CN117751123A - 5-fluoro-7H-pyrrolo [2,3-d ] pyrimidines as Wee-1 inhibitors - Google Patents

5-fluoro-7H-pyrrolo [2,3-d ] pyrimidines as Wee-1 inhibitors Download PDF

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CN117751123A
CN117751123A CN202280052786.4A CN202280052786A CN117751123A CN 117751123 A CN117751123 A CN 117751123A CN 202280052786 A CN202280052786 A CN 202280052786A CN 117751123 A CN117751123 A CN 117751123A
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membered
och
heterocycloalkyl
cycloalkyl
compound
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谢雨礼
吴应鸣
钱立晖
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Wigen Biomedicine Technology Shanghai Co Ltd
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Wigen Biomedicine Technology Shanghai Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • C07D487/04—Ortho-condensed systems

Abstract

Disclosed are 5-fluoro-7H-pyrrolo [2,3-d ] as Wee-1 inhibitors]Pyrimidine compounds. In particular to a compound shown in a general formula (I) and a preparation method thereof, and application of the compound shown in the general formula (I) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as a Wee-1 inhibitor. The compound and various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof can be used for preparing medicaments for treating or preventing diseases related to Wee-1 protein kinase.

Description

5-fluoro-7H-pyrrolo [2,3-d ] pyrimidines as Wee-1 inhibitors
The present application claims priority from chinese patent application 202111013816.4, whose filing date is 2021, 8, 31. The present application refers to the entirety of the above-mentioned chinese patent application.
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a condensed-cyclic compound with a Wee1 kinase inhibition effect, a preparation method thereof and application of the compound in preparing medicines for treating or preventing related diseases mediated by Wee 1.
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): p.3159-64 ].
Cell cycle checkpoints are activated mainly after DNA damage, playing an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoints blocks the cell cycle to promote DNA repair. Inhibiting the function of check point, DNA damage can not be repaired, and cells undergo apoptosis. Compared with normal cells, the functions of p53 protein, which is an important protein of a G1 phase checkpoint, of various tumor cells are damaged, and DNA damage is repaired mainly by activating the G2 phase checkpoint, so that apoptosis is avoided. 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): p.186-91 ].
In addition to its role in the G2 checkpoint, wee-1 has been shown to be involved in functions closely related to tumorigenesis and progression such as DNA synthesis, DNA homologous repair, post-chromosomal histone modification [ J Cell Biol,2011.194 (4): p.567-79 ]. In a number of tumors including liver cancer, breast cancer, cervical cancer, melanoma, and lung cancer [ PLoS One,2009.4 (4): p.e 5120; hepatology,2003.37 (3): p.534-43; mol Cancer,2014.13:p.72 ], wee-1 expression was greatly elevated. While the high expression of Wee-1 is positively correlated with the poor development and prognosis of tumors, suggesting that Wee-1 kinase may be involved in tumor development and progression. Studies in vitro cell models and in vivo animal models have shown that inhibition of Wee-1 activity while inducing DNA damage can significantly inhibit the growth of a variety of tumors [ Cancer Biol Ther,2010.9 (7): p.514-22; mol Cancer Ther,2009.8 (11): p.2992-3000 ].
Thus, the development of specific, high activity small molecule inhibitors of Wee-1 kinase would be of great clinical value for tumor therapy, especially in targeting tumors such as P53 deleted G1 checkpoints that are impaired.
Disclosure of Invention
The invention provides a compound shown in a general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
In the general formula (1):
x is CH or N;
ring A is (C5-C11) partially unsaturated cycloalkyl or (5-11 membered) partially unsaturated heterocycloalkyl;
each R 1 independently-H, -D, halogen, -OH, - (CH) 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 、-S(O) 2 NR 3 R 4 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 and-S (O) 2 NR 3 R 4 The method comprises the steps of carrying out a first treatment on the surface of the Or 2 adjacent R 1 Together with the atoms to which they are attached, can constitute a (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, -D, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 and-S (O) 2 NR 3 R 4 The method comprises the steps of carrying out a first treatment on the surface of the Or 2R on the same carbon atom on ring A 1 Together with the carbon atoms to which they are attached, can constitute a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 and-S (O) 2 NR 3 R 4 ；
Ring B is (C6-C14) aryl or (5-11 membered) heteroaryl;
each R 2 independently-H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-OR 3 、-(CH 2 ) n NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) m NR 3 R 4 、-N(R 4 )(CH 2 ) m NR 3 R 4 、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 、-S(O) 2 NR 3 R 4 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (3-15 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (C6-C10) aryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (3-15 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (C6-C10) aryl may be optionally substituted by 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-OR 3 、-(CH 2 ) n NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) m NR 3 R 4 、-N(R 4 )(CH 2 ) m NR 3 R 4 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (3-15 membered) heterocycloalkyl, (5-9 membered) heteroaryl, (C6-C10) aryl and-R 5 The method comprises the steps of carrying out a first treatment on the surface of the Or two adjacent R 2 Together with the atoms to which they are attached, can form a (5-9 membered) heterocycloalkyl or (C5-C9) cycloalkyl group, wherein said (5-9) heterocycloalkyl or (C5-C9) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-OR 3 、-(CH 2 ) n NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) m NR 3 R 4 、-N(R 4 )(CH 2 ) m NR 3 R 4 、-C(O)R 3 、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 、-S(O) 2 NR 3 R 4 、 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (4-9 membered) heterocycloalkyl, (5-9 membered) heteroaryl and (C6-C10) aryl;
R 3 and R is 4 Each independently is-H, (C1-C6) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, or R on the same nitrogen atom 3 And R is 4 Together with the N atom to which they are attached can constitute a (3-6 membered) heterocycloalkyl group, which heterocycloalkyl group can be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 6 and-OR 6 ；
R 5 Is a (3-11 membered) heterocycloalkyl, wherein said heterocycloalkyl may be optionally substituted with 1,2,3 or 4 of the following groups: h, R A-5, 3 、-OR 3 and-NR 3 R 4 ；
R 6 is-H, (C1-C6) alkyl or (C3-C6) cycloalkyl; and
p is an integer of 0, 1 or 2, q is an integer of 1,2,3 or 4, r is an integer of 1,2 or 3, s is an integer of 0, 1,2,3 or 4, n is an integer of 0, 1,2 or 3, and m is an integer of 1,2 or 3.
In another preferred embodiment, wherein in the general formula (1), the ring A is a (C5-C7) partially unsaturated cycloalkyl group or a (5-7 membered) partially unsaturated heterocycloalkyl group.
In another preferred embodiment, wherein in the general formula (1), the ring a is: preferably is More preferablyMore preferably
In another preferred embodiment, wherein in the general formula (1), each R 1 Is independently-H, -D, -F, -Cl-Br, -I, -OH, -CH 2 OR 3 、-CH 2 NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-SR 3 、-S(O) 2 R 3 、-S(O) 2 NR 3 R 4 (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -OH, -OCH 3 、-N(CH 3 ) 2 and-CN; or 2 adjacent R 1 Can together with the atoms to which they are attached form a (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (5-7 membered) heterocycloalkylThe radical or (C3-C6) cycloalkyl may optionally be substituted by 1,2,3 or 4 of the following radicals: -H, -F, -Cl, -Br, -I, -CH 3 、-OH、-CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-N(CH 3 ) 2 and-CN; or 2R on the same carbon atom on ring A 1 Together with the carbon atoms to which they are attached, can constitute a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH 3 、-OH、-CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-N(CH 3 ) 2 and-CN.
In another preferred embodiment, wherein in the general formula (1), each R 1 Independently is: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-OCF 3 、-NH 2 、-N(CH 3 ) 2 、-CN、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)N(CH 3 ) 2 、-NHC(O)CH 3 、-N(CH 3 )-C(O)CH 3 、-NHS(O) 2 CH 3 、-N(CH 3 )-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 CH 3 、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 、-CD 3 、 Or 2 adjacent R 1 Can be co-composed with the atoms to which they are attachedPreferably each R 1 Is independently-H, -D, -F, -OH, -CD 3 、 And q is 2 or 4; more preferably each R 1 Independently is: -H, -OH,-NH 2 、 or-CD 3 And q is 2 or 4; more preferably each R 1 Independently is-H, -OH,or-NH 2 And q is 2.
In another preferred embodiment, wherein in the general formula (1), the structural unitThe method comprises the following steps: preferably is
In another preferred embodiment, wherein in the general formula (1), the B ring is a (C6-C10) aryl group or a (5-to 10-membered) heteroaryl group.
In another preferred embodiment, wherein in the general formula (1), the B ring is: preferably is More preferably
In another preferred embodiment, wherein in the general formula (1), each R 2 Is independently-H, -F, -Cl-Br, -I, -OH, -CH 2 OR 3 、-(CH 2 ) 2 OR 3 、-(CH 2 ) 3 OR 3 、-OR 3 、-CH 2 NR 3 R 4 、-(CH 2 ) 2 NR 3 R 4 、-(CH 2 ) 3 NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) 2 NR 3 R 4 、-N(R 4 )(CH 2 ) 2 NR 3 R 4 、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) 2 R 3 、-SR 3 、-S(O) 2 NR 3 R 4 (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, -CH 2 - (4-11 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (5-9 membered) aryl, wherein said (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, -CH 2 - (4-11 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (5-9 membered) aryl independently optionally substituted by 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、 Or two adjacent R's on the B ring 2 The atoms to which each is attached can together form a (5-7 membered) heterocycloalkyl or (C5-C7) cycloalkyl group, wherein said (5-7) heterocycloalkyl or (C5-C7) cycloalkyl group is independently optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OH、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、-C(O)CH 3 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 NH 2 、-S(O) 2 N(CH 3 ) 2 、
In another preferred embodiment, wherein in the general formula (1), each R 2 Is independently-H, -F, -Cl-Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 3 OCH 3 、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH 2 NH 2 、-(CH 2 ) 2 NH 2 、-(CH 2 ) 3 NH 2 、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCF 3 、-OCF 2 H、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 NH 2 、-S(O) 2 N(CH 3 ) 2 、 Preferably R 2 Independently is-H, -F-Cl, -Br, -I, -CH 2 OCH 3 、-(CH 2 ) 3 OCH 3 、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH 2 NH 2 、-(CH 2 ) 2 NH 2 、-(CH 2 ) 3 NH 2 、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCF 3 、-OCF 2 H、-CH 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、 More preferably R 2 Independently is-H,
In another preferred embodiment, wherein in the general formula (1), two R's adjacent to each other on the B ring 2 Together with the atoms to which they are attached, can form a (5-7 membered) heterocycloalkyl, wherein said heterocycloalkyl is: or two adjacent R's on the B ring 2 Together with the atoms to which they are attached, form a (5-7 membered) cycloalkyl group, wherein said cycloalkyl group is:and wherein the heterocycloalkyl and cycloalkyl groups may be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OH、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、-C(O)CH 3 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 NH 2 、-S(O) 2 N(CH 3 ) 2 、 preferably-H, - (CH) 2 ) 2 OCH 3 、-(CH 2 ) 2 OH、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、 More preferably-H,
In another preferred embodiment, wherein in the general formula (1), the structural unitThe method comprises the following steps:
preferably is
In another embodiment of the invention, the compound of formula (1) has one of the following structures:
it is another object of the present invention to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, as an active ingredient.
Still another object of the present invention is to provide the use of the compound represented by the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition described above for the preparation of a medicament for treating, modulating or preventing a disease associated with the Wee-1 protein. Wherein the disease is preferably cancer, and the cancer is blood cancer and solid tumor.
Still another object of the present invention is to provide a method for treating, modulating or preventing a disease associated with Wee-1 protein, comprising administering to a subject a therapeutically effective amount of a compound of formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.
Through synthesis and careful study of a variety of novel compounds involved in having Wee-1 inhibitory effects, the inventors have found that among the compounds of formula (1), the compounds unexpectedly have very potent Wee-1 inhibitory activity.
It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
Synthesis of Compounds
The process for preparing the compound of the general formula (1) of the present invention is specifically described below, but these specific processes do not constitute any limitation on the present invention.
