CN117343062A - Pyrazolopyrimidinone compound, preparation method and application thereof - Google Patents

Pyrazolopyrimidinone compound, preparation method and application thereof Download PDF

Info

Publication number
CN117343062A
CN117343062A CN202310679246.5A CN202310679246A CN117343062A CN 117343062 A CN117343062 A CN 117343062A CN 202310679246 A CN202310679246 A CN 202310679246A CN 117343062 A CN117343062 A CN 117343062A
Authority
CN
China
Prior art keywords
alkyl
compound
pharmaceutically acceptable
cycloalkyl
alkylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310679246.5A
Other languages
Chinese (zh)
Inventor
易磊
张禹
花海清
朱忠远
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yingen Biotechnology Shanghai Co ltd
Yinen Biopharmaceutical Suzhou Co ltd
Original Assignee
Yingen Biotechnology Shanghai Co ltd
Yinen Biopharmaceutical Suzhou Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yingen Biotechnology Shanghai Co ltd, Yinen Biopharmaceutical Suzhou Co ltd filed Critical Yingen Biotechnology Shanghai Co ltd
Publication of CN117343062A publication Critical patent/CN117343062A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a substituted pyrazine compound, a pharmaceutical composition containing the same and application thereof. Specifically, the invention relates to a compound shown in a formula (I) or a pharmaceutically acceptable form thereof, which shows good Wee1 inhibition activity, can be used as a high-efficiency Wee1 inhibitor and is used for preventing and/or treating Wee1 related diseases.

Description

Pyrazolopyrimidinone compound, preparation method and application thereof
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 one aspect, the 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,
ring a is selected from phenyl and 5-10 membered heteroaryl;
the B ring is selected from phenyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl;
Q 1 selected from N and CR a ，R a Selected from H, halogen, -OH, -NH 2 、-NHC 1-6 Alkyl, -C 1-6 Alkyl-halo C 1-6 An alkyl group;
L 1 selected from single bonds, -C 2-4 Alkenylene-, -C 2-4 Alkynylene-, -C (O) -C 2-4 Alkynylene radicals,-C 1-6 alkylene-C 2-4 Alkynylene-, -C (O) NH-, -NHC (O) NH-, -S (O) 2 -、-S(O) 2 NH-、-NHS(O) 2 -、-C 1-6 alkylene-C (O) -, -C 1-6 alkylene-C (O) N (R) b ) -; the C is 1-6 Alkylene, C 2-4 Alkenylene and C 2-4 Alkynylene radicals are each optionally substituted with one or more radicals selected from halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halo C 1-6 Alkyl, oxo, hydroxy, -CN and-NH 2 Is substituted by a substituent of (a);
L 2 selected from single bond, -NH-, -S-, -C (O) NH-, and-NHC (O) -;
L 3 selected from single bond, -CH 2 -, -C (O) NH-and-C (O) -;
and when L 1 In the case of a single bond, one of the following two conditions must be satisfied:
i)L 3 is a single bond, and L 2 Is not NH; ii) L 3 Is not a single bond;
R 1 selected from-C 3-6 Cycloalkyl and 4-12 membered heterocyclyl; the C is 3-6 Cycloalkyl and 4-12 membered heterocyclyl are each optionally substituted with one OR more substituents selected from halogen, oxo, -OR b 、-NR b R c 、-C 1-6 Alkyl, -halo C 1-6 Alkyl, -halo C 1-6 Alkoxy, -C 1-6 alkylene-OR b 、-C 1-6 alkylene-NR b R c 、-C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -SR b 、-CN、-C(O)R b 、-C(O)OR b 、-C(O)NR b R c 、-NR b C(O)R c 、-NR b C(O)OR c 、-S(O) 2 R b and-NR b S(O) 2 R c Is substituted by a substituent of (a);
or R is 1 Selected from-C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with one OR more groups selected from halogen, -OR b and-NR b R c Is substituted by a substituent of (a);
R b 、R c each independently selected from H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and 4-12 membered heterocycloalkyl; the C is 1-6 Alkyl, C 3-6 Cycloalkyl and 4-12 membered heterocyclyl are each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN and-NH 2 Is substituted by a substituent of (a);
R 2 each independently selected from H, halogen, hydroxy, -CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 3-6 Cycloalkyl and 4-6 membered heterocyclyl; the C is 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 3-6 Cycloalkyl and 4-6 membered heterocyclyl are each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN, -NH 2 and-C 1-6 Substituent substitution of alkyl;
or any two adjacent R 2 Together with the atoms to which they are attached form a 5-7 membered heterocyclic group, a 5-6 membered heteroaromatic ring and C 5-7 Cycloalkyl; the 5-7 membered heterocyclic group, the 5-6 membered heteroaromatic ring and C 5-7 Cycloalkyl groups are each optionally substituted with one or more groups selected from halogen, -hydroxy, -CN, -NH 2 and-C 1-6 Substituent substitution of alkyl;
R 3 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 and 5-6 membered heteroaryl; the C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents selected from halogen, oxo, hydroxy, -CN, -NH 2 、-C 1-6 Substituent substitution of alkyl;
R 4 each independently selected from halogen, cyano, nitro, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-6 membered heteroaryl, -OR d 、-SR d 、-NR d R e 、-NR d C(O)R e 、-NR d S(O) 2 R e 、-C(O)R d 、-C(O)NR d R e 、-S(O) 2 NR d R e 、-S(O) 2 NHR d And-n=s (O) R d R e The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents selected from halogen, oxo, hydroxy, -CN, -NH 2 、-C 1-6 Alkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 Alkyl, -C 1-6 alkylene-CN, -halo C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl and-C 1-6 alkylene-S (O) 2 C 1-6 Substituent substitution of alkyl;
R d 、R e each independently selected from H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and 4-12 membered heterocycloalkyl; the C is 1-6 Alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocycloalkyl, each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN, -NH 2 Is substituted by a substituent of (a);
alternatively, any two adjacent R 4 Together with the atoms to which they are attached form C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl, 5-6 membered heteroaryl; the C is 5-8 Cycloalkyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, -NH 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-CN, -halo C 1-6 Alkyl substituent substitution;
m, n are each independently selected from 0, 1, 2, 3 and 4.
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, the compound of formula (I) or a pharmaceutically acceptable form thereof, ring a is selected from phenyl, pyridinyl, thienyl and pyrazolyl; preferably, the a ring is selected from phenyl and thienyl.
In some embodiments of the invention, the compound of formula (I) or a pharmaceutically acceptable form thereof, the B ring is selected from phenyl, pyridyl, pyrimidinyl, thienyl and thiazolyl; preferably, the B ring is selected from pyridinyl and phenyl.
In some embodiments of the invention, the compound of formula (I) or a pharmaceutically acceptable form thereof, Q 1 Selected from N, CH, CF, C-NH 2 、C-CH 3 And C-OH; preferably Q 1 CH.
In some embodiments of the invention, the compound of formula (I) or a pharmaceutically acceptable form thereof, L 1 Selected from single bonds, -C 2-4 Alkenylene-, -C 2-4 Alkynylene-, -C (O) -C 2-4 Alkynylene group-, -C 1-6 alkylene-C 2-4 Alkynylene-, -C (O) NH-, -NHC (O) -; preferably L 1 Selected from-ethynylene-, -C (O) -ethynyl-, -CH 2 -ethynyl-, -C (O) NH-and-NHC (O) -; more preferably L 1 Selected from ethynylene and-CH 2 -ethynylene-.
In some embodiments of the invention, the compound of formula (I) or a pharmaceutically acceptable form thereof, L 2 Selected from single bond, -NH-, -S-, -C (O) NH-, and-NHC (O) -; preferably L 2 Selected from-NH-, -C (O) NH-and-NHC (O) -; preferably L 2 Selected from-NH-.
In some embodiments of the invention, the compound of formula (I) or a pharmaceutically acceptable form thereof, L 3 Selected from single bond, -CH 2 -and-C (O) -; preferably L 3 Selected from single bonds and-CH 2 -; preferably L 3 Selected from single bonds.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable form thereof, R 1 Selected from 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl optionally being substituted with one or more substituents selected from halogen, oxo, -OH, -OCH 3 、-NH 2 、-N(C 1-3 Alkyl group 2 、-C 1-3 Alkyl, -C 3-6 Cycloalkyl radicals(ii) halo C 1-3 Alkyl, -halo C 1-3 Alkoxy, -CH 2 OH、-C 1-3 alkylene-N (C) 1-3 Alkyl group 2 、-CN、-C(O)OC 1-3 Alkyl and-S (O) 2 C 1-3 Substituent substitution of alkyl;
preferably, R 1 Selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, epoxyhexenyl, and piperazinyl; the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, epoxyhexenyl and piperazinyl are each independently optionally substituted with one or more groups selected from F, cl, -OH, -OCH 3 、-NH 2 、-N(CH 3 ) 2 -halomethyl, -halomethoxy, -CH 2 OH、-C 1-3 alkylene-N (CH) 3 ) 2 、-CN、-C(O)OCH 3 and-S (O) 2 CH 3 Is substituted by a substituent of (a); alternatively, each of the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, epoxyhexenyl and piperazinyl groups independently is optionally substituted with one or more groups selected from-CH 3 、-CD 3 、-CH(CH 3 ) 2 And substituents for cyclopropyl;
preferably, R 1 Selected from the group consisting ofAlternatively, R 1 Selected from the group consisting of
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable form thereof, R 1 Selected from-C 1-3 Alkyl, said-C 1-3 Alkyl is optionally substituted with one or more groups selected from F, cl, -OH, -OCH 3 、-NH 2 、-N(CH 3 ) 2 、-CH 3 -halomethyl, -halomethoxy, -CH 2 OH、-C 1-3 alkylene-N (CH) 3 ) 2 、-CN、-C(O)OCH 3 、-CD 3 、-CH(CH 3 ) 2 Cyclopropyl and-S (O) 2 CH 3 Is substituted by a substituent of (a); preferably, R 1 Selected from the group consisting of
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable form thereof, R 1 -L 1 -is selected from
Preferably, R 1 -L 1 -is selected from
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable form thereof, R 2 Each independently selected from H, F, cl, hydroxy, -C 1-3 Alkyl, -OC 1-3 Alkyl, said C 1-3 Alkyl optionally substituted with one or more substituents selected from F, cl, hydroxy and-CN; alternatively, R 2 Each independently selected from-CN;
or any two adjacent R 2 Together with the atoms to which they are attached, form a five membered heteroaryl group and a five membered heterocyclyl group; the five membered heterocyclyl and five membered heteroaryl are each optionally substituted with one or more groups selected from F, cl, -OH, -CN, -NH 2 、-CH 3 Is substituted by a substituent of (a);
preferably, R 2 Selected from H, F, cl, -CH 3 、OCH 3 and-CH 2 OH; or any two adjacent R 2 Together with the atoms to which they are attached form pyrazolyl and pyrrolyl; alternatively, R 2 Each independently selected from-CHF 2 、-OCHF 2 、-CF 3 or-CN;
preferably, R 2 Is H; alternatively, R 2 Each independently selected from-CHF 2 、-OCHF 2 -CN and-CH 2OH.
In some embodiments of the inventionIn the compound of formula (I) or a pharmaceutically acceptable form thereof, R 3 Selected from-CH 3 、-CH 2 CH 3 Cyclopropyl, isopropyl, allyl, propargyl, -CH 2 -cyclopropyl and-CH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R 3 Selected from allyl, or R 3 Selected from isopropyl groups.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable form thereof, R 4 Selected from-C 1-6 Alkyl, -C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl and-n=s (O) (CH 3 ) 2 The C is 1-6 Alkyl and-C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN, -NH 2 、-C 1-6 Alkyl, -C 1-3 alkylene-OH, -C 1-3 alkylene-OC 1-3 Alkyl, -C 1-3 alkylene-CN, -halo C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl and-C 1-3 alkylene-S (O) 2 C 1-3 Substituent substitution of alkyl;
preferably, R 4 Selected from-C 1-3 Alkyl and-C 3-6 Cycloalkyl group, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from F, cl, oxo, hydroxy, -CN, -NH 2 、-Me、-CH 2 OH、-CH 2 OMe、-CH 2 -CN、-CF 3 、-CH 2 CF 3 、-S(O) 2 CH 3 、-CH 2 S(O) 2 CH 3 Is substituted by a substituent of (a);
more preferably, R 4 Selected from the group consisting ofAlternatively, R 4 Selected from->
In some embodiments of the invention, the compound of formula (I) or a pharmaceutically acceptable form thereof, any two ofAdjacent R 4 To which atoms are attached to form C 5-6 Cycloalkyl and 5-6 membered heterocyclyl; the C is 5-6 Cycloalkyl and 5-6 membered heterocyclyl are each optionally substituted with one or more groups selected from F, cl, hydroxy, -CN, -NH 2 、-CH 3 、-CH 2 CH 3 、-CH 2 OH、-CH 2 CN、-CHF 2 、-CH 2 F and-CF 3 Is substituted by a substituent of (a);
preferably, any two adjacent R 4 The atoms to which they are attached form cyclopentane; the cyclopentane is optionally substituted with one or more groups selected from hydroxy, -CH 3 、-CH 2 CH 3 and-CN.
In certain preferred embodiments of the present invention, certain groups in the compounds of formula (IIa), (IIa-1A), (IIa-1) or pharmaceutically acceptable salts thereof are defined as follows, and the unrecited groups are as described in any of the embodiments of the present application (abbreviated as "in some embodiments of the present invention").
In some embodiments of the invention, the invention provides a compound having a structure represented by formula (IIa):
wherein,
Z 1 、Z 2 、Z 3 each independently selected from N and CH;
m, n are each independently selected from 0, 1, 2, 3 and 4;
the remaining groups are as defined in any one of the schemes of formula (I);
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
In some embodiments of the invention, the invention provides a compound having the formula (IIa-1):
wherein,
n is selected from 0, 1, 2 and 3;
the remaining groups are as defined in any one of the schemes of formula (I);
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
In some embodiments of the invention, the compounds of formula (IIa) and formula (IIa-1), or pharmaceutically acceptable forms thereof, L 1 Selected from the group consisting of ethenylene, ethynylene, -C (O) -ethynyl, -C (O) NH-, and-NHC (O) -; preferably L 1 Selected from ethynylene, -C (O) -ethynyl, -C (O) NH-, and-NHC (O) -; more preferably L 1 Selected from ethynylene, -C (O) NH-, and-NHC (O) -; more preferably L 1 Selected from ethynylene and-CH 2 -ethynylene-.
