CN116836184A - Preparation and application of Wee1 kinase inhibitor - Google Patents
Preparation and application of Wee1 kinase inhibitor Download PDFInfo
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- CN116836184A CN116836184A CN202210299440.6A CN202210299440A CN116836184A CN 116836184 A CN116836184 A CN 116836184A CN 202210299440 A CN202210299440 A CN 202210299440A CN 116836184 A CN116836184 A CN 116836184A
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- 238000002360 preparation method Methods 0.000 title abstract description 85
- 101150040313 Wee1 gene Proteins 0.000 title abstract description 9
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 21
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 77
- 229910052736 halogen Inorganic materials 0.000 claims description 74
- 150000002367 halogens Chemical class 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 229910052760 oxygen Inorganic materials 0.000 claims description 43
- 229910052717 sulfur Inorganic materials 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 36
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 229910052805 deuterium Inorganic materials 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 15
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- 125000004429 atom Chemical group 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
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- 150000002431 hydrogen Chemical class 0.000 claims description 4
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- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The invention discloses a preparation method and application of a Wee1 kinase inhibitor, in particular to a compound shown as a formula (I) or a formula (II) and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound and or the pharmaceutically acceptable salts thereof, and application of the compound or the pharmaceutically acceptable salts in medicines for treating or preventing Wee1 kinase related diseases, particularly tumors, which are heterocyclic ringsThe compound and the preparation process of the medicine composition of the compound or its pharmaceutically acceptable salt are also disclosed. Wherein each substituent of the general formula (I) or the general formula (II) is as defined in the specification.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a novel compound with a Wee1 kinase inhibition effect, a preparation method thereof and application of the novel compound in preparation of antitumor drugs.
Background
Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 phase checkpoint of the G1 (cell resting phase) to S phase (DNA synthesis phase) transition, the G2 phase checkpoint of the G2 (cell division preparation phase) to M (cell division phase) phase transition, and the spindle checkpoints of the M phase metanase to anaphase (cell division phase post-phase) transition. Wee-1 protein kinase plays an important role in the G2 phase checkpoint. The entry of cells into the M phase depends on CDK1 kinase activity, and Wee-1 inhibits CDK1 activity by phosphorylating Tyr15 of CDK1 protein, preventing cells from entering the M phase (cell division phase). While the Polo kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein and promotes cells to enter M phase. As can be seen, wee-1 kinase activity determines the activity of the G2 checkpoint, which in turn regulates the G2 to M phase transition of cells [ Cell Cycle,2013,12 (19): 3159-64 ].
When the DNA of the cell is damaged, the inspection of the G1 phase, the S phase and the G2 phase delays the cell from entering the division phase, so that time is striven for repairing the damaged DNA before the cell enters the division phase, and the integrity of the genome is ensured. The key regulator of the G1 checkpoint, P53, is a mutant form in many malignant cells (PNAS, 2007,104 (10): 3753-3758). Tumor cells deficient in P53 function, when DNA is damaged, cannot block the cell cycle in G1 phase and are therefore more dependent on the G2 phase checkpoint. For DNA damage, the G2 phase checkpoint inhibits CDK1 phosphorylation via two pathways that are parallel and interconnected, thereby delaying the cell from entering the dividing phase. Ataxia Telangiectasia Mutated (ATM) protein kinase or Ataxia Telangiectasia Related (ATR) protein kinase is activated according to the type of DNA damage (Oncotarget, 2016,7 (31): 49902-49946).
Thus, inhibition of the G2 phase checkpoint can selectively kill tumor cells. While the important role of Wee-1 kinase activity in the G2 phase checkpoints suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage, inhibiting Wee-1 activity can promote unrepaired tumor cells after DNA damage to enter the M phase, and induce apoptosis [ Curr Clin Pharmacol,2010.5 (3): 186-91].
WEE1 is overexpressed in many malignancies, such as liver cancer, breast cancer, glioblastoma, melanoma, adult and pediatric brain tumors. Some of the tumor cells have abnormal G1 checkpoints, and if WEE1 activity is inhibited, the check point in the G2 phase fails, and at this time, cells with unrepaired damaged DNA continue to divide, and finally divide and die. (Molecular Cancer Therapeutics,2013,12 (12): 2675-2684.) inhibition of WEE1 activity, whether by pyrimidine derivatives (PD 0166285) or small interfering RNA knockdown, renders ovarian, colon, cervical, osteosarcoma, glioblastoma and lung cancer cells more susceptible to DNA damage resulting from radiation and topoisomerase inhibition. Thus, both WEE1 inhibitor single and combination have a wide development space (cancer biology & Therapy,2010,9 (7): 523-525).
The Wee1 inhibitor AZD1775 of AstraZeneca has entered phase II clinical trials with more than 30 clinical trials are being developed and have shown good therapeutic efficacy. Currently, related Wee1 inhibitor patents are mainly: WO2007126122, WO2008133866, WO2011034743, WO2013039854, WO2018090939, WO2018133829, WO2019011228, WO2019037678, WO2019085933, WO2019173082, WO2020083404, WO2020192581, WO2020221358, WO2021043152. However, there is currently no such target product on the market. Therefore, it is of great importance to develop inhibitors that inhibit this target more efficiently.
Disclosure of Invention
A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph or an isomer thereof, wherein the compound of the general formula (I) has the structure:
wherein, the liquid crystal display device comprises a liquid crystal display device,
each L 1 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each L 2 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each X is 1 、X 2 Independently at each occurrence selected from N or CR 9 ;
When a is a single bond, X 3 Select NR 1 Or NH;
when a is a double bond, X 3 Selecting N;
each ring B is independently selected at each occurrence from a 3-8 membered heterocyclic ring, said 3-8 membered heterocyclic ring independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each B is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 11 Substituted or unsubstituted;
each Ar is provided with 1 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 1 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 12 Substituted or unsubstituted;
Each Ar is provided with 2 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 2 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 13 Substituted or unsubstituted;
each R 10 Independently at each occurrence selected from deuterium, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 or-C 3-6 Carbocyclyl; each R 9 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 9 、R 11 、R 12 、R 13 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 9 、R 11 、R 12 、R 13 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 1 Independently at each occurrence selected from Or->-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2- Alkynyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 、-C 3-6 Carbocyclyl, 3-8 membered heterocycle; the 3-8 membered heterocycle independently at each occurrence comprises 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each R 1 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
wherein:
each L 3 Independently at each occurrence selected from bond, O, NH, CO, or S;
each ring A is C 3-10 Carbocycles, saidMay be attached to the same carbon atom of the ring a or to different atoms;
each R 2 is-OR 6 、-NR 6 R 7 、-SR 6 、-S(=O)R 6 、-S(=O) 2 R 6 A 5-to 10-membered heteroaryl or a 3-to 10-membered heterocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprising 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o) 2 Each R3 is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 19 Substituted or unsubstituted;
each R 3 And R is 4 Independently at each occurrence selected from deuterium, hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 or-C 3-10 Carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprise 1, 2, 3 or 4 groups selected from N, 0, S, S =0 or S (=o) 2 Is a heteroatom of (2); each R 3 And R is 4 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 5 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprises 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o) 2 Is a heteroatom of (2); each R 3 And R is 4 Independently at each occurrence is optionally substituted with 1, 2,3. 4, 5 or 6 are selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each Ar is provided with 3 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 3 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 13 Substituted or unsubstituted;
each R 13 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 12 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 6 And R is 7 At each occurrenceIndependently selected from hydrogen or-C1-6 alkyl, each R 6 And R is 7 Independently optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted; or R is 7 And R is 7 Together with the N atom to which they are attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further comprise 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2, and said 3-10 membered heterocyclic ring is independently optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted;
each R 8 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -O-C 1-6 Alkylene- (halogen) 1-3 、-SC 1-6 Alkyl, -S-C 1-6 Alkylene- (halogen) 1-3 、-NC 1- 6 C 1-6 、-C 1-6 alkylene-NC 1-6 Alkyl C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl, -S (O) 2 NC 1-6 Alkyl C 1-6 Alkyl or-C 3-6 Carbocyclyl;
n is selected from 0, 1, 2, 3, 4, 5 or 6;
s is selected from 0, 1, 2, 3, 4, 5 or 6;
p is selected from 0, 1, 2, 3, 4, 5 or 6;
q is selected from 0, 1, 2, 3, 4, 5 or 6.