The compounds of formula (1) 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 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 4 th Ed., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 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 represented by the general formula (1), wherein the compound represented by the general formula (1) can be prepared by the following general reaction scheme 1:
general reaction scheme 1
Embodiments of compounds of formula (1) may be prepared according to general scheme 1, wherein R 1 、R 2 Ring X, s, q, A and ring B are as defined above, H represents hydrogen, N represents nitrogen, Z represents chlorine, bromine or iodine. As shown in general reaction scheme 1, compounds 1-1 and 1-2 undergo substitution reaction under basic conditions to form compounds 1-3, and compounds 1-3 react with compounds 1-4 to form target compounds 1-5.
Further forms of the compounds
By "pharmaceutically acceptable" is meant herein a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and which is relatively non-toxic, e.g., administration of a material to an individual does not cause an undesired biological effect or interact in a deleterious manner with any of the components thereof in which it is contained.
The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered, and does not abrogate the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and other organic acids, and an acidic amino acid, e.g., aspartic acid, glutamic acid.
References to pharmaceutically acceptable salts are understood to include solvent-added forms or crystalline forms, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1) are conveniently prepared or formed in accordance with the methods described herein. For example, the hydrate of the compound of formula (1) is conveniently prepared by recrystallisation from a mixed solvent of water/organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, solvated forms are considered to correspond to unsolvated forms.
In other specific embodiments, the compounds of formula (1) are prepared in different forms including, but not limited to, amorphous, crushed and nano-sized forms. In addition, the compound of formula (1) includes crystalline forms and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.
In another aspect, the compounds of formula (1) may have chiral centers and/or axial chiralities and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomeric forms. Each chiral center or axial chiral will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) And C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For another example, deuterium can be substituted for a hydrogen atom to form a deuterated compound, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, and generally deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, prolonging in vivo half-life of drugs, and the like, compared to non-deuterated drugs. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Terminology
The terms used in the present application, including the specification and claims, are defined as follows, unless otherwise indicated. It must be noted that, in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used, if not otherwise indicated. In this application, the use of "or" and "means" and/or "unless otherwise indicated.
Unless otherwise specified, for convenience in compound naming, definition of the a ring in this application assumes that the a ring is named as a separate group (without merging with other rings). In the general formula (1), the A ring is condensed with an adjacent group.
Unless otherwise specified, "alkyl" refers to saturatedIncluding straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, particularly alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH 3 、CH 3 CH 2 、CF 3 、CHF 2 、CF 3 CH 2 、CF 3 (CH 3 )CH、 i Pr、 n Pr、 i Bu、 n Bu or t Bu。
Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, and includes straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl are preferred.
Unless otherwise specified, "alkynyl" refers to unsaturated aliphatic hydrocarbon groups containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, for example ethynyl, 1-propynyl or 1-butynyl.
Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), a partially unsaturated cycloalkyl may be referred to as "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl groups may optionally be oxidized to form oxo or thioionic groups. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, cycloalkyl contains 0, 1, or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups may be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused with aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups may be fused to aryl and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, pinyl, carenyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexane, and the like.
Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH 3 、OCF 3 、CHF 2 O、CF 3 CH 2 O、 i- PrO、 n- PrO、 i- BuO、 n- BuO or t- BuO。
Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, an aryl group being monocyclic or polycyclic, e.g., a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.
Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), heteroaryl being monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzene Benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrole [3,2-b ]]Pyridyl, 1H-pyrrole [2,3-c ]]Pyridyl, 1H-pyrrole [3,2-c ]]Pyridyl, 1H-pyrrole [2,3-b ]]A pyridyl group,
Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If the heterocycloalkyl group contains at least one double bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl group contains at least one triple bond, then the partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form oxo or thioxo groups or other oxidized bonds (e.g., C (O), S (O), C (S) or S (O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl groups may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains from 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains from 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are benzo derivatives having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azepine, thienyl, or the like. The heterocycloalkyl group containing the fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro [5.5 ] ]Undecyl, 1-oxa-8-azaspiro [4.5 ]]Decyl radical,Piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3, 4-tetrahydroquinolinyl, tropanyl, 4,5,6, 7-tetrahydrothiazolo [5,4-c ]]Pyridyl, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyllactam, valerolactam, imidazolone, hydantoin, dioxolanyl, phthalimido, pyrimidine-2, 4 (1H, 3H) -dione, 1, 4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S, S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyronyl, tetrahydrothienyl, 2-azaspiro [3.3 ]]Heptyl, indolinyl, and,
Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted with F, cl, br or I, preferably F or Cl, in any combination.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Substituent "-O-CH 2 -O- "means that two oxygen atoms in the substituent are attached to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, such as:
when a linking groupWhen the number is 0, such as- (CH) 2 ) 0 -it is meant that the linking group is a single bond.
When one of the variables is selected from a bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in X-L-Y represents a bond, it is indicated that the structure is in fact X-Y.
The term "membered ring" includes any cyclic structure. The term "meta" is meant to indicate the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings and cyclopentyl, pyrrolyl, furanyl and thiophenyl are five-membered rings.
The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keys And straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key
Unless otherwise indicated, use ofRepresents a single bond or a double bond.
Specific pharmaceutical and medical terminology
The term "acceptable" as used herein, means that a prescription component or active ingredient does not unduly adversely affect the health of the general therapeutic objective.
The terms "treat," "course of treatment," or "therapy" as used herein include alleviation, inhibition, or amelioration of symptoms or conditions of a disease; inhibit the occurrence of complications; improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, a compound or pharmaceutical composition, upon administration, may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, delay of onset, slow progression, or decrease in duration. Whether stationary or temporary, continuous or intermittent, may be due to or associated with administration.
"active ingredient" refers to a compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the invention may contain one or more asymmetric centers (chiral centers or axial chiralities) and thus appear as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
The terms "compound", "composition", "agent" or "pharmaceutical (medicine or medicament)" are used interchangeably herein and refer to a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic effects when administered to an individual (human or animal).
The term "administration (administered, administering or administeration)" as used herein refers to the administration of the compound or composition directly, or the administration of a prodrug (pro), derivative (derivative), or analog (analog) of the active compound, and the like.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the average value, as determined by one of ordinary skill in the art. Except in the experimental examples, or where otherwise explicitly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, ratios of amounts, and the like) are to be understood to be modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties. At least these numerical parameters should be construed as indicating the number of significant digits and by applying ordinary rounding techniques.
