Claims for Patent: 8,969,388
✉ Email this page to a colleague
Summary for Patent: 8,969,388
Title: | Substituted pyrazolone compounds and methods of use |
Abstract: | 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. |
Inventor(s): | Xi; Ning (Newbury Park, CA), Wu; Yanjun (Dongguan, CN), Liao; Min (Dongguan, CN), Feng; Yanming (Dongguan, CN) |
Assignee: | Sunshine Lake Pharma Co., Ltd. (Dongguan, Guangdong, CN) Calitor Sciences, LLC (Newbury Park, CA) |
Application Number: | 13/945,925 |
Patent Claims: | 1. A compound of Formula (I): ##STR00091## 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.sup.aR.sup.b, OR.sup.a, --N(R.sup.c)C(.dbd.O)R.sup.d or --N(R.sup.c)C(.dbd.O)OR.sup.a; W is CR.sup.7 or N; each of X, Y and Z is independently H, D, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
--(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.7)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.7)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected
from O, S and N, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl or --(C.sub.1-C.sub.4)alkylene-(5-10 membered heteroaryl), wherein each of the (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
--(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.7)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.7)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl and
--(C.sub.1-C.sub.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.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sup.a, NR.sup.aR.sup.b,
--(C.sub.1-C.sub.4)alkylene-OR.sup.a and --(C.sub.1-C.sub.4)alkylene-NR.sup.aR.sup.b; each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently H, D, F, Cl, Br, CN, N.sub.3, OR.sup.a, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl; each of R.sup.a, R.sup.b and R.sup.c is independently H, (C.sub.1-C.sub.6)aliphatic, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)cycloalkyl,
--(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected
from O, S and N, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl or --(C.sub.1-C.sub.4)alkylene-(5-10 membered heteroaryl), with the proviso wherein R.sup.a and R.sup.b are bonded to the same nitrogen atom, R.sup.a and R.sup.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.sub.1-C.sub.6)aliphatic, (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.6)cycloalkyl,
--(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl,
--(C.sub.1-C.sub.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.sub.3, OH, NH.sub.2, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy and (C.sub.1-C.sub.6)alkylamino; and R.sup.d is H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.7)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.7)heterocyclyl or
(C.sub.6-C.sub.10)aryl, with the proviso where each R.sup.1, R.sup.2, R.sup.3, R.sup.5 (or R.sup.4), R.sup.6 and R.sup.7 is H, R.sup.4 (or R.sup.5) is F, R.sup.d is not (C.sub.3-C.sub.7)heterocyclyl, wherein each of the (C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.7)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.7)heterocyclyl and (C.sub.6-C.sub.10)aryl is optionally substituted with 1, 2, 3 or 4 substitutents independently selected
from D, F, Cl, Br, CN, OR.sup.a, NR.sup.aR.sup.b, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.4)alkylene-OR.sup.a and --(C.sub.1-C.sub.4)alkylene-NR.sup.aR.sup.b.
2. The compound according to claim 1, wherein Q is NR.sup.aR.sup.b, --N(R.sup.c)C(.dbd.O)R.sup.d or --N(R.sup.c)C(.dbd.O)OR.sup.a. 3. The compound according to claim 1, wherein each of X, Y and Z is independently H, D, (C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.6)cycloalkyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)heterocyclyl, phenyl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, --(C.sub.1-C.sub.2)alkylene-phenyl or --(C.sub.1-C.sub.2)alkylene-(5-10 membered heteroaryl), wherein each of the (C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.6)cycloalkyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)heterocyclyl, phenyl, 5-10 membered heteroaryl, --(C.sub.1-C.sub.2)alkylene-phenyl and --(C.sub.1-C.sub.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.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, OR.sup.a, NR.sup.aR.sup.b, --(C.sub.1-C.sub.2)alkylene-OR.sup.a and --(C.sub.1-C.sub.2)alkylene-NR.sup.aR.sup.b. 4. The compound according to claim 1, wherein each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently H, D, F or Cl. 5. The compound according to claim 1, wherein each of R.sup.a, R.sup.b and R.sup.c is independently H, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.3-C.sub.6)cycloalkyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl or --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)heterocyclyl, with the proviso where R.sup.a and R.sup.b are bonded to the same nitrogen atom, R.sup.a and R.sup.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.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.3-C.sub.6)cycloalkyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.