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 compound of Formula (I):
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
Q is NR a R b , OR a , —N(R c )C(═O)R d or —N(R c )C(═O)OR 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 )alkyl ene-(5-10 membered heteroaryl) is 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), with the proviso wherein R a and R b are bonded to the same nitrogen atom, R a and R b , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered heterocyclic ring, 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, —(C 1 -C 4 )alkyl ene-(5-10 membered heteroaryl) and 3-8 membered heterocyclic ring is 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 H, (C 1 -C 6 )alkyl, (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 or (C 6 -C 10 )aryl, with the proviso where each R 1 , R 2 , R 3 , R 5 (or R 4 ), R 6 and R 7 is H, R 4 (or R 5 ) is F, R d is not (C 3 -C 7 )heterocyclyl, wherein each of the (C 1 -C 6 )alkyl, —(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 and (C 6 -C 10 )aryl is 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 compound according to claim 1 , wherein Q is NR a R b , —N(R c )C(═O)R d or —N(R c )C(═O)OR a .
3. The compound according to claim 1 , wherein each of X, Y and Z is independently H, D, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl, phenyl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, —(C 1 -C 2 )alkylene-phenyl or —(C 1 -C 2 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl, phenyl, 5-10 membered heteroaryl, —(C 1 -C 2 )alkylene-phenyl and —(C 1 -C 2 )alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F, Cl, Br, CN, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, OR a , NR a R b , —(C 1 -C 2 )alkylene-OR a and —(C 1 -C 2 )alkylene-NR a R b .
4. The compound according to claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is independently H, D, F or Cl.
5. The compound according to claim 1 , wherein each of R a , R b and R c is independently H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl or —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl, with the proviso where R a and R b are bonded to the same nitrogen atom, R a and R b , together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered heterocyclic ring, wherein each of the (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl and 3-8 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N 3 , OH, NH 2 , (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy and (C 1 -C 3 )alkylamino.
6. The compound according to claim 1 , wherein R d is independently H, D, (C 1 -C 4 )alkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl or —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl, with the proviso where each R 1 , R 2 , R 3 , R 5 (or R 4 ), R 6 and R 7 is H, R 4 (or R 5 ) is F, R d is not (C 3 -C 6 )heterocyclyl, wherein each of the (C 1 -C 4 )alkyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl and —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CN, OR a , NR a R b , (C 1 -C 3 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, —(C 1 -C 2 )alkylene-OR a and —(C 1 -C 2 )alkylene-NR a R b .
7. The compound according to claim 1 , wherein Q is NH 2 or —N(R c )C(═O)R d .
8. The compound according to claim 1 , wherein each of X, Y and Z is independently H, D, methyl, ethyl, phenyl or phenyl group substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F and Cl.
9. The compound according to claim 1 , wherein Q is:
10. The compound according to claim 1 having Formula (II):
wherein:
Q is NR a R b , —N(R c )C(═O)R d or —N(R c )C(═O)OR a ;
each of X, Y and Z is independently H, D, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (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 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, —(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 3 -C 7 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl, —(C 1 -C 4 )alkylene-(C 3 -C 8 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is 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 a , R b and R c is independently H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (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 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, —(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 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, 5-10 membered heteroaryl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3 or 4 substituents 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 (C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, OH, NH 2 , (C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylamino.
11. The compound according to claim 10 , wherein Q is NR a R b or —N(R c )C(═O)R d .
12. The compound according to claim 10 , wherein each of X, Y and Z is independently H, D, (C 1 -C 4 )alkyl or phenyl, wherein each of the (C 1 -C 4 )alkyl and phenyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F and Cl.
13. The compound according to claim 10 , wherein each of R a , R b and R c is independently H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl or —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl, wherein each of the (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, —(C 1 -C 2 )alkylene-(C 3 -C 6 )cycloalkyl and —(C 1 -C 2 )alkylene-(C 3 -C 6 )heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents 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.
14. The compound according to claim 10 , wherein R d is Me, Et, n-Pr or i-Pr.
15. The compound according to claim 10 , wherein Q is NH 2 or —N(R c )C(═O)R d .
16. The compound according to claim 10 , wherein each of X, Y and Z is independently H, D, Me, CH 2 D, CHD 2 , CD 3 , ethyl, propyl, isopropyl, phenyl or phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from D, F and Cl.
17. The compound according to claim 10 , wherein Q is:
18. The compound of claim 1 having one of the following structures:
19. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
20. The pharmaceutical 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 pharmaceutical composition according to claim 20 , wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabectedin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, trastuzumab or a combination thereof.
22. A method of treating a proliferative disorder in a patient by administering to the patient the compound according to claim 1 , wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, a cancer of the head and neck, prostate cancer, pancreatic cancer, a cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis.
23. A method of treating a proliferative disorder in a patient by administering to the patient the pharmaceutical composition according to claim 19 , wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, skin cancer, thyroid cancer, a cancer of the head and neck, prostate cancer, pancreatic cancer, a cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis.