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CN119497714A - A pyrimido five-membered heterocyclic compound, preparation method and use thereof - Google Patents

A pyrimido five-membered heterocyclic compound, preparation method and use thereof Download PDF

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Publication number
CN119497714A
CN119497714A CN202380053251.3A CN202380053251A CN119497714A CN 119497714 A CN119497714 A CN 119497714A CN 202380053251 A CN202380053251 A CN 202380053251A CN 119497714 A CN119497714 A CN 119497714A
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alkyl
optionally substituted
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halogen
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易磊
张禹
花海清
朱忠远
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Yingen Biotechnology Shanghai Co ltd
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Yinen Biopharmaceutical Suzhou 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

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Abstract

Relates to a pyrimido five-membered heterocyclic compound, a preparation method and application thereof, and a pharmaceutical composition containing the pyrimido five-membered heterocyclic compound. In particular to a compound shown in a formula (I) or a pharmaceutically acceptable form thereof, which shows good Wee1 inhibition activity and can be used as a high-efficiency Wee1 inhibitor for preventing and/or treating Wee1 related diseases.

Description

Pyrimidine five-membered heterocyclic compound, preparation method and application thereof
The present application claims priority from China patent application 2022108377886 with application date 2022/7/15, china patent application 2023103912164 with application date 2023/4/12 and China patent application 2023108424468 with application date 2023/7/10. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The present invention relates to the field of pharmaceutical chemistry, and in particular to pyrazolopyrimidinone compounds useful as Wee1 inhibitors, methods for their preparation, pharmaceutical compositions and their use for the prevention and/or treatment of Wee1 kinase related diseases.
Background
The cell cycle is a highly regulated and controlled process. The normal cell cycle has checkpoints at the G1/S, S and G2/M transitions, leaving enough time for DNA damage repair. Because of TP53 mutations, many human cancer cells are poorly regulated by G1/S checkpoints and thus are severely dependent on G2/M checkpoint regulation. Wee1 kinase is a key regulator of the G2/M checkpoint (C.J.Matheson, D.S.Backos, P.Reigan, trends in Pharmacological Sciences,2016, 37:872), an atypical tyrosine kinase that phosphorylates Cdk1 (also known as Cdc 2) on tyrosine 15 (Y15), resulting in its functional inactivation. Cdk1 recruits cyclin a and B to initiate mitosis. The abrogation of the G2 checkpoint by Wee1 inhibitors may selectively sensitize P53-deficient cancer cells to DNA damage, avoiding effects on surrounding normal tissues. Wee1 also regulates CDK activity in the S phase, preventing induction of DNA damage during normal S phase progression. Furthermore, wee1 plays a positive regulatory role in Homologous Recombination (HR) repair, an important pathway for DNA double strand break repair.
Wee1 is highly expressed in many cancers, including breast cancer, lung cancer, cervical cancer, head and neck cancer, ovarian cancer, prostate cancer, melanoma, leukemia, glioblastoma, medulloblastoma, hepatocellular carcinoma. Furthermore, the high expression of Wee1 is associated with poor prognosis for multiple types of cancer. Inhibition of Wee1 kinase activity to remove the G2/M checkpoint function is a potential strategy to drive tumor cells into unplanned mitosis, thereby experiencing mitotic disorders leading to cell death. This way of cells not completing DNA replication and being forced into mitosis is very toxic to the cells, representing a novel mechanism for inducing tumor cell death. Therefore, the Wee1 inhibitor has good application prospect as a medicament.
Some inhibitors of Wee1 have been reported (e.g., WO2007126122A1, WO2019173082A1, WO2018011569A1, WO2018162932A1, WO2018090939, WO2019074981, etc.), but there remains a need in the art for new inhibitors of Wee1, particularly inhibitors of Wee1 having high activity and other superior properties, to meet clinically unmet drug use needs.
Disclosure of Invention
In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof,
Wherein,
The A ring is selected from phenyl, 5-10 membered heteroaryl ring, optionally substituted with one or more R a;
Each R a is independently selected from H, halogen, -OH, -CN, -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1- 6 alkyl) 2、-C2-4 alkenyl, -C 2-4 alkynyl, each of said C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl optionally substituted with one or more substituents selected from hydrogen, halogen, oxo, -OH, -CN, -NH 2、-C1-6 alkyl;
R 1 is selected from halogen, -CN, C 1-6 alkyl, halogenated C 1-6 alkyl, -C 3-12 cycloalkyl, 4-12 membered heterocyclyl, -O- (4-12 membered heterocyclyl), -N (R b) - (4-12 membered heterocyclyl), -C (O) NR bRd、-N＝S(O)RbRd, -said C 1-6 alkyl, C 3-12 cycloalkyl, 4-12 membered heterocyclyl are each optionally substituted with one OR more groups selected from halogen, oxo, -CN, -OR b、-NRbRd、-C1- 6 alkyl, -halogenated C 1-6 alkyl, -halogenated C 1-6 alkoxy, -C 1-6 alkylene-OR b、-C1-6 alkylene-NR bRd、-C3-8 cycloalkyl, substituted with 4-8 membered heterocyclyl 、-SRb、-C(O)Rb、-C(O)ORb、-C(O)NRbRd、-N(Rb)C(O)Rd、-N(Rb)C(O)ORd、-S(O)2Rd、-N(Rb)S(O)2Rd, further, said C 3-8 cycloalkyl, The 4-8 membered heterocyclyl each optionally being substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -C 1-6 alkyl, -halo C 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2;
R b、Rd is independently selected from H, -C 1-6 alkyl, -C 3-6 cycloalkyl, 4-12 membered heterocyclyl, each of said C 1-6 alkyl, C 3-6 cycloalkyl, 4-12 membered heterocyclyl being optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -NH 2、-N(C1-6 alkyl) 2、-C1-6 alkylene-OH, -OC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N (C 1-6 alkyl) 2;
R 2 is selected from hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, heteroaryl optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -NH 2、-C1-6 alkyl;
The B ring is selected from phenyl and 5-10 membered heteroaryl, wherein the B ring is optionally substituted by one or more substituents selected from hydrogen, halogen, -CN and-OCH 3;
The E ring is selected from-C 3-12 cycloalkyl, 4-12 membered heterocyclyl, said E ring optionally substituted with one or more R c;
Each R c is independently selected from hydrogen, halogen, -OH, oxo, cyano, -C 1-6 alkyl, -OC 1-6 alkyl;
X is selected from CH or N;
L 1 is selected from the group consisting of a single bond, -C 1-6 alkylene-, -C 3-6 cycloalkylene-, - (3-6 membered heterocyclylene) -, -NHC (O) -S (O) 2-(C1-6 alkylene) -, -C (O) C 1-6 alkylene-, -C (O) C 3-6 cycloalkylene-, -C (O) - (3-6 membered heterocyclylene) -and-C (O) -, wherein each of said C 1-6 alkylene, 3-6 membered heterocyclylene and C 3-6 cycloalkylene is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, oxo, -OH and amino;
r 3 is selected from the following conditions:
i) When L 1 is a single bond, R 3 is selected from cyano, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2、-NHC(O)C1-6 alkyl, -C (O) C 1-6 alkyl, -NHC (O) OC 1-6 alkyl, -S (O) 2C1-6 alkyl, each of said C 1-6 alkyl optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, cyano, -O- (C 1-6 alkyl);
ii) when L 1 is not a single bond, R 3 is selected from halogen, amino, -OH, cyano, -haloC 1-6 alkyl, -S (O) 2C1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl-N (C 1-6 alkyl) 2、-NH-C(O)O(C1-6 alkyl), -N (C 1-6 alkyl) -C (O) OC 1-6 alkyl, -OC (O) NH 2、-OC(O)NHC1-6 alkyl and-N (C 1-6 alkyl) C (O) C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from halogen, oxo, -OH, amino and-O- (C 1-6 alkyl).
In some embodiments of the invention, when L 1 is a single bond, R 3 may also be cyano.
In some embodiments of the invention, when L 1 is a single bond, R 3 is selected from the group consisting of-OC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2、-NHC(O)C1-6 alkyl, -C (O) C 1-6 alkyl, -NHC (O) OC 1-6 alkyl, -S (O) 2C1-6 alkyl; the C 1-6 alkyl groups are each optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, cyano, -O- (C 1-6 alkyl).
The pharmaceutically acceptable form of the present invention is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein,
Ring a is selected from phenyl, pyridinyl, thiophenyl, and pyrazolyl, said ring a optionally substituted with one or more R a, each R a is independently selected from H, F, cl, -OH, -C 1-3 alkyl, and-OC 1-3 alkyl, said C 1-3 alkyl optionally substituted with one or more substituents selected from F, cl, -OH, and-CN;
Preferably, the A ring is selected from phenyl optionally substituted with one or more R a, each R a is independently selected from H, F, cl, -OH, -C 1-3 alkyl and-OC 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more substituents selected from F, cl, -OH and-CN;
More preferably, the A ring is selected from phenyl optionally substituted with one or more R a, R a is selected from H, F, cl, -CH 3、-OCH3 and-CH 2 OH.
