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Generated: September 22, 2017

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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:14/181,670
Patent Claims:1. A compound having Formula (I): ##STR00060## or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, 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 ##STR00061## 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; 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, --(C.sub.1-C.sub.4)alkylene-(5-10 membered heteroaryl), or R.sup.a and R.sup.b are taken together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic ring, wherein each of the above substituents 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 W.sub.1 is N or CR.sup.c; and each of W.sub.2 and W.sub.3 is independently CR.sup.c.

3. The compound according to claim 1, wherein Z is CN, N.sub.3, or ##STR00062##

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.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.2-C.sub.4)alkenyl, and (C.sub.2-C.sub.4)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.3)alkyl, (C.sub.1-C.sub.3)haloalkyl, (C.sub.2-C.sub.4)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, or OCH.sub.2CH.sub.3.

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: ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##

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 selected from 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 the activity of a protein kinase in a biological sample comprising contacting a biological sample with the compound according to claim 1, wherein the protein kinase is PI3K, mTOR or a combination thereof.

15. A method of inhibiting the activity of a protein kinase in a biological sample comprising contacting a biological sample with the pharmaceutical composition according to claim 9, wherein the protein kinase is PI3K, mTOR or a combination thereof.

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Inventors Patent Expiration Status Orphan Source
Genentech
RITUXAN
rituximab
VIAL1037050011997-11-26► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXsearch
Genentech
HERCEPTIN
trastuzumab
VIAL; INTRAVENOUS1037920011998-09-25► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXOrphansearch
Genzyme
CAMPATH
alemtuzumab
VIAL; INTRAVENOUS1039480012001-05-07► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXOrphansearch
Genzyme
CAMPATH
alemtuzumab
VIAL; INTRAVENOUS1039480022001-05-07► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXOrphansearch
Genzyme
LEMTRADA
alemtuzumab
INJECTABLE;INJECTION1039480032001-05-07► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXOrphansearch
Imclone
ERBITUX
cetuximab
VIAL; INTRAVENOUS1250840012004-06-18► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXOrphansearch
Genentech
AVASTIN
bevacizumab
VIAL; INTRAVENOUS1250850012004-02-26► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXsearch
Genentech
AVASTIN
bevacizumab
VIAL; INTRAVENOUS1250850022004-02-26► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXsearch
Amgen
VECTIBIX
panitumumab
INJECTABLE; IV (INFUSION)1251470012006-09-27► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXsearch
Amgen
VECTIBIX
panitumumab
INJECTABLE; IV (INFUSION)1251470022006-09-27► Subscribe CALITOR SCIENCES, LLC (Newbury Park, CA) SUNSHINE LAKE PHARMA CO., LTD. (Dongguan, Guangdong, CN) Xi; Ning (Newbury Park, CA) ► SubscribeRXsearch
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International Patent Family for Patent: ► Subscribe

Country Document Number Publication Date
Australia2014219256Feb 16, 2017
Australia2014219256Jul 30, 2015
Canada2898294Aug 28, 2014
European Patent Office2958564Dec 30, 2015
European Patent Office2958564Oct 26, 2016
Hong Kong1218385Feb 17, 2017
Japan2016509056Mar 24, 2016
South Korea20150118102Oct 21, 2015
Mexico2015010700Jan 23, 2017
Russian Federation2015131467Mar 24, 2017
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