In some embodiments, each R 1 Selected from the following structures:
the pharmaceutically acceptable salt is selected from the following compounds, isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof:
a compound having the general formula (II), a stereoisomer, a pharmaceutically acceptable salt, a polymorph or an isomer thereof, wherein the compound of the general formula (II) has the structure:
wherein, the liquid crystal display device comprises a liquid crystal display device,
each L 1 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each L 2 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each X is 1 、X 2 Independently at each occurrence selected from N or C;
each R 1 Independently at each occurrence selected from deuterium, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, phenyl, 6 membered heteroaryl, -C 1-6 Alkylene- (halogen) 1-3 、-C 1-6 Alkenylene- (halogen) 1-3 、-C 1-6 Alkynylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 1 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 2 Each heteroaryl independently at each occurrence is selected from phenyl, naphthyl, 6 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 2 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted;
each ring B is independently selected at each occurrence from a 3-8 membered heterocyclic ring, said 3-8 membered heterocyclic ring independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each B is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 9 Substituted or unsubstituted;
each Ar is provided with 2 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 2 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 10 Substituted or unsubstituted;
each R 8 、R 9 、R 10 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl;
each R 6 And R is 7 Independently at each occurrence selected from hydrogen or-C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN;
in some embodiments, the compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof:
another object of the present invention is a pharmaceutical composition comprising a pharmacologically acceptable excipient or carrier, and the compound of formula (1A) or formula (1B), an isomer thereof or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient.
A further object of the present invention is to provide the use of the above-mentioned compound of the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease related to Wee1 mediated diseases.
Certain chemical terms
Unless stated to the contrary, the following terms used in the specification and claims.
The expression "C" as used herein has the following meaning x-y "means a range of carbon number wherein x and y are integers, e.g. C 3-8 Cycloalkyl represents a cyclic alkyl group having a structure of 3-Cycloalkyl of 8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C 3-8 "also includes any subrange therein, e.g. C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 Etc.
"alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.
"alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.
"alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.
"cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decalin, which cycloalkyl groups may be substituted or unsubstituted.
"heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of the present application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic mono-or bi-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic mono-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
"spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having one atom in common between the monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl groups are classified as mono-spiro heterocyclyl, bi-spiro heterocyclyl or multi-spiro according to the number of common spiro atoms between ringsHeterocyclyl groups, preferably mono-and di-spirocycloalkyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro-cyclic group. Non-limiting examples of spiroheterocyclyl groups include:
"fused heterocyclyl" means a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
"heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, the heteroaryl group is preferably a 5-8 membered heteroaryl group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.
"halogen" means fluorine, chlorine, bromine or iodine.
"hydroxy" means-OH, "amino" means-NH 2 "amido" means-NHCO-, -cyano "means-CN," nitro "means-CN," Isocyano "means-NC," trifluoromethyl "means-CF 3 。
The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to an atom other than carbon and hydrogen, the heteroatom being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.
The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur, e.g., an "optionally alkyl-substituted heterocyclic group" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.
"substituted" means that one or more atoms, preferably 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. It goes without saying that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, the substituents being in their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. The substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl groups, and the like.
"pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and further exert biological activity.
"isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.
The compounds of the invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as cis or trans configuration.
The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.
It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.
"isotopes" are all isotopes of atoms that are present in compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, each such as, but not limited to 2 H、 3 H、 13 C、 14 C、 15 N、 18 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
By "prodrug" is meant that the compounds of the invention may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present invention which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the invention according to well known methods.
"pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the invention containing acidic groups may be present in salt form and may be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups may be present in salt form and may be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
Thus, in the present application, when referring to "a compound", "a compound of the application" or "a compound of the application" all such compound forms, e.g. prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers and mixtures thereof are included.
Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).
As used herein, the term "cancer" includes various malignant tumors that Bruton's tyrosine kinase participates in, including but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyodur, cellular cancer, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular cancer), more particularly liver cancer, gastric cancer and bladder cancer.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The term "polymorph" or "polymorphic form" as used herein means that a compound of the present invention has a plurality of crystalline forms, some compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.
Intermediate compounds of the invention and polymorphs thereof are also within the scope of the present invention.
Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.
The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.
The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including
(i) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;
(ii) Inhibiting the disease or disorder, i.e., controlling its progression;
(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;
(iv) Relieving symptoms caused by diseases or symptoms.
The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.
The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
Synthesis of Compounds
The process for preparing the compounds of formula (I) or (II) according to the invention is described in detail below, but these particular processes do not constitute any limitation on the invention.
The compounds of formula (I) or (II) described above may be synthesized using standard synthetic techniques or well known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials for the synthesis of the compounds of formula (I) or (II) may be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY th Ed., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY th Ed., vols.A and B (Plenum 2000, 2001), green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3< rd > ed., (Wiley 1999). The general method of preparation of the compounds may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.
In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as the reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the explanation below. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compound of formula (II) or formula (II), which is prepared by the following method:
Method A
Method B
Method C
Method D
Detailed description of the preferred embodiments
The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which, however, should not be regarded as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis can be synthesized conventionally according to the literature (reaxys) or purchased.
Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers such as chemblocks Inc, astatech Inc or michelin and these reagents were used directly without further purification unless otherwise indicated.
Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using dry tubes; glassware drying and/or heat drying.
Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Therno LCD Fleet type (ESI) liquid chromatograph-mass spectrometer.
Nuclear magnetic data (1H NMR) using Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instruments, the solvent used for nuclear magnetic data was CDCl 3 、CD 3 OD、D 2 O, DMS-d6, etc., based on tetramethylsilane (0.000 ppm) or on residual solvent (CDCl) 3 :7.26ppm;CD 3 OD:3.31ppm;D 2 O4.79 ppm; d6-DMSO:2.50 ppm) when peak shape diversity is indicated, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).
Example 1
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) pyrimido [4,5-d ] pyrimidin-4 (3H) -one (compound 1)
First step preparation of 3- (2, 6-dichlorophenyl) -7-methylthiopyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione
10g of ethyl 4-amino-2- (methylthio) pyrimidine-5-carboxylate were dissolved in 150ML of DMF, then 3.15g of NaH were added and stirred at room temperature for 5 minutes. 9.70g of 2, 6-dichlorobenzyl isocyanate was added to the reaction solution, and stirred at room temperature for 1 hour. Ethyl acetate and 1N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. Washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The precipitated solid was solidified with methanol, and the solid was removed by filtration to obtain 13.7g of 3- (2, 6-dichlorophenyl) -7- (methylthio) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione as a white solid compound.
LC/MS(ESI):m/z=355[M+H] + .
Second step preparation of 2-chloro-3- (2, 6-dichlorophenyl) -7-methylthiopyrimidine [4,5-d ] pyrimidin-4 (3H) -one
3- (2, 6-dichlorophenyl) -7- (methylthio) pyrimidine [4,5-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (5.31 g 15 mmol) was dissolved in POCl 3 To (80 mL) was added a small amount of N, N-dimethylaniline, and the mixture was heated under reflux with stirring for 4 hours. Then pouring into ice water for quenching, and filtering to obtain a solid productWashing with water, and drying to obtain crude yellow solid 2-chloro-3- (2, 6-dichlorophenyl) -7- (methylthio) pyrimidine [4,5-d ]]Pyrimidin-4 (3H) -one (4.86 g, 78%) was used for the next reaction without further purification.
