.sup.5a is independently H, R.sup.6R.sup.6aNC(.dbd.O)--, R.sup.6OC(.dbd.O)--, R.sup.6C(.dbd.O)--, R.sup.6R.sup.6aNS(.dbd.O)--, R.sup.6OS(.dbd.O)N--, R.sup.6S(.dbd.O)--, R.sup.6R.sup.6aNSO.sub.2N--, R.sup.6OSO.sub.2--, R.sup.6SO.sub.2--, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl, with the proviso that where R.sup.5 and R.sup.5a are bonded to the same nitrogen atom, R.sup.5 and R.sup.5a, together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, including spiro and fused bicyclic rings; each of R.sup.6 and R.sup.6a is independently H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl; wherein each of R.sup.5aR.sup.5N--, --C(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)OR.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, OR.sup.5, NR.sup.5, CR.sup.4R.sup.4a, CR.sup.4, (CR.sup.4R.sup.4a).sub.m, --NR.sup.5C(O)--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5C(.dbd.S)--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5a--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5--(CR.sup.4R.sup.4a).sub.pC(.dbd.O)--, --NR.sup.5--(CR.sup.4R.sup.4a).sub.pC(.dbd.S)--, --NR.sup.5S(O).sub.r--, --NR.sup.5S(.dbd.O)(CR.sup.4R.sup.4a).sub.p--, --C(.dbd.O)NR.sup.5--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5--(CR.sup.4R.sup.4a).sub.p--S(.dbd.O),.sub.r--, R.sup.5aR.sup.5N-alky, R.sup.5S(.dbd.O)-alkyl, R.sup.5R.sup.5aN--C(.dbd.O)-alkyl, R.sup.5aR.sup.5N-alkoxy, R.sup.5S(.dbd.O).sub.r-alkoxy, R.sup.5R.sup.5aN--C(.dbd.O)--alkoxy, R.sup.6R.sup.6aNC(.dbd.O)--, R.sup.6OC(.dbd.O)--, R.sup.6C(.dbd.O)--, R.sup.6R.sup.6aNS(.dbd.O)--, R.sup.6OS(.dbd.O)--, R.sup.6S(.dbd.O)--, R.sup.6R.sup.6aNSO.sub.2--, R.sup.6OSO.sub.2--, R.sup.6SO.sub.2--, hydroxy-substituted cyclopropylalkoxy, R.sup.5S(.dbd.O).sub.2O-substituted cyclopropylalkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl, spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino, spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiro heterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spiro bicyclyl --C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)O--, spiro heterobicyclyl-C(.dbd.O)--, spiro heterobicyclyl-C(.dbd.O)O--, spiro bicyclylamino-C(.dbd.O)--, spiro heterobicyclylamino-C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)NR.sup.5--, or spiro heterobicyclyl-C(.dbd.O)NR.sup.5--, aryl, heteroaryl, arylaliphatic and heteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, heterocyclyl and carbocyclyl is independently substituted or unsubstituted. 2. The compound according to claim 1, wherein R.sup.3 is independently H, F, Cl, Br, --CN, C.sub.1-3 aliphatic, C.sub.1-3 alkoxy, or C.sub.1-3 haloalkyl. 3. The compound according to claim 1, wherein Q.sub.1 is ##STR00090## wherein Ar is substituted or unsubstituted aryl or heteroaryl; and s is 0 or 1. 4. The compound according to claim 1, wherein Q.sub.2 is ##STR00091## 5. The compound according to claim 1, wherein X.sub.1 is O or NR.sup.5. 6. The compound according to claim 1, wherein Z.sub.1 of formula (IIb) is NH; and the substructure defined by X.sub.1, U.sub.1 and R.sup.3 of Formula I is: ##STR00092## 7. The compound according to claim 1, wherein: R.sup.1 is --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, R.sup.5S(.dbd.O)-alkyl, R.sup.5R.sup.5aNC(.dbd.)