In some embodiments of the invention, the invention provides a compound having the formula (IIa-1A) or a pharmaceutically acceptable form thereof:
wherein,
L 1 、R 1 、R 2 、R 3 、R 4 n and m are each as defined in any one of the schemes of formula (I);
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
In some embodiments of the invention, the invention provides a compound having the formula (IIa-1B):
wherein,
L 1 、R 1 、R 2 、R 3 、R 4 and m is each as defined in any one of the schemes of formula (I);
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
In some embodiments of the invention, the invention provides a compound having the formula (IIa-1A) or a pharmaceutically acceptable form thereof:
wherein,
L 1 selected from-C 2-4 Alkenylene-, -C 2-4 Alkynylene-, -C (O) -C 2-4 Alkynylene-, -C (O) NH-, -NHC (O) NH-, -S (O) 2 -、-S(O) 2 NH-and-NHS (O) 2 -; the C is 2-4 Alkenylene, C 2-4 Alkynylene optionally being substituted with one or more groups selected from halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halo C 1-6 Alkyl, oxo, hydroxy, -CN, -NH 2 Is substituted by a substituent of (a); preferably L 1 Selected from ethynylene, -propynylene-, -C (O) NH-, and-NHC (O) -;
R 1 selected from-C 1-3 Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl; the-C 1-3 Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl are each independently optionally substituted with one or more groups selected from F, cl, -OH, -OCH 3 、-NH 2 、-N(CH 3 ) 2 、-CH 3 -halomethyl, -halomethoxy, -CH 2 OH、-C 1-3 Alkylene groupbase-N (CH) 3 ) 2 、-CN、-C(O)OCH 3 、-CD 3 、-CH(CH 3 ) 2 Cyclopropyl, isopropyl and-S (O) 2 CH 3 Is substituted by a substituent of (a); preferably, the-C 1-3 Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl are each independently optionally substituted with one or more groups selected from-N (CH 3 ) 2 、-C 1-3 alkylene-N (CH) 3 ) 2 、-OH、-CH 3 、-CD 3 Cyclopropyl, isopropyl.
R 2 Each independently selected from H, F, cl, hydroxy, -CN, -C 1-3 Alkyl, -OC 1-3 Alkyl, said C 1-3 Alkyl optionally substituted with one or more substituents selected from F, cl, hydroxy and-CN;
R 3 selected from allyl;
R 4 selected from-C 1-3 Alkyl and-C 3-6 Cycloalkyl, said C 1-3 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from F, cl, oxo, hydroxy, -CN, -NH 2 、-Me、-CH 2 OH、-CH 2 OMe、-CH 2 -CN、-CF 3 、-CH 2 CF 3 、-S(O) 2 CH 3 、-CH 2 S(O) 2 CH 3 Is substituted by a substituent of (a); preferably, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from hydroxyl groups.
n is selected from 0, 1, 2 and 3;
m is selected from 0, 1, 2 and 3;
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
In some embodiments of the invention, the invention provides a compound having the formula (IIa-1B):
wherein,
L 1 selected from ethynylene and-propynylene-;
R 1 selected from-C 1-3 Alkyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl; the-C 1-3 Alkyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl are each independently optionally substituted with one or more substituents selected from F, cl, -OH, -OCH 3 、-NH 2 、-N(CH 3 ) 2 、-CH 3 -halomethyl, -halomethoxy, -CH 2 OH、-C 1-3 alkylene-N (CH) 3 ) 2 、-CN、-C(O)OCH 3 、-CD 3 、-CH(CH 3 ) 2 Cyclopropyl and-S (O) 2 CH 3 Is substituted by a substituent of (a);
R 2 each independently selected from H, F, cl, hydroxy, -CN, -C 1-3 Alkyl, -OC 1-3 Alkyl, said C 1-3 Alkyl optionally substituted with one or more substituents selected from F, cl, hydroxy and-CN;
R 3 selected from allyl;
R 4 selected from-C 1-3 Alkyl and-C 3-6 Cycloalkyl group, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from F, cl, oxo, hydroxy, -CN, -NH 2 、-Me、-CH 2 OH、-CH 2 OMe、-CH 2 -CN、-CF 3 、-CH 2 CF 3 、-S(O) 2 CH 3 、-CH 2 S(O) 2 CH 3 Is substituted by a substituent of (a);
m is selected from 0, 1, 2 and 3;
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
In yet another aspect, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, as shown below:
those skilled in the art will appreciate that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from the combination of technical features or preferred technical features of one embodiment with technical features or preferred technical features of another embodiment are also included within the scope of the present invention.
In yet another aspect, the present invention provides a process for the preparation of a compound of formula (IIa), said process comprising the steps of:
method A: a process for the preparation of a compound of formula IIa comprising the steps of: 1. the compound IN-3 is obtained by substitution reaction or coupling reaction of the compound IN-1 and the compound IN-2; 2. the compound IN-2 is firstly reacted with an oxidant to generate an intermediate sulfoxide, and then the intermediate sulfoxide and the compound IN-4 are subjected to substitution reaction to obtain the compound of the formula IIa.
Method B: a process for the preparation of a compound of formula IIa comprising the steps of: 1. the compound IN-3 is obtained by substitution reaction or coupling reaction of the compound IN-1 and the compound IN-2; 2. the compound IN-2 is reacted with an oxidizing agent to form a compound IN-5;3. the compounds IN-5 and IN-6 undergo substitution reaction under alkaline conditions to give compounds of formula IIa.
Wherein X represents a halogen leaving group and the remaining groups are as defined in formula (IIa).
In some embodiments of the invention, X is preferably chlorine, bromine;
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 as 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 methods may be selected from, but are 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 the invention comprises: (a) a first container; (b) A pharmaceutical composition in a first container, wherein the composition comprises: a first therapeutic agent comprising: the compounds of the invention or pharmaceutically acceptable forms thereof, or mixtures thereof; (c) Optionally package insert indicating that the pharmaceutical composition may be used for the treatment of 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. Alternatively, 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. Alternatively, 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 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 a method for preventing or treating a Wee1 kinase-associated disease, in combination with a compound as described herein or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, in a further therapeutic method, including, but not limited to: radiation therapy, chemotherapy therapy, immunotherapy, or a combination thereof.
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 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: age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; duration of symptoms; as well as other variables that may be adjusted by the respective 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 compositions or compounds of the present invention may be administered in divided doses from 4 times per day to 1 time per 3 days, and the amount administered 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 of the following technical effects: (1) high inhibitory activity against Wee1 kinase; (2) Excellent physicochemical properties (e.g., solubility, physical and/or chemical stability); (3) Excellent pharmacokinetic properties (e.g., good bioavailability, proper half-life, and duration of action); (4) Excellent safety (lower toxicity and/or fewer side effects, wider therapeutic window), etc.
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 such terms as "comprising" encompass the meaning of "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 "is understood to cover any subrange therein as well as every point value, e.g. C 2-5 、C 3-4 、C 1 - 2 、C 1-3 、C 1-4 、C 1-5 Etc. and C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Etc. For example, the expression "C 3-10 "also should be understood in a similar manner, for example, any subrange and point value contained therein, e.g., C 3-9 、C 6-9 、C 6-8 、C 6 - 7 、C 7-10 、C 7-9 、C 7-8 、C 8-9 Etc. and C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 Etc. 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 The "alkyl group" is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl or the like. The alkyl groups in the present invention are optionally substituted with one or more substituents described herein.
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 radical 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. Alkylene groups in the present invention are optionally substituted with one or moreEach of the substituents described herein is substituted.
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, the term "C" as used herein 2-6 Alkenylene "refers to alkenylene having 2 to 6 carbon atoms (e.gEtc.), optionally substituted with one or more (e.g., 1-3) substituents described herein.
