Substituted pyrazolone compounds and methods of use
The present invention provides novel substituted pyrazolone compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. 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.
1. A method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with a compound of Formula (I):
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, or a pharmaceutically acceptable salt thereof, wherein:
Q is D, —N(R c )C(═O)NR a R b , —N(R c )C(═O)R d , —C(═O)NR a R b , —N(R c )S(═O)NR a R b , —N(R c )S(═O)R a , —N(R c )S(═O) 2 NR a R b or —N(R c )S(═O) 2 R a ;
W is CR 7 or N;
each of X, Y and Z is independently H, D, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Cl, Br, CN, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, OR a , NR a R b , —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b ;
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is independently H, D, F, Cl, Br, CN, N 3 , OR a , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl;
each of R a , R b and R c is independently H, (C 1 -C 6 )aliphatic, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )aliphatic, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is unsubstituted or optionally substituted with 1, 2, 3 or 4 substitutents independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylamino; and
R d is D, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is unsubstituted or optionally substituted with 1, 2, 3 or 4 substitutents independently selected from D, F, Cl, Br, CN, OR a , NR a R b , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b .
2. The method of claim 1 , wherein the protein kinase is a receptor tyrosine kinase.
3. The method of claim 2 , wherein the receptor tyrosine kinase is VEGFR, c-Met, Ron, Axl or a combination thereof.
4. A method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with a pharmaceutical composition comprising a compound of Formula (I):
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, or a pharmaceutically acceptable salt thereof, wherein:
Q is D, —N(R c )C(═O)NR a R b , —N(R c )C(═O)R d , —C(═O)NR a R b , —N(R c )S(═O)NR a R b , —N(R c )S(═O)R a , —N(R c )S(═O) 2 NR a R b or —N(R c )S(═O) 2 R a ;
W is CR 7 or N;
each of X, Y and Z is independently H, D, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is unsubstituted or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Cl, Br, CN, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, OR a , NR a R b , —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b ;
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is independently H, D, F, Cl, Br, CN, N 3 , OR a , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl;
each of R a , R b and R c is independently H, (C 1 -C 6 )aliphatic, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )aliphatic, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is unsubstituted or optionally substituted with 1, 2, 3 or 4 substitutents independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylamino; and
R d is D, (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is unsubstituted or optionally substituted with 1, 2, 3 or 4 substitutents independently selected from D, F, Cl, Br, CN, OR a , NR a R b , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C 1 -C 4 )alkylene-OR a and —(C 1 -C 4 )alkylene-NR a R b ;
and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
5. The method of claim 4 , wherein the protein kinase is receptor tyrosine kinase.
6. The method of claim 5 , wherein the receptor tyrosine kinase is VEGFR, c-Met, Ron, Axl or a combination thereof.