Unless defined otherwise herein, the meanings of scientific and technical terms used herein are the same as commonly understood by one of ordinary skill in the art. Furthermore, as used in this specification, the singular noun encompasses the plural version of the noun without conflict with the context; plural nouns as used also encompasses singular versions of the noun.
Therapeutic use
The compounds or pharmaceutical compositions of formula (1) of the present invention are generally useful for inhibiting Wee-1 kinase and thus are useful in the treatment of one or more conditions associated with Wee-1 kinase activity. Accordingly, in certain embodiments, the present invention provides a method for treating a Wee-1 kinase mediated condition comprising the step of administering to a patient in need thereof a compound of the general formula (1), or a pharmaceutically acceptable composition thereof, of the present invention.
In some embodiments, there is provided a method for treating cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancers include, but are not limited to, hematological malignancies (leukemias, lymphomas, myelomas including multiple myelomas, myelodysplastic syndromes, and myeloproliferative syndromes), and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancers and osteosarcomas, as well as stromal tumors), among others. In other embodiments, the hematological malignancy and solid tumor include, but are not limited to, leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastasis.
Route of administration
The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
"pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soya oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agents (e.g. tween ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
Detailed Description
The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present invention. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. Various changes and modifications to the present invention will become apparent to those skilled in the art upon reading the present description, and such equivalents fall within the scope of the present application.
In all of the embodiments described herein, the present invention, 1 H-NMR was recorded on a Varian Mercury 400 Nuclear magnetic resonance apparatus, chemical shifts being expressed as delta (ppm); the silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
The invention adopts the following abbreviations: ac (Ac) 2 O represents acetic anhydride; (Boc) 2 O represents di-tert-butyl dicarbonate; CDCl 3 Represents deuterated chloroform; cs (cells) 2 CO 3 Represents cesium carbonate; etOAc represents ethyl acetate; hexane represents n-Hexane; HPLC means high performance liquid chromatography; meCN represents acetonitrile; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; dioxane represents 1, 4-Dioxane; DMF represents N, N-dimethylformamide; DMP stands for Dess-Martin oxidant; DMAP represents 4- (dimethylamino) pyridine; DMSO represents dimethylsulfoxide; etOH stands for ethanol; etMgBr represents ethylmagnesium bromide; hr represents hours; IPA represents isopropanol; min represents minutes; k (K) 2 CO 3 Represents potassium carbonate; KOAc represents potassium acetate; KOH represents potassium hydroxide; k (K) 3 PO 4 Represents potassium phosphate; min represents minutes; meOH represents methanol; meMgBr stands for methyl magnesium bromide; MS stands for mass spectrum; msOH represents methanesulfonic acid; m-CPBA represents m-chloroperoxybenzoic acid; n-BuLi represents n-butyllithium; NMR represents nuclear magnetic resonance; NIS stands for iodinated succinimide; pd/C represents palladium on carbon; pd (PPh) 3 ) 4 Represents tetrakis triphenylphosphine palladium; pd (Pd) 2 (dba) 3 Represents tris (dibenzylideneacetone) dipalladium (0); pd (dppf) Cl 2 Represents [1,1' -bis (diphenylphosphine) ferrocene]Palladium (II) dichloride; PE represents petroleum ether; POBr 3 Represents phosphorus oxybromide; POCl (Point of care testing) 3 Represents phosphorus oxychloride; TEA represents triethylamine; TFA represents trifluoroacetic acid; t (T) 3 P represents 1-propyl phosphoric anhydride; xantPhos represents 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; tfOH represents trifluoromethanesulfonic acid; TLC stands for thin layer chromatography; XPhos represents 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylAnd (3) biphenyl.
Preparation example 1 Synthesis of intermediate A-1
Step 1: synthesis of Compound int_A-1-2:
Int_A-1-1 hydrochloride (10.0 g,46.10 mmol) was dissolved in TfOH (50.0 mL) and NIS (15.7 g,69.88 mmol) was added under nitrogen at 0deg.C. The reaction solution was stirred at room temperature for 16 hours. LC-MS monitoring showed the reaction ended. The reaction solution was cooled to room temperature, poured into ice water, pH was adjusted to 8-9 with dilute NaOH solution, and filtered to give black solid int_A-1-2 (14 g,46.0mmol, crude product), which was directly used for the next reaction.
ESI-MS m/z:305[M+H] + 。
Step 2: synthesis of Compound int_A-1-3:
int_A-1-2 (14.0 g,46.0 mmol), (Boc) 2 O (25.1 g,115mmol,26.4 mL) was dissolved in DCM (200 mL) and TEA (14.0 g,138mmol,19.2 mL) was added at room temperature. The reaction solution was stirred at room temperature for 16 hours. LC-MS monitoring showed the reaction ended. To the reaction was added water (100 mL), the aqueous phase was extracted with dichloromethane (150 mL x 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product (1.1 mg, crude product). Crude product Purification by column chromatography (SiO) 2 EtOAc/pe=0/1-1/9) to give a white solid (10 g, yield: 53.7%).
ESI-MS m/z:349[M+H] + 。
Step 3: synthesis of Compound int_A-1-5:
int_A-1-3 (3.00 g,7.42 mmol), int_A-1-4 (3.19 g,37.1 mmol), cesium carbonate (4.84 g,14.8 mmol) and Pd (dppf) Cl 2 .CH 2 Cl 2 (602 mg, 742. Mu. Mol) was dissolved in 1, 4-dioxane (40 mL) and water (4 mL), and the mixture was heated to 100℃under argon atmosphere and stirred for 5 hours. LC-MS monitoring showed the reaction ended. The reaction solution was spin-dried, and the crude product was purified by column chromatography (SiO 2 EtOAc/pe=0/1-1/9) to give a white solid (1.4 g, yield: 59.3%). 1 H NMR(400MHz,DMSO-d 6 )δ7.95(d,J＝2.0Hz,1H),7.62(d,J＝2.3Hz,1H),4.62(br s,2H),3.63(br t,J＝5.9Hz,2H),2.98(t,J＝5.9Hz,2H),2.04-1.94(m,1H),1.47-1.35(m,9H),1.05-0.93(m,2H),0.74-0.62(m,2H)。
Step 4: synthesis of Compound int_A-1-6:
int_A-1-5 (1 g,3.14 mmol) was dissolved in dichloromethane (100 mL), trifluoroacetic acid (20 mL) was added and reacted at room temperature for 2 hours, and LC-MS monitoring showed the reaction to be ended. The reaction solution was concentrated under reduced pressure to give a yellow solid (680 mg, crude product). The crude product was used directly in the next reaction.