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, the term "C" as used herein 2-6 Alkynylene "refers to alkynylene groups having 2 to 6 carbon atoms (e.gEtc.), optionally substituted with one or more (e.g., 1-3) substituents described herein.
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, including fused, bridged or spiro rings, such as bicyclo [1.1.1 ]Amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl and bicyclo [5.2.0]Nonyl, decalin, and the like. For example, "C 3-12 Cycloalkyl "refers to cycloalkyl having 3 to 12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). Cycloalkyl or cycloalkylene groups in the present invention are optionally substituted with one or more substituents described herein.
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 heterocycloalkyl, heterocycloalkylene or heterocyclyl groups of the present invention are optionally substituted with one or more substituents described herein (e.g., oxo).
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; the term also encompasses the case where a heteroaryl or heteroaromatic ring may optionally be further fused to an aryl, or heteroaryl ring to form a fused ring.
Herein, a text isThe term "haloalkyl" refers to an alkyl group as described above wherein one or more hydrogen atoms are replaced with halogen, alone or in combination with other groups. For example, the term "C 1-6 Haloalkyl "means C optionally substituted with one or more (e.g., 1-3) halogens 1-6 An alkyl group. 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, -CH 2 F、-CHF 2 、-CF 3 、-CCl 3 、-C 2 F 5 、-C 2 Cl 5 、-CH 2 CF 3 、-CH 2 Cl or-CH 2 CH 2 CF 3 Etc. Haloalkyl groups in the present invention are optionally substituted with one or more substituents described herein.
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, substituent X and substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, then when substituent X is hydrogen, substituent Y may be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl; 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 with … …," it may or may not be substituted. 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 hereinWedge shaped->Or virtual wedge +.>Depicting 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 stereochemistryChemical treatment. 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 reviews of suitable salts see, e.g., "Remington's Pharmaceutical Sciences", mack Publishing Company, easton, pa., (2005); and "manual of pharmaceutically acceptable salts: properties, selection and application "(Handbook of Pharmaceutical Salts: properties, selection, and Use), stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention 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 heterocyclic and tertiary amines are well known to those skilled in the art and include oxidizing heterocyclic 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 (dioxanes) such as dimethyl dioxirane. These methods for preparing nitrogen oxides have been widely described and reviewed in the literature, see for example: 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. Bundegaard (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.
Thin layer chromatography purification was performed using a fume bench produced GF 254 (0.4-0.5 nm) silica gel plate.
The reaction is monitored by Thin Layer Chromatography (TLC) or liquid chromatography mass spectrometry (LC-MS) using a developing reagent system including but not limited to: the volume ratio of the solvent is adjusted according to the polarity of the compound, or triethylamine and the like are 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.
Unless otherwise specified in the examples, the reaction temperature was room temperature (20℃to 30 ℃).
Unless otherwise indicated, the reagents used in the examples were purchased from Acros Organics, aldrich Chemical Company, nanjing medical stone technology or Shanghai Summit medicine technology, among others.
Example 1:
intermediate preparation example 1: preparation of 4- (1-methylpiperidin-4-yl) ethynyl) aniline (Compound A1)
The first step: preparation of tert-butyl 4- (4-nitrophenyl) ethynyl) piperidine-1-carboxylate (Compound A1-2)
Under nitrogen, A1-1a (5.00 g,23.91 mmol), A1-1b (5.31 g,26.28 mmol), pd (PPh) 3 ) 4 (2.76g，2.39mmol)、CuI(0.91g，4.77mmol)、Et 3 N (6.65 mL) was added to tetrahydrofuran (35 mL) and reacted at 80℃for 5 hours. After completion of the reaction, the filtrate was filtered, concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give Compound A1-2 (5.60 g, 70.9%).
And a second step of: preparation of 4- (4-nitrophenyl) ethynyl) piperidine (Compounds A1-3)
Compound A1-2 (5.60 g,16.95 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (15 mL) was added, stirred at room temperature for 30min, after completion of the reaction, concentrated to dryness under reduced pressure, dichloromethane was added to the remaining crude product, saturated sodium carbonate solution was added with stirring to adjust pH to about 8, the solution was separated, the organic phase was temporarily stored, the aqueous phase was back-extracted with dichloromethane twice, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give compound A1-3 (3.5 g, 89.7%).
And a third step of: preparation of 1-methyl-4- (4-nitrophenyl) ethynyl) piperidine (Compounds A1-4)
A1-3 (3.5 g,15.20 mmol) and 30% formaldehyde solution (60 mL) were added to methanol (32 mL), followed by acetic acid (2.5 mL), stirred for 30min, and NaBH was added 3 CN (1.43 g,22.80 mmol), at 25℃for 12 hours, 2M NaHCO was slowly added to the reaction mixture after completion of the reaction 3 The pH of the aqueous solution is 8-9, the reaction solution is extracted by ethyl acetate, the organic phase is dried and concentrated to dryness, and the crude product is purified by silica gel column chromatography to obtain the compound A1-4 (1.85 g, 50%).
Fourth step: preparation of 4- (1-methylpiperidin-4-yl) ethynyl) aniline (Compound A1)
Compound A1-4 (1.85 g,7.57 mmol) was dissolved in methanol (8 mL) and a solution of ammonium chloride (1 g,18.70 mmol) in water (8 mL) was added. The reaction was warmed to 80 ℃, iron powder (1.76 g,31.42 mmol) was slowly added and stirred at 80 ℃ for 30 minutes. After completion of the TLC detection reaction, the reaction solution was filtered, and the filtrate was dried by spin. The crude product was purified by column chromatography on silica gel to give compound A1 (0.95 g, 61%).
Intermediate preparation example 2: preparation of N- (3- (hydroxymethyl) -4- ((1-methylpiperidin-4-yl) ethynyl) phenyl) carboxamide (Compound A17)
The first step: preparation of N- (4-bromo-3- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -2, 2-trifluoroacetamide (Compound A17-2)
To a solution of compound A17-1 (3.2 g,10.1 mmol) in methylene chloride (40 mL) cooled to 0deg.C was added dropwise trifluoromethanesulfonic anhydride (3.3 g,15.2 mmol) and triethylamine (2.0 g,20.3 mmol) and stirred at room temperature for 1h. After the reaction was completed, the water-quenched solution was added and extracted 2 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give compound a17-2 (3.4 g, 82%).
And a second step of: preparation of tert-butyl 4- ((2- (((tert-butyldimethylsilyl) oxy) methyl) -4- (2, 2-trifluoroacetamido) phenyl) ethynyl) piperidine-1-carboxylate (Compound A17-3)
Compound A17-2 (2.9 g,7.0 mmol), compound A1-1a (1.5 g,7.0 mol), pd (PPh 3) 2 Cl 2 (494.1 mg,0.7 mmol), cuI (267.5 mg,1.41 mmol) and triethylamine (2.1 g,21.1 mmol) were dissolved in DMF (30 mL) and reacted with microwaves at 80℃for 3 hours under nitrogen protection. After completion of the reaction, water and ethyl acetate were added, the mixture was stirred, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give compound a17-3 (2.3 g, 60%).