LC/MS(ESI):m/z=374[M+H] + .
Third step, preparation of 2- (tetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -3- (2, 6-dichlorophenyl) -7-methylsulfanyl-pyrimidine [4,5-d ] pyrimidin-4 (3H) -one
2-chloro-3- (2, 6-dichlorophenyl) -7- (methylthio) pyrimidine [4,5-d]Pyrimidine-4 (3H) -one (373 mg,1 mmol), hexahydro-7 a-methanol (53 mg,0.33 mmol), potassium carbonate (62 mg,0.45 mmol) as a catalytic amount of potassium iodide and DMF (10 mL) were mixed, heated to 120℃and reacted with stirring for 4 hours. Cooling to room temperature, evaporating under reduced pressure, and performing column chromatography to obtain off-white solid 2- (tetrahydro-1H-pyridine ring-7 a (5H) -yl) methoxy) -7- (methylthio) pyrimidine [4,5-d ]]Pyrimidin-4 (3H) -one (416 mg, 87%). LC/MS (ESI) m/z=479 [ M+H ] ] + .
Fourth step, preparation of 2- (tetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -3- (2, 6-dichlorophenyl) -7-methylsulfonylpyrimidine [4,5-d ] pyrimidin-4 (3H) -one
2- (tetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -7- (methylthio) pyrimidine [4,5-d]Pyrimidin-4 (3H) -one (382 mg,0.8 mmol) was dissolved in 10mLCH 2 Cl 2 To this, m-chloroperoxybenzoic acid (522 mg,3 mmol) was added and stirred at room temperature for 2 hours. CH for reaction solution 2 Cl 2 Dilute and use saturated NaHCO 3 And Na (Na) 2 S 2 O 3 And (5) cleaning. MgSO for organic layer 4 Drying, evaporating under reduced pressure, and column chromatography to obtain yellow solid 2- (tetrahydro-1H-pyridine ring-7 a (5H) -yl) methoxy) -7-methylsulfonyl pyrimidine [4,5-d ]]Pyrimidin-4 (3H) -one (390 mg, 96%). LC/MS (ESI) m/z=511 [ M+H ]] + .
Fifth step preparation of 2- (tetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one
2- (tetrahydro-1H-pyrazin-7 a (5H) -yl) methoxy) -7-methylsulfonyl pyrimidine [4,5-d ]]Pyrimidin-4 (3H) -one (51 mg,0.1 mmol) was dissolved in 10ml DMF and DIPEA (65 mg,0.5 mmol) and 4- (4-methyl) were addedThe piperazin-1-yl) aniline (23 mg,0.12 mmol) was stirred at room temperature for 24 hours. Pouring ice water, filtering to obtain crude product, and separating by flash column to obtain yellow solid 2- (tetrahydro-1H-pyridine ring-7 a (5H) -yl) methoxy) -7- ((4- (4-methylpiperazine-1-yl) phenyl) amino) pyrimidine [4,5-d ]Pyrimidin-4 (3H) -one (50 mg, 83%). 1 H NMR(300MHz,DMSO-d 6 )δ10.77(s,1H),9.12(s,1H),7.42-7.99(m,4H),6.88-7.29(m,3H),4.41(s,2H),3.46-3.61(m,4H),3.01-3.15(m,4H),2.48–2.58(m,4H),2.01-2.27(m,5H),1.87-1.96(m,4H),1.78-1.80(m,2H),1.69-1.76(m,2H);LC/MS(ESI):m/z=622.2[M+H] + .
Example 2
Preparation of 3- (2, 6-difluorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) pyrimido [4,5-d ] pyrimidin-4 (3H) -one (compound 2)
Compound 2 (51 mg, 86% yield) was obtained by a method similar to example 1. LC/MS (ESI) m/z=589.3 [ M+H ]] + 。
Example 3
Preparation of 3- (2, 6-dimethylphenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) pyrimido [4,5-d ] pyrimidin-4 (3H) -one (compound 3)
Compound 3 (45 mg, 78% yield) was obtained by a method similar to example 1. 1 H NMR(300MHz,CDCl 3 )δ9.22(s,1H),7.06-7.78(m,7H),4.19(s,2H),3.31(m,4H),2.60-2.68(m,6H),2.40(s,3H),2.15(s,6H),2.07-2.19(m,2H),1.87-1.98(m,4H),1.66-1.80(m,2H);LC/MS(ESI):m/z=581.3[M+H] + 。
Example 4
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((adamantan-1-yl) methoxy) pyrimido [4,5-d ] pyrimidin-4 (3H) -one (compound 4)
Compound 4 (53 mg, 82% yield) was obtained in a similar manner to example 1. 1 H NMR(300MHz,DMSO-d 6 )δ10.78(s,1H),9.12(s,1H),7.42-7.80(m,4H),6.88-7.28(m,3H),4.04(s,2H),3.46-3.61(m,4H),3.01-3.15(m,4H),2.01(m,3H),1.69-1.72(m,12H);LC/MS(ESI):m/z=647.2[M+H] + 。
Example 5
Preparation of 3- (2, 6-difluorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((adamantan-1-yl) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 5)
Compound 5 (56 mg, yield 91%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=614 [ M+H ] ] + 。
Example 6
Preparation of 3- (2, 6-dimethylphenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((adamantan-1-yl) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 6)
Compound 6 (50 mg, yield 83%) was obtained by a method similar to example 1. 1 H NMR(300MHz,CDCl 3 )δ9.22(s,1H),7.06-7.78(m,7H),3.93(s,2H),2.01(m,3H),1.70-1.76(m,12H);LC/MS(ESI):m/z=606.3[M+H] + 。
Example 7
Preparation of 2- (adamantan-1-ylmethoxy) -3- (2, 6-dichlorophenyl) -7- ((3-methyl-1, 2,3, 4a, 5-hexahydrobenzo [ b ] pyrazino [1,2-d ] [1,4] oxazin-8-yl) amino) pyrimidin [4,5-d ] pyrimidin-4 (3H) -one (Compound 7)
Compound 7 (53 mg, 78% yield) was obtained by a method similar to that of example 6. LC/MS (ESI) m/z=675.3 [ M+H ]] + 。
Example 8
Preparation of 2- (adamantan-1-ylmethoxy) -3- (2, 6-dichlorophenyl) -7- ((4- (1-methylpiperidin-4-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 8)
Compound 8 (49 mg, 76% yield) was obtained in a similar manner to example 6. LC/MS (ESI) m/z=646 [ M+H ]] + 。
Example 9
Preparation of 2- (adamantan-1-ylmethoxy) -3- (2, 6-dichlorophenyl) -7- ((2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (Compound 9)
Compound 9 (56 mg, yield 87%) was obtained by a method similar to example 6. LC/MS (ESI) m/z=646.3 [ M+H ] ] + 。
Example 10
Preparation of 2- (adamantan-1-ylmethoxy) -3- (2, 6-dichlorophenyl) -7- ((2 '-methyl-2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinolin ] -7' -yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 10)
Obtained in a similar manner to example 6To compound 10 (46 mg, 72% yield). LC/MS (ESI) m/z=644.2 [ M+H ]] + 。
Example 11
Preparation of 2- (adamantan-1-ylmethoxy) -3- (2, 6-dimethylphenyl) -7- ((2 '-methyl-2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinolin-7' -yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 11)
Compound 11 (41 mg, yield 69%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=603.3 [ M+H ]] + 。
Example 12
Preparation of 2- (adamantan-1-ylmethoxy) -3- (2, 6-dimethylphenyl) -7- ((2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (Compound 12)
Compound 12 (51 mg, yield 84%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=605.3 [ M+H ]] + 。
Example 13
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 13)
First step, preparation of 3- (2, 6-dichlorophenyl) -7-methylsulfonyl pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione
3- (2, 6-dichlorophenyl) -7-methylthiopyrimidine [4,5-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (3.82 g,8 mmol) was dissolved in 50mLCH 2 Cl 2 In the above, m-chloroperoxybenzoic acid (5.22 g,30 mmol) was added and the mixture was cooled to room temperatureStirring is carried out for 2 hours. CH for reaction solution 2 Cl 2 Dilute and use saturated NaHCO 3 And Na (Na) 2 S 2 O 3 And (5) cleaning. MgSO for organic layer 4 Drying, evaporating under reduced pressure, and column chromatography to obtain yellow solid 3- (2, 6-dichlorophenyl) -7-methylsulfonyl pyrimidine [4,5-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (2.84 g, 92%). LC/MS (ESI) m/z=388 [ M+H ]] + .
