Claims for Patent: 10,227,328

Summary for Patent: 10,227,328

Title:	Heterocyclic compound and pharmaceutical composition comprising same
Abstract:	The present invention relates to a novel heterocyclic compound inhibiting a cyclin-dependent kinase (CDK) and a pharmaceutical composition comprising the same as an effective ingredient. The heterocyclic compound according to the present invention or pharmaceutically acceptable salt thereof can be effectively used in treating or preventing cancers, degenerative brain diseases, etc.
Inventor(s):	Min; Changhee (Daejeon, KR), Oh; Byungkyu (Gyeryong-si, KR), Kim; Yongeun (Daejeon, KR), Park; Changmin (Daejeon, KR)
Assignee:	BEYONDBIO INC. (Daejeon, KR)
Application Number:	15/546,714
Patent Claims:	1. A compound of formula (I) or pharmaceutically acceptable salt thereof: ##STR00148## wherein, X is nitrogen, Y and Z are carbon; R.sub.1 is phenyl, pyridine, or pyrimidine substituted or unsubstituted with one or more substituents selected from the group consisting of hydroxy, amino, and halogen; R.sub.2 is hydrogen; and R.sub.3 is pyrimidine substituted or unsubstituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, tetrahydropyranyl, piperidinyl substituted or unsubstituted with C.sub.1-C.sub.6 alkyl, morpholino, piperazinyl substituted or unsubstituted with C.sub.1-C.sub.6 alkyl, amino, C.sub.1-C.sub.6 alkylamino, and halogen. 2. The compound according to claim 1 or pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds: 2,6-bis(2-aminopyrimidin-4-yl)pyridin-3-ol; 2'-amino-6-(2-aminopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol; 2-(2-aminopyrimidin-4-yl)-6-(4-hydroxyphenyl)pyridin-3-ol; 2'-amino-6-(2-aminopyrimidin-4-yl)-[2,4'-bipyridin]-5-ol; 6-(2-aminopyrimidin-4-yl)-[2,3'-bipyridin]-5-ol; 6-(2-aminopyrimidin-4-yl)-[2,4'-bipyridin]-5-ol; 2-(2-aminopyrimidin-4-yl)-6-(3-hydroxyphenyl)pyridin-3-ol; 6-(2-aminopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol; 6-(4-amino-2-fluorophenyl)-2-(2-aminopyrimidin-4-yl)pyridin-3-ol; 6-(3-aminophenyl)-2-(2-aminopyrimidin-4-yl)pyridin-3-ol; 2-(2-aminopyrimidin-4-yl)-6-(2-fluoro-4-hydroxyphenyl)pyridin-3-ol; 6-(3-amino-2-fluorophenyl)-2-(2-aminopyrimidin-4-yl)pyridin-3-ol; 2-(2-aminopyrimidin-4-yl)-6-(3-fluoro-4-hydroxyphenyl)pyridin-3-ol; 2-(2-aminopyrimidin-4-yl)-6-(2,3-difluoro-4-hydroxyphenyl)pyridin-3-ol; 2'-amino-6-(2-aminopyrimidin-4-yl)-[2,4'-bipyridin]-3',5-diol; 2'-amino-6-(2-amino-6-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-- ol; 6-(2-amino-6-methylpyrimidin-4-yl)-[2,4'-bipyridin]-5-ol; 6-(2-amino-6-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol; 2-(2-amino-6-methylpyrimidin-4-yl)-6-(4-hydroxyphenyl)pyridin-3-ol; 2-(2-amino-6-methylpyrimidin-4-yl)-6-(2,3-difluoro-4-hydroxyphenyl)pyridi- n-3-ol; 2-(2-amino-6-methylpyrimidin-4-yl)-6-(2-fluoro-4-hydroxyphenyl)pyr- idin-3-ol; 2-(2-amino-6-methylpyrimidin-4-yl)-6-(3-aminophenyl)pyridin-3-o- l; 2'-amino-6-(2-amino-6-isopropylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridi- n]-5-ol; 2'-amino-6-(2-amino-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3- '-fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(piperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[2,4'-bip- yridin]-5-ol; 2'-amino-6-(2-amino-6-(1-methylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-ethylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[2- ,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-propylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluor- o-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-methylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-ethylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluoro-[2- ,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-propylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluor- o-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-5-methyl-6-(1-methylpiperidin-4-yl)pyrimidin-4-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-ethylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-- fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-5-methyl-6-(1-propylpiperidin-4-yl)pyrimidin-4-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)- -3'-fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-5-methyl-6-(1-methylpiperidin-3-yl)pyrimidin-3-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-5-methyl-6-(1-propylpiperidin-3-yl)pyrimidin-4-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-3-yl)-5-methylpyrimidin-4-yl)- -3'-fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-5-ethyl-6-(1-isopropylpiperidin-4-yl)pyrimidin-4-yl)-- 3'-fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-propylpyrimidin-4-yl)- -3'-fluoro-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-morpholinopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin- ]-5-ol; 