--C.sub.1-6 alkyl, R.sup.5S(.dbd.O)--alkoxy, R.sup.5R.sup.5aNC(.dbd.O)-alkoxy, hydroxy-substituted C.sub.1-6aminoalkoxy, amino-substituted C.sub.1-6 haloalkoxy, hydroxy-substituted C.sub.1-6 haloalkoxy, C.sub.4-10heterocyclyl(aminoC.sub.1-6alkoxy), C.sub.1-10 heteroaryl(hydroxyalkoxy), hydroxy-substituted cyclopropyl C.sub.1-6alkoxy, R.sup.5S(.dbd.O).sub.2O-substituted cyclopropyl C.sub.1-6alkoxy, C.sub.5-12 spiro bicyclyl, C.sub.5-12 spiro heterobicyclyl, C.sub.5-12 spiro bicyclyl C.sub.1-6 aliphatic, C.sub.5-12 spiro heterobicyclyl C.sub.1-6 aliphatic, C.sub.5-12-spiro heterobicycloxo C.sub.1-6 alkoxy, C.sub.5-12 spiro heterobicyclylamino C.sub.1-6 alkoxy, C.sub.5-12 spiro bicyclyl --C(.dbd.O)--, C.sub.5-12 spiro bicyclyl-C(.dbd.O)O--, C.sub.5-12 spiro heterobicyclyl-C(.dbd.O)--, C.sub.5-12 spiro heterobicyclyl-C(.dbd.O)O--, C.sub.5-12 spiro bicyelylamino-C(.dbd.O)--, C.sub.5-12 spiro heterobicyclylamino-C(.dbd.O)--, C.sub.5-12 spiro bicyclyl-C(.dbd.O)NR.sup.5--, C.sub.5-12 spiro heterobicyclyl-C(.dbd.O)NR.sup.5--; or R.sup.1 is ##STR00093## ##STR00094## ##STR00095## wherein each of X.sub.4 and X.sub.4'is independently (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2; each of m and n is independently 0, 1 or 2; and t is 1, 2 or 3; and R.sup.2 is H, halo, cyano(CN), R.sup.5aR.sup.5N--C.sub.1-6 alkoxy, optionally substituted C.sub.1-6 alkoxy, C.sub.1-6 hydroxyalkoxy, C.sub.1-6 aminoalkoxy, C.sub.1-6 hydroxy-substituted aminoalkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6 alkylamino C.sub.1-6 alkoxy, C.sub.1-6 alkoxy C.sub.1-6 alkoxy, C.sub.4-10 heterocyclyloxy C.sub.1-6 alkoxy, C.sub.5-12 spiro bicyclyl, C.sub.5-12 spiro bicycloxy, C.sub.5-12 spiro bicyclylamino, C.sub.5-12 spiro bicycloxo C.sub.1-6 alkoxy, C.sub.5-12 spiro bicyclylamino C.sub.1-6 alkoxy, C.sub.5-12 fused heterobicyclyl, C.sub.5-12 fused heterobicycloxy, C.sub.5-12 fused heterobicyclylamino, C.sub.5-12 fused heterobicycloxo C.sub.1-6 alkoxy, C.sub.5-12 fused heterobicyclylamino C.sub.1-6 alkoxy, C.sub.5-12 spiro bicyclyl, C.sub.5-12 spiro heterobicyclyl, C.sub.5-12 spiro bicyclyl C.sub.1-6 aliphatic, C.sub.5-12 spiro heterobicyclyl C.sub.1-6 aliphatic, C.sub.5-12 spiro heterobicycloxo C.sub.1-6 alkoxy, C.sub.5-12 spiro heterobicyclylamino C.sub.1-6 alkoxy, C.sub.5-12 spiro bicyclyl --C(.dbd.O)--, C.sub.5-12 spiro bicyclyl-C(.dbd.O)O--, C.sub.5-12 spiro heterobicyclyl-C(.dbd.O)--, C.sub.5-12 spiro heterobicyclyl-C(.dbd.O)O--, C.sub.5-12 spiro bicyclylamino-C(.dbd.O)--, C.sub.5-12 spiro heterobicyclylamino-C(.dbd.O)--, C.sub.5-12 spiro bicyclyl-C(.dbd.O)NR.sup.5--, or C.sub.5-12 spiro heterobicyclyl-C(.dbd.O)NR.sup.5--, C.sub.6-10 aryl, C.sub.1-10 heteroaryl, C.sub.6-10 aryl C.sub.1-6 aliphatic or C.sub.1-10 heteroaryl C.sub.1-6 aliphatic. 8. The compound according to claim 1, wherein R.sup.1 has one of the following structures: ##STR00096## ##STR00097## ##STR00098## wherein each of X.sub.4 and X.sub.4' is independently (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2; each of m and n is independently 0, 1 or 2; and t is 1, 2 or 3. 9. The compound of claim 1 having one of the following structures: ##STR00099## ##STR00100## ##STR00101## ##STR00102## or a stereoisomer, a geometric isomer, a tautomer, an N oxide, or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1 having one of the following structures: ##STR00103## ##STR00104## ##STR00105## ##STR00106## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide or a pharmaceutically acceptable salt thereof. 11. A compound of Formula V: ##STR00107## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, or a pharmaceutically acceptable salt thereof, wherein: Q.sub.2 has Formula (III): ##STR00108## R.sup.1 is --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, R.sup.5S(.dbd.O)-alkyl, R.sup.5R.sup.5aN--C(.dbd.O)-alkyl, R.sup.5S(.dbd.O)-alkoxy, R.sup.5R.sup.5aN--C(.dbd.O)-alkoxy, hydroxy-substituted aminoalkoxy, amino-substituted haloalkoxy, hydroxy-substituted haloalkoxy, heterocyclyl(aminoalkoxy), heteroaryl(hydroxyalkoxy), hydroxy-substituted cyclopropylalkoxy, R.sup.5S(.dbd.O).sub.2O-substituted cyclopropylalkoxy, spiro bicyclyl, spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy, spiro