Second step preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione
3- (2, 6-dichlorophenyl) -7-methylsulfonylpyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (1.16 g,3 mmol) was dissolved in 25ml DMF, DIPEA (1.94 g,15 mmol) and 4- (4-methylpiperazin-1-yl) aniline (0.48 g,0.12 mmol) were added and stirred at room temperature for 24 hours. Ice water was poured and filtered to give crude product which was then separated via flash column to give 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (1.33 g, 89%) as a yellow solid.
LC/MS(ESI):m/z=499[M+H] + 。
Third step preparation of 2-chloro-3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one
3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d]Pyrimidine-2, 4 (1H, 3H) -dione (1.25 g 2.5 mmol) was dissolved in POCl 3 To (20 mL) was added a small amount of N, N-dimethylaniline, and the mixture was heated under reflux with stirring for 4 hours. Then pouring into ice water for quenching, filtering to obtain a solid product, washing with water, and drying to obtain crude yellow solid 2-chloro-3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazine-1-yl) phenyl) amino) pyrimidine [4,5-d]Pyrimidin-4 (3H) -one (0.93 g, 72%) was used for the next reaction without further purification. LC/MS (ESI) m/z=517 [ M+H ]] + .
Fourth step preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one
2-chloro-3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d]Pyrimidin-4 (3H) -one (5)2mg,0.1 mmol), N-methylpyrrolidine-2-methanol (23 mg,0.2 mmol), potassium carbonate (62 mg,0.45 mmol) catalytic amount of potassium iodide and DMF (10 mL) were mixed, heated to 120℃and stirred for 4 hours. Cooling to room temperature, pouring into water, filtering to obtain crude product, and performing column chromatography to obtain off-white solid 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidine [4,5-d ]Pyrimidin-4 (3H) -one (53 mg, 92%). LC/MS (ESI) m/z=576 [ M+H ]] + .
Example 14
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1- (dimethylaminomethyl) cyclopropane) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 14)
Compound 14 (51 mg, yield 84%) was obtained by a method similar to example 13. LC/MS (ESI) m/z=610.2 [ M+H ]] + 。
Example 15
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1- (pyrrolidin-1-methyl) cyclopropane) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 15)
Compound 15 (58 mg, 91% yield) was obtained by a method similar to that of example 13. LC/MS (ESI) m/z=636.2 [ M+H ]] + 。
Example 16
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1-methylpiperidin-3-yl) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 16)
Compound 16 (47 mg, 88% yield) was obtained by a method similar to that of example 13. LC/MS (ESI) m/z=610 [ M+H ]] + 。
Example 17
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1, 4-dimethylpiperazin-2-yl) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 17)
Compound 17 (49 mg, 79% yield) was obtained by a method similar to that of example 13. LC/MS (ESI) m/z=625 [ M+H ]] + 。
Example 18
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- (3- (dimethylamino) propoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 18)
Compound 18 (49 mg, 84% yield) was obtained in a similar manner to example 13. LC/MS (ESI) m/z=584 [ M+H ]] + 。
Example 19
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dichlorophenyl) -6- ((3-methyl-1, 2,3, 4a, 5-hexahydrobenzo [ b ] pyrazino [1,2-d ] [1,4] oxazin-8-yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (Compound 19)
Compound 19 (60 mg, 92% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=650.2 [ M+H ]] + 。
Example 20
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dichlorophenyl) -7- ((4- (1-methylpiperidin-4-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 20)
Compound 20 (50 mg, yield 81%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=621.2 [ M+H ]] + 。
Example 21
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dichlorophenyl) -7- ((2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 21)
Compound 21 (53 mg, 86% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=621.2 [ M+H ]] + 。
Example 22
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dichlorophenyl) -7- ((2 '-methyl-2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinolin ] -7' -yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 22)
Compound 22 (46 mg, yield 74%) was obtained by analogy with example 1. LC/MS (ESI) m/z=619.2 [ M+H ]] + 。
Example 23
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dimethylphenyl) -7- ((2 '-methyl-2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinolin-7' -yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 23)
Compound 23 (50 mg, 86% yield) was obtained in a similar manner to example 3. LC/MS (ESI) m/z=578.3 [ M+H ]] + 。
Example 24
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dimethylphenyl) -7- ((3-methyl-1, 2,3, 4a, 5-hexahydrobenzo [ b ] pyrazino [1,2-d ] [1,4] oxazin-8-yl) amino) pyrimidin [4,5-d ] pyrimidin-4 (3H) -one (Compound 24)
Compound 24 (55 mg, 91% yield) was obtained by a method similar to that of example 3. LC/MS (ESI) m/z=609.3 [ M+H ]] + 。
Example 25
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dimethylphenyl) -7- ((4- (1-methylpiperidin-4-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 25)
Compound 25 (50 mg, 89% yield) was obtained in a similar manner to example 3. LC/MS (ESI) m/z=580 [ M+H ]] + 。
Example 26
Preparation of 2- ((hexahydro-1H-pyrrolin-7 a-yl) methoxy) -3- (2, 6-dimethylphenyl) -7- ((2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 26)
Compound 26 (45 mg, 77% yield) was obtained in a similar manner to example 3. LC/MS (ESI) m/z=580 [ M+H ]] + 。
Example 27
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2-benzyloxypyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 27)
Compound 27 (52 mg, 88% yield) was obtained in a similar manner to example 13. LC/MS (ESI) m/z=589 [ M+H ]] + 。
Example 28
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((pyridin-3-yl) methoxy) pyrimidine [4,5-d ] pyrimidin-4 (3H) -one (compound 28)
Compound 28 (49 mg, yield 83%) was obtained by a method similar to example 13. LC/MS (ESI) m/z=590 [ M+H ] ] + 。
Example 29
Preparation of N- (3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -4-oxo-3, 4-dihydropyrimidin [4,5-d ] pyrimidin-2-yl) nicotinamide (compound 29)
Compound 29 (48 mg, 79% yield) was obtained by a method similar to that of example 3. LC/MS (ESI) m/z=603 [ M+H ]] + 。
Example 30
Preparation of N- (3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -4-oxo-3, 4-dihydropyrimidine [4,5-d ] pyrimidin-2-yl) furan-2-carboxamide (compound 30)
Compound 30 (50 mg, yield 84%) was obtained by a method similar to example 3. LC/MS (ESI) m/z=592 [ M+H] + 。
Example 31
Preparation of N- (3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -4-oxo-3, 4-dihydropyrimidine [4,5-d ] pyrimidin-2-yl) oxazole-2-carboxamide (Compound 31)
Compound 31 (53 mg, 89% yield) was obtained in a similar manner to example 3. LC/MS (ESI) m/z=593 [ M+H ]] + 。
Example 32
Preparation of N- (3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -4-oxo-3, 4-dihydropyrimidine [4,5-d ] pyrimidin-2-yl) -1-methyl-1H-pyrazole-5-carboxamide (compound 32)
Compound 32 (51 mg, yield 85%) was obtained by a method similar to example 3. LC/MS (ESI) m/z=606 [ M+H ] ] + 。
Example 33
Preparation of 1-benzyl-3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (Compound 33)
First step preparation of 1-benzyl-3- (2, 6-dichlorophenyl) -7- (methylthio) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione
3- (2, 6-dichlorophenyl) -7- (methylthio) pyrimidine [4,5-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (354 mg,1 mmol), benzyl chloride (151 mg,1.2 mmol), potassium carbonate (620 mg,4.5 mmol) catalytic amounts of potassium iodide and DMF (25 mL) were mixed, heated to 120℃and reacted with stirring for 4 hours. Cooled to room temperature, poured into water and filtered to obtain off-white solid 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidine [4,5-d]Pyrimidin-4 (3H) -one (277 mg, 78%). LC/MS (ESI) m/z=446 [ M+H ]] + 。
Second step, preparation of 1-benzyl-3- (2, 6-dichlorophenyl) -7-methylsulfonyl pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione
3- (2, 6-dichlorophenyl) -7-methylthiopyrimidine [4,5-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (311 mg,0.7 mmol) was dissolved in 10mLCH 2 Cl 2 To this solution, m-chloroperoxybenzoic acid (319 mg,2.1 mmol) was added and stirred at room temperature for 2 hours. CH for reaction solution 2 Cl 2 Dilute and use saturated NaHCO 3 And Na (Na) 2 S 2 O 3 And (5) cleaning. MgSO for organic layer 4 Drying, evaporating under reduced pressure, and column chromatography to obtain yellow solid 1-benzyl-3- (2, 6-dichlorophenyl) -7-methylsulfonyl pyrimidine [4,5-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (290 mg, 87%). LC/MS (ESI) m/z=478 [ M+H ]] + .