In some embodiments of the invention, the A ring is preferably phenyl, more preferably
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 1 is selected from C 1-6 alkyl, 4-6 membered heterocyclyl, C 4-6 cycloalkyl, -O- (4-6 membered heterocyclyl), -NH- (4-6 membered heterocyclyl), -C (O) N (C 1-6 alkyl) 2, each of said 4-6 membered heterocyclyl and C 4- 6 cycloalkyl being optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -OCH 3、-NH2、-N(C1-3 alkyl) 2、-C1-3 alkyl, -halo C 1-3 alkyl, -halo C 1-3 alkoxy, -C 1-3 alkylene-OH, -C 1-3 alkylene-N (C 1-3 alkyl) 2、-C(O)OC1- 3 alkyl, and-S (O) 2C1-3 alkyl;
preferably, R 1 is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with one or more substituents selected from F, cl, -OH, -CN, oxo, -OCH 3、-NH2、-N(CH3)2、-C1-3 alkyl, -halo C 1-3 alkyl, -halo C 1-3 alkoxy, -C 1-3 alkylene-OH, -C 1-3 alkylene-N (CH 3)2、-C(O)OC1-3 alkyl, and-S (O) 2C1-3 alkyl;
Preferably, R 1 is selected from
In some embodiments of the invention R 1 is preferably a 4-12 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl, still more preferably a6 membered heterocyclyl, said heterocyclyl being optionally substituted with one or more-C 1-6 alkyl or-deuterated C 1-6 alkyl, preferably with one or more-C 1-3 alkyl or-deuterated C 1-3 alkyl, more preferably with-CH 3 or-CD 3. Wherein the heteroatoms in the heterocyclic group are selected from N, O and S, preferably N. The number of hetero atoms in the heterocyclic group is 1,2 or 3, preferably 1 or 2.
In some embodiments of the invention, R 1 is preferably piperidinyl, tetrahydropyridinyl, or piperazinyl optionally substituted with one or more-C 1-3 alkyl or-deuterated C 1-3 alkyl, more preferably piperazinyl optionally substituted with one or more-CH 3 or-CD 3.
In some embodiments of the invention, R 1 is preferably selected fromPreferably is
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 2 is selected from-CH 3、-CH2CH3, cyclopropyl, isopropyl, allyl, propargyl, -CH 2 -cyclopropyl, -CH 2CF3, preferably R 2 is selected from allyl.
In some embodiments of the invention, R 2 is preferably-C 2-6 alkenyl, more preferably-C 2-4 alkenyl, even more preferably allyl.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein ring B is selected from phenyl, pyridinyl, pyrimidinyl, thiophenyl, and thiazolyl, said ring B being optionally substituted with one or more substituents selected from hydrogen, halogen, and-CN;
preferably, the B ring is selected from pyridinyl and phenyl.
In some embodiments of the invention, the B ring is preferably a 5-10 membered heteroaryl, more preferably a 5-6 membered heteroaryl, even more preferably a 6 membered heteroaryl. Wherein the heteroatom in the heteroaryl group is selected from N, O and S, preferably N. The number of heteroatoms in the heteroaryl group is 1 or 2, preferably 1.
In some embodiments of the invention, the B ring is preferably pyrimidinyl or pyridinyl, more preferably pyridinyl, even more preferably
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the E ring is selected from the group consisting of 4-6 membered heterocyclyl, said E ring being optionally substituted with one or more R c, each R c being independently selected from the group consisting of hydrogen, F, cl, -OH, oxo, -CN, -CH 3、-OCH3;
Preferably, the E ring is selected from azetidinyl, pyrrolidinyl, and piperidinyl.
In some embodiments of the invention, the E ring is preferably azetidinyl or pyrrolidinyl, more preferablyFurther preferred isThe E ring is optionally substituted with one or more R c, each R c is independently selected from H, F, cl, -OH, -CN, -CH 3、-OCH3.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein L 1 is selected from the group consisting of methylene, -C (O) -methylene-O-, and-C (O) -, wherein the methylene is optionally substituted with one or more substituents selected from the group consisting of hydrogen, F, and-CH 3. In some embodiments of the invention, L 1 is preferably selected from the group consisting of single bonds, -C 1-6 alkylene-, -C 3-6 cycloalkylene-, and-C (O) -, said-C 1-6 alkylene-preferably being-C 1-3 alkylene-, more preferably methylene, -said-C 3-6 cycloalkylene-preferably being cyclopropylene.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 3 is selected from:
i) When L 1 is a single bond, R 3 is selected from-OCH 3、-NHCH3、-NHC(O)CH3、-C(O)CH3 and-S (O) 2CH3;
ii) when L 1 is not a single bond, R 3 is selected from F, amino 、-OH、-CN、-CHF2、-CH2F、-S(O)2CH3、-OCH3、-OCHF2、-NH-C(O)OCH3;, preferably R 3 is selected from F, -OH, -CN, -NH 2-CHF2、-S(O)2CH3 and-CH 3.
In some embodiments of the invention, R 3 is preferably selected from:
i) When L 1 is a single bond, R 3 is selected from cyano, -OC 1-6 alkyl and-S (O) 2C1-6 alkyl, wherein said-OC 1-6 alkyl is optionally substituted with one or more substituents selected from halogen, -OC 1-6 alkyl is preferably-O-halogenated C 1-3 alkyl, more preferably-OCF 2, -S (O) 2C1-6 alkyl is preferably-S (O) 2C1-3 alkyl, more preferably-S (O) 2CH3;
ii) L 1 is-C 1-6 alkylene-, -C 3-6 Cycloalkylene-or-C (O) - (preferably-C 1-6 alkylene-, more preferably-C 1-3 alkylene-) R 3 is selected from halogen, Amino, -OH, cyano, C 1-6 alkyl, -halogenated C 1-6 alkyl, -S (O) 2C1-6 alkyl and-OC 1-6 alkyl, said-halogenated C 1-6 alkyl is preferably-halogenated C 1-3 alkyl, more preferably fluorinated C 1-3 alkyl, such as CHF 2 or CH 2 F, said-S (O) 2C1- 6 alkyl is preferably-S (O) 2C1-3 alkyl, more preferably-S (O) 2CH3, and said-OC 1-6 alkyl is preferably-OC 1-3 alkyl, more preferably-OCH 3.
In some embodiments of the invention, when L 1 is methylene, R 3 is selected from halogen, amino, -OH, cyano, C 1-6 alkyl, -haloC 1-6 alkyl, -S (O) 2C1-6 alkyl, and-OC 1-6 alkyl, preferably halogen, amino, -OH, cyano, C 1-3 alkyl, -haloC 1-3 alkyl, -S (O) 2C1-3 alkyl, and-OC 1-3 alkyl.
In some embodiments of the invention, the building blocksPreferably selected fromMore preferably
In some embodiments of the invention, the building blocksPreferably selected from
In some embodiments of the invention, the building blocksIs that Preferably is
In some embodiments of the invention, the building blocksPreferably is
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, is selected from the group consisting of:
Wherein R 1 is as described in any one of the present inventions;
The E ring is selected from 4-6 membered heterocyclyl, said E ring optionally substituted with one or more R c, each R c is independently selected from hydrogen, F, cl, -OH, oxo, -CN, -CH 3、-OCH3, preferably, the E ring is selected from azetidinyl, pyrrolidinyl and piperidinyl;
L 1 is as described in any one of the present inventions;
r 3 is as defined in any one of the present inventions.
In some embodiments of the invention, in the compounds of formula (I-1), the E ring is preferably azetidinyl or pyrrolidinyl, more preferablyMore preferablyThe E ring is optionally substituted with one or more R c, each R c is independently selected from H, F, cl, -OH, -CN, -CH 3、-OCH3.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, is selected from the group consisting of:
wherein,
R a is selected from H, F, cl, -OH, -CN, -C 1-3 alkyl, and-OC 1-3 alkyl, said C 1-3 alkyl optionally being substituted with one or more substituents selected from F, cl, -OH, and-CN;
R 1-1 is selected from H, -C 1-6 alkylene-OH, -C 1-6 alkyl, -halogenated C 1-6 alkyl, and-deuterated C 1-6 alkyl;
the E ring is selected from 4-6 membered heterocyclic groups, the hetero atoms of the 4-6 membered heterocyclic groups are N, and the number of the hetero atoms is 1,2 or 3;
the E ring is optionally substituted with one or more R c, each R c is independently selected from H, F, cl, -OH, -CN, -C 1-6 alkylene-OH, -C 1-6 alkyl, and-halogenated C 1-6 alkyl;
R 3 is selected from-CN, -C (O) NH 2、-OC(O)NH2、-OC1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2、-NHC(O)C1- 6 alkyl-C (O) C 1-6 alkyl, -NHC (O) OC 1-6 alkyl, -S (O) 2C1-6 alkyl-C 1-6 alkyl S (O) 2C1-6 alkyl, -halogenated C 1-6 alkyl, -O-halogenated C 1-3 alkyl, -C 1-6 alkyl-CN, C 1-6 alkyl-OH, C 1-6 alkyl-NH 2、-C1-6 alkyl OC 1-6 alkyl and-cyclopropyl-OH; the C 1-6 alkyl groups are each optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, amino and cyano.
In some embodiments of the invention, a compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R a is selected from H, F, cl, -CH 3、-CN、-OCH3, and-CH 2 OH.
In some embodiments of the invention, in the compounds of formula (I-2), R 1-1 is selected from-C 1-6 alkyl and-deuterated C 1-6 alkyl, said-C 1-6 alkyl is preferably-C 1-3 alkyl, more preferably-CH 3, and said-deuterated C 1-6 alkyl is preferably-deuterated C 1-3 alkyl, more preferably-CD 3.
In some embodiments of the invention, a compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 1-1 is-CH 3 or-CD 3.
In some embodiments of the invention, a compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the E ring is selected from azetidinyl, pyrrolidinyl, and piperidinyl.
In some embodiments of the invention, a compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein each R c is independently selected from hydrogen, F, cl, -OH, -CN, -CH 3、-OCH3, and-CH 2 OH.