2'-amino-6-(2-amino-6-(dimethylamino)pyrimidin-4-yl)-3'-fluoro-[2,- 4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol; 6-(2-amino-6-chloropyrimidin-4-yl)-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-- ol; 2'-amino-6-(2-amino-5-ethylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-- 5-ol; 2'-amino-6-(2-amino-5-propylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridi- n]-5-ol; 2'-amino-6-(2-amino-5-isopropylpyrimidin-5-yl)-3'-fluoro-[2,4'-bi- pyridin]-5-ol; 2'-amino-3'-fluoro-6-(2-(methylamino)-6-(1-methylpiperidin-4-yl)pyrimidin- -4-yl)-[2,4'-bipyridin]-5-ol; 2'-amino-6-(2-amino-5,6-dimethylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin- ]-5-ol; 2,6-bis(2-aminopyrimidin-4-yl)pyridin-3-ol 3hydrochloride; 2,6-bis(2-aminopyrimidin-4-yl)pyridin-3-ol oxalate; 2,6-bis(2-aminopyrimidin-4-yl)pyridin-3-ol malonate; 2,6-bis(2-aminopyrimidin-4-yl)pyridin-3-ol sulfate; 2'-amino-4-(2-aminopyrimidin-4-yl)-[2,4'-bipyridin]-5-ol oxalate; 2'-amino-6-(2-aminopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol 3hydrochloride; 2'-amino-6-(2-aminopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol acetate; 2'-amino-6-(2-aminopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-- ol oxalate; 2'-amino-6-(2-aminopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-ol 2malonate; 2-(2-aminopyrimidin-4-yl)-6-(2-fluoro-4-hydroxyphenyl)pyridin-3-ol 2hydrochloride; 2'-amino-6-(2-amino-6-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-- ol 3hydrochloride; 2'-amino-6-(2-amino-6-morpholinopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin- ]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-morpholinopyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin- ]-5-ol acetate; 2'-amino-6-(2-amino-6-(dimethylamino)pyrimidin-4-yl)-3'-fluoro-[2,4'-bipy- ridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol 5hydrochloride; 2'-amino-6-(2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol acetate; 2'-amino-6-(2-amino-(6-(1-methylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-- [2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-methylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol 2acetate; 2'-amino-6-(2-amino-6-(1-methylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol oxalate; 2'-amino-6-(2-amino-6-(1-methylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol malonate; 2'-amino-6-(2-amino-6-isopropylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]- -5-ol 3hydrochloride; 2'-amino-6-(2-amino-6-isopropylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]- -5-ol 2acetate; 2'-amino-6-(2-amino-6-(piperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[2,4'-bip- yridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(piperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[2,4'-bip- yridin]-5-ol acetate; 2'-amino-6-(2-amino-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3'-fluoro- -[2,4'-bipyridin]-5-ol 3hydrochloride; 2'-amino-6-(2-amino-6-(1-ethylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[2- ,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-propylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)pyrimidin-4-yl)-3'-fluor- o-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-methylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-ethylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluoro-[2- ,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-propylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluoro-[- 2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-3-yl)pyrimidin-4-yl)-3'-fluor- o[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-5-methyl-6-(1-methylpiperidin-4-yl)pyrimidin-4-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-ethylpiperidin-4-yl)-5-methylpyrimidin-4-yl)-3'-- fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-5-methyl-6-(1-propylpiperidin-4-yl)pyrimidin-4-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-methylpyrimidin-4-yl)- -3'-fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-5-methyl-6-(1-methylpiperidin-3-yl)pyrimidin-3-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-5-methyl-6-(1-propylpiperidin-3-yl)pyrimidin-4-yl)-3'- -fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-3-yl)-5-methylpyrimidin-4-yl)- -3'-fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; 2'-amino-6-(2-amino-5-methylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-- ol 3hydrochloride; 2'-amino-6-(2-amino-5,6-dimethylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin- ]-5-ol 3hydrochloride; 2'-amino-6-(2-amino-5-ethylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-o- l 3hydrochloride; 2'-amino-6-(2-amino-5-propylpyrimidin-4-yl)-3'-fluoro-[2,4'-bipyridin]-5-- ol 3hydrochloride; 2'-amino-6-(2-amino-5-isopropylpyrimidin-5-yl)-3'-fluoro-[2,4'-bipyridin]- -5-ol 3hydrochloride; 2'-amino-6-(2-amino-5-ethyl-6-(1-isopropylpiperidin-4-yl)pyrimidin-4-yl)-- 3'-fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride; and 2'-amino-6-(2-amino-6-(1-isopropylpiperidin-4-yl)-5-propylpyrimidin-4-yl)- -3'-fluoro-[2,4'-bipyridin]-5-ol 4hydrochloride. 