IMIDAZO[1,2-b]PYRIMIDO[4,5-d]PYRIDAZIN-5(6H)-ONES AND THE USE THEREOF

• US 20200131192A1
• Filed: 07/10/2018
• Published: 04/30/2020
• Est. Priority Date: 07/10/2017
• Status: Active Grant

• Current Assignee: Impact Therapeutics, Inc.
• Original Assignee: Impact Therapeutics, Inc.
• Inventors: CAI, Suixiong, TIAN, Ye Edward, DONG, Zhiqiang, WANG, Xiaozhu
• Granted Patent: US 11,345,710 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/12 in which the condensed system contains three hetero rings
• CPC Class Codes: C07D 487/14 Ortho-condensed systems

Abstract

Disclosed are imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one compounds, specifically represented by the Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein A and R₁-R₅ are defined herein. Compounds having Formula I are Wee1 kinase inhibitors. Therefore, compounds of the disclosure may be used to treat diseases caused by abnormal Wee1 activity.

Claims

1. A compound having the Formula I:

2. The compound of claim 1, wherein A is N, R₁ and R₂ are each optionally substituted aryl, and R₃-R₅ is H.

3. The compound of claim 1, wherein said compound has Formula II:

4. The compound of claim 3, wherein R₃-R₅ are H or optionally substituted C_1-6 alkyl and Ar₁ and Ar₂ are each optionally substituted phenyl.

5. The compound of claim 1, wherein said compound is selected from the group consisting of:

6-(2-chloro-6-fluorophenyl)-2-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-difluorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino) imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-difluorophenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-fluoro-6-methylphenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-fluoro-6-methylphenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino) imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-methylphenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-methylphenyl)-2-((3,5-dimethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-difluorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-difluorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-difluorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino) imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-fluorophenyl)-2-((3-fluoro-5-methyl-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(piperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-fluoro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-((3S,5R)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-fluoro-5-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-5-methoxy-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-fluoro-4-(1-methylpiperidin-4-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-4-(1-methylpiperidin-4-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-fluoro-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((2,4,4,5-tetramethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-bromo-6-fluorophenyl)-2-((3-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-bromo-6-chlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-bromo-6-chlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-bromo-6-chlorophenyl)-2-((3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-bromo-6-chlorophenyl)-2-((3-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-bromo-6-chlorophenyl)-2-((3-fluoro-5-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-fluoro-6-methylphenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-fluoro-6-methylphenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-methylphenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-methylphenyl)-2-((3-fluoro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2-chloro-6-methylphenyl)-2-((3-chloro-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-8-methylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-9-methylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-9-methylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-fluoro-5-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-9-methylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-9-ethylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-9-ethylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-9-isopropylimidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-(2,6-dichlorophenyl)-2-((3-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)9-(hydroxymethyl)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

6-allyl-2-((3-methyl-4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)imidazo[1,2-b]pyrimido[4,5-d]pyridazin-5(6H)-one;

or a pharmaceutically acceptable salt or prodrug thereof.

6-7. -7. (canceled)

8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, further comprising at least one known anticancer agent, or a pharmaceutically acceptable salt of said anticancer agent.

10. The pharmaceutical composition of claim 8, wherein said composition includes at least one of the following anticancer drugs:

busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2′

-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, campath, panitumumab, metazotuzumab, navuzumab, pymzumab, remoluzumab, bevacizumab, partuzumab, trastuzumab, cetuximab, obinutuzumab, olfamzumab, rituximab, alemtuzumab, tiemuzumab, toximab, bentuximab, daremuzumab, errotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimma, avastin, trastuzumab, rituximab, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, aletinib, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temsirolimus, everolimus, vorinostat, romidepsin, panobinostat, belinostat, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer therapeutic vaccine), palbociclib, olaparib, niraparib, rucaparib and talazoparib.

11. The compound of claim 2, wherein R₁ is selected from phenyl which is optionally substituted by 1-4 groups selected from halo and C₁-C₆ alkyl.

12. The compound of claim 2, wherein R₂ is selected from phenyl and tetrahydroisoquinolinyl optionally substituted by one, two, three, or four selected from the group consisting of:

halo, C₁-C₆ alkyl, oxy group, and heterocyclic group optionally substituted by 1-4 selected from the group consisting of C₁-C₆ alkyl and —

NR_aR_b, wherein R_a and R_b are each independently H and C₁-C₆ alkyl.

13. The compound of claim 12, wherein the heterocyclic group is piperazinyl or piperidinyl.

14. The compound of claim 4, wherein Ar₁ is phenyl optionally substituted by 1-4 groups selected from halo and C₁-C₆ alkyl.

15. The compound of claim 4, wherein Ar₂ is phenyl substituted by piperazinyl which is optionally substituted or phenyl substituted by piperidyl which is optionally substituted.

16. The compound of claim 15, wherein piperazinyl is optionally substituted by 1-3 C₁-C₆ alkyl and piperidyl is optionally substituted by one group selected from C₁-C₆ alkyl and —

NR_aR_b, wherein R_a and R_b are each independently H or C₁-C₆ alkyl.

17. The compound of claim 3, wherein the compound of Formula II has a structure represented by Formula III:

18. The compound of claim 17, wherein:

Ar₁ is selected from phenyl substituted by 2 substituents selected from halo and C₁-C₆ alkyl; and

Ar₂ is selected from substituted phenyl, of which the substituents are selected from;

halo, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

piperazinyl optionally substituted by 1-3 C₁-C₆ alkyl;

piperidinyl optionally substituted by one substituent selected from C₁-C₆ alkyl and —

NR_aR_b; and

tetrahydroisoquinolinyl optionally substituted by 1-3 C₁-C₆ alkyl;

wherein R_a and R_b are each independently H or C₁-C₆ alkyl.

19. The compound of claim 17, wherein:

Ar₁ is di-substituted phenyl substituted by substituents selected from halo and C₁-C₃ alkyl at two meta-positions;

Ar₂ is phenyl substituted by 1, 2, or 3 substituents selected from halo, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

piperazinyl optionally substituted by 1-3 C₁-C₆ alkyl;

piperidinyl substituted by 1 substituent selected from C₁-C₆ alkyl and —

NR_aR_b; and

tetrahydroisoquinolinyl substituted by 1-3 C₁-C₆ alkyl;

wherein R_a and R_b are independently H and C₁-C₄ alkyl.

20. The compound of claim 17, wherein:

Ar₁ is selected from the following;

21. A method for treating a Wee1-mediated disease, comprising administering to a mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable salt or prodrug thereof.

22. The method of claim 21, wherein said disease is cancer selected from the group consisting of liver cancer, melanoma, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms'"'"' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head and neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi'"'"'s sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, and prostatic carcinoma.