ESI-MS m/z:219[M+H] + 。
Step 5: synthesis of Compound int_A-1-7:
Int_A-1-6 (680 mg,3.12 mmol) and DIPEA (805 mg,6.23 mmol) were dissolved in dichloromethane (2 mL) and methanol (20 mL), aqueous formaldehyde (37-40%, 1 mL) and sodium borohydride acetate (1.32 g,6.23 mmol) were added and reacted at room temperature for 1 hour, which was monitored by LC-MS and the reaction was completed. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a solid product (575 mg, yield: 79.3%).
ESI-MS m/z:233[M+H] + 。
Step 6: synthesis of intermediate A-1:
int_A-1-7 (500 mg,2.15 mmol) and palladium on carbon (50 mg,10% purity) were suspended in methanol (25 mL) and reacted under hydrogen pressure (25 psi) at 25℃for 5 hours. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure, followed by column chromatography to give a solid (418 mg, yield: 96%).
1 H NMR(400MHz,DMSO)δ6.06(s,2H),4.67(s,2H),3.29(s,2H),2.71(t,J＝6.0Hz,2H),2.55(t,J＝6.0Hz,2H),2.28(s,3H),1.72(tt,J＝8.4,5.3Hz,1H),0.89–0.77(m,2H),0.48–0.41(m,2H)。
MS(ESI):203[M+H] + 。
Preparation examples 2-9 Synthesis of intermediates A-2 to A-9
Using the above synthesis procedure, the target intermediates A-2 to A-9 in Table 1 can be obtained using different starting materials.
TABLE 1
Preparation examples 10-12 Synthesis of intermediates B-1, B-2 and B-3
Step 1: synthesis of Compound int_B-1-2:
to int_B-1-1 (90 g,1.07mol,94.74 mL) and acrylonitrile (28.39 g,534.97mmol,35.48 mL) were added tetrahydropyrrole (1.92 g,26.96mmol,2.25 mL) and acetic acid (236.44 mg,3.94mmol, 225.18. Mu.L). The mixture was heated to 120℃under nitrogen for 16 hours. The reaction solution was cooled to room temperature, and acetic acid was removed by concentration under reduced pressure to give a crude product (100 g, yield: 68.1%) which was directly used in the next reaction.
MS(ESI):138[M+H] + 。
Step 2: synthesis of Compound int_B-1-3:
to int_B-1-2 (40 g,291.59 mmol) was added sulfuric acid (243.09 g,2.48mol,132.11 mL). The mixture was heated to 40 ℃ under nitrogen protection and reacted for 12 hours. The reaction solution was cooled to room temperature, pH was adjusted to 7 to 8 with aqueous ammonia, and the mixture was filtered and dried under reduced pressure to give a crude product (20 g, yield: 25.4%) which was directly used in the next reaction.
MS(ESI):136[M+H] + 。
Step 3: synthesis of Compound int_B-1-4:
Int_B-1-3 (17 g,125.77 mmol) was dissolved in phosphorus oxychloride (84.08 g,548.38mmol,50.96 mL) and N, N-dimethylaniline (15.24 g,125.77mmol,15.94 mL) was added slowly. The mixture was heated to 100 ℃ under nitrogen protection and reacted for 8 hours. Cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water for quenching, extracting the water phase with ethyl acetate (200 mL x 3), drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and carrying out column chromatography on the crude productSilica Flash Column, eluent of 0-10% ethyl acetate/Petroleum ether gradient) to give a yellow solid (14 g, yield: 72.5%).
Step 4: synthesis of Compound int_B-1-5:
int_B-1-4 (14 g,91.14 mmol) was dissolved in toluene (420 mL) and phosphine tribromooxide (57.48 g,200.51mmol,20.38 mL) was slowly added. The mixture was reacted at 130℃for 16 hours under nitrogen blanket. The reaction solution was cooled to room temperature, the solvent was removed under reduced pressure and the pH was adjusted to 7 to 8 with 1M aqueous sodium hydroxide solution. The mixture was poured into ice water, the aqueous phase was extracted with ethyl acetate (200 ml x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product (14.51 g). The crude product was used directly in the next reaction.
MS(ESI):198[M+H] + 。
Step 5: synthesis of Compound int_B-1-6:
int_B-1-5 (15.50 g, 78)26 mmol) in dichloromethane (150 mL) was added slowly m-CPBA (23.83 g,117.39mmol,85% purity). The mixture was reacted at room temperature for 16 hours. The reaction solution was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (200 ml x 3) and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product is subjected to column chromatographySilica Flash Column, eluent of 0-60% ethyl acetate/Petroleum ether gradient) to give a brown solid (10 g, yield: 59.7%).
Step 6: synthesis of Compound int_B-1-7:
int_B-1-6 (7 g,32.70 mmol) was dissolved in acetic anhydride (104.32 g,1.02mol,95.71 mL). The mixture was heated to 120℃and reacted for 16 hours. The reaction solution was cooled to room temperature, and acetic anhydride was removed under reduced pressure. The residue was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (100 ml x 3) and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product is subjected to column chromatographySilica Flash Column, eluent of 0-30% ethyl acetate/Petroleum ether gradient) gave a yellow oil (7.1 g, yield: 84.8%).
MS(ESI):256[M+H] + 。
Step 7: synthesis of Compound int_B-1-8:
int_B-1-7 (7.1 g,27.72 mmol) was dissolved To ethanol (75 mL) was added KOH (1.63 g,29.11 mmol). The mixture was reacted at room temperature for 5 hours. To the reaction solution was added 30mL of water, and ethanol was removed under reduced pressure. The aqueous phase was extracted with dichloromethane (100 ml x 3) and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product is subjected to column chromatographySilica Flash Column, eluent of 0-50% ethyl acetate/Petroleum ether gradient) gave a yellow oil (5.3 g, yield: 89.3%).
