IP Library › Granted Patent US 12,673,951
Granted Patent B2
US 12,673,951 · App. 17/626,029 · Granted Jul 7, 2026

Substituted pyrazoloquinazolinone compounds and application thereof

Inventors: Sui Xiong Cai (Shanghai, CN); Ye Edward Tian (Shanghai, CN); Xiaozhu Wang (Nanjing, CN)
Assignee: Impact Therapeutics (Shanghai) Inc
C07D487/04A61K31/519A61K45/06A61P35/00
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Quick Facts
Patent No.
US 12,673,951
App. No.
17/626,029
Filed
Jan 10, 2022
Granted
Jul 7, 2026
Kind
B2
Art Unit
1625
USPC
514/267
Abstract

A compound of formula I, or a stereoisomer, tautomer, N-oxide, hydrate, isotope-substituted derivative, or solvate thereof, or a pharmacologically acceptable salt thereof, or a mixture thereof, of a prodrug thereof. The compound of formula I is a kinase inhibitor which can be used for treating clinical disorder caused by DDR deficiencies, such as cancers.

Claims (88)

1 . A compound having the Formula I:

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein:

A 1 , A 2 and A 3 each are CR 4 , CR 5 and CR 6 , respectively;

B 1 is CH, B 2 is N, B 3 is CH and B 4 is CH; or

B 1 is CH, B 2 is CR 8 , B 3 is CH and B 4 is CH;

R 1 is C 1-4 alkyl or tetrahydropyranyl, optionally substituted by 1-4 C 1-6 alkyl groups;

R 2 is C 1-6 alkyl;

R 3 is C 1-6 alkoxy substituted by —NR 11 R 12 , wherein R 11 and R 12 each are independently H or C 1-6 alkyl, or R 11 and R 12 together with the N atom to which they are both bonded links to form an optionally substituted 4-8 membered heterocyclic group; or R 3 is piperidinyl substituted by —NR 11 R 12 , wherein R 11 and R 12 each are independently H or C 1-6 alkyl; and

R 4 , R 5 , and R 6 are H; and

R 8 is H, halogen, C 1-4 alkyl, or halo C 1-4 alkyl;

wherein the compound of Formula I is not 9-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one.

2 . The compound of claim 1 , wherein

R 2 is C 1-4 alkyl.

3 . The compound of claim 1 , wherein the compound has Formula IIa or IIb:

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein

R 7 , R 9 , and R 10 are H.

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

9-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(methylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(ethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-fluorophenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one; and

9-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof.

5 . A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate or a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable carrier.

6 . The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition further comprises at least one known anticancer drug, or its pharmaceutically acceptable salts.

7 . The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition further comprises 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, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, ofatumumab, avastin, trastuzumab, rituximab, imatinib, gefitinib, erlotinib, lapatinib, sorafinib, sunitinib, nilotinib, dasatinib, pazopanib, bortezomib, torisel, everolimus, vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer therapeutic vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib or senaparib.

8 . The pharmaceutical composition of claim 5 , wherein the compound of Formula I has a structure of Formula IIa or IIb:

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, wherein R 7 , R 9 , and R 10 are H.

9 . The pharmaceutical composition of claim 5 , wherein the compound is selected from the group consisting of:

9-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(methylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(ethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-fluorophenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one; and

9-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof.

10 . A method for treating or disease caused by DDR functional deficiencies or benefiting from the inhibition of kinase activity comprising administering a subject in need thereof an effective amount of a compound of claim 1 , or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a pharmaceutical composition comprising the compound, or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate or a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition optionally further comprises at least one known anticancer drug or its pharmaceutically acceptable salts.

11 . The method of claim 10 , wherein the disease is cancer.

12 . The method of claim 11 , wherein the cancer is selected from 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, b prostatic carcinoma.

13 . The method of claim 10 , wherein the at least one known anticancer drug is one or more of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, ofatumumab, avastin, trastuzumab, rituximab, imatinib, gefitinib, erlotinib, lapatinib, sorafinib, sunitinib, nilotinib, dasatinib, pazopanib, bortezomib, torisel, everolimus, vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer therapeutic vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib or senaparib.

14 . The method of claim 13 , wherein the subject is treated in combination with radiotherapy.

15 . The method of claim 10 , wherein the compound is selected from the group consisting of:

9-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(methylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(ethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(3-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(4-(dimethylamino)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-fluorophenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one;

9-(4-(3-(dimethylamino)propoxy)-3-(trifluoromethyl)phenyl)-1-isopropyl-3-methylpyrazolo[1,5-c]quinazolin-2(3H)-one; and

9-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-c]quinazolin-2(3H)-one;

or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof.

16 . The compound of claim 1 , wherein

R 3 is selected from the group consisting of:

17 . The compound of claim 1 , wherein

R 1 is selected from a group consisting of:

18 . The compound of claim 1 , wherein:

B 2 is CR 8 , wherein R 8 is halogen or halo C 1-4 alkyl; A 3 is CH; R 1 is tetrahydropyranyl or C 1-4 alkyl; R 2 is C 1-4 alkyl; R 3 is C 1-6 alkoxy substituted by —NR 11 R 12 , wherein R 11 and R 12 each are independently H and C 1-4 alkyl, or R 11 and R 12 together with the N atom to which they are attached form a 4-8 membered heterocyclic group optionally substituted by 1-2 C 1-4 alkyl; or

B 2 is CR 8 , wherein R 8 is halogen or halo C 1-4 alkyl; A 3 is CH; R 1 is tetrahydropyranyl; R 2 is C 1-4 alkyl; R 3 is C 1-6 alkoxy substituted by —NR 11 R 12 or piperidinyl, wherein R 11 and R 12 each are independently H or C 1-4 alkyl; or

B 2 is CR 8 , wherein, R 8 is halogen or halo C 1-4 alkyl; A 3 is CH, R 1 is C 1-4 alkyl; R 2 is C 1-4 alkyl; R 3 is C 1-6 alkoxy substituted by —NR 11 R 12 , wherein R 11 and R 12 each are independently H or C 1-4 alkyl, or R 11 and R 12 together with the N atom to which they are attached form a 4-8 membered heterocyclic group optionally substituted by 1-2 C 1-4 alkyl; or

B 2 is N; A 3 is CR 6 ; R 1 is C 1-4 alkyl; R 2 is C 1-4 alkyl; R 3 is C 1-6 alkoxy substituted by —NR 11 R 12 , wherein R 6 is H; R 11 and R 12 each are independently H or C 1-4 alkyl, or R 11 and R 12 together with the N atom to which they are attached form a 4-8 membered heterocyclic group optionally substituted by 1-2 C 1-4 alkyl.

19 . The compound of claim 18 , wherein the 4-8 membered heterocylic group is piperidinyl.

20 . The compound of claim 1 , wherein R 8 is halogen or halo C 1-4 alkyl.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2022
From: CAI, SUI XIONG; TIAN, YE EDWARD; WANG, XIAOZHU
To: IMPACT THERAPEUTICS (SHANGHAI), INC.
Reel/Frame 060227/0660 →
Priority Claims (1)
CN 201910628148.2 · Jul 10, 2019 · national
Continuity (1)
Related Publication 20220259211A1 · Aug 18, 2022
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