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Last Updated: March 28, 2024

Claims for Patent: 9,926,324


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Summary for Patent: 9,926,324
Title:Heteroaromatic compounds as PI3 kinase modulators and methods of use
Abstract: The present invention provides heteroaromatic derivatives and pharmaceutical acceptable salts and formulations thereof useful in modulating the protein kinase activity, especially phosphatidylinositol 3-kinases (PI3 kinases) and mTOR, and in modulating inter- and/or intra-cellular signaling 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)
Assignee: CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN)
Application Number:14/076,256
Patent Claims:1. A compound of Formula (I): ##STR00112## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically salt or a prodrug thereof, wherein: each of W.sub.1, W.sub.2 and W.sub.3 is independently N or CR.sup.c; Z is D, CN, N.sub.3 or ##STR00113## X is H, D, (C.sub.1-C.sub.6)alkyl, (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)cycloalkyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, 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.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.6-C.sub.10)aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N.sub.3, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, --C(.dbd.O)NR.sup.aR.sup.b, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.4)alkylene-CN, --(C.sub.1-C.sub.4)alkylene-OR.sup.a, --(C.sub.1-C.sub.4)alkylene-NR.sup.aR.sup.b, (C.sub.6-C.sub.10)aryl and 5-10 membered heteroaryl; Y is (C.sub.1-C.sub.6)alkyl, (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)cycloalkyl, --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)heterocyclyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, 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.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.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N.sub.3, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, --C(.dbd.O)NR.sup.aR.sup.b, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.4)alkylene-CN, --(C.sub.1-C.sub.4)alkylene-OR.sup.a, --(C.sub.1-C.sub.4)alkylene-NR.sup.aR.sup.b, (C.sub.6-C.sub.10)aryl and 5-10 membered heteroaryl; R.sup.1 is H, D, Cl, OR.sup.a, NR.sup.aR.sup.b, (C.sub.1-C.sub.6)aliphatic or (C.sub.3-C.sub.6)cycloalkyl, wherein each of the (C.sub.1-C.sub.6)aliphatic and (C.sub.3-C.sub.6)cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, CN, N.sub.3, OR.sup.a, SR.sup.a and NR.sup.aR.sup.b, provided that when each of W.sub.1, W.sub.2 and W.sub.3 is CH, R.sup.1 is not H or NH.sub.2; each R.sup.a and R.sup.b 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.6-C.sub.10)aryl or --(C.sub.1-C.sub.4)alkylene-(5-10 membered heteroaryl); or when 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)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl and 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)alkoxy, and (C.sub.1-C.sub.6)alkylamino; and each R.sup.c is independently H, D, F, Cl, Br, I, N.sub.3, CN, OH, NH.sub.2, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of the (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylamino, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)heterocyclyl, (C.sub.6-C.sub.10)aryl and 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)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy and (C.sub.1-C.sub.6)alkylamino.

2. The compound according to claim 1, wherein each of W.sub.1 and W.sub.2 is independently N or CR.sup.c, W.sub.3 is CR.sup.c.

3. The compound according to claim 1, wherein Z is CN, N.sub.3 or ##STR00114##

4. The compound according to claim 1, wherein X is H, D, (C.sub.1-C.sub.6)alkyl, (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)cycloalkyl or --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)heterocyclyl, 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.1-C.sub.4)alkylene-(C.sub.3-C.sub.6)cycloalkyl and --(C.sub.1-C.sub.4)alkylene-(C.sub.3-C.sub.6) heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N.sub.3, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, --C(.dbd.O)NR.sup.aR.sup.b, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl.

5. The compound according to claim 1, wherein Y is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl or 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein each of the (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl and 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, CN, N.sub.3, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, --C(.dbd.O)NR.sup.aR.sup.b, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl and 5-10 membered heteroaryl.

6. The compound according to claim 1, wherein R.sup.1 is H, D, Cl, CH.sub.3, CH.sub.2CH.sub.3, CF.sub.3, CH.sub.2CF.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, NH.sub.2, NHCH.sub.3 or N(CH.sub.3).sub.2, provided that when each of W.sub.1, W.sub.2 and W.sub.3 is CH, R.sup.1 is not H or NH.sub.2.

7. The compound according to claim 1, wherein each R.sup.c is independently H, D, F, Cl, N.sub.3, CN, NH.sub.2, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, (C.sub.1-C.sub.3)alkylamino, (C.sub.3-C.sub.6)cycloalkyl or (C.sub.3-C.sub.6)heterocyclyl, wherein each of the (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, (C.sub.1-C.sub.3)alkylamino, (C.sub.3-C.sub.6)cycloalkyl and (C.sub.3-C.sub.6)heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, CN, N.sub.3, OH, NH.sub.2, (C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl and (C.sub.1-C.sub.3)haloalkyl.

8. The compound according to claim 1 having one of the following structures: ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133##

9. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

10. The pharmaceutical composition according to claim 9 further comprising an additional therapeutic agent which comprising a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis or a combination thereof.

11. The pharmaceutical composition according to claim 10, wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, 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, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, tositumomab, trastuzumab, or a combination thereof.

12. A method of treating or lessening the severity of a proliferative disorder in a patient by administering to the patient the compound according to claim 1, wherein the proliferative disorder is glioblastoma.

13. A method of treating or lessening the severity of a proliferative disorder in a patient by administering to the patient the pharmaceutical composition according to claim 9, wherein the proliferative disorder is glioblastoma.

14. A method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound according to claim 1.

15. The method of claim 14, wherein the protein kinase is a receptor tyrosine kinase.

16. The method of claim 15, wherein the receptor tyrosine kinase is PI3K, mTOR or a combination thereof.

17. A method of inhibiting or modulating the activity of a protein kinase in a biological sample comprising contacting a biological sample with the pharmaceutical composition according to claim 9.

18. The method of claim 17, wherein the protein kinase is receptor tyrosine kinase.

19. The method of claim 18, wherein the receptor tyrosine kinase is PI3K, mTOR or a combination thereof.

Details for Patent 9,926,324

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Genentech, Inc. RITUXAN rituximab Injection 103705 11/26/1997 ⤷  Try a Trial 2032-11-14
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 09/25/1998 ⤷  Try a Trial 2032-11-14
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 02/10/2017 ⤷  Try a Trial 2032-11-14
Genzyme Corporation CAMPATH alemtuzumab Injection 103948 05/07/2001 ⤷  Try a Trial 2032-11-14
Genzyme Corporation LEMTRADA alemtuzumab Injection 103948 11/14/2014 ⤷  Try a Trial 2032-11-14
Genzyme Corporation CAMPATH alemtuzumab Injection 103948 10/12/2004 ⤷  Try a Trial 2032-11-14
Eli Lilly And Company ERBITUX cetuximab Injection 125084 02/12/2004 ⤷  Try a Trial 2032-11-14
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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