MS(ESI):214[M+H] + 。
Step 8: synthesis of Compound int_B-1-9:
int_B-1-8 (5.3 g,24.76 mmol) was dissolved in dichloromethane (60 mL) and DMP (21.00 g,49.52 mmol) was added. The mixture was reacted at room temperature for 5 hours. The reaction was filtered, the filtrate was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate and the aqueous phase was extracted with dichloromethane (150 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product is subjected to column chromatographySilica Flash Column, eluent of 0-50% ethyl acetate/Petroleum ether gradient) gives a green oil (4 g, yield: 76.2%).
MS(ESI):212[M+H] + 。
Step 9: synthesis of intermediate B-1:
int_B-1-9 (3 g,14.15 mmol) was dissolved inToluene (10 mL) was added EtMgBr (3M, 14.15 mL) at 0deg.C under nitrogen. The mixture was allowed to react at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution and the aqueous phase extracted with ethyl acetate (150 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product is subjected to column chromatography Silica Flash Column, eluent of 0-30% ethyl acetate/Petroleum ether gradient) to give a grey solid (1.6 g, yield: 49.6%).
MS(ESI):242[M+H] + 。
Step 10: synthesis of intermediates B-2 and B-3:
chiral resolution of int_B-1 (10 g,41.30 mmol) by preparative supercritical fluid chromatography (prep SFC) (SFC chiral resolution conditions: instrument: waters SFC350; column: DAICEL CHIRALPAK AD (250 mm. Times. 50mm,10 um); mobile phase: A: CO) 2 Isopropanol (0.05% diethylamine); gradient: 15% -15% of B%; flow rate: 200mL/min; column temperature: 40 ℃ C.), and the segmented solution was concentrated under reduced pressure and lyophilized to give yellow oily substance B-2 (peak 1,4.2g, yield: 42%) and yellow oil B-3 (peak 2,4.2g, yield: 42%).
B-2： 1 H NMR(400MHz,DMSO-d 6 )δ＝7.61(d,J＝7.8Hz,1H),7.43(d,J＝8.0Hz,1H),5.15-5.10(m,1H),2.94-2.80(m,1H),2.68(ddd,J＝5.5,8.5,16.6Hz,1H),2.15(ddd,J＝5.5,8.3,13.5Hz,1H),2.02-1.92(m,1H),1.90-1.76(m,1H),1.71-1.59(m,1H),0.84(t,J＝7.4Hz,3H)。
B-3： 1 H NMR(400MHz,DMSO-d 6 )δ＝7.61(d,J＝8.0Hz,1H),7.43(d,J＝7.9Hz,1H),5.12(br s,1H),2.93-2.82(m,1H),2.75-2.64(m,1H),2.19-2.09(m,1H),1.96(ddd,J＝5.5,8.5,13.5Hz,1H),1.90-1.76(m,1H),1.72-1.59(m,1H),0.84(t,J＝7.4Hz,3H)。
Preparation example 13 Synthesis of intermediate B-4
Step 1: synthesis of Compound B-4:
int_B-1-9 (1 g,4.72 mmol) was dissolved in tetrahydrofuran (10 mL) and MeMgBr (3M, 3.14 mL) was added at 0deg.C under nitrogen. The mixture was allowed to react at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution and the aqueous phase extracted with ethyl acetate (150 ml x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product is subjected to column chromatographySilica Flash Column, eluent of 0-30% ethyl acetate/Petroleum ether gradient) gives a green oil (0.44 g, yield: 38.9%).
1 HNMR:(400MHz,DMSO-d6)δ＝7.72-7.59(m,1H),7.43(d,J＝7.9Hz,1H),7.30(d,J＝ 7.9Hz,1H),5.25(s,1H),2.92-2.82(m,1H),2.75-2.66(m,1H),2.11-2.05(m,2H),1.41(s,3H)。
MS(ESI):228[M+H] + 。
Synthesis of intermediates B-5 to B-36 of preparation examples 14 to 45
Using the above synthesis procedure, the target intermediates B-5 to B-36 in Table 2 can be obtained using different starting materials.
TABLE 2
EXAMPLE 1 Synthesis of Compound 5
Step 1: synthesis of Compound int_5-2:
int_5-1 (2.5 g,14.57 mmol), B-3 (3.7 g,15.3 mmol), cuI (2.9 g,15.3 mmol), K 2 CO 3 (3 g,21.8 mmol), N, N' -dimethylethylenediamine (1.35 g,15.3 mmol) was dissolved in dioxane (100 mL), and the reaction was performed at 80℃overnight under argon, monitored by LC-MS, filtered after completion of the reaction, the filtrate was concentrated, and the residue was chromatographed on a column (DCM/MeOH=100/1 to 20/1) to give a pale yellow solid (1.56 g, yield 32.2%).
MS(ESI):333[M+H] + .
Step 2: synthesis of Compound 5:
int_5-2 (332 mg,1.0 mmol) was dissolved in 1,4-dioxane (20 mL) and A-2 (162 mg,1.0 mmol) Pd was added 2 (dba) 3 (45.7 mg,0.05 mmol), xanphos (57.8 mg,0.1 mmol) and Cs 2 CO 3 (651.6 mg,2 mmol) at 80deg.C overnight, monitored by LC-MS, and the reaction was complete. The solvent was dried under reduced pressure and the residue was chromatographed on a column of silica gel (DCM/meoh=100/1 to 10/1) to give the compound (38 mg, yield 8.3%) as a pale yellow solid.
MS(ESI):459[M+H] + .
EXAMPLE 2 Synthesis of Compound 6
Step 1: synthesis of Compound int_6-2:
int_6-1 (2.5 g,14.57 mmol), B-2 (3.7 g,15.3 mmol), cuI (2.9 g,15.3 mmol), K 2 CO 3 (3 g,21.8 mmol), N, N' -dimethylethylenediamine (1.35 g,15.3 mmol) was dissolved in dioxane (100 mL), and the reaction was performed at 80℃overnight under argon, monitored by LC-MS, filtered after completion of the reaction, the filtrate was concentrated, and the residue was chromatographed on a column (DCM/MeOH=100/1 to 20/1) to give a pale yellow solid (1.6 g, 33% yield).