In some embodiments of the invention, a compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 3 is selected from-CN, -C (O) NH 2、-OC(O)NH2、-O-C1-3 alkyl, -C 1-3 alkyl-OH, -S (O) 2CH3、-CH2S(O)2CH3, -halo C 1-3 alkyl, -O-halo C 1- 3 alkyl, -C 1-3 alkyl-CN, and-C 1-3 alkyl-O-C 1-3 alkyl.
In some embodiments of the invention, a compound of formula (I) or formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 3 is selected from-CN, -CH 2OH、-CHF2、-CH2 F, and-CF 3.
In some embodiments of the invention, a compound of formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein,
R a is selected from H, F, cl, -CH 3、-CN、-OCH3, and-CH 2 OH;
R 1-1 is-CH 3 and-CD 3;
the E ring is selected from azetidinyl, pyrrolidinyl, and piperidinyl;
The E ring is optionally substituted with one or more R c, each R c is independently selected from hydrogen, F, cl, -OH, -CN, -CH 3、-OCH3, and-CH 2 OH;
R 3 is selected from-CN, -C (O) NH 2、-OC(O)NH2、-O-C1-3 alkyl, -C 1-3 alkyl-OH, -S (O) 2CH3、-CH2S(O)2CH3, -halogenated C 1-3 alkyl-O-halogenated C 1-3 alkyl, -C 1-3 alkyl-CN and-C 1-3 alkyl-O-C 1-3 alkyl; preferably, R 3 is selected from the group consisting of-CN, -CH 2OH、-CHF2、-CH2 F and-CF 3.
In some embodiments of the invention, a compound of formula (I-2) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, is selected from the group consisting of:
wherein,
R 1-1、Rc、R3、Ra is as defined in any one of the present inventions.
In some embodiments of the invention, a compound of formula (I-3) or formula (I-4) or formula (I-5) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein,
R 1-1 is-CH 3 and-CD 3;
R a is selected from H, F, cl, -CH 3、-CN、-OCH3, and-CH 2 OH;
R c is each independently selected from the group consisting of hydrogen, F, cl, -OH, -CN, -CH 3、-OCH3, and-CH 2 OH;
R 3 is selected from-CN, -C (O) NH 2、-OC(O)NH2、-O-C1-3 alkyl, -C 1-3 alkyl-OH, -S (O) 2CH3、-CH2S(O)2CH3, -halogenated C 1-3 alkyl-O-halogenated C 1-3 alkyl, -C 1-3 alkyl-CN and-C 1-3 alkyl-O-C 1-3 alkyl; preferably, R 3 is selected from the group consisting of-CN, -CH 2OH、-CHF2、-CH2 F and-CF 3.
In some embodiments of the invention, a compound of formula (I-2) or formula (I-3) or formula (I-4) or formula (I-5) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, is selected from the group consisting of:
Wherein R c、R3、Ra is as described in any one of the present inventions.
In some embodiments of the invention, a compound of formula (I-3-1) or formula (I-3-2) or formula (I-4-1) or formula (I-4-2) or formula (I-5-1) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein,
R a is selected from H, F, cl, -CH 3、-CN、-OCH3, and-CH 2 OH;
R c is each independently selected from the group consisting of hydrogen, F, cl, -OH, -CN, -CH 3、-OCH3, and-CH 2 OH;
R 3 is selected from-CN, -C (O) NH 2、-OC(O)NH2、-O-C1-3 alkyl, -C 1-3 alkyl-OH, -S (O) 2CH3、-CH2S(O)2CH3, -halogenated C 1-3 alkyl-O-halogenated C 1-3 alkyl, -C 1-3 alkyl-CN and-C 1-3 alkyl-O-C 1-3 alkyl.
Preferably, R 3 is selected from the group consisting of-CN, -CH 2OH、-CHF2、-CH2 F and-CF 3.
In the present invention, when L 1 is a single bond, R 3 is selected from cyano, -OC 1-6 alkyl, -NHC 1-6 alkyl, -NHC (O) C 1-6 alkyl, -C (O) C 1- 6 alkyl, -NHC (O) OC 1-6 alkyl, -S (O) 2C1-6 alkyl, each of said C 1-6 alkyl being optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, cyano, -O- (C 1-6 alkyl).
In the present invention, the compound is not the following compound:
In the present invention, the 5-to 10-membered heteroaryl ring is preferably a 5-to 6-membered heteroaryl, more preferably a pyridyl or pyrimidinyl.
The halogen or halo is preferably fluoro, chloro or bromo, more preferably fluoro.
The-C 1-6 alkyl is preferably-C 1-3 alkyl, more preferably methyl, ethyl or isopropyl.
The-OC 1-6 alkyl group is preferably-OC 1-3 alkyl, more preferably methoxy.
The-NHC 1-6 alkyl group is preferably-NHC 1-3 alkyl.
The-N (C 1-6 alkyl) 2 is preferably-N (C 1-3 alkyl) 2.
The-NHC (O) C 1-6 alkyl group is preferably a-NHC (O) C 1-3 alkyl group.
The-C 2-6 alkenyl group is preferably-C 2-4 alkenyl group, more preferably vinyl or propenyl.
The-C 2-6 alkynyl group is preferably-C 2-4 alkynyl group, more preferably ethynyl or propynyl.
The-halogenated C 1-6 alkyl is preferably-halogenated C 1-3 alkyl, more preferably-halogenated methyl or-halogenated ethyl.
The-C 3-12 cycloalkyl group is preferably-C 3-8 cycloalkyl group, more preferably-C 3-6 cycloalkyl group.
The-4-12 membered heterocyclic group is preferably a-4-8 membered heterocyclic group, more preferably a-4-6 membered heterocyclic group, further preferably azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl.
The-halogenated C 1-6 alkoxy group is preferably-halogenated C 1-3 alkoxy group, more preferably-halogenated methoxy group or-halogenated ethoxy group.
The-C 1-6 alkylene-is preferably-C 1-3 alkylene-, more preferably-methylene, -ethylene or propylene.
The-C 3-6 -cycloalkylene-is preferably-cyclopropylene.
The-NHC (O) -S (O) 2-(C1-6 alkylene) preferably-NHC (O) -S (O) 2-(C1-3 alkylene) -.
The-C (O) C 1-6 alkylene-is preferably-C (O) C 1-3 alkylene-.
The-C (O) C 1-6 alkyl group is preferably a-C (O) C 1-3 alkyl group.
The-NHC (O) OC 1-6 alkyl group is preferably a-NHC (O) OC 1-3 alkyl group.
The-S (O) 2C1-6 alkyl group is preferably-S (O) 2C1-3 alkyl group, more preferably-S (O) 2CH3 alkyl group.
The-NHC 1-6 alkyl-N (C 1-6 alkyl) 2 is preferably-NHC 1-3 alkyl-N (C 1-3 alkyl) 2.
The-NH-C (O) O (C 1-6 alkyl) group is preferably-NH-C (O) O (C 1-3 alkyl).
The-N (C 1-6 alkyl) -C (O) OC 1-6 alkyl group is preferably-N (C 1-3 alkyl) -C (O) OC 1-3 alkyl.
The-OC (O) NHC 1-6 alkyl group is preferably-OC (O) NHC 1-3 alkyl.
The-N (C 1-3 alkyl) C (O) C 1-3 alkyl is preferably-N (C 1-3 alkyl) C (O) C 1-3 alkyl.
The present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, the compound is selected from:
In yet another aspect, the present invention provides a process for the preparation of a compound of formula (I), said process comprising the steps of:
1. The compound IN1-1 and IN1-2 are subjected to substitution reaction or metal catalytic (such as Pd (PPh 3) 4、PdCl2(dpPf)2) coupling reaction IN the presence of organic base (such as Et 3 N, DIPEA, N-methylmorpholine, DBU, sodium hydride and the like) or inorganic base (such as potassium carbonate, cesium carbonate and the like) IN organic solvent (such as DMF, DMSO, NMP, dioxane, dichloromethane, toluene, tetrahydrofuran, chloroform, acetonitrile and the like) to obtain the compound IN1-3, wherein the compound IN1-3 is subjected to the substitution reaction with the compound IN1-4 IN the presence of oxidant (such as m-CPBA, potassium persulfate and the like) to obtain the intermediate sulfoxide, and then the compound IN1-3 is subjected to the substitution reaction with the base (such as Et 3 N, DIPEA, N-methylmorpholine, DBU, sodium hydride and the like) to obtain the compound of formula (I).
Wherein LG 1 represents a halogen leaving group, the remaining groups being as defined in formula (I).
In some embodiments of the invention, LG 1 is preferably chloro, bromo;
The starting materials for the preparation process of the present invention may be from commercial sources or may be prepared according to known methods.
It will be appreciated by those skilled in the art that the order of the reaction steps may be appropriately adjusted, as well as the addition or omission of protection/deprotection reaction steps, depending on the desired product structure to be obtained.
In yet another aspect, the invention provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
It is a further object of the present invention to provide a method of preparing a pharmaceutical composition of the present invention, comprising combining a compound of the present invention or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.
Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the invention are pharmaceutically acceptable carriers, examples of suitable pharmaceutically acceptable carriers being described in Remington's Pharmaceutical Sciences (2005).
The pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms of a human or animal patient. For example, various suitable dosage forms may be formulated depending on the route of administration.
In other embodiments, administration of a compound or pharmaceutical composition of the invention may be combined with additional methods of treatment. The additional treatment method may be selected from, but is not limited to, radiation therapy, chemotherapy, immunotherapy, or a combination thereof.
The invention also relates to a pharmaceutical formulation comprising a compound of the invention or a pharmaceutically acceptable form thereof, or a mixture thereof, as an active ingredient, or a pharmaceutical composition of the invention. In some embodiments, the formulation is in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.