bicyclylamino, spiro bicycloxoalkoxy, spiro heterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spiro bicyclyl-C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)O--, spiro heterobicyclyl-C(.dbd.O)--, spiro heterobicyclyl--C(.dbd.O)O--, spiro bicyclylamino-C(.dbd.O)--, spiro heterobicyclylamino-C(.dbd.O)--, spiro bicyclylN--C(.dbd.O)NR.sup.5--, or spiro heterobicyclyl-C(.dbd.O)NR.sup.5--; or R.sup.1 is ##STR00109## ##STR00110## wherein each of X.sub.4 and X.sub.4' is independently (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2; each of m and n is independently 0, 1 or 2; and t is 1, 2 or 3; R.sup.2 is H, halo, cyano, hydroxyl, R.sup.5aR.sup.5N--, --C(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)OR.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, R.sup.5aR.sup.5N-alkyl, R.sup.5S(.dbd.O)-alkyl, R.sup.5R.sup.5aN--C(.dbd.O)-alkyl, R.sup.5aR.sup.5N-alkoxy, R.sup.5S(.dbd.O)-alkoxy, R.sup.5R.sup.5aN--C(.dbd.O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl, spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino, spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiro heterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spiro bicyclyl-C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)O--, spiro heterobicyclyl-C(.dbd.O)--, spiro heterobicyclyl-C(.dbd.O)O--, spiro bicyclylamino-C(.dbd.O)--, spiro heterobicyclylamino-C(.dbd.O)--, spiro bicyclyl--C(.dbd.O)NR.sup.5--, or spiro heterobicyclyl-C(.dbd.O)NR.sup.5--, aryl, heteroaryl, arylaliphatic or heteroarylaliphatic, with the proviso that when alkoxy or alkylamino is substituted, each of alkoxy or alkylamino is independently substituted with one or more hydroxy groups, amino groups or substituted amino groups; R.sup.3 is H, F, Cl, Br, I, --CN, hydroxyl, R.sup.5aR.sup.5N--, aliphatic, alkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkyl aliphatic, cycloalkylalkoxy, or heterocyclylalkoxy; each of U.sub.1 and U.sub.2 is independently CR.sup.4 or N; V is NR.sup.5R.sup.5a, OR.sup.5, aliphatic, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic, or heteroarylaliphatic; each of W.sub.1, W.sub.2, W.sub.3 and W.sub.4 is independently CR.sup.4R.sup.4aNR.sup.5, CR.sup.4 or N; X.sub.1 is (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2, where m is 0, 1 or 2; each of X.sub.2 and X.sub.3 is independently O, S or NR.sup.5; each of Z.sub.1 and Z.sub.2 is independently NR.sup.5 or CR.sup.4R.sup.4a; each of R.sup.4 and R.sup.4a is independently H, F, Cl, Br, I, --CN, hydroxyl, --NR.sup.5aR.sup.5, alkoxy, cycloalkoxy, heterocycloalkoxy, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl, with the proviso that where R.sup.4 and R.sup.4a are bonded to the same carbon atom, R.sup.4 and R.sup.4a, together with the carbon atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring; each of R.sup.5 and R.sup.5a is independently H, R.sup.6R.sup.6aNC(.dbd.O)--, R.sup.6OC(.dbd.O)--, R.sup.6C(.dbd.O)--, R.sup.6R.sup.6aNS(.dbd.O)--, R.sup.6OS(.dbd.O)--, R.sup.6S(.dbd.O)--, R.sup.6R.sup.6aNSO.sub.2--, R.sup.6OSO.sub.2--, R.sup.6SO.sub.2--, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl, with the proviso that where R.sup.5 and R.sup.5a are bonded to the same nitrogen atom, R.sup.5 and R.sup.5a, together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, including spiro and fused bicyclic rings; each of R.sup.6 and R.sup.6ais independently H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl; wherein each of R.sup.5aR.sup.5N--, --C(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)OR.