MS(ESI):333[M+H] + .
Step 2: synthesis of Compound 6:
int_6-2 (332 mg,1.0 mmol) was dissolved in 1,4-dioxane (20 mL) and A-2 (162 mg,1.0 mmol) Pd was added 2 (dba) 3 (45.7 mg,0.05 mmol), xanphos (57.8 mg,0.1 mmol) and Cs 2 CO 3 (651.6 mg,2 mmol) at 80deg.C overnight, monitored by LC-MS, and the reaction was complete. The solvent was dried under reduced pressure and the residue was chromatographed on a column of silica gel (DCM/meoh=100/1 to 10/1) to give the compound (32 mg, yield 6.9%) as a pale yellow solid.
MS(ESI):459[M+H] + .
Examples 3-52 Synthesis of Compounds 1-4 and 7-52
Using the above synthetic methods, the target compounds 1-4 and 7-52 of Table 3 can be obtained using different starting materials (different intermediates A, different intermediates B, and other different intermediates).
TABLE 3 Table 3
EXAMPLE 53 in vitro inhibition of the enzyme Activity assay of recombinant protein Wee-1 by the Compounds of the invention
The inhibition of the enzyme activity of recombinant protein Wee-1 by the compounds was determined using HTRF method. Specifically, the following is described.
After incubation of DMSO or a gradient of compound (up to 200nM,1:5 gradient) and recombinant protein in kinase buffer for 30 min at 37℃the reaction is initiated by addition of substrate after addition of Fluorescein-PolyGAT and ATP. After 90 minutes of reaction at room temperature, the antibody and the detection solution are added, and after 60 minutes of incubation at room temperature, fluorescence values (excitation wavelength: 340nm, emission wavelength: 495 and 520 nm) are read, the fluorescence intensity ratio of 520nm/495nm is calculated, and compared with the DMSO group, the compound inhibition percentage and the IC are calculated 50 . The results are shown in Table 4 below.
TABLE 4 inhibitory Activity of the compounds of the invention on the recombinant protein Wee-1 (IC 50 ,nM)
Compounds of formula (I) IC 50 Compounds of formula (I) IC 50 Compounds of formula (I) IC 50 Compounds of formula (I) IC 50
1 +++ 2 +++ 3 +++ 4 +++
5 +++ 6 +++ 7 +++ 8 +++
9 +++ 10 +++ 11 +++ 12 +++
13 +++ 14 +++ 15 +++ 16 +++
17 +++ 18 +++ 19 +++ 20 +++
21 +++ 22 +++ 23 +++ 24 +++
25 +++ 26 +++ 27 +++ 28 +++
29 +++ 30 +++ 31 +++ 32 +++
33 +++ 34 +++ 35 +++ 36 +++
37 +++ 38 +++ 39 +++ 40 +++
41 +++ 42 +++ 43 +++ 44 +++
45 +++ 46 +++ 47 +++ 48 +++
49 +++ 50 +++ 51 +++ 52 +++
++ + representing IC 50 Less than or equal to 10nM
++ means IC 50 10nM to 50nM
+ represents IC 50 Greater than 50nM
As can be seen from the data in Table 4, the compounds of the present invention have a better inhibitory activity on the enzymatic activity of recombinant protein Wee-1.
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the invention. Accordingly, the scope of the invention is defined by the appended claims.

Claims (16)

  1. A compound represented by general formula (1) or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
    in the general formula (1):
    x is CH or N;
    ring A is (C5-C11) partially unsaturated cycloalkyl or (5-11 membered) partially unsaturated heterocycloalkyl;
    each R 1 independently-H, -D, halogen, -OH, - (CH) 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 、-S(O) 2 NR 3 R 4 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 and-S (O) 2 NR 3 R 4 The method comprises the steps of carrying out a first treatment on the surface of the Or 2 adjacent R 1 Together with the atoms to which they are attached, can constitute a (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, -D, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 and-S (O) 2 NR 3 R 4 The method comprises the steps of carrying out a first treatment on the surface of the Or 2R on the same carbon atom on ring A 1 Together with the carbon atoms to which they are attached, can constitute a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-(CH 2 ) n NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 and-S (O) 2 NR 3 R 4 ；
    Ring B is (C6-C14) aryl or (5-11 membered) heteroaryl;
    each R 2 independently-H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-OR 3 、-(CH 2 ) n NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) m NR 3 R 4 、-N(R 4 )(CH 2 ) m NR 3 R 4 、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 、-S(O) 2 NR 3 R 4 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (3-15 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (C6-C10) aryl, wherein said (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (3-15 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (C6-C10) aryl may be optionally substituted by 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-OR 3 、-(CH 2 ) n NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) m NR 3 R 4 、-N(R 4 )(CH 2 ) m NR 3 R 4 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (3-15 membered) heterocycloalkyl, (5-9 membered) heteroaryl, (C6-C10) aryl and-R 5 The method comprises the steps of carrying out a first treatment on the surface of the Or two adjacent R 2 Together with the atoms to which they are attached, can form a (5-9 membered) heterocycloalkyl or (C5-C9) cycloalkyl group, wherein said (5-9) heterocycloalkyl or (C5-C9) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 3 、-OH、-(CH 2 ) n OR 3 、-OR 3 、-(CH 2 ) n NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) m NR 3 R 4 、-N(R 4 )(CH 2 ) m NR 3 R 4 、-C(O)R 3 、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) p R 3 、-S(O) 2 NR 3 R 4 、 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, -CH 2 - (4-9 membered) heterocycloalkyl, (5-9 membered) heteroaryl and (C6-C10) aryl;
    R 3 and R is 4 Each independently is-H, (C1-C6) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, or R on the same nitrogen atom 3 And R is 4 Together with the N atom to which they are attached can constitute a (3-6 membered) heterocycloalkyl group, which heterocycloalkyl group can be optionally substituted with 1,2,3 or 4 of the following groups: -H, halogen, R 6 and-OR 6 ；
    R 5 Is a (3-11 membered) heterocycloalkyl, wherein said heterocycloalkyl may be optionally substituted with 1,2,3 or 4 of the following groups: h, R A-5, 3 、-OR 3 and-NR 3 R 4 ；
    R 6 is-H, (C1-C6) alkyl or (C3-C6) cycloalkyl; and
    p is an integer of 0, 1 or 2, q is an integer of 1,2,3 or 4, r is an integer of 1,2 or 3, s is an integer of 0, 1,2,3 or 4, n is an integer of 0, 1,2 or 3, and m is an integer of 1,2 or 3.