Third step, preparation of 1-benzyl-3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione
1-benzyl-3- (2, 6-dichlorophenyl) -7-methylsulfonylpyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (95 mg,0.2 mmol) was dissolved in 10ml DMF, DIPEA (78 mg,0.6 mmol) and 4- (4-methylpiperazin-1-yl) aniline (46 mg,0.24 mmol) were added and stirred at room temperature for 24 hours. Ice water was poured and filtered to give crude product, which was then separated by flash column to give off-white solid 1-benzyl-3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (104 mg, 89%).
LC/MS(ESI):m/z=589[M+H] + 。
Example 34
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1- (pyridin-4-ylmethyl) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (compound 34)
Compound 96 (88 mg, yield 74%) was obtained by a method similar to example 33. LC/MS (ESI) m/z=590 [ M+H ] ] + 。
Example 35
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1- ((hexahydro-1H-pyrrolin-7 a-yl) methyl) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (Compound 36)
Compound 36 (97 mg, 78% yield) was obtained by a method similar to that of example 33. LC/MS (ESI) m/z=622 [ M+H ]] + 。
Example 36
Preparation of 1-benzyl-3- (2, 6-dimethylphenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (Compound 36)
Compound 36 (95 mg, yield 87%) was obtained by a method similar to example 33. LC/MS (ESI) m/z=548 [ M+H ]] + 。
Example 37
Preparation of 3- (2, 6-dimethylphenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1- (pyridin-4-ylmethyl) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (Compound 37)
Compound 37 (83 mg, 76% yield) was obtained by a method similar to that of example 33. LC/MS (ESI) m/z=549.3 [ M+H ]] + 。
Example 38
Preparation of 3- (2, 6-dimethylphenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1- ((hexahydro-1H-pyrrolin-7 a-yl) methyl) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (Compound 38)
Compound 38 (72 mg, 62% yield) was obtained in a similar manner to example 33. LC/MS (ESI) m/z=581 [ M+H ] ] + 。
Example 39
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1- ((1- ((dimethylamino) methyl) cyclopropyl) methyl) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (compound 39)
Compound 39 (84 mg, 69% yield) was obtained by a method similar to that of example 33. LC/MS (ESI) m/z=610 [ M+H ]] + 。
Example 40
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1- ((1- (pyrrolidin-1-ylmethyl) cyclopropyl) methyl) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (compound 40)
Compound 40 (91 mg, 72% yield) was obtained by a method similar to that of example 33. LC/MS (ESI) m/z=636 [ M+H ]] + 。
Example 41
Preparation of 3- (2, 6-dichlorophenyl) -7- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1- (adamantan-1-ylmethyl) pyrimidine [4,5-d ] pyrimidine-2, 4 (1H, 3H) -dione (Compound 41)
Compound 41 (87 mg, 67% yield) was obtained by a method similar to that of example 33. LC/MS (ESI) m/z=647 [ M+H ]] + 。
Similar to the synthesis of 1-41, the following compounds can be obtained:
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example 42
Preparation of 2-propenyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 42)
First step preparation of 2-propenyl-6-chloro-1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one
To a solution of methyl 4, 6-dichloropyridazine-3-carboxylate (9.89 g,47.8 mmol) in 150mL of THF was added DIPEA (20.8 mL,120 mmol) and tert-butyl 1-allylhydrazinecarboxylate (8.22 g,47.8 mmol), the reaction was refluxed for 72 hours and then concentrated in vacuo. Et is added to the residue 2 O (50 ml), filtered, the filtrate was reduced in evaporation, the residue was cooled in an ice bath, and TFA (40 ml) was then added. The resulting solution was stirred at room temperature for 1h, then at 70℃for 1h. The evaporation was reduced, the residue was dissolved in THF (50 ml) and cooled in an ice bath, then N was addedaH (75 ml). The resulting solution was stirred at RT for 15 min and then adjusted to ph=3 by adding acetic acid. The evaporation was reduced, 100ml of chloroform and 100ml of water were then added, and the organic phase was washed with 50ml of saturated saline, anhydrous Mg 2 SO 4 Dried, concentrated in vacuo, and slurried with n-hexane. With ethanol and Et 2 O washes the solid precipitate and then dries under vacuum to give the yellow solid compound 2-propenyl-6-chloro-1, 2-dihydro-3H-pyrazolo [4,3-c]Pyridazin-3-one (4.41 g, 44%). LC/MS (ESI) m/z=211 [ M+H ]] + .
Second step preparation of 2-propenyl-6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one
2-propenyl-6-chloro-1, 2-dihydro-3H-pyrazolo [4,3-c]Pyridazin-3-one (2.1 g,10 mmol), 5- (4-methylpiperazin-1-yl) -2-aminopyridine (1.92 g,10 mmol), potassium carbonate (6.21 g,45 mmol) catalytic amounts of potassium iodide and DMF (80 mL) were mixed, heated to 120℃and reacted with stirring for 4 hours. Cooling to room temperature, pouring into water, filtering to obtain crude product, and performing column chromatography to obtain off-white solid 2-propenyl-6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c]Pyridazin-3-one (2.89 g, 79%). LC/MS (ESI) m/z=367 [ M+H ]] + .
Third step preparation of 2-propenyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one
To a stirred solution of 2-propenyl-6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (73 mg,0.2 mmol) and 2- (6-bromo-2-pyridinyl) propan-2-ol (52 mg,0.24 mmol) in 10mL dioxane was added copper iodide (38 mg,0.20 mmol), potassium carbonate (42 mg,0.3 mmol) and N, N' -dimethylethylenediamine (20 mg,0.22 mmol) and stirred overnight at 80 ℃. After the reaction is completed, the solvent is removed under reduced pressure; the residue was diluted with water and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain 2-propenyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (48 mg, yield 48%).