And a third step of: preparation of N- (3- (((tert-butyldimethylsilyl) oxy) methyl) -4- (piperidin-4-ylethynyl) phenyl) -2, 2-trifluoroacetamide (Compound A17-4)
Compound A17-4 (2.3 g,4.3 mmol) was dissolved in DCM (50 mL), cooled to 0deg.C, TFA (5 mL) was added, followed by transfer to room temperature and stirring continued for 15min. After the reaction is completed, saturated NaHCO is added into the reaction solution 3 The pH of the solution was adjusted to about 7, and extracted with ethyl acetate 2 times. The organic phases were combined and washed with water, brine, and then Na 2 SO 4 After drying, filtration and concentration under reduced pressure. The residue was purified by column chromatography to give compound A17-4 (0.63 g, 33%).
Fourth step: preparation of N- (3- (((tert-butyldimethylsilyl) oxy) methyl) -4- ((1-methylpiperidin-4-yl) ethynyl) phenyl) -2, 2-trifluoroacetamide (Compound A17-5)
Compound A17-4 (100 mg,0.22 mmol), paraformaldehyde (22 mg,0.66 mmol) and TIPT (77 mg,0.26 mmol) were dissolved in MeOH (10 mL) and stirred at 50℃for 18h. Subsequently adding NaBH to the mixture 3 CN (35 mg,0.26 mmol) was stirred for 1 hour at 50 ℃. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound a17-5 (100 mg, 80%).
Fifth step: preparation of (5-amino-2- ((1-methylpiperidin-4-yl) ethynyl) phenyl) methanol (Compound A17-6)
Compound A17-5 (100 mg,0.22 mmol) was dissolved in MeOH (10 mL) and NaOH (47 mg,0.27 mmol) was added at room temperature. The mixture was stirred at 50℃for 4 hours. After completion of the reaction, the residue was purified by reverse-phase column chromatography to give compound a17-6 (50 mg, 94%).
Sixth step: preparation of N- (3- (hydroxymethyl) -4- ((1-methylpiperidin-4-yl) ethynyl) phenyl) carboxamide (Compound A17)
Anhydrous formic acid (0.5 mL), acetic anhydride (2.5 mL) were mixed and stirred at 70 ℃ for 1h. The solution was cooled to 0deg.C, a solution of Compound A17-6 (50 mg,0.2 mmol) in THF (2 mL) was added at this temperature, and the solution was stirred at 0deg.C for 1h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography to give compound a17 (25 mg, 45%).
Intermediates A2 to a20 were synthesized according to the similar method as in intermediate preparation example 1 and intermediate preparation example 2.
Preparation example 1 preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (4- (1-methylpiperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 1) trifluoroacetate
The first step: preparation of 2-allyl-1- (6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- (methylsulfanyl) -1H-pyrazolo [3,4-d ] pyrimidin-3 (2H) -one (Compounds 1-3)
Compound 1-1 (2 g,9.0 mmol), compound 1-2 (2.5 g,11.7 mmol), cuprous iodide (1.7 g,9.0 mmol), potassium carbonate (1.7 g,12.6 mmol) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (1.4 g,9.9 mmol) were added to dioxane (35 mL), reacted at 95℃for 4 hours, cooled to room temperature, aqueous ammonia was added, ethyl acetate was extracted 3 times, the organic phase was combined and concentrated, and the residue was chromatographed on silica gel to give Compound 1-3 (2.6 g, yield: 81%).
And a second step of: preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (4- (1-methylpiperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 1)
Compound 1-3 (200 mg,0.56 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL), potassium hydrogen peroxymonosulfate complex salt (282 mg,1.68 mmol) was added, stirred at room temperature for 2 hours, water was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude intermediate compound; the crude product was dissolved in toluene (5 mL), compound A1 (180 mg,0.84 mmol) and DIPEA (0.8 mL) were added sequentially, heated to 80℃and reacted for 4 hours, the reaction mixture was concentrated, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous trifluoroacetic acid) to give trifluoroacetate salt of compound 1 (30 mg, 8.4%).
MS(ESI)m/z:524.2[M+H] +
1 HNMR(400MHz,DMSO-d 6 ):δ10.43(s,1H)，9.40–9.23(m,1H)，8.94(s,1H)，8.12–8.07(m,1H)，7.81–7.74(m,3H)，7.64(dd,J＝7.60,2.00Hz,1H)，7.44(d,J＝8.40Hz,1H)，7.37(d,J＝8.64Hz,1H)，5.73–5.61(m,1H)，5.35(s,1H)，5.01(dd,J＝10.32,1.40Hz,1H)，4.82(dd,J＝17.20,1.52Hz,1H)，4.69(d,J＝5.60Hz,2H)，3.46–3.43(m,2H),3.20–3.15(m,1H),3.02–2.94(m,2H)，2.86–2.78(m,3H)，2.19–2.15(m,1H)，1.99–1.92(m,1H)，1.81–1.68(m,2H)，1.46(s,6H)..
Preparation example 2: preparation of 2-allyl-1- (6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- ((4- ((1-methylazetidin-3-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 25)
Crude compound 25 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous formic acid) to give compound 25.
MS(ESI)m/z:496.3[M+H] +
1 HNMR(400MHz,CD 3 OD):δ8.86(s,1H),8.01(t,J＝7.92Hz,1H),7.79(d,J＝7.92Hz,1H),7.71–7.68(m,3H),7.37–7.35(m,2H),5.79–5.69(m,1H),5.03(dd,J＝10.24,1.36Hz,1H),5.03(dd,J＝17.12,1.36Hz,1H),4.84–4.82(m,2H),3.73–3.69(m,2H),3.47–3.44(m,1H),3.28–3.24(m,2H),2.35(s,3H),1.57(s,6H)..
Preparation example 3: preparation of 2-allyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((4- (3- (4- (methyl-d 3) piperazin-1-yl) propyl-1-yn-1-yl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 51)
/>
Crude compound 51 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% ammonium bicarbonate aqueous solution) to give compound 51.
MS(ESI)m/z:542.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ10.46(s,1H),8.93(s,1H),8.12(t,J＝12.1Hz,1H),7.78(d,J＝8.7Hz,2H),7.74(d,J＝8.0Hz,1H),7.64(d,J＝7.6Hz,1H),7.40(d,J＝8.7Hz,2H),5.68(dd,J＝17.0,10.3Hz,1H),5.34(s,1H),5.00(dd,J＝10.3,1.1Hz,1H),4.83(dd,J＝17.1,1.3Hz,1H),4.69(d,J＝5.8Hz,2H),3.50(s,2H),2.55(s,4H),2.49–2.45(m,4H),1.46(s,6H).
Preparation example 4: preparation of 2-allyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((4- ((1-isopropylazetidin-3-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 26)
Crude compound 26 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to afford compound 26.
MS(ESI)m/z:524.4[M+H] +
1 HNMR(400MHz,CD 3 OD):δ8.88(s,1H),8.04(t,J＝7.84Hz,1H),7.79(d,J＝7.96Hz,1H),7.71–7.68(m,3H),7.37–7.35(m,2H),5.79–5.69(m,1H),5.06(dd,J＝10.28,1.36Hz,1H),4.92(dd,J＝16.88,1.36Hz,1H),4.84–4.82(m,2H),3.71–3.67(m,2H),3.44–3.41(m,1H),3.24–3.20(m,2H),2.52–2.45(m,1H),1.60(s,6H),0.99(d,J＝6.24Hz,6H).
Preparation example 5: preparation of 2-allyl-1- (6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- ((4- ((1-methylazetidin-3-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 27)
Crude compound 27 was synthesized in a similar manner to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate solution) to give compound 27.