  2. The compound of claim 1, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), ring a is a (C5-C7) partially unsaturated cycloalkyl or a (5-7 membered) partially unsaturated heterocycloalkyl.
  3. The compound of claim 2, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), ring a is:
  4. a compound according to any one of claims 1 to 3, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R in the general formula (1) 1 Is independently-H, -D, -F, -Cl-Br, -I, -OH, -CH 2 OR 3 、-CH 2 NR 3 R 4 、-OR 3 、-NR 3 R 4 、-CN、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-SR 3 、-S(O) 2 R 3 、-S(O) 2 NR 3 R 4 (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl may each independently be optionally substituted with 1,2,3 or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -OH, -OCH 3 、-N(CH 3 ) 2 and-CN; or 2 adjacent R 1 Together with the atoms to which they are attached, can constitute a (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH 3 、-OH、-CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-N(CH 3 ) 2 and-CN; or 2R on the same carbon atom on ring A 1 Together with the carbon atoms to which they are attached, can constitute a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, wherein said (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group may be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH 3 、-OH、-CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-N(CH 3 ) 2 and-CN.
  5. The compound of claim 4, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R in the general formula (1) 1 Independently is: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-CH 2 N(CH 3 ) 2 、-OCH 3 、-OCF 3 、-NH 2 、-N(CH 3 ) 2 、-CN、-C(O)NH 2 、-C(O)NH(CH 3 )、-C(O)N(CH 3 ) 2 、-NHC(O)CH 3 、-N(CH 3 )-C(O)CH 3 、-NHS(O) 2 CH 3 、-N(CH 3 )-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 CH 3 、-S(O) 2 NH 2 、-S(O) 2 NH(CH 3 )、-S(O) 2 N(CH 3 ) 2 、-CD 3 、 Or 2 adjacent R 1 Can be co-composed with the atoms to which they are attached
  6. The compound according to any one of claims 1 to 5, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), the structural unitThe method comprises the following steps:
  7. the compound of any one of claims 1-6, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), the B ring is a (C6-C10) aryl or a (5-10 membered) heteroaryl.
  8. The compound of claim 7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), the B ring is:
  9. the compound of any one of claims 1-8, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R in the general formula (1) 2 Is independently-H, -F, -Cl-Br, -I, -OH, -CH 2 OR 3 、-(CH 2 ) 2 OR 3 、-(CH 2 ) 3 OR 3 、-OR 3 、-CH 2 NR 3 R 4 、-(CH 2 ) 2 NR 3 R 4 、-(CH 2 ) 3 NR 3 R 4 、-NR 3 R 4 、-CN、-O(CH 2 ) 2 NR 3 R 4 、-N(R 4 )(CH 2 ) 2 NR 3 R 4 、-C(O)NR 3 R 4 、-NR 4 C(O)R 3 、-NR 4 S(O) 2 R 3 、-S(O) 2 R 3 、-SR 3 、-S(O) 2 NR 3 R 4 (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, -CH 2 - (4-11 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (5-9 membered) aryl, wherein said (C1-C4) alkyl,(C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, -CH 2 - (4-11 membered) heterocycloalkyl, (5-9 membered) heteroaryl or (5-9 membered) aryl independently optionally substituted by 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、 Or two adjacent R's on the B ring 2 The atoms to which each is attached can together form a (5-7 membered) heterocycloalkyl or (C5-C7) cycloalkyl group, wherein said (5-7) heterocycloalkyl or (C5-C7) cycloalkyl group is independently optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OH、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、-C(O)CH 3 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 NH 2 、-S(O) 2 N(CH 3 ) 2 、
  10. The compound of claim 9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein each R in the general formula (1) 2 Is independently-H, -F, -Cl-Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 3 OCH 3 、-CH 2 OH、-(CH 2 ) 2 OH、-(CH 2 ) 3 OH、-CH 2 NH 2 、-(CH 2 ) 2 NH 2 、-(CH 2 ) 3 NH 2 、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-OCF 3 、-OCF 2 H、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 NH 2 、-S(O) 2 N(CH 3 ) 2 、
  11. The compound of claim 9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), two adjacent R's on the B ring 2 Together with the atoms to which they are attached, can form a (5-7 membered) heterocycloalkyl, wherein said heterocycloalkyl is: or two adjacent R's on the B ring 2 Together with the atoms to which they are attached, form a (5-7 membered) cycloalkyl group, wherein said cycloalkyl group is: and wherein the heterocycloalkyl and cycloalkyl groups may be optionally substituted with 1,2,3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3 、-(CH 2 ) 2 OCH 3 、-(CH 2 ) 2 OH、-OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 、-CH 2 N(CH 3 ) 2 、-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 ) 2 、-CN、-O(CH 2 ) 2 N(CH 3 ) 2 、-NH-(CH 2 ) 2 N(CH 3 ) 2 、-N(CH 3 )-(CH 2 ) 2 N(CH 3 ) 2 、-C(O)CH 3 、-C(O)NH 2 、-C(O)N(CH 3 ) 2 、-S(O) 2 CH 3 、-SCH 3 、-S(O) 2 NH 2 、-S(O) 2 N(CH 3 ) 2 、
  12. The compound of any one of claims 1-11, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), the structural unitThe method comprises the following steps:
  13. the compound of any one of claims 1-12, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), wherein the compound has one of the following structures:
  14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to any one of claims 1 to 13, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.
  15. Use of a compound according to any one of claims 1-13, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for the treatment or prevention of a disease associated mediated by Wee-1.
  16. The use of claim 15, wherein the disease is cancer, the cancer is hematological cancer and solid tumors.
CN202280052786.4A 2021-08-31 2022-08-31 5-fluoro-7H-pyrrolo [2,3-d ] pyrimidines as Wee-1 inhibitors Pending CN117751123A (en)

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