LC/MS(ESI):m/z=502[M+H] + .
Example 43
Preparation of 2-propenyl-1- (6- (2-hydroxypropyl-2-yl) phenyl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 43)
Compound 43 (62 mg, yield 62%) was obtained by a method similar to example 42. LC/MS (ESI) m/z=501 [ M+H ]] + 。
Example 44
Preparation of (R) -2-propenyl-1- (7-ethyl-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 44)
Compound 44 (54 mg, 51% yield) was obtained by a method similar to that of example 42. LC/MS (ESI) m/z=528 [ M+H ]] + 。
Example 45
Preparation of (R) -2-propenyl-1- (7-ethyl-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) -6- ((4- (4-methylpiperazin-1-yl) phenyl) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 45)
Compound 45 (60 mg, 57% yield) was obtained in a similar manner to example 44. LC/MS (ESI) m/z=527 [ M+H ]] + 。
Example 46
Preparation of 2-propenyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((3-methyl-1, 2,3, 4a, 5-hexahydrobenzo [ b ] pyrazino [1,2-d ] [1,4] oxazin-8-yl) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 46)
Compound 46 (48 mg, 45% yield) was obtained by a method similar to that of example 45. LC/MS (ESI) m/z=529 [ M+H ]] + 。
Example 47
Preparation of (R) -2-propenyl-1- (7-ethyl-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) -6- ((3-methyl-1, 2,3, 4a, 5-hexahydrobenzo [ b ] pyrazino [1,2-d ] [1,4] oxazin-8-yl) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 47)
Compound 47 (53 mg, 48% yield) was obtained by a method similar to that of example 45. LC/MS (ESI) m/z=555 [ M+H ]] + 。
Example 48
Preparation of (R) -2-propenyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 48)
Compound 48 (57 mg, 58% yield) was obtained by a method similar to that of example 43. LC/MS (ESI) m/z=500 [ M+H ]] + 。
Example 49
Preparation of (R) -2-propenyl-1- (7-ethyl-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) -6- (2 '-methyl-2', 3 '-dihydro-1' H-spiro [ cyclopropan-1, 4 '-isoquinolin ] -7' -yl) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 49)
Compound 49 (56 mg, 54% yield) was obtained in a similar manner to example 45. LC/MS (ESI) m/z=524 [ M+H ]] + 。
Example 50
Preparation of (R) -2-propenyl-1- (7-ethyl-7-hydroxy-6, 7-dihydro-5H-cyclopenta [ b ] pyridin-2-yl) -6- ((2, 4-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 51)
Compound 50 (50 mg, 48% yield) was obtained in a similar manner to example 45. LC/MS (ESI) m/z=526 [ M+H ]] + 。
Example 51
Preparation of 2- (2, 6-dichlorophenyl) -1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (Compound 94)
First step preparation of 2- (2, 6-dichlorophenyl) -6-chloro-1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one
To a solution of methyl 4, 6-dichloropyridazine-3-carboxylate (9.89 g,47.8 mmol) in 150mL of THF was added DIPEA (20.8 mL,120 mmol) and 2, 6-dichlorophenylhydrazine hydrochloride (10.18 g,47.8 mmol), the reaction was refluxed for 72 hours, and then concentrated in vacuo. Et is added to the residue 2 O (50 ml), filtered, the filtrate was reduced in evaporation, the residue was cooled in an ice bath, and TFA (40 ml) was then added. The resulting solution was stirred at room temperature for 1h, then at 70℃for 1h. The evaporation was reduced, the residue was dissolved in THF (50 ml) and cooled in an ice bath, then NaH (75 ml) was added. At RT The resulting solution was stirred for 15 minutes and then adjusted to ph=3 by the addition of acetic acid. The evaporation was reduced, 100ml of chloroform and 100ml of water were then added, and the organic phase was washed with 50ml of saturated saline, anhydrous Mg 2 SO 4 Dried, concentrated in vacuo, and slurried with n-hexane. With ethanol and Et 2 O washes the solid precipitate and then dries under vacuum to give the yellow solid compound 2- (2, 6-dichlorophenyl) -6-chloro-1, 2-dihydro-3H-pyrazolo [4, 3-c)]Pyridazin-3-one (8.13 g, 54%).
LC/MS(ESI):m/z=316[M+H] + .
Second step preparation of 2- (2, 6-dichlorophenyl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one
2- (2, 6-dichlorophenyl) -6-chloro-1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (1.58 g,5 mmol), 5- (4-methylpiperazin-1-yl) -2-aminopyridine (0.96 g,5 mmol), potassium carbonate (3.45 g,25 mmol) catalytic amounts of potassium iodide and DMF (50 mL) were mixed, heated to 120℃and reacted with stirring for 4 hours. Cooled to room temperature, poured into water and filtered to give crude product which was column chromatographed to give off-white solid 2- (2, 6-dichlorophenyl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one (1.86 g, 79%).
LC/MS(ESI):m/z=471[M+H] + 。
Third step preparation of 2- (2, 6-dichlorophenyl) -1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ] pyridazin-3-one
To 2- (2, 6-dichlorophenyl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazolo [4,3-c ]]To a stirred solution of pyridazin-3-one (94 mg,0.2 mmol) and 2- (6-bromo-2-pyridinyl) propan-2-ol (52 mg,0.24 mmol) in 10mL dioxane was added CuI (38 mg,0.2 mmol), K 2 CO 3 (42 mg,0.3 mmol) and N, N' -dimethylethylenediamine (20 mg,0.22 mmol) and stirred at 80℃overnight. After the reaction is completed, the solvent is removed under reduced pressure; the residue was diluted with water and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtainThe crude product was purified by flash chromatography to give 2- (2, 6-dichlorophenyl) -1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -1, 2-dihydro-3H-pyrazole [4,3-c]Pyridazin-3-one (52 mg, 43% yield).
LC/MS(ESI):m/z=607[M+H] + 。
Example 52
Preparation of 6-propenyl-5- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -3- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -5, 6-dihydro-3H-pyrazolo [3,4-e ] [1,2,4] triazin-7-one (Compound 101)
First step preparation of 6-propenyl-3- (methylthio) -5, 6-dihydro-3H-pyrazolo [3,4-e ] [1,2,4] triazin-7-one
3-methylsulfanyl-5-chloro- [1,2,4]To a solution of triazine-6-carboxylic acid ethyl ester (11.1 g,47.8 mmol) in 150mL of THF was added DIPEA (20.8 mL,120 mmol) and tert-butyl 1-allylhydrazinecarboxylate (8.23 g,47.8 mmol), the reaction was refluxed for 72 hours and then concentrated in vacuo. Et is added to the residue 2 O (50 ml), filtered, the filtrate was reduced in evaporation, the residue was cooled in an ice bath, and TFA (40 ml) was then added. The resulting solution was stirred at room temperature for 1h, then at 70℃for 1h. The evaporation was reduced, the residue was dissolved in THF (50 ml) and cooled in an ice bath, then NaOH (75 ml) was added. The resulting solution was stirred at RT for 15 min and then adjusted to ph=3 by adding acetic acid. The evaporation was reduced, 100ml of chloroform and 100ml of water were then added, and the organic phase was washed with 50ml of saturated saline, anhydrous Mg 2 SO 4 Dried, concentrated in vacuo, and slurried with n-hexane. With ethanol and Et 2 O washes the solid precipitate and then dries under vacuum to give the yellow solid compound 6-propenyl-3- (methylthio) -5, 6-dihydro-3H-pyrazolo [3,4-e][1,2,4]Triazin-7-one (5.0 g, 47%).