It is a further object of the invention to provide an article of manufacture, for example in the form of a kit. Articles of manufacture as used herein are intended to include, but are not limited to, kits and packages. The article of manufacture of the invention comprises (a) a first container, (b) a pharmaceutical composition in the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the invention or a pharmaceutically acceptable form thereof, or a mixture thereof, (c) optionally, package insert(s) indicating that the pharmaceutical composition is useful for treating a neoplastic disorder (as defined below), and (d) a second container.
The first container is a container for containing a pharmaceutical composition. The container may be used for preparation, storage, transportation and/or independent/batch sales. The first container is intended to encompass a bottle, a can, a vial, a flask, a syringe, a tube (e.g., for a cream product), or any other container for preparing, containing, storing, or dispensing a pharmaceutical product.
The second container is a container for holding the first container and optionally packaging instructions. Examples of the second container include, but are not limited to, a box (e.g., a carton or plastic box), a box, a carton, a bag (e.g., a paper or plastic bag), a pouch, and a coarse cloth bag. The package insert may be physically adhered to the exterior of the first container via a tie, glue, staple, or other means of adhesion, or it may be placed inside the second container without any physical means of adhesion to the first container. Or the package insert is located outside of the second container. When located outside the second container, it is preferred that the package insert is physically adhered via a tie, glue, staple or other means of adhesion. Or it may abut or contact the exterior of the second container without physical adhesion.
The package insert is a trademark, label, logo, etc. listing information related to the pharmaceutical composition located in the first container. The information listed is typically determined by a regulatory agency (e.g., the U.S. food and drug administration) that governs the area in which the article is to be sold. Preferably, the package insert specifically lists the indication for which the pharmaceutical composition is approved. The package insert may be made of any material from which information contained therein or thereon may be read. Preferably the package insert is a printable material (e.g. paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (e.g. printed or applied).
In yet another aspect, the invention provides the use of a compound described herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a Wee1 kinase-associated disease.
In yet another aspect, the invention provides the use of a compound described herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, in the preparation of a Wee1 inhibitor. In the application, the Wee1 inhibitor can be used in a mammalian organism, and can also be used in vitro, mainly used for experimental application, for example, the Wee1 inhibitor can be used as a standard sample or a control sample for comparison, or can be prepared into a kit according to a conventional method in the field for rapid detection of the inhibition effect of Wee 1.
In a further aspect, the invention provides the use of a compound as described herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of cancer. In further embodiments, the cancers include, but are not limited to, breast, colorectal, colon, lung and prostate cancer, as well as bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervical and vulva cancer, as well as leukemias including Chronic Lymphocytic Leukemia (CLL), acute Lymphoblastic Leukemia (ALL) and Chronic Myelogenous Leukemia (CML), multiple myeloma and lymphoma.
In some embodiments, the lung cancer is lung adenocarcinoma. The colorectal cancer is colorectal adenocarcinoma.
In yet another aspect, the invention provides a method for preventing or treating a Wee1 kinase associated disease, the method comprising administering to a subject in need thereof a compound as described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention.
In yet another aspect, the invention provides a compound as described herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a Wee1 kinase-associated disease.
In yet another aspect, the invention provides methods for preventing or treating Wee1 kinase-associated diseases, in combination with additional therapeutic methods, including, but not limited to, radiation therapy, chemotherapy, immunotherapy, or a combination thereof, of a compound as described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention.
In some embodiments, the Wee1 kinase-associated disease is a disease that is sensitive or responsive to Wee1 kinase inhibition.
In some embodiments, the Wee1 kinase-associated disease is cancer. In further embodiments, the cancers include, but are not limited to, breast, colorectal, colon, lung and prostate cancer, as well as bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervical and vulva cancer, as well as leukemias including Chronic Lymphocytic Leukemia (CLL), acute Lymphoblastic Leukemia (ALL) and Chronic Myelogenous Leukemia (CML), multiple myeloma and lymphoma. In some embodiments, the lung cancer is lung adenocarcinoma. The colorectal cancer is colorectal adenocarcinoma.
In a further preferred embodiment, the compounds of the invention may be used in combination with chemoradiotherapy or immunotherapy for the prevention or treatment of cancer.
The dosing regimen may be adjusted to provide the best desired response. For example, when administered in the form of an injection, a single bolus, bolus and/or continuous infusion, and the like, may be administered. For example, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. Generally, the dosage of treatment will vary depending on considerations such as the age, sex, and general health of the patient to be treated, the frequency of treatment and the nature of the effect desired, the extent of tissue damage, the duration of symptoms, and other variables that may be adjusted by the individual physician. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions. The amount and regimen of administration of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical arts. For example, the composition or compound of the present invention may be administered in divided doses from 4 times per day to 1 time per 3 days, and the amount of administration may be, for example, 0.01 to 1000 mg/time. The required dose may be administered in one or more doses to achieve the desired result. The pharmaceutical composition according to the present invention may also be provided in unit dosage form.
The invention provides a novel high-activity Wee1 inhibitor, which can realize at least one technical effect of (1) high inhibition activity on Wee1 kinase, (2) excellent physicochemical properties (such as solubility, physical and/or chemical stability), (3) excellent pharmacokinetic properties (such as good bioavailability, proper half-life and duration of action), and (4) excellent safety (lower toxicity and/or less side effect and wider treatment window).
General terms and definitions
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will appreciate that the terms such as "comprising" encompass "consisting of.
The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.
Unless otherwise stated, concentrations are by weight and proportions (including percentages) are by mole.
The term "one or more" or similar expression "at least one" may denote, for example, 1,2, 3,4, 5,6, 7, 8, 9, 10 or more.
When lower and upper limits of a range of values are disclosed, any number and any range encompassed within the range are specifically disclosed. In particular, each range of values (in the form "about a to b", or equivalently, "about a-b") of values disclosed herein is understood to mean each value and range encompassed within the broader range.
For example, the expression "C 1-6" should be understood to encompass any subrange therein as well as every point value, e.g., C 2-5、C3-4、C1-2、C1-3、C1-4、C1-5, etc., as well as C 1、C2、C3、C4、C5、C6, etc. For example, the expression "C 3-10" should also be understood in a similar manner, e.g., any subrange and point values contained therein, such as C 3-9、C6-9、C6-8、C6-7、C7-10、C7-9、C7-8、C8-9 and the like, and C 3、C4、C5、C6、C7、C8、C9、C10 and the like, may be covered. Also for example, the expression "3-10 membered" should be understood to encompass any subrange therein as well as every point value therein, e.g., 3-4 membered, 3-5 membered, 3-6 membered, 3-7 membered, 3-8 membered, 3-9 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 5-7 membered, 5-8 membered, 6-7 membered, etc., as well as 3,4, 5,6, 7,8, 9,10 membered, etc. Also for example, the expression "5-10 membered" should be understood in a similar manner, e.g. any subrange and point value contained therein, e.g. 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-7 membered, 6-8 membered, 6-9 membered, 6-10 membered, 7-8 membered etc. and 5,6, 7,8, 9,10 membered etc.
The term "alkyl" as used herein, alone or in combination with other groups, refers to a saturated straight or branched hydrocarbon group. As used herein, the term "C 1-6 alkyl" refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1,2, 3,4, 5, or 6 carbon atoms). "C 1- 6 alkyl" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like.
The term "alkenyl" as used herein, alone or in combination with other groups, refers to a straight or branched hydrocarbon group containing one or more double bonds. Illustrative examples of alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, and the like. Illustrative examples of C2-6 alkenyl groups having more than one double bond include butadienyl, pentadienyl, hexadienyl and hexatrienyl groups and branched forms thereof. The position of the unsaturated bond (double bond) may be at any position of the carbon chain.
The term "alkynyl" as used herein, alone or in combination with other groups, refers to an unsaturated straight or branched chain alkynyl group, such as ethynyl, 1-propynyl, propargyl, butynyl, and the like.
The term "alkylene" as used herein, alone or in combination with other groups, refers to a saturated straight or branched divalent hydrocarbon radical. As used herein, the term "C 1-6 alkylene" refers to a saturated straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms. "C 1-6 alkylene" includes, for example, but is not limited to, methylene, ethylene, propylene, butylene, and the like.
The term "alkenylene", as used herein alone or in combination with other groups, refers to a straight or branched chain divalent aliphatic hydrocarbon radical having one or more carbon-carbon double bonds, to which two radicals (or fragments) may be attached to either the same or different carbon atoms. For example, as used herein, the term "C 2-6 alkenylene" refers to alkenylenes having 2 to 6 carbon atoms (e.g Etc.).
The term "alkynylene" as used herein, alone or in combination with other groups, refers to a straight or branched chain divalent aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, to which the two groups (or fragments) are attached, each to a different carbon atom. For example, as used herein, the term "C 2-6 alkynylene" refers to alkynylene groups having 2 to 6 carbon atoms (e.gEtc.).
The term "alicyclic" or "alicyclic ring" as used herein, alone or in combination with other groups, refers to a mono-or polycyclic (including fused, bridged, and spiro rings, such as bicyclic) aliphatic hydrocarbon ring system, including cycloalkyl, cycloalkenyl, cycloalkyne rings, and the like.
The term "cycloalkyl", "carbocycle" or "cycloalkylene", as used herein, alone or in combination with other groups, refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include, but are not limited to, monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, and the like, or bicyclic cycloalkyl groups including fused, bridged or spiro rings such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [5.2.0] nonyl, decalinyl, and the like. For example, "C 3-12 cycloalkyl" refers to cycloalkyl groups having 3 to 12 ring carbon atoms (e.g., 3,4, 5, 6,7, 8, 9, 10, 11, or 12).