3. A pharmaceutical composition comprising the compound according to claim 1 or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 4. The pharmaceutical composition according to claim 3, wherein the compound of formula (I) or pharmaceutically acceptable salt thereof is administered in combination with one or more anticancer agents selected from the group consisting of capecitabine, 5-fluorouracil, thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbin, gemcitabine, pemetrexed, etoposide, vincristine, citarabine, cyclophosphamide, iphosphamide, tamoxifen, anastrozole, retrozole, exemestane, fulvestrant, temozolomide, camustine, lomustine, epirubicine, eribulin, toremifene, goserelin, megestrol, vinblastine, bendamustine, thiotepa, bleomycin, topotecan, leucovorin, trifluridine, tipiracil, mitomycin C, aldesleukin, temsirolimus, everolimus, mitoxantrone, mecloretamine, methotrexate, trastuzumab, bevacizumab, cetuximab, aflibercept, pertuzumab, ramucirumab, panitumumab, nivolumab, necitumumab, pembrolizumab, obinutuzumab, ofatumumab, erlotinib, gefitinib, sorafenib, lapatinib, palbociclib, regorafenib, imatinib, sunitinib, axitinib, pazopanib, apatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and procarbazine. 5. The pharmaceutical composition according to claim 3, wherein the compound of formula (I) or pharmaceutically acceptable salt thereof is administered in combination with one or more drugs for treating a degenerative brain disease selected from the group consisting of levodopa, bromocriptine, ropinirole, pramipexole, rotigotine, trihexyphenidyl, benztropine, procyclidine, entacapone, selegiline, rasagiline, amantadine, tetrabenazine, donepezil, rivastigmine, galantamine and memantine. 6. The pharmaceutical composition according to claim 3, wherein the compound of formula (I) or pharmaceutically acceptable salt thereof is administered in combination with temozolomide. 7. A method for treating Alzheimer disease in a subject in need thereof, comprising administering a composition comprising the compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 to the subject. 8. A method for inhibiting a cyclin dependent kinase (CDK) in a subject, comprising administering a composition comprising the compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 to the subject. 9. A method for treating cancer in a subject in need thereof, comprising administering an effective amount of a composition comprising the compound of formula (I) or pharmaceutically acceptable salt thereof according to claim 1 to the subject, wherein said cancer is selected from the group consisting of colon cancer, lung cancer, glioma, and brain cancer. 10. The method according to claim 9, which further comprises administering one or more anticancer agents selected from the group consisting of capecitabine, 5-fluorouracil, thioguanine, chlorambucil, oxaliplatin, cisplatin, carboplatin, paclitaxel, docetaxel, irinotecan, doxorubicin, vinorelbin, gemcitabine, pemetrexed, etoposide, vincristine, citarabine, cyclophosphamide, iphosphamide, tamoxifen, anastrozole, retrozole, exemestane, fulvestrant, temozolomide, camustine, lomustine, epirubicine, eribulin, toremifene, goserelin, megestrol, vinblastine, bendamustine, thiotepa, bleomycin, topotecan, leucovorin, trifluridine, tipiracil, mitomycin C, aldesleukin, temsirolimus, everolimus, mitoxantrone, mecloretamine, methotrexate, trastuzumab, bevacizumab, cetuximab, aflibercept, pertuzumab, ramucirumab, panitumumab, nivolumab, necitumumab, pembrolizumab, obinutuzumab, ofatumumab, erlotinib, gefitinib, sorafenib, lapatinib, palbociclib, regorafenib, imatinib, sunitinib, axitinib, pazopanib, apatinib, ceritinib, crizotinib, osimertinib, bosutinib, dasatinib, nilotinib, ponatinib, hydroxyurea, and procarbazine. 11. The method according to claim 9, which further comprises administering temozolomide. 12. The method according to claim 6, which further comprises administering one or more drugs selected from the group consisting of levodopa, bromocriptine, ropinirole, pramipexole, rotigotine, trihexyphenidyl, benztropine, procyclidine, entacapone, selegiline, rasagiline, amantadine, tetrabenazine, donepezil, rivastigmine, galantamine and memantine.

Details for Patent 10,227,328

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2035-02-04
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2035-02-04
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2035-02-04