LC/MS(ESI):m/z=224[M+H] + 。
Second step preparation of 6-propenyl-5- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -3- (methylthio) -5, 6-dihydro-3H-pyrazolo [3,4-e ] [1,2,4] triazin-7-one
To 6-propenyl-3- (methylthio) -5, 6-dihydro-3H-pyrazole [3,4-e][1,2,4]Triazin-7-one (224 mg,1 mmol) and 2- (6-bromo-2-pyridinyl) propan-2-ol (260 mg,1.2 mmol) are dissolved in 20mL dioxane and CuI (190 mg,1 mmol), K are added with stirring 2 CO 3 (210 mg,1.5 mmol) and N, N' -dimethylethylenediamine (100 mg,1.1 mmol) and stirred at 80℃overnight. After the reaction is completed, the solvent is removed under reduced pressure; the residue was diluted with water and extracted with ethyl acetate (10 ml x 3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain 6-propenyl-5- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -3- (methylsulfanyl) -5, 6-dihydro-3H-pyrazolo [3,4-e][1,2,4]Triazin-7-one (258 mg, 72% yield).
LC/MS(ESI):m/z=359[M+H] + 。
Third step preparation of 6-propenyl-3- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -5, 6-dihydro-3H-pyrazolo [3,4-e ] [1,2,4] triazin-7-one
The 6-propenyl-5- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -3- (methylthio) -5, 6-dihydro-3H-pyrazolo [3,4-e][1,2,4]Triazin-7-one (180 mg,0.5 mmol) is dissolved in 10mLCH 2 Cl 2 To this, m-chloroperoxybenzoic acid (522 mg,6 mmol) was added and stirred at room temperature for 2 hours. CH for reaction solution 2 Cl 2 Dilute and use saturated NaHCO 3 And Na (Na) 2 S 2 O 3 And (5) cleaning. MgSO for organic layer 4 Drying, evaporating under reduced pressure, and column chromatography to obtain yellow solid 6-propenyl-3- (methylsulfonyl) -5, 6-dihydro-3H-pyrazolo [3,4-e][1,2,4]Triazin-7-one (183mg, 94%). LC/MS (ESI) m/z=391 [ M+H ]] + 。
Fourth step preparation of 6-propenyl-5- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -3- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -5, 6-dihydro-3H-pyrazolo [3,4-e ] [1,2,4] triazin-7-one
6-propenyl-3- (methylsulfonyl) -5, 6-dihydro-3H-pyrazolo [3,4-e][1,2,4]Triazin-7-one (117 mg,0.3 mmol) is dissolved in 25ml DMF and addedDIPEA (194 mg,1.5 mmol) and 4- (4-methylpiperazin-1-yl) aniline (70 mg,0.36 mmol) and stirred at room temperature for 24 hours. Pouring ice water, filtering to obtain crude product, and separating by flash column to obtain yellow solid 6-propenyl-3- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -5, 6-dihydro-3H-pyrazole [3,4-e][1,2,4]Triazin-7-one (133 mg, 89%). 1H NMR (400 MHz, DMSO-d 6) 10.13 (m, 1H), 7.56-8.10 (m, 6H), 5.67 (dd, 1H), 5.31 (br, 1H), 5.01 (dd, 1H), 4.69-4.84 (m, 3H), 3.51-3.88 (m, 4H), 3.11-3.23 (m, 4H), 2.43 (s, 3H), 1.47 (s, 6H); LC/MS (ESI) m/z=502 [ M+H ]] + .
Similar synthetic routes to 43-52 can afford the following compounds:
Example 53: biological Activity test
The invention is further explained below in connection with test examples, but these implementations are not meant to limit the scope of the invention.
Test example 1, compound inhibition Wee-1 enzyme Activity assay
Compounds were assayed for inhibition of Wee-1 kinase activity using the Lanthra Screen Wee-1 kinase kit (invitrogen). Plates were read after 4-fold gradient dilutions from 0.2mM working concentration, 10 dilutions, 5. Mu.LWee-1 kinase (final concentration 5 nM), 5. Mu.L Eu-Anti-GSTAntibody (final concentration 2 nM) mix and 5. Mu.L kinase tracker 178 (final concentration 50 nM) in DMSO were thoroughly mixed and incubated for one hour at room temperature. Minimum signal values were obtained from medium alone (cell number zero), inhibition%o = (maximum signal value compound signal value)/(maximum signal value—minimum signal value x 100%, data were processed using graphpad prism5 software IC was calculated by sigmoidal dose response curve fitting 50 Values. Wherein "A" represents IC 50 Less than or equal to 10nM; "B" means 10nM<IC 50 Less than or equal to 500nM; "C" means 500nM<IC 50 Less than or equal to 2000nM; "D" means 2000nM<IC 50 。
TABLE 1 IC of the compounds of the invention inhibiting Wee1 kinase Activity 50
Compounds of formula (I) | IC 50 | Compounds of formula (I) | IC 50 | Compounds of formula (I) | IC 50 |
1 | A | 8 | A | 15 | A |
2 | A | 9 | A | 16 | A |
3 | A | 10 | A | 17 | A |
4 | A | 12 | A | 18 | A |
5 | A | 13 | A | 101 | A |
6 | A | 14 | A | 103 | A |
Test example 2 measurement of cell proliferation Activity of Compounds
The inhibition of proliferation of human non-small cell lung cancer cells NCI-H23 by the test compounds was determined using CellTiter-Glo < TM > living cell assay kit. Wherein the culture medium is added with fetal bovine serum and McCoy's 5A culture medium with the final concentration of 10%.
The test steps are as follows: digesting NCI-H23 cells which have reached 80% cell fusion with pancreatin, centrifuging, re-suspending, preparing 6000 cells/mL NCI-H23 cell suspension with culture medium, adding 96-well cell culture plate (90 μl/well), and placing in culture medium containing 5% CO 2 Is cultured at 37 ℃. After 24 hours of cell culture, the reference compound table and test compound were dissolved in DMSO to a concentration of 30 mM. Culture medium with NCI-H23Further diluting the diluted compound mother liquor, and transferring the diluted mixture to corresponding cell plates, respectively, with a final concentration of 1 μm (as IC 50 Initial concentration tested), 9 concentrations were four-fold diluted, 9 concentrations being: 10. Mu.M, 2.5. Mu.M, 0.625. Mu.M, 0.156. Mu.M, 0.039. Mu.M, 0.0098. Mu.M, 0.0024. Mu.M, 0.0006. Mu.M and 0.000015. Mu.M, and centrifuging, and standing in a medium containing 5% CO 2 Is cultured at 37℃for 3 days. The 96-well cell culture plate was removed, cellTiterGlo (CTG, chemiluminescent cell Activity detection kit) reagent (100. Mu.L/well) was added, mixed well and centrifuged, and incubated at room temperature for 10 minutes. The absorbance at a wavelength of 450nm was measured on a SpectraMax M5 Reader after gentle shaking, and the inhibition was calculated using the absorbance at 650nm as a reference (i.e., 450nm absorbance-650 nm absorbance). IC was performed using software Graphpad Prism 6 and using the calculation formula XY-analysis/Nonlinear regression (cut fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters) 50 Curve fitting and calculation of IC 50 Values. Wherein "A" represents IC 50 Less than or equal to 10nM; "B" means 10nM<IC 50 Less than or equal to 500nM; "C" means 500nM<IC 50 Less than or equal to 2000nM; "D" means 2000nM<IC 50 。
TABLE 2 IC of the compounds of the invention that inhibit NCI-H23 cell growth 50
Compounds of formula (I) | IC 50 | Compounds of formula (I) | IC 50 | Compounds of formula (I) | IC 50 |
1 | B | 4 | B | 34 | C |
3 | B | 33 | C | 101 | B |
Although the invention has been described in detail hereinabove, those skilled in the art will appreciate that various modifications and changes can be made thereto without departing from the spirit and scope of the invention. The scope of the invention is not limited by the detailed description set forth above, but rather is to be attributed to the claims.