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.sub.3, OH, NH.sub.2, (C.sub.1-C.sub.3)haloalkyl, (C.sub.1-C.sub.3)alkoxy and (C.sub.1-C.sub.3)alkylamino. 6. The compound according to claim 1, wherein R.sup.d is independently H, D, (C.sub.1-C.sub.4)alkyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl or --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)heterocyclyl, with the proviso where each R.sup.1, R.sup.2, R.sup.3, R.sup.5 (or R.sup.4), R.sup.6 and R.sup.7 is H, R.sup.4 (or R.sup.5) is F, R.sup.d is not (C.sub.3-C.sub.6)heterocyclyl, wherein each of the (C.sub.1-C.sub.4)alkyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl and --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CN, OR.sup.a, NR.sup.aR.sup.b, (C.sub.1-C.sub.3)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, --(C.sub.1-C.sub.2)alkylene-OR.sup.a and --(C.sub.1-C.sub.2)alkylene-NR.sup.aR.sup.b. 7. The compound according to claim 1, wherein Q is NH.sub.2 or --N(R.sup.c)C(.dbd.O)R.sup.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: ##STR00092## ##STR00093## 10. The compound according to claim 1 having Formula (II): ##STR00094## wherein: Q is NR.sup.aR.sup.b, --N(R.sup.c)C(.dbd.O)R.sup.d or --N(R.sup.c)C(.dbd.O)OR.sup.a; each of X, Y and Z is independently H, D, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.7)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.7)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl or --(C.sub.1-C.sub.4)alkylene-(5-10 membered heteroaryl), wherein each of the (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.7)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.8)cycloalkyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.7)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl and --(C.sub.1-C.sub.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.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, OR.sup.a, NR.sup.aR.sup.b, --(C.sub.1-C.sub.4)alkylene-OR.sup.a and --(C.sub.1-C.sub.4)alkylene-NR.sup.aR.sup.b; each of R.sup.a, R.sup.b and R.sup.c is independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)cycloalkyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl or --(C.sub.1-C.sub.4)alkylene-(5-10 membered heteroaryl), wherein each of the (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl, 5-10 membered heteroaryl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)cycloalkyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.6-C.sub.10)aryl and --(C.sub.1-C.sub.4)alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N.sub.3, OH, NH.sub.2, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy and (C.sub.1-C.sub.6)alkylamino; and R.sup.d is (C.sub.1-C.sub.6)alkyl, wherein the (C.sub.1-C.sub.6)alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, OH, NH.sub.2, (C.sub.1-C.sub.6)alkoxy and (C.sub.1-C.sub.6)alkylamino. 11. The compound according to claim 10, wherein Q is NR.sup.aR.sup.b or --N(R.sup.c)C(.dbd.O)R.sup.d. 12. The compound according to claim 10, wherein each of X, Y and Z is independently H, D, (C.sub.1-C.sub.4)alkyl or phenyl, wherein each of the (C.sub.1-C.sub.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.sup.a, R.sup.b and R.sup.c is independently H, (C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl or --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)heterocyclyl, wherein each of the (C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)cycloalkyl and --(C.sub.1-C.sub.2)alkylene-(C.sub.3-C.sub.6)heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N.sub.3, OH, NH.sub.2, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy and (C.sub.1-C.sub.6)alkylamino. 14. The compound according to claim 10, wherein R.sup.d is Me, Et, n-Pr or i-Pr. 15. The compound according to claim 10, wherein Q is NH.sub.2 or --N(R.sup.c)C(.dbd.O)R.sup.d. 16. The compound according to claim 10, wherein each of X, Y and Z is independently H, D, Me, CH.sub.2D, CHD.sub.2, CD.sub.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: ##STR00095## 18. The compound of claim 1 having one of the following structures: ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## 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. |
Details for Patent 8,969,388
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Genentech, Inc. | RITUXAN | rituximab | Injection | 103705 | 11/26/1997 | ⤷ Try a Trial | 2032-07-28 |
Idec Pharmaceuticals Corp. | RITUXAN | rituximab | Injection | 103737 | 02/19/2002 | ⤷ Try a Trial | 2032-07-28 |
Genentech, Inc. | HERCEPTIN | trastuzumab | For Injection | 103792 | 09/25/1998 | ⤷ Try a Trial | 2032-07-28 |
Genentech, Inc. | HERCEPTIN | trastuzumab | For Injection | 103792 | 02/10/2017 | ⤷ Try a Trial | 2032-07-28 |
Glaxosmithkline Llc | BEXXAR | tositumomab and iodine i-131 tositumomab | Injection | 125011 | 06/27/2003 | ⤷ Try a Trial | 2032-07-28 |
Eli Lilly And Company | ERBITUX | cetuximab | Injection | 125084 | 02/12/2004 | ⤷ Try a Trial | 2032-07-28 |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
Make Better Decisions: Try a trial or see plans & pricing
Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.