MS(ESI)m/z:522.4[M+H] +
1 HNMR(400MHz,CD 3 OD):δ8.88(s,1H),8.03(t,J＝7.92Hz,1H),7.79(d,J＝7.92Hz,1H),7.72–7.69(m,3H),7.45–7.32(m,2H),5.82–5.69(m,1H),5.07(m,1H),4.94(m,1H),4.85–4.81(m,2H),3.78–3.69(m,2H),3.46–3.43(m,1H),3.28–3.23(m,2H),2.10–1.94(m,1H),1.59(s,6H),1.42–1.29(m,1H),0.56–0.32(m,3H).
Preparation example 6: preparation of 2-allyl-6- ((4- (3- (dimethylamino) propyl-1-yn-1-yl) phenyl) amino) -1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 28)
Crude compound 28 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to give compound 28.
MS(ESI)m/z:484.3[M+H] +
1 HNMR(400MHz,CD 3 CN):δ8.82(s,1H),8.50(s,1H),8.03(t,J＝7.96Hz,1H),7.76-7.71(m,3H),7.59(d,J＝7.72Hz,1H),7.45–7.42(m,2H),5.79–5.69(m,1H),5.03(dd,J＝10.28,1.48Hz,1H),4.92(dd,J＝17.12,1.52Hz,1H),4.74–4.72(m,2H),3.76(s,1H),3.45(s,2H),2.32(s,6H),1.54(s,6H).
Preparation example 7: preparation of 2-allyl-6- ((4- (3-hydroxy-3-methylbut-1-yn-1-yl) phenyl) amino) -1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 29)
Crude compound 29 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to afford compound 29.
MS(ESI)m/z:485.2[M+H] +
1 HNMR(400MHz,DMSO-d 6 ):δ10.37(s,1H),8.89(s,1H),8.11(t,J＝7.72Hz,1H),7.79 -7.74(m,3H),7.64(d,J＝7.68Hz,1H),7.36(d,J＝8.68Hz,2H),5.72–5.63(m,1H),5.44(s,1H),5.35(s,1H),5.00(dd,J＝10.28,1.36Hz,1H),4.83(dd,J＝16.88,1.36Hz,1H),4.69(d,J＝5.92Hz,2H),1.47(s,12H).
Preparation example 8: preparation of 2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- ((4- (3-morpholin-1-yl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 30)
Crude compound 30 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% ammonium bicarbonate aqueous solution) to give compound 30.
MS(ESI)m/z:526.1[M+H] +
1 HNMR(400MHz,CD 3 OD):δ8.88(s,1H),8.93–8.84(m,1H),8.10–7.99(m,1H),7.79 -7.67(m,4H),7.38(dd,J＝8.8,2.4Hz,2H)5.78–5.66(m,1H),5.05(d,J＝10.28,1H),4.95–4.93(m,1H),4.83(d,J＝5.6Hz,2H),3.78–3.72(m,4H),3.54(d,J＝2.52Hz,2H),2.73–2.64(m,4H),1.59(s,6H).
Preparation example 9: preparation of 2-allyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((4- (3- (pyrrolidin-1-yl) propyl-1-yn-1-yl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 32)
Crude compound 32 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% ammonium bicarbonate aqueous solution) to give compound 32.
MS(ESI)m/z:510.1[M+H] +
1 HNMR(400MHz,DMSO-d 6 ):δ10.44(s,1H),8.92(s,1H),8.10(t,J＝7.96Hz,1H),7.91–7.38(m,3H),7.64(d,J＝7.6Hz,1H),7.40(d,J＝8.80Hz,2H),5.68(m,1H),5.28-5.40(m,1H),5.00(d,J＝10.42Hz,1H),4.83(d,J＝17.12Hz,1H),4.70(d,J＝5.60Hz,2H),3.58(s,2H),2.62-2.54(m,4H),1.75-1.71(m,4H),1.47(s,6H).
Preparation example 10: preparation of 2-allyl-1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -6- ((4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 23)
Crude compound 23 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% ammonium bicarbonate aqueous solution) to give compound 23.
MS(ESI)m/z:527.3[M+H] +
1 H NMR(400MHz,CD 3 OD)δ8.85(s,1H),8.53(s,2H),8.00(d,J＝7.9Hz,1H),7.76(d,J＝7.92Hz,1H),7.67(d,J＝8.52Hz,3H),7.33(d,J＝8.70Hz,2H),5.72(ddt,J＝16.42,10.28,6.12Hz,1H),5.05(d,J＝1.2Hz,1H),4.90(dd,J＝17.12,1.28Hz,1H),4.81(d,J＝6.10Hz,2H),3.30(s,2H),3.14–2.82(m,3H),2.19–2.10(m,2H),1.99–1.89(m,2H),1.57(s,6H).
Preparation example 11 preparation of 2-allyl-1- (6- (1-hydroxycyclopropyl) pyridin-2-yl) -6- ((4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 42)
Crude compound 42 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate solution) to give compound 42.
MS(ESI)m/z:525.2[M+H] +
1 H NMR(400MHz,MeOD)δ8.88(s,1H),8.23–8.11(m,2H),8.01(s,1H),7.65(d,J＝8.72Hz,2H),7.33(d,J＝8.72Hz,2H),5.81–5.65(m,1H),5.09–4.89(m,2H),4.87(s,1H),3.23(d,J＝7.24Hz,2H),2.82(s,2H),2.65(s,1H),2.35(s,2H),2.02–1.92(m,2H),1.78(dd,J＝9.12,4.2Hz,2H),1.19(t,J＝7.26Hz,3H).
Preparation example 12 preparation of 2-allyl-6- ((4- (3- ((3S, 5R) -3, 5-dimethyl-4- (methyl-d 3) piperazin-1-yl) prop-1-yn-1-yl) phenyl) amino) -1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 31).
Crude compound 31 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to give compound 31.
MS(ESI)m/z:570.3[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ10.45(s,1H),8.92(s,1H),8.23(s,1H),8.11(t,J＝8.0Hz,1H),7.76(dd,J＝16.0,8.4Hz,3H),7.64(d,J＝7.8Hz,1H),7.41(d,J＝8.6Hz,2H),5.68(dq,J＝10.4,6.0Hz,1H),5.00(d,J＝10.3Hz,1H),4.83(d,J＝17.2Hz,1H),4.69(d,J＝5.6Hz,2H),3.45(s,2H),2.70(d,J＝10.6Hz,2H),2.20(s,2H),2.03(t,J＝8.4Hz,2H),1.46(s,6H),1.00(d,J＝6.0Hz,6H).
Preparation example 13: preparation of 2-allyl-1- (6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- ((3-methyl-4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 36)
The first step: preparation of 2-allyl-1- (6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- (methylsulfonyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 13-1)
Compounds 1-3 (837 mg,2.34 mmol) were dissolved in tetrahydrofuran/water (10 mL/10 mL) at room temperature and potassium peroxomonosulphonate (4.33 g,7.03 mmol) was added and reacted for 2 hours. The reaction solution was diluted with water and extracted 3 times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by column chromatography to give compound 13-1 (601 mg, 66%).
Second step preparation of 2-allyl-1- (6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- ((3-methyl-4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound 36)
Compound A16 (50 mg,0.19 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), cooled to 0deg.C, naH (25 mg,0.63mmol, 60%) was added under nitrogen, and stirred for 25min. Then, a tetrahydrofuran solution (1 mL) of Compound 13-1 (86 mg,0.22 mmol) was slowly added dropwise thereto, and after the completion of the addition, the mixture was transferred to room temperature and stirred for 2 hours. The reaction solution was dried by spin-drying, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate solution) to give compound 36 (9.8 mg, 6%).