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, OR.sup.5, NR.sup.5, CR.sup.4R.sup.4a, CR.sup.4, (CR.sup.4R.sup.4a).sub.m, --NR.sup.5C(O)--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5C(.dbd.S)--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5a--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5--(CR.sup.4R.sup.4a).sub.pC(.dbd.O)--, --NR.sup.5--(CR.sup.4R.sup.4a).sub.pC(.dbd.S)--, --NR.sup.5S(O).sub.r--, --NR.sup.5S(.dbd.O)(CR.sup.4R.sup.4a).sub.p--, --C(.dbd.O)NR.sup.5--(CR.sup.4R.sup.4a).sub.p--, --NR.sup.5--(CR.sup.4R.sup.4a).sub.p--S(.dbd.O).sub.r--, R.sup.5aR.sup.5N-alkyl, R.sup.5(S.dbd.O)-alkyl, R.sup.5R.sup.5aN--(C.dbd.O)-alkyl, R.sup.5aR.sup.5N-alkoxy, R.sup.5(S.dbd.O)-alkoxy, R.sup.5R.sup.5aN--(C.dbd.O)-alkoxy, R.sup.6R.sup.6aNC(.dbd.O)--, R.sup.6OC(.dbd.O)--, R.sup.6C(.dbd.O)--, R.sup.6R.sup.6aNS(.dbd.O)--, R.sup.6OS(.dbd.O)--, R.sup.6S(.dbd.O)--, R.sup.6R.sup.6aNSO.sub.2--, R.sup.6OSO.sub.2--, R.sup.6SO.sub.2--, hydroxy-substituted cyclopropylalkoxy, R.sup.5S(.dbd.O).sub.2O-substituted cyclopropylalkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, spiro bicyclyl, spiro heterobicyclyl, spiro bicyclyl aliphatic, spiro heterobicyclyl aliphatic, spiro bicycloxy, spiro heterobicycloxy, spiro bicyclylamino, spiro heterobicyclylamino, spiro bicycloxoalkoxy, spiro heterobicycloxoalkoxy, spiro bicyclylaminoalkoxy, spiro heterobicyclylaminoalkoxy, spiro bicyclyl-C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)O--, spiro heterobicyclyl-C(.dbd.O)--, spiro heterobicyclyl-C(.dbd.O)O--, spiro bicyclylamino-C(.dbd.O)--, spiro heterobicyclylamino-C(.dbd.O)--, spiro bicyclyl-C(.dbd.O)NR.sup.5--, or spiro heterobicyclyl-C(.dbd.O)NR.sup.5--, aryl, heteroaryl, arylaliphatic and heteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, heterocyclyl and carbocyclyl is independently substituted or unsubstituted. 12. The compound according to claim 11, wherein R.sup.3 is independently H, F, Cl, Br, --CN, C.sub.1-3 aliphatic, C.sub.1-3 alkoxy, or C.sub.1-3 haloalkyl. 13. The compound according to claim 11, wherein the substructure defined by Z.sub.1, Z.sub.2, X.sub.2, X.sub.3 and V of Formula (V) is ##STR00111## wherein Ar is substituted or unsubstituted aryl or heteroaryl; and s is 0 or 1. 14. The compound according to claim 11, wherein Q.sub.2 is ##STR00112## 15. The compound according to claim 11, wherein X.sub.1 is O or NR.sup.5. 16. The compound according to claim 11, wherein the substructure defined by X.sub.1, U.sub.1 and R.sup.3 is ##STR00113## 17. The compound according to claim 11, wherein R.sup.1 is one of the following structures: ##STR00114## ##STR00115## wherein each of X.sub.4 and X.sub.4' is independently (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2; each of m and n is independently 0, 1 or 2; and t is 1, 2 or 3. 18. The compound of claim 11 having one of the following structures: ##STR00116## ##STR00117## ##STR00118## ##STR00119## or a stereoisomer, a geometric isomer, a tautomer, an N--oxide, or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 20. The composition according to claim 19 further comprising a therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis, and combinations thereof. 21. The composition according to claim 20, wherein the additional therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabin, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, iressa, sorafenib, sunitinib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide, tositumomab (Bexxar), trabedectin, Avastin (bevacizumab), Herceptin (trastuzumab), Erbitux (cetuximab), Vectibix (panitumumab), or a combination thereof. 