The term "heterocycloalkyl" or "heterocyclyl", as used herein, alone or in combination with other groups, refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged or spiro) non-aromatic group having ring atoms made up of carbon atoms and at least one (e.g., 1,2,3 or 4) heteroatom selected from nitrogen, oxygen and sulfur. If valence requirements are met, the heterocycloalkyl group may be attached to the remainder of the molecule through any one of the ring atoms. For example, "3-8 membered heterocycloalkyl" refers to heterocycloalkyl having 3 to 8 ring atoms. Common heterocycloalkyl groups include, but are not limited to, oxiranyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolane, and the like.
The term "heteroaryl" or "heteroaromatic ring" as used herein, alone or in combination with other groups, refers to an aromatic ring having a conjugated pi-electron system in which one or more (e.g., 1,2, or 3) ring atoms are heteroatoms selected from N, O, P and S, with the remaining ring atoms being C. Heteroaryl or heteroaromatic rings may be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group may contain 5-12 (e.g., 5,6,7,8, 9, 10, 11, or 12) ring atoms, particularly 5,6, 9, 10 ring atoms. Examples of heteroaryl groups are, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and the term also encompasses the case where the heteroaryl or heteroaromatic ring may optionally be further fused to an aryl, or heteroaryl ring to form a fused ring.
The term "haloalkyl" as used herein, alone or in combination with other groups, refers to an alkyl group as described above wherein one or more hydrogen atoms are replaced with a halogen. For example, the term "C 1-6 haloalkyl" refers to a C 1-6 alkyl group optionally substituted with one or more (e.g., 1-3) halogens. It will be appreciated by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. Examples of haloalkyl groups are, for example -CH2F、-CHF2、-CF3、-CCl3、-C2F5、-C2Cl5、-CH2CF3、-CH2Cl or-CH 2CH2CF3, etc.
The term "alkoxy" when used herein, alone or in combination with other groups, means an alkyl group, as described above, attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, t-butoxy, pentoxy, and the like.
The term "halogen" as used herein, alone or in combination with other groups, refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). The term "hydroxy" as used herein, alone or in combination with other groups, refers to-OH.
The term "cyano" when used herein, alone or in combination with other groups, refers to-CN.
The term "nitro" as used herein, alone or in combination with other groups, refers to-NO 2.
The term "amino" as used herein, alone or in combination with other groups, refers to-NH 2.
The term "oxo" as used herein, alone or in combination with other groups, refers to = O.
The term "each independently" as used herein means that at least two groups (or fragments) present in the structure, which have the same or similar value ranges, may have the same or different meanings in the particular case. For example, the substituents X and Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, then when the substituent X is hydrogen, the substituent Y may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl, and similarly when the substituent Y is hydrogen, the substituent X may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl
The term "substituted" and other variants thereof herein means that one or more (e.g., 1,2,3, or 4) atoms or groups of atoms (e.g., hydrogen atoms) on the indicated atom is replaced by other equivalents, provided that the normal valency of the indicated atom or group in the present case is not exceeded, and that a stable compound is capable of being formed. If an atom or group of atoms is described as "optionally substituted," it may be either substituted or unsubstituted. Unless otherwise indicated, the attachment site of a substituent herein may be from any suitable position of the substituent. When a bond in a substituent is shown as passing through a chemical bond between two atoms interconnected in a ring system, then it is meant that the substituent may be attached to any one of the ring-forming atoms in the ring system.
Solid lines may be used hereinSolid wedge shapeOr virtual wedge shapeDepicting the carbon-carbon bonds of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, compounds of the present invention may exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the present invention or metabolites thereof directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts see, e.g., "Remington's Pharmaceutical Sciences", mack Publishing Company, easton, pa., (2005), and "handbook of pharmaceutically acceptable salts: methods for preparing pharmaceutically acceptable salts of the compounds of the invention, property, selection and application "(Handbook of Pharmaceutical Salts：Properties,Selection,and Use),Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)., are known to those skilled in the art.
As used herein, the term "ester" means an ester derived from a compound described herein, including physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention may themselves be esters.
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming nitrogen oxides because nitrogen requires available lone pair electrons to oxidize to oxides. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitroxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxirane) such as dimethyl dioxirane. These methods for preparing nitrogen oxides have been described and reviewed extensively in the literature, see, e.g., T.L.Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750 (A.R.Katritzky and A.J.Boulton, eds., ACADEMIC PRESS), and G.W.H.Cheeseman and E.S.G.Werstiuk, ADVANCES IN Heterocyclic Chemistry, vol.22, pp 390-392 (A.R.Katritzky and A.J.Boulton, eds., ACADEMIC PRESS).
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by assay methods. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel DELIVERY SYSTEMS", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,2006, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The invention also encompasses methods of preparing the compounds described herein. It will be appreciated that the compounds of the present invention may be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction may be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for effecting the conversion.
The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating one or more symptoms of a target disorder or condition.
The term "effective amount" (e.g., "therapeutically effective amount" or "prophylactically effective amount") as used herein refers to an amount of an active ingredient that, upon administration, will achieve a desired effect to some extent, e.g., to alleviate one or more symptoms of the condition being treated or to prevent the appearance of the condition or symptoms thereof.
As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
Detailed Description
The invention includes all combinations of the specific embodiments recited. Further embodiments and applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. All publications, patents, and patent applications cited herein, including references, are incorporated by reference in their entirety for all purposes.
The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Examples
The present invention will be described in further detail with reference to the following examples and test examples, which do not limit the scope of the present invention and may be modified without departing from the scope of the present invention.
Mass Spectrometry (MS) was determined using an Agilent (ESI) mass spectrometer, manufacturer Agilent, model Agilent 6120B.
Preparation High Performance Liquid Chromatography (HPLC) A liquid chromatograph (YMC, ODS, 250X 20mm column) was used for the preparation of Shimadzu LC-8A.
The purification by thin layer chromatography adopts a silica gel plate of GF 254 (0.4-0.5 nm) produced by a smoke table.
The reaction is monitored by Thin Layer Chromatography (TLC) or liquid chromatography mass spectrometry (LC-MS) using a developing solvent system including but not limited to dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system, the volume ratio of the solvent being adjusted according to the polarity of the compound, or triethylamine being added.
Column chromatography generally uses 200-300 mesh silica gel from Qingdao ocean as stationary phase. The eluent system comprises but is not limited to a methylene dichloride system, a methanol system, a normal hexane system and an ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and the like can be added for adjustment.
If the examples are not specified, the reaction temperature is room temperature (20 ℃ C. To 30 ℃ C.).
Unless otherwise indicated, the reagents used in the examples were purchased from Acros Organics, ALDRICH CHEMICAL Company, nanjing's medical science and technology, or Shanghai Summit's medical science and technology, among others.
EXAMPLE 1 preparation of Compounds
PREPARATION EXAMPLE 1 preparation of 2-allyl-1- (6- (3- (hydroxymethyl) azetidin-1-yl) pyridin-2-yl) -6- (4- (4-methylpiperazin-1-yl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (preparation of Compound A1)
First step preparation of 2-bromo-6- (3- ((tert-butyldiphenylsilyl) oxy) methyl) azetidin-1-yl) pyridine (Compound A1-2)
A1-1 (3.60 g,11.08 mmol), 2, 6-dibromopyridine (2.62 g,11.08 mmol), potassium carbonate (3.06 g,22.16 mmol) were added to dioxane (35 mL), and the mixture was heated to 80℃with stirring for 4hrs. After completion of the reaction was confirmed by TLC, water was added to the reaction mixture, extraction was performed with ethyl acetate, the combined organic phases were washed with brine, dried over saturated sodium sulfate, and concentrated under reduced pressure to give crude product, which was purified by column chromatography to give compound A1-2 (1.4 g, yield 26.2%).
Second step preparation of 2-allyl-1- (6- (3- ((tert-butyldiphenylsilyl) oxy) methyl) azetidin-1-yl) pyridin-2-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound A1-4)
Compound A1-3 (300 mg,1.35 mmol), compound A1-2 (779 mg,1.61 mmol), cuprous iodide (257 mg,1.35 mmol), potassium carbonate (279 mg,2.02 mmol) and N, N' -dimethylethylenediamine (131 mg,1.49 mmol) were added to dioxane (5 ml), and the mixture was heated to 95℃under nitrogen for reaction for 12 hours. LCMS monitoring showed complete reaction of starting material. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give Compound A1-4 (400 mg, 47.6%).
Third step preparation of 2-allyl-1- (6- (3- (tert-butyldiphenylsilyl) oxy) methyl) azetidin-1-yl) pyridin-2-yl) -6- (4- (4-methylpiperazin-1-yl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound A1-6)
Compound A1-4 (200 mg,0.32 mmol) was dissolved in toluene (2 mL), and m-chloroperoxybenzoic acid (69 mg,0.32mmol, 80%) was added at 25℃and reacted at this temperature for 1 hour, followed by compound N, N-diisopropylethylamine (215.80 mg,1.67 mmol) and compound A1-5 (67 mg,0.35 mmol) and the reaction was continued for 16 hours. LCMS showed complete reaction, water was added to the reaction, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified on a silica gel column to give compound A1-6 (100 mg, 40%).
Fourth step 2-allyl-1- (6- (3- (hydroxymethyl) azetidin-1-yl) pyridin-2-yl) -6- (4- (4-methylpiperazin-1-yl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (preparation of Compound A1)
[1] Compound A1-6 (100 mg,0.13 mmol) was dissolved in methanol (3 mL), reacted for 2 hours after adding ammonia fluoride (14.5 mg,0.39 mmol), LCMS showed complete reaction, the reaction solution was filtered and concentrated under reduced pressure, and the crude product was purified by preparative HPLC to give compound A1 (10 mg, 14.5%).