MS(ESI)m/z:541.3[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ10.37(s,1H),8.91(s,1H),8.07(t,J＝7.9Hz,1H),7.82–7.74(m,2H),7.64(d,J＝7.4Hz,1H),7.49(d,J＝7.8Hz,1H),7.29(d,J＝8.4Hz,1H),5.74–5.60(m,1H),5.34(s,1H),4.99(d,J＝11.4Hz,1H),4.82(d,J＝17.1Hz,1H),4.69(d,J＝5.9Hz,2H),2.64(d,J＝21.7Hz,3H),2.36(s,3H),2.16(s,2H),1.85(s,2H),1.64(dd,J＝8.6,4.1Hz,2H),1.46(s,6H).
Preparation example 14: preparation of 2-allyl-6- ((3- (hydroxymethyl) -4- ((1-methylpiperidin-4-yl) ethynyl) phenyl) amino) -1- (6- (2-hydroxypropyl-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 52)
Crude compound 52 was synthesized by a similar method to that of preparation 13, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to afford compound 52.
MS(ESI)m/z:554.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ10.44(s,1H),8.91(s,1H),8.20(s,1H),8.06(t,J＝7.9Hz,2H),7.84(d,J＝8.0Hz,1H),7.59(dd,J＝13.7,8.5Hz,2H),7.29(d,J＝8.4Hz,1H),5.67(ddt,J＝16.5,10.2,5.9Hz,1H),5.00(dt,J＝10.2,1.4Hz,1H),4.82(dq,J＝17.0,1.5Hz,1H),4.71(d,J＝6.0Hz,2H),4.65(s,2H),2.72–2.61(m,3H),2.22(s,5H),1.88(ddt,J＝13.7,6.9,3.5Hz,2H),1.65(dtd,J＝12.3,8.6,3.5Hz,2H),1.46(s,6H).
Preparation example 15: preparation of 2-allyl-6- ((3- (difluoromethyl) -4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 34)
Crude compound 34 was synthesized by a similar method to that of preparation 13, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to afford compound 34.
MS(ESI)m/z:577.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ10.63(s,1H),8.95(s,1H),8.24(s,1H),8.02(t,J＝7.8Hz,2H),7.79(d,J＝8.0Hz,1H),7.73(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.48(d,J＝8.0Hz,1H),7.15(t,J＝52Hz,1H),5.72–5.63(m,1H),5.34(s,1H),5.00(d,J＝12.4Hz,1H),4.82(d,J＝15.8Hz,2H),4.70(d,J＝3.6Hz,1H),2.67–2.58(m,3H),2.16–2.10(m,2H),1.70–1.67(m,2H),1.65–1.61(m,2H),1.46(s,6H).
Preparation example 16: preparation of 2-allyl-6- ((3- (difluoromethoxy) -4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 35)
Crude compound 35 was synthesized by a similar method to that of preparation 1, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% ammonium bicarbonate aqueous solution) to give compound 35.
MS(ESI)m/z:593.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),8.95(s,1H),8.03(t,J＝7.8Hz,1H),7.81(s,1H),7.72(d,J＝7.8Hz,1H),7.64(dd,J＝11.6,7.8Hz,2H),7.43(d,J＝8.6Hz,1H),7.12(t,J＝73.8Hz,1H),5.67(ddd,J＝16.2,11.0,5.1Hz,1H),5.34(s,1H),5.04–4.96(m,1H),4.82(dd,J＝17.2,1.4Hz,1H),4.69(d,J＝5.8Hz,2H),2.68(dd,J＝7.2,5.2Hz,3H),2.30(d,J＝19.8Hz,2H),1.86(s,2H),1.72–1.58(m,2H),1.46(s,6H).
Preparation example 17: preparation of 2-allyl-1- (2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl) -6- ((4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 53)
The first step: preparation of 2-allyl-1- (2- (2-hydroxy-prop-2-yl) pyrimidin-4-yl) -6- (methylsulfanyl) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 17-2)
Compound 17-2 was synthesized by a similar method as the first step of preparation 1.
Preparation of 2-allyl-1- (2- (2-hydroxy-propan-2-yl) pyrimidin-4-yl) -6- ((4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 53)
Crude compound 53 was synthesized by a similar method to that of preparation 13, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to give compound 53.
MS(ESI)m/z:528.3[M+H] +
1 H NMR(400MHz,CD 3 OD)δ8.89(s,1H),8.81(d,J＝5.7Hz,1H),8.48(s,1H),8.11(s,1H),7.69(d,J＝8.5Hz,2H),7.42(d,J＝8.5Hz,2H),5.79–5.64(m,1H),5.04(ddd,J＝26.2,17.6,3.8Hz,4H),3.34(s,2H),3.11(d,J＝17.0Hz,3H),2.16(s,2H),1.98(s,2H).
Preparation example 18: preparation of 2-allyl-1- (5-fluoro-6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- ((4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 54)
/>
Crude compound 54 was synthesized by a similar procedure as in preparation 17, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to afford compound 54.
MS(ESI)m/z:545.3[M+H] +
1 H NMR(400MHz,CD 3 OD)δ8.86(s,1H),7.83(dd,J＝10.2,6.9Hz,2H),7.66(d,J＝8.7Hz,2H),7.36(d,J＝8.7Hz,2H),5.73(ddt,J＝16.4,10.3,6.1Hz,1H),5.00(ddd,J＝18.4,13.7,1.2Hz,2H),4.76(d,J＝6.1Hz,2H),3.26(s,2H),2.94(s,3H),2.12(s,2H),1.93(s,2H),1.63(d,J＝0.9Hz,6H).
Preparation example 19: preparation of 2-allyl-1- (6- (2-hydroxy-prop-2-yl) pyridin-2-yl) -6- ((2-methoxy-4- ((1- (methyl-d 3) piperidin-4-yl) ethynyl) phenyl) amino) -1, 2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (compound 55)
Crude compound 55 was synthesized by a similar method to that of preparation 13, and the crude product was purified by HPLC (mobile phase A: acetonitrile, mobile phase B:0.05% aqueous ammonium bicarbonate) to afford compound 55.
MS(ESI)m/z:557.3[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ10.42(s,1H),8.87(s,1H),8.08–8.06(m,1H),7.82–7.74(m,2H),7.60(d,J＝7.4Hz,1H),7.46(d,J＝7.8Hz,1H),7.26(d,J＝8.4Hz,1H),5.72–5.56(m,1H),5.31(s,1H),4.94(d,J＝11.4Hz,1H),4.80(d,J＝17.2Hz,1H),4.64(d,J＝5.8Hz,2H),3.86(s,3H),2.66–2.62(m,3H),2.14(s,2H),1.84(s,2H),1.64(dd,J＝8.6,4.2Hz,2H),1.46(s,6H).
Example 2: wee1 enzyme activity inhibition experiment
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 reaction 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 40minh, 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
Compounds of formula (I) IC 50 (nM)
Compound 1 2.19
Compound 25 2.56
Compound 26 3.48
Compound 27 7.79
Compounds of formula (I)28 1.25
Compound 29 3.13
Compound 30 2.80
Compound 32 1.92
Compound 31 2.12
Compound 34 1.28
Compound 35 1.21
Compound 36 0.98
Compound 52 0.95
Compound 53 5.60
Compound 54 1.21
Compound 55 1.32
The results show that the compounds of the application have better Wee1 enzyme inhibition activity.