22. A compound of Formula (I): ##STR00120## or a stereoisomer, a geometric isomer, a tautomer, an N--oxide, or a pharmaceutically acceptable salt thereof, wherein: Q.sub.1 is formula (IIb): ##STR00121## Q.sub.2 is formula (III): ##STR00122## R.sup.1 is: ##STR00123## ##STR00124## wherein each of X.sub.4 and X.sub.4' is independently (CR.sup.4R.sup.4a).sub.m, NR.sup.5, O, S, S.dbd.O or SO.sub.2; each of m and n is independently 0, 1 or 2; and t is 1, 2 or 3; R.sup.2 is H, halo, cyano, hydroxyl, R.sup.5aR.sup.5N--, --C(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)NR.sup.5R.sup.5a, --OC(.dbd.O)OR.sup.5, --NR.sup.5C(.dbd.O)NR.sup.5R.sup.5a, --NR.sup.5C(.dbd.O)OR.sup.5a, --NR.sup.5C(.dbd.O)--R.sup.5a, R.sup.5R.sup.5aN--O.sub.2S--, R.sup.5O.sub.2S--, R.sup.5O.sub.2SR.sup.5aN--, R.sup.5aR.sup.5N-alkyl, R.sup.5(S.dbd.O)-alkyl, R.sup.5R.sup.5aN--(C.dbd.O)alkyl, R.sup.5aR.sup.5N-alkoxy, R.sup.5(S.dbd.O)-alkoxy, R.sup.5R.sup.5aN--(C.dbd.O)-alkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, with the proviso that when alkoxy or alkylamino is substituted, each of alkoxy or alkylamino is independently substituted with one or more hydroxy groups, amino groups or substituted amino groups; R.sup.3 is H, F, Cl, Br, I, --CN, hydroxyl, R.sup.5aR.sup.5N--, or aliphatic; each of U.sub.1 and U.sub.2 is independently CR.sup.4 or N; V is NR.sup.5R.sup.5a, OR.sup.5, aliphatic, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylaliphatic, or heteroarylaliphatic; each of W.sub.1, W.sub.2, W.sub.3 and W.sub.4 is independently CR.sup.4 or N; each of X.sub.1, X.sub.2 and X.sub.3 is independently O; each of Z.sub.1 and Z.sub.2 is independently NR.sup.5 or CR.sup.4R.sup.4a; each of R.sup.4 and R.sup.4a is independently H, F, Cl, Br, I, --CN, hydroxyl, --NR.sup.5aR.sup.5, alkoxy, cycloalkoxy or aliphatic, with the proviso that where R.sup.4 and R.sup.4a are bonded to the same carbon atom, R.sup.4 and R.sup.4a, together with the carbon atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered carbocyclic or heterocyclic ring; each of R.sup.5 and R.sup.5a is independently H, aliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl, with the proviso that where R.sup.5 and R.sup.5a are bonded to the same nitrogen atom, R.sup.5 and R.sup.5a, together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, including spiro and fused bicyclic rings; each of R.sup.6 and R.sup.6a is independently H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl, or carbocyclyl; wherein each of hydroxy-substituted cyclopropylalkoxy, R.sup.5S(.dbd.O).sub.2O-substituted cyclopropylalkoxy, aliphatic, alkoxy, hydroxyalkoxy, aminoalkoxy, hydroxy-substituted aminoalkoxy, haloalkoxy, amino-substituted haloalkoxy, alkylamino haloalkoxy, hydroxy-substituted haloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, arylalkoxy, heterocyclylalkoxy, carbocyclylalkoxy, heterocyclyl(hydroxyalkoxy), carbocyclyl(hydroxyalkoxy), aryl(hydroxyalkoxy), aryloxyalkoxy, aryloxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, (heterocyclo)hydroxyalkoxy, azidoalkoxy, aryl, heteroaryl, arylaliphatic and heteroarylaliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, arylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, heterocyclyl and carbocyclyl is independently substituted or unsubstituted. 23. The compound according to claim 1, wherein: the substructure defined by X.sub.1, U.sub.1 and R.sup.3 of Formula (I) is ##STR00125## Q.sub.1 is ##STR00126## wherein Ar is substituted or unsubstituted aryl; Q.sub.2 iS ##STR00127## R.sup.1 is ##STR00128## wherein each of X.sub.4 and X.sub.4' is O, R.sup.5a is H, and t is 3; and R.sup.2 is H.

Details for Patent 8,293,897

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2028-10-14
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2028-10-14
Glaxosmithkline Llc	BEXXAR	tositumomab and iodine i-131 tositumomab	Injection	125011	06/27/2003		2028-10-14
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2028-10-14