LCMS(ESI)m/z:528.1[M+H]+;
1H NMR(400MHz,CD3OD)δppm 8.79(s,1H),7.70(t,J＝7.6Hz,1H),7.59(br d,J＝8.8Hz,2H),7.05(d,J＝7.6Hz,1H),6.97(d,J＝9.2Hz,2H),6.34(d,J＝8.0Hz,1H),5.70-5.82(m,1H),5.09(dd,J＝10.2,1.2Hz,1H),5.01(dd,J＝17.2,1.2Hz,1H),4.76(br d,J＝6.4Hz,2H),4.11(t,J＝8.4Hz,2H),3.82(dd,J＝8.4,5.2Hz,2H),3.77(d,J＝6.4Hz,2H),3.18-3.24(m,4H),2.63-2.69(m,4H),2.51-2.41(m,1H),2.38(s,3H).
Preparation example 2 preparation of Compound A9S
First step preparation of Compound A9S-2
A9S-1 (0.36 g,4.13 mmol), 2, 6-dibromopyridine (1 g,4.13 mmol), potassium carbonate (1.14 g,8.26 mmol) were added to dimethyl sulfoxide (8 mL), and the mixture was heated to 80℃with stirring to react for 2 hours. After completion of the reaction was confirmed by TLC, water was added to the reaction mixture, which was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over saturated sodium sulfate, and concentrated under reduced pressure to give crude product, which was purified by column chromatography to give compound A9S-2 (0.6 g, yield 60%).
Second step, preparation of Compound A9S-3
Compound A9S-2 (600 mg,2.47 mmol), compound A1-3 (268 mg,2.47 mmol), cuprous iodide (48 mg,0.25 mmol), potassium carbonate (279 mg,4.94 mmol) were added to dioxane (5 ml), and the mixture was heated to 95℃under nitrogen for reaction for 12 hours. LCMS monitoring showed complete reaction of starting material. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give Compound A9S-3 (300 mg, yield 32%).
Third step, preparation of Compound A9S
Compound A9S-3 (45 mg,0.2 mmol) was dissolved in toluene (2 mL), m-CPBA (43 mg,0.2mmol, 80%) was added at 25℃and reacted at this temperature for 1 hour, followed by compound N, N-diisopropylethylamine (168 mg,1.3 mmol) and compound A1-5 (100 mg,0.26 mmol) and the reaction was continued for 16 hours. LCMS showed complete reaction, water was added to the reaction, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude purified by reverse HPLC to give compound A9S (10 mg, yield 10%).
LCMS(ESI)m/z:528.2[M+H]+;
1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.79(s,1H),8.30(s,1H),7.74(d,J＝8.2Hz,1H),7.60(s,2H),7.04(d,J＝7.6Hz,1H),6.96-6.84(m,2H),6.46(d,J＝8.2Hz,1H),5.68(ddt,J＝16.4,10.2,5.8Hz,1H),5.04(dt,J＝10.4,1.4Hz,1H),4.92(dt,J＝17.2,1.6Hz,1H),4.59(s,2H),4.27(t,J＝7.0Hz,1H),3.93-3.75(m,2H),3.68(td,J＝5.8,5.2,3.2Hz,2H),3.09(t,J＝5.0Hz,4H),2.45(t,J＝5.0Hz,4H),2.34-2.13(m,5H).
The following compounds were synthesized by referring to the procedure of preparation example 1 or preparation example 2,
Preparation 3 reference compound 1 and reference compound 2 were prepared according to the methods of example 131 and example 19 of patent WO 2023072301.
EXAMPLE 2 Wee1 enzyme Activity inhibition assay
In the Wee1 enzyme activity inhibition experiments, ADP-Glo luminescent kit was used to examine the effect of different compounds on the Wee1 enzyme activity, where the Wee1 enzyme was purchased from Carna bioscience, poly (Lys Tyr (4:1)) as enzyme substrate. After incubation of the compound (highest concentration 1000nM, 3-fold gradient dilution) with Wee1 (2 nM) for 30min, adding the reaction substrate and ATP, reacting at room temperature for 1h, adding ADP-Glo stop reagent, reacting at room temperature in the dark for 40min, adding ADP-Glo kinase detection reagent, incubating at room temperature in the dark for 1h, detecting Luminescence value of Lumineancence, and calculating half inhibition concentration of the compound on enzyme activity.
TABLE 1 Wee1 enzyme activity inhibition test results
The result shows that the compound has better Wee1 enzyme inhibition activity.
Example 3 cell proliferation inhibition experiment
In a427 cells, the effect of each compound on cell proliferation was examined. Specifically, after incubation of the gradient diluted compounds for 120h,Chemiluminescent cell viability assay (i.e., CTG method) evaluates and calculates the half maximal inhibitory concentration (IC 50) of the compound on these several strains of cells.
TABLE 2 inhibition of proliferation activity of compounds on different cells
++++:IC50＜200nM;+++：200nM＜IC50<400nM;++>400nM
The results show that the compound of the application has better cell proliferation inhibition activity.
Example 4 cell proliferation inhibition experiment two
The effect of each compound on cell proliferation was examined in HT29, SNU5, SNU16, A427 cells. Specifically, after incubation of the gradient diluted compounds for 120h,Chemiluminescent cell viability assay (i.e., CTG method) evaluates and calculates the half maximal inhibitory concentration (IC 50) of the compound on these several strains of cells.
TABLE 3 inhibition of proliferation activity of compounds against various cells
The results show that the compounds of the application have better cell proliferation inhibition activity in HT29 and SNU16 cells compared with AZD 1775.
EXAMPLE 5 Balb/c mouse Pharmacokinetic (PK) study
Compound A9S, AZD1775 was administered to female and male Balb/c mice by intravenous and intragastric administration, respectively, to examine pharmacokinetic properties. The intravenous dose was 1mg/kg, the drug solvent was 5% DMSO+5% Solutol+90% Saline, the parenteral dose was 10mg/kg, and the drug solvent was 0.5% MC (sodium methylcellulose). Blood was collected at various time points after intravenous and intragastric administration, anticoagulated with edta.k2 and stored at-80 ℃.
The blood or plasma samples are subjected to LC-MS/MS analysis after treatment with precipitated proteins. Pharmacokinetic parameters were calculated using the non-compartmental model using WinNonlin 6.3 software, the results are given in table 4 below.
TABLE 4 pharmacokinetic parameters of Compounds in blood in Male and female Balb/c miceNote that "/" indicates the absence of
Conclusion that the compound A9S achieves higher exposure in the systemic circulation of female and male mice at the dosage of 1mg/Kg for injection and 10mg/Kg for oral administration, has the comprehensive properties remarkably superior to those of AZD1775, and shows excellent pharmacokinetic properties.
Example 6 Biochemical hERG inhibition assay
1. Experimental materials
Stable expression of hERG channel (Cat. K1236) HEK 293 (human embryonic kidney cells, purchased from Invitrogen) culture of stably transfected cell lines cells were cultured in medium containing 85% DMEM, 10% dialyzed fetal calf serum, 0.1mM NEAA, 25mM HEPES, 100U/mL penicillin-streptomycin, 5. Mu.g/mL Blasticidin and 400. Mu.g/ML GENETICIN, cells were cultured in cell culture flasks at 25cm 2、5％CO2, 37 ℃. Cells were passaged about three times per week using TrypLE TM Express, maintained at a confluency of about 40% to 80%. Cells were induced with doxycycline (1. Mu.g/mL) for 48 hours prior to the experiment. On the day of the experiment, the induced cells were resuspended and seeded onto 3.5cm cell culture dishes (5×10 5 cells/3.5 cm cell culture dishes) containing coverslips prior to use and cultured in medium without Blasticidin and Geneticin.
Note that the number of cell line passages used in the safety evaluation test was less than 60.
2. Working solution preparation of test compounds
The compound was dissolved in DMSO and formulated at 30mM, 10mM, 3.33mM, 1.11mM and 0.37mM. The extracellular fluids were then added separately, with the final concentrations of test compounds being 30. Mu.M, 10. Mu.M, 3.33. Mu.M, 1.11. Mu.M and 0.37. Mu.M, and the final concentration of DMSO being 0.1%.
3. Experimental protocol
1) Cover slips with a large number of single HEK 293 hERG cells on the surface were taken, placed in a continuous recording pool on an inverted microscope, extracellular fluid (approximately 1ml per minute) was perfused and recorded continuously, waiting for current to stabilize. 2) HERG channel currents of individual cells were recorded using a standard whole cell recording mode. The membrane voltage is clamped at-80 mV, the cells are stimulated by +20mV voltage for 5s to activate the hERG potassium channel, repolarization is carried out to-50 mV for 5s, an outward tail current is generated, continuous perfusion is carried out until the current is stable, and the tail current peak value is the reference current value. 3) And then, the extracellular fluid containing the drug to be detected is perfused and continuously recorded until the inhibition effect of the drug on hERG current reaches a stable state, and at the moment, the tail current peak value is the current value after drug addition. 4) The cells are again perfused with extracellular solution until hERG current reverts to or approaches the level prior to drug addition, and perfusion testing can continue for other concentrations or drugs. One or more compounds or drug concentrations can be tested on each cell. 5) Dofetilide (TRC) was used as a positive control in the experiment to ensure that the cells used responded normally.
4. Data acceptance criteria
The following criteria are used to determine the acceptability of the data.
1) Initial sealing resistance >1gΩ;
2) The leakage current is at any time less than 50% of the control peak tail current;
3) Peak tail amplitude >250pA;
4) The film resistance Rm is more than 500MΩ;
5) An access resistance (Ra) <15mΩ;
6) The apparent drop in peak current is <2.5%/min.