Claims (8)
1. A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph or an isomer thereof, wherein the compound of the general formula (I) has the structure:
wherein, the liquid crystal display device comprises a liquid crystal display device,
each L 1 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each L 2 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each of which isX 1 、X 2 Independently at each occurrence selected from N or CR 9 ;
When a is a single bond, X 3 Select NR 1 Or NH;
when a is a double bond, X 3 Selecting N;
each ring B is independently selected at each occurrence from a 3-8 membered heterocyclic ring, said 3-8 membered heterocyclic ring independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each B is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 11 Substituted or unsubstituted;
each Ar is provided with 1 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 1 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 12 Substituted or unsubstituted;
each Ar is provided with 2 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 2 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 13 Substituted or unsubstituted;
each R 10 Independently at each occurrence selected from deuterium, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -C 1-6 Alkylene- (OR) 6 ) 1-3 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 or-C 3-6 Carbocyclyl; each R 9 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 9 、R 11 、R 12 、R 13 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 9 、R 11 、R 12 、R 13 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 1 Independently at each occurrence selected from Or->-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2- Alkynyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 、-C 3-6 Carbocyclyl, 3-8 membered heterocycle; the 3-8 membered heterocycle independently at each occurrence comprises 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each R 1 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
wherein:
each L 3 Independently at each occurrence selected from bond, O, NH, CO, or S;
each ring A is C 3-10 Carbocycles, saidMay be attached to the same carbon atom of the ring a or to different atoms;
each R 2 is-OR 6 、-NR 6 R 7 、-SR 6 、-S(=O)R 6 、-S(=O) 2 R 6 A 5-to 10-membered heteroaryl or a 3-to 10-membered heterocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprising 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o) 2 Each R3 is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or6R 19 Substituted or unsubstituted;
each R 3 And R is 4 Independently at each occurrence selected from deuterium, hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 or-C 3-10 Carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprise 1, 2, 3 or 4 groups selected from N, 0, S, S =0 or S (=o) 2 Is a heteroatom of (2); each R 3 And R is 4 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 5 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl, each heterocyclyl and heteroaryl independently at each occurrence comprises 1, 2, 3 or 4 groups selected from N, O, S, S =o or S (=o) 2 Is a heteroatom of (2); each R 3 And R is 4 At each timeIndependently at the occurrence optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each Ar is provided with 3 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 3 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 13 Substituted or unsubstituted;
each R 13 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 -C1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 12 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 6 And R is 7 Independently at each occurrence selected from hydrogen or-C1-6 alkyl, each R 6 And R is 7 Independently optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted; or R is 7 And R is 7 Together with the N atom to which they are attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further comprise 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2, and said 3-10 membered heterocyclic ring is independently optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted;
each R 8 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -O-C 1-6 Alkylene- (halogen) 1-3 、-SC 1-6 Alkyl, -S-C 1-6 Alkylene- (halogen) 1-3 、-NC 1-6 C 1-6 、-C 1-6 alkylene-NC 1-6 Alkyl C 1-6 Alkyl, -C (=o) C 1-6 Alkyl, -C (=o) OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C (=O) C 1-6 Alkyl, -S (O) 2 NC 1-6 Alkyl C 1-6 Alkyl or-C 3-6 Carbocyclyl;
n is selected from 0, 1, 2, 3, 4, 5 or 6;
s is selected from 0, 1, 2, 3, 4, 5 or 6;
p is selected from 0, 1, 2, 3, 4, 5 or 6;
q is selected from 0, 1, 2, 3, 4, 5 or 6.
2. A compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 1, wherein R 1 Selected from the following structures:
3. a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claims 1-2, selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
4. A compound having the general formula (II), a stereoisomer, a pharmaceutically acceptable salt, a polymorph or an isomer thereof, wherein the compound of the general formula (II) has the structure:
Wherein, the liquid crystal display device comprises a liquid crystal display device,
each L 1 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each L 2 Independently at each occurrence selected from the group consisting of bond, O, NH, CH 2 CO or S;
each X is 1 、X 2 Independently at each occurrence selected from N or C;
each R 1 Independently at each occurrence selected from deuterium, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, phenyl, 6 membered heteroaryl, -C 1-6 Alkylene- (halogen) 1-3 、-C 1-6 Alkenylene- (halogen) 1-3 、-C 1-6 Alkynylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl; each R 1 Independently optionally substituted with 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR 6 、-NR 6 R 7 、-CN、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 or-S (O) 2 NR 6 R 7 Substituted or unsubstituted;
each R 2 Each heteroaryl independently at each occurrence is selected from phenyl, naphthyl, 6 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, each heteroaryl independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar is provided with 2 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 8 Substituted or unsubstituted;
each ring B is independently selected at each occurrence from a 3-8 membered heterocyclic ring, said 3-8 membered heterocyclic ring independently at each occurrence comprising 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each B is independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 9 Substituted or unsubstituted;
each Ar is provided with 2 Independently at each occurrence selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl being inIndependently for each occurrence 1, 2, 3 or 4 heteroatoms selected from N, O, or S; each Ar is provided with 2 Independently at each occurrence optionally substituted with 1, 2, 3, 4, 5 or 6R 10 Substituted or unsubstituted;
each R 8 、R 9 、R 10 Independently at each occurrence selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN, -OR 6 、-C 1-6 Alkylene- (OR) 6 ) 1-3 、-O-C 1-6 Alkylene- (halogen) 1-3 、-SR 6 、-S-C 1-6 Alkylene- (halogen) 1-3 、-NR 6 R 7 、-C 1-6 alkylene-NR 6 R 7 、-C(=O)R 6 、-C(=O)OR 6 、-OC(=O)R 6 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-S(O) 2 NR 6 R 7 or-C 3-6 Carbocyclyl;
each R 6 And R is 7 Independently at each occurrence selected from hydrogen or-C 1-6 Alkyl, -C 1-6 Alkylene- (halogen) 1-3 、C 1-6 Heteroalkyl, -CN;
5. a compound of formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to claim 4, selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
6. A pharmaceutical composition comprising a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.
7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a composition according to claim 6 in the manufacture of a medicament for the treatment of a disease associated with WEE1 activity.
8. The use according to claim 7, wherein the disease associated with WEE1 activity is liver cancer, breast cancer, glioblastoma, melanoma, adult brain tumor, childhood brain tumor, ovarian cancer, colon cancer, cervical cancer, osteosarcoma, lung cancer, gastric cancer, head and neck cancer or leukemia.
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CN202210299440.6A CN116836184A (en) | 2022-03-25 | 2022-03-25 | Preparation and application of Wee1 kinase inhibitor |
PCT/CN2023/073788 WO2023179196A1 (en) | 2022-03-25 | 2023-01-30 | Preparation and application of wee1 kinase inhibitor |
TW112108797A TW202346307A (en) | 2022-03-25 | 2023-03-09 | Preparation and application of wee1 kinase inhibitor |
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PE20080695A1 (en) * | 2006-04-27 | 2008-06-28 | Banyu Pharma Co Ltd | DIHYDROPIRAZOLOPYRIMIDINONE DERIVATIVES AS KINASE WEEL INHIBITORS |
CA2745959A1 (en) * | 2008-12-12 | 2010-06-17 | Msd K.K. | Dihydropyrimidopyrimidine derivatives |
TWI532742B (en) * | 2011-02-28 | 2016-05-11 | 艾伯維有限公司 | Tricyclic inhibitors of kinases |
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CN112442049A (en) * | 2019-09-03 | 2021-03-05 | 微境生物医药科技(上海)有限公司 | Pyrimidine derivatives as Wee1 inhibitors |
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