5. Experimental results
Table 5 herg inhibition assay results
The conclusion is that the test result shows that compared with AZD1775, a reference compound 1 and a reference compound 2, the compound has weak inhibition effect on hERG potassium channels and better drug forming property.
Example 7 Biochemical CYP enzyme (cytochrome P450) inhibition assay
1. Test system:
P450-GloTM CYP1A2 Screening System,(Promega);
P450-GloTM CYP2D6 Screening System,(Promega);
P450-GloTM CYP3A4 Screening System,(Promega)。
2. test instrument:
BMG PHERAstar FS Luminescent。
3. the test method comprises the following steps:
The test was performed according to the kit instructions, respectively, as follows:
3.1. Inhibition of CYP1 A2:
Test group test groups test compounds of different concentrations were added to microwell plates, luciferin-ME (100. Mu.M), K 3PO4 (100 mM) and CYP1A2 (0.01 pmol/. Mu.L) were added to each well, pre-incubated for 10min at room temperature, followed by addition of NADPH regeneration system, reaction for 30min at room temperature, final addition of an equal volume of detection buffer, incubation for 20min at room temperature, and chemiluminescent detection.
The negative control group is the same experimental method as the test group, except that no compound to be tested is added.
Blank control group the experimental procedure was the same as the test group except that no test compound was added and CYP1A2 was replaced with CYP1A2 Membrance (0.01 pmol/. Mu.L).
3.2. Inhibition of CYP2D 6:
Test group test groups test compounds of different concentrations were added to microwell plates, luciferin-ME EGE (3. Mu.M), K 3PO4 (100 mM) and CYP2D6 (5 nM) were added to each well, pre-incubated for 10min at room temperature, followed by addition of NADPH regeneration system, reaction at 37℃for 30min, final addition of an equal volume of detection buffer, incubation for 20min at room temperature, and chemiluminescent detection.
The negative control group is the same experimental method as the test group, except that no compound to be tested is added.
Blank control group the experimental procedure was the same as the test group except that no test compound was added and CYP2D6 was replaced with CYP2D6 Membrance (5 nM).
3.3. Inhibition of CYP3 A4:
Test group test groups test compounds of different concentrations were added to microwell plates, luciferin-IPA (3. Mu.M), K 3PO4 (100 mM) and CYP3A4 (2 nM) were added to each well, pre-incubated for 10min at room temperature, followed by addition of NADPH regeneration system, reaction for 30min at room temperature, and finally addition of an equal volume of detection buffer, incubation for 20min at room temperature, followed by chemiluminescent detection.
The negative control group is the same experimental method as the test group, except that no compound to be tested is added.
Blank control group the experimental procedure was the same as the test group except that no test compound was added and CYP3A4 was replaced with CYP3A4 Membrance (2 nM).
4. And (3) data processing:
Percentage inhibition = (1- (chemiluminescent signal value of test compound concentration group-chemiluminescent signal value of blank control group)/(chemiluminescent signal value of negative control group-chemiluminescent signal value of blank control group)) × 100%.
When the percent inhibition is between 30-80%, the half inhibition concentration (IC 50) or range of compounds to CYP enzyme is estimated according to the following formula: IC 50 = X (1-percent inhibition)/percent inhibition, where X is the test concentration of the compound.
5. Test results:
Inhibition of three CYP enzymes by the compounds of the invention was measured as described above and the results are shown in Table 5 below.
Table 5 CYP enzyme inhibition test results
6. Conclusion:
The results show that the compound of the invention has no obvious inhibition effect on all 3 main CYP enzyme subtypes, and the potential drug interaction possibility is relatively low and is superior to that of the reference compound 1 and the reference compound 2.
The above embodiments do not limit the solution of the application in any way. Various modifications of the application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims (17)

  1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite or prodrug thereof,
    Wherein,
    The A ring is selected from phenyl, 5-10 membered heteroaryl ring, optionally substituted with one or more R a;
    Each R a is independently selected from H, halogen, -OH, -CN, -C 1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1- 6 alkyl) 2、-C2-4 alkenyl, -C 2-4 alkynyl, each of said C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl optionally substituted with one or more substituents selected from hydrogen, halogen, oxo, -OH, -CN, -NH 2、-C1-6 alkyl;
    R 1 is selected from halogen, -CN, C 1-6 alkyl, halogenated C 1-6 alkyl, -C 3-12 cycloalkyl, 4-12 membered heterocyclyl, -O- (4-12 membered heterocyclyl), -N (R b) - (4-12 membered heterocyclyl), -C (O) NR bRd、-N＝S(O)RbRdd, -said C 1-6 alkyl, C 3-12 cycloalkyl, 4-12 membered heterocyclyl are each optionally substituted with one OR more groups selected from halogen, oxo, -CN, -OR b、-NRbRd、-C1- 6 alkyl, -halogenated C 1-6 alkyl, -halogenated C 1-6 alkoxy, -C 1-6 alkylene-OR b、-C1-6 alkylene-NR bRd、-C3-8 cycloalkyl, substituted with 4-8 membered heterocyclyl 、-SRb、-C(O)Rb、-C(O)ORb、-C(O)NRbRd、-N(Rb)C(O)Rd、-N(Rb)C(O)ORd、-S(O)2Rd、-N(Rb)S(O)2Rd, further, said C 3-8 cycloalkyl, The 4-8 membered heterocyclyl each optionally being substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -C 1-6 alkyl, -halo C 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2;
    R b、Rd is independently selected from H, -C 1-6 alkyl, -C 3-6 cycloalkyl, 4-12 membered heterocyclyl, each of said C 1-6 alkyl, C 3-6 cycloalkyl, 4-12 membered heterocyclyl being optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -NH 2、-N(C1-6 alkyl) 2、-C1-6 alkylene-OH, -OC 1-6 alkyl, -C 1-6 alkylene-NHC 1-6 alkyl, -C 1-6 alkylene-N (C 1-6 alkyl) 2;
    R 2 is selected from hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, heteroaryl optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -NH 2、-C1-6 alkyl;
    The B ring is selected from phenyl and 5-10 membered heteroaryl, wherein the B ring is optionally substituted by one or more substituents selected from hydrogen, halogen, -CN and-OCH 3;
    The E ring is selected from-C 3-12 cycloalkyl, 4-12 membered heterocyclyl, said E ring optionally substituted with one or more R c;
    Each R c is independently selected from hydrogen, halogen, -OH, oxo, cyano, -C 1-6 alkyl, -OC 1-6 alkyl;
    X is selected from CH or N;
    L 1 is selected from the group consisting of a single bond, -C 1-6 alkylene-, -C 3-6 cycloalkylene-, - (3-6 membered heterocyclylene) -, -NHC (O) -S (O) 2-(C1-6 alkylene) -, -C (O) C 1-6 alkylene-, -C (O) C 3-6 cycloalkylene-, -C (O) - (3-6 membered heterocyclylene) -and-C (O) -, wherein each of said C 1-6 alkylene, 3-6 membered heterocyclylene and C 3-6 cycloalkylene is optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, oxo, -OH and amino;
    r 3 is selected from the following conditions:
    i) When L 1 is a single bond, R 3 is selected from cyano, -OC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2、-NHC(O)C1-6 alkyl, -C (O) C 1-6 alkyl, -NHC (O) OC 1-6 alkyl, -S (O) 2C1-6 alkyl, each of said C 1-6 alkyl optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, cyano, -O- (C 1-6 alkyl);
    ii) when L 1 is not a single bond, R 3 is selected from halogen, amino, -OH, cyano, -haloC 1-6 alkyl, -S (O) 2C1-6 alkyl, -OC 1-6 alkyl, -NHC 1-6 alkyl-N (C 1-6 alkyl) 2、-NH-C(O)O(C1-6 alkyl), -N (C 1-6 alkyl) -C (O) OC 1-6 alkyl, -OC (O) NH 2、-OC(O)NHC1-6 alkyl and-N (C 1-6 alkyl) C (O) C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from halogen, oxo, -OH, amino and-O- (C 1-6 alkyl).
  2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein,
    Ring a is selected from phenyl, pyridinyl, thiophenyl, and pyrazolyl, said ring a optionally substituted with one or more R a, each R a is independently selected from H, F, cl, -OH, -C 1-3 alkyl, and-OC 1-3 alkyl, said C 1-3 alkyl optionally substituted with one or more substituents selected from F, cl, -OH, and-CN;
    Preferably, the A ring is selected from phenyl optionally substituted with one or more R a, each R a is independently selected from H, F, cl, -OH, -C 1-3 alkyl and-OC 1-3 alkyl, said C 1-3 alkyl being optionally substituted with one or more substituents selected from F, cl, -OH and-CN;
    More preferably, the A ring is selected from phenyl optionally substituted with one or more R a, R a is selected from H, F, cl, -CH 3、-OCH3 and-CH 2 OH.
  3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 1 is selected from C 1-6 alkyl, 4-6 membered heterocyclyl, C 4-6 cycloalkyl, -O- (4-6 membered heterocyclyl), -NH- (4-6 membered heterocyclyl), -C (O) N (C 1-6 alkyl) 2, each of said 4-6 membered heterocyclyl and C 4-6 cycloalkyl optionally substituted with one or more substituents selected from halogen, oxo, -OH, -CN, -OCH 3、-NH2、-N(C1-3 alkyl) 2、-C1-3 alkyl, -halo C 1-3 alkyl, -halo C 1-3 alkoxy, -C 1-3 alkylene-OH, -C 1-3 alkylene-N (C 1-3 alkyl) 2、-C(O)OC1-3 alkyl, and-S (O) 2C1-3 alkyl;
    preferably, R 1 is selected from pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydropyridinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with one or more substituents selected from F, cl, -OH, -CN, oxo, -OCH 3、-NH2、-N(CH3)2、-C1-3 alkyl, -halo C 1-3 alkyl, -halo C 1-3 alkoxy, -C 1-3 alkylene-OH, -C 1-3 alkylene-N (CH 3)2、-C(O)OC1-3 alkyl, and-S (O) 2C1-3 alkyl;
    Preferably, R 1 is selected from
  4. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 2 is selected from-CH 3、-CH2CH3, cyclopropyl, isopropyl, allyl, propargyl, -CH 2 -cyclopropyl, -CH 2CF3, preferably R 2 is selected from allyl.
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein ring B is selected from phenyl, pyridinyl, pyrimidinyl, thienyl, and thiazolyl, the ring B being optionally substituted with one or more substituents selected from hydrogen, halogen, and-CN;
    preferably, the B ring is selected from pyridinyl and phenyl.
  6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the E ring is selected from 4-6 membered heterocyclyl, wherein the E ring is optionally substituted with one or more R c, each R c is independently selected from hydrogen, F, cl, -OH, oxo, -CN, -CH 3、-OCH3;
    Preferably, the E ring is selected from azetidinyl, pyrrolidinyl, and piperidinyl.
  7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein L 1 is selected from the group consisting of methylene, -C (O) -methylene-O-, and-C (O) -, wherein the methylene is optionally substituted with one or more substituents selected from the group consisting of hydrogen, F, and-CH 3.
  8. The compound of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 3 is selected from:
    i) When L 1 is a single bond, R 3 is selected from-OCH 3、-NHCH3、-NHC(O)CH3、-C(O)CH3 and-S (O) 2CH3;ii)L1 is not a single bond, R 3 is selected from F, amino 、-OH、-CN、-CHF2、-CH2F、-S(O)2CH3、-OCH3、-OCHF2、-NH-C(O)OCH3;, preferably R 3 is selected from F, -OH, -CN, -NH 2-CHF2、-S(O)2CH3 and-CH 3.
  9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, selected from the group consisting of:
    wherein,
    R 1 is as defined in claim 3;
    The E ring is selected from 4-6 membered heterocyclyl, said E ring optionally substituted with one or more R c, each R c is independently selected from hydrogen, F, cl, -OH, oxo, -CN, -CH 3、-OCH3, preferably, the E ring is selected from azetidinyl, pyrrolidinyl and piperidinyl;
    L 1 is as defined in claim 7;
    r 3 is as defined in claim 8.
  10. A compound according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, selected from the group consisting of:
    wherein,
    The E ring is selected from 4-6 membered heterocyclic groups, the hetero atoms of the 4-6 membered heterocyclic groups are N, and the number of the hetero atoms is 1,2 or 3;
    the E ring is optionally substituted with one or more R c, each R c is independently selected from H, F, cl, -OH, -CN, -C 1-6 alkylene-OH, -C 1-6 alkyl, and-halogenated C 1-6 alkyl;
    R 3 is selected from-CN, -C (O) NH 2、-OC(O)NH2、-OC1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2、-NHC(O)C1- 6 alkyl-C (O) C 1-6 alkyl, -NHC (O) OC 1-6 alkyl, -S (O) 2C1-6 alkyl-C 1-6 alkyl S (O) 2C1-6 alkyl, -halogenated C 1-6 alkyl, -O-halogenated C 1-3 alkyl, -C 1-6 alkyl-CN, C 1-6 alkyl-OH, C 1-6 alkyl-NH 2、-C1-6 alkyl OC 1-6 alkyl and-cyclopropyl-OH; the C 1-6 alkyl groups are each optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, amino and cyano.
  11. The compound of claim 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof,
    Wherein,
    R a is selected from H, F, cl, -CH 3、-CN、-OCH3, and-CH 2 OH;
    R 1-1 is-CH 3 or-CD 3;
    the E ring is selected from azetidinyl, pyrrolidinyl, and piperidinyl;
    The E ring is optionally substituted with one or more R c, each R c is independently selected from hydrogen, F, cl, -OH, -CN, -CH 3、-OCH3, and-CH 2 OH;
    R 3 is selected from-CN, -C (O) NH 2、-OC(O)NH2、-O-C1-3 alkyl, -C 1-3 alkyl-OH, -S (O) 2CH3、-CH2S(O)2CH3, -halogenated C 1-3 alkyl-O-halogenated C 1-3 alkyl, -C 1-3 alkyl-CN and-C 1-3 alkyl-O-C 1-3 alkyl; preferably, R 3 is selected from the group consisting of-CN, -CH 2OH、-CHF2、-CH2 F and-CF 3.
  12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, which satisfies one or more of the following conditions:
    1) L 1 is a single bond, and the total number of the components is a single bond, R 3 is selected from the group consisting of-OC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2、-NHC(O)C1-6 alkyl-C (O) C 1- 6 alkyl, -NHC (O) OC 1-6 alkyl, -S (O) 2C1-6 alkyl; each of said C 1-6 alkyl groups being optionally substituted with one or more substituents selected from hydrogen, halogen, -OH, cyano, -O- (C 1-6 alkyl);
    2) Ring A is phenyl, preferably
    3) R 1 is a 4-12 membered heterocyclyl, preferably a 4-6 membered heterocyclyl, more preferably a6 membered heterocyclyl, said heterocyclyl optionally being substituted by one or more-C 1-6 alkyl or-deuterated C 1-6 alkyl, preferably by one or more-C 1-3 alkyl or-deuterated C 1-3 alkyl, more preferably by-CH 3 or-CD 3;
    4) R 2 is-C 2-6 alkenyl, preferably-C 2-4 alkenyl, more preferably allyl;
    5) Ring B is a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl, more preferably a6 membered heteroaryl, even more preferably pyridinyl, particularly preferably
    6) Ring E is azetidinyl or pyrrolidinyl, preferablyMore preferablyThe E ring is optionally substituted with one or more R c, each R c is independently selected from H, F, cl, -OH, -CN, -CH 3、-OCH3;
    7) L 1 is selected from the group consisting of a single bond, -C 1-6 alkylene-, -C 3-6 cycloalkylene-, and-C (O) -, said-C 1-6 alkylene-preferably being-C 1-3 alkylene-, more preferably methylene, -C 3-6 cycloalkylene-preferably being cyclopropylene;
    8) R 3 is selected from:
    i) When L 1 is a single bond, R 3 is selected from cyano, -OC 1-6 alkyl and-S (O) 2C1-6 alkyl, wherein said-OC 1-6 alkyl is optionally substituted with one or more substituents selected from halogen, -OC 1-6 alkyl is preferably-O-halogenated C 1-3 alkyl, more preferably-OCF 2, -S (O) 2C1-6 alkyl is preferably-S (O) 2C1-3 alkyl, more preferably-S (O) 2CH3;
    ii) L 1 is-C 1-6 alkylene-, -C 3-6 cycloalkylene-or-C (O) -, preferably-C 1-6 alkylene-, more preferably-C 1-3 alkylene-, R 3 is selected from halogen, Amino, -OH, cyano, C 1-6 alkyl, -halogenated C 1-6 alkyl, -S (O) 2C1-6 alkyl and-OC 1-6 alkyl, said-halogenated C 1-6 alkyl is preferably-halogenated C 1-3 alkyl, more preferably fluorinated C 1-3 alkyl, such as CHF 2 or CH 2 F, said-S (O) 2C1-6 alkyl is preferably-S (O) 2C1-3 alkyl, more preferably-S (O) 2CH3, said-OC 1-6 alkyl is preferably-OC 1-3 alkyl, more preferably-OCH 3;
    9) In the compound of formula (I-2), R 1-1 is selected from the group consisting of-C 1-6 alkyl and-deuterated C 1-6 alkyl, the-C 1-6 alkyl is preferably-C 1-3 alkyl, more preferably-CH 3, and the-deuterated C 1-6 alkyl is preferably-deuterated C 1-3 alkyl, more preferably-CD 3.
  13. The compound of claim 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, that satisfies one or more of the following conditions:
    1) L 1 is methylene and R 3 is selected from halogen, amino, -OH, cyano, C 1-6 alkyl, -haloC 1-6 alkyl, -S (O) 2C1-6 alkyl and-OC 1-6 alkyl, preferably halogen, amino, -OH, cyano, C 1-3 alkyl, -haloC 1-3 alkyl, -S (O) 2C1-3 alkyl and-OC 1-3 alkyl;
    2) R 1 is piperidinyl, tetrahydropyridinyl or piperazinyl optionally substituted with one or more-C 1-3 alkyl or-deuterated C 1-3 alkyl, preferably piperazinyl optionally substituted with one or more-CH 3 or-CD 3, preferably R 1 is selected from Preferably is
    3) Structural unitSelected from the group consisting ofPreferably is
    4) Structural unitSelected from the group consisting of
    5) Structural unitIs that Preferably is
    Preferably, the structural unitIs that
  14. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, selected from the group consisting of:
    wherein:
    R 1-1、Rc、R3、Ra is as defined in any one of claims 1 to 13;
    preferably, the compound is selected from:
    wherein:
    r c、R3、Ra is as defined in any one of claims 1 to 13.
  15. A compound according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, selected from the group consisting of:
  16. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
  17. Use of a compound according to any one of claims 1-15 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, oxynitride, isotopic label, metabolite or prodrug thereof or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the prevention and/or treatment of cancer or for the manufacture of a Wee1 inhibitor, preferably one or more of the following cancers selected from breast cancer, colorectal cancer, colon cancer, lung cancer, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, oesophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical and vulval cancer, leukemia, multiple myeloma and lymphoma.
CN202380053251.3A 2022-07-15 2023-07-14 A pyrimido five-membered heterocyclic compound, preparation method and use thereof Pending CN119497714A (en)

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