Example 3: cell proliferation inhibition assay
The effect of each compound on cell proliferation was examined in cells such as A427, NCI-H1299, CAPAN-1, NCI-H82, etc. Specifically, after incubation of the gradient diluted compounds for 72h or 144h,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
The results show that the compounds have better cell proliferation inhibition activity.
The above embodiments are not intended to limit the aspects of the present application in any way. Various modifications of the invention, 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 application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated by reference in its entirety.

Claims (20)

1. 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 and 5-10 membered heteroaryl;
the B ring is selected from phenyl, 5-10 membered heteroaryl and 5-6 membered heterocyclyl;
Q 1 selected from N and CR a ，R a Selected from H, halogen, -OH, -NH 2 、-NHC 1-6 Alkyl, -C 1-6 Alkyl-halo C 1-6 An alkyl group;
L 1 selected from single bonds, -C 2-4 Alkenylene-, -C 2-4 Alkynylene-, -C (O) -C 2-4 Alkynylene group-, -C 1-6 alkylene-C 2-4 Alkynylene-, -C (O) NH-, -NHC (O) NH-, -S (O) 2 -、-S(O) 2 NH-、-NHS(O) 2 -、-C 1-6 alkylene-C (O) -, -C 1-6 alkylene-C (O) N (R) b ) -; the C is 1-6 Alkylene, C 2-4 Alkenylene and C 2-4 Alkynylene radicals are each optionally substituted with one or more radicals selected from halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halo C 1-6 Alkyl, oxo, hydroxy, -CN and-NH 2 Is substituted by a substituent of (a);
L 2 selected from single bond, -NH-, -S-, -C (O) NH-, and-NHC (O) -;
L 3 selected from single bond, -CH 2 -, -C (O) NH-and-C (O) -;
and when L 1 In the case of a single bond, one of the following two conditions must be satisfied:
i)L 3 is a single bond, and L 2 Is not NH; ii) L 3 Is not a single bond;
R 1 selected from-C 1-6 Alkyl, -C 3-6 Cycloalkyl and 4-12 membered heterocyclyl; the-C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-12 membered heterocyclyl are each optionally substituted with one OR more substituents selected from halogen, oxo, -OR b 、-NR b R c 、-C 1-6 Alkyl, -halo C 1-6 Alkyl, -halo C 1-6 Alkoxy, -C 1-6 alkylene-OR b 、-C 1-6 alkylene-NR b R c 、-C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -SR b 、-CN、-C(O)R b 、-C(O)OR b 、-C(O)NR b R c 、-NR b C(O)R c 、-NR b C(O)OR c 、-S(O) 2 R b and-NR b S(O) 2 R c Is substituted by a substituent of (a);
R b 、R c each independently selected from H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and 4-12 membered heterocycloalkyl; the C is 1-6 Alkyl, C 3-6 Cycloalkyl and 4-12 membered heterocyclyl are each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN and-NH 2 Is substituted by a substituent of (a);
R 2 each independently selected from H, halogen, hydroxy, -CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、-C 2-4 Alkenyl, -C 2-4 Alkynyl, -C 3-6 Cycloalkyl and 4-6 membered heterocyclyl; the C is 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 3-6 Cycloalkyl and 4-6 membered heterocyclyl are each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN, -NH 2 and-C 1-6 Substituent substitution of alkyl;
or any two adjacent R 2 Together with the atoms to which they are attached form a 5-7 membered heterocyclic group, a 5-6 membered heteroaromatic ring and C 5-7 Cycloalkyl; the 5-7 membered heterocyclic group, the 5-6 membered heteroaromatic ring and C 5-7 Cycloalkyl groups are each optionally substituted with one or more groups selected from halogen, -hydroxy, -CN, -NH 2 and-C 1-6 Substituent substitution of alkyl;
R 3 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 and 5-6 membered heteroaryl; the C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents selected from halogen, oxo, hydroxy, -CN, -NH 2 、-C 1-6 Substituent substitution of alkyl;
R 4 each independently selected from halogen, cyano, nitro, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 5-6 membered heteroaryl, -OR d 、-SR d 、-NR d R e 、-NR d C(O)R e 、-NR d S(O) 2 R e 、-C(O)R d 、-C(O)NR d R e 、-S(O) 2 NR d R e 、-S(O) 2 NHR d And-n=s (O) R d R e The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted with one or more substituents selected from halogen, oxo, hydroxy, -CN, -NH 2 、-C 1-6 Alkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-OC 1-6 Alkyl, -C 1-6 alkylene-CN, -halo C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl and-C 1-6 alkylene-S (O) 2 C 1-6 Substituent substitution of alkyl;
R d 、R e each independently selected from H, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and 4-12 membered heterocycloalkyl; the C is 1-6 Alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocycloalkyl, each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN, -NH 2 Is substituted by a substituent of (a);
alternatively, any two adjacent R 4 Together with the atoms to which they are attached form C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl, 5-6 membered heteroaryl; the C is 5-8 Cycloalkyl, 5-8 membered heterocyclyl, 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, -NH 2 、-C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-CN, -halo C 1-6 Alkyl substituent substitution;
m, n are each independently selected from 0, 1, 2, 3 and 4.
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, pyridyl, thienyl, and pyrazolyl; preferably, the a ring is selected from phenyl and thienyl.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein the B ring is selected from phenyl, pyridyl, pyrimidinyl, thienyl and thiazolyl; preferably, the B ring is selected from pyridinyl and phenyl.
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 Q 1 Selected from N, CH, CF, C-NH 2 、C-CH 3 And C-OH; preferably Q 1 CH.
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 L 1 Selected from single bonds, -C 2-4 Alkenylene-, -C 2-4 Alkynylene-, -C (O) -C 2-4 Alkynylene group-, -C 1-6 alkylene-C 2-4 Alkynylene-, -C (O) NH-, -NHC (O) -; preferably L 1 Selected from-ethynylene-, -C (O) -ethynyl-, -CH 2 -ethynyl-, -C (O) NH-and-NHC (O) -; preferably L 1 Selected from-ethynylene-, -CH 2 -ethynyl-.
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 L 2 Selected from single bond, -NH-, -S-, -C (O) NH-, and-NHC (O) -; preferably, the method comprises the steps of,L 2 selected from the group consisting of-NH-, -C (O) NH-and-NHC (O) -.
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 3 Selected from single bond, -CH 2 -and-C (O) -; preferably L 3 Selected from single bonds and-CH 2 -。
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 1 Selected from 5-6 membered heterocyclyl, said 5-6 membered heterocyclyl optionally being substituted with one or more substituents selected from halogen, oxo, -OH, -OCH 3 、-NH 2 、-N(C 1-3 Alkyl group 2 、-C 1-3 Alkyl, -C 3-6 Cycloalkyl, -halo C 1-3 Alkyl, -halo C 1-3 Alkoxy, -CH 2 OH、-C 1-3 alkylene-N (C) 1-3 Alkyl group 2 、-CN、-C(O)OC 1-3 Alkyl and-S (O) 2 C 1-3 Substituent substitution of alkyl;
preferably, R 1 Selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, epoxyhexenyl, and piperazinyl, each independently optionally substituted with one or more groups selected from F, cl, -OH, -OCH 3 、-NH 2 、-N(CH 3 ) 2 -halomethyl, -halomethoxy, -CH 2 OH、-C 1-3 alkylene-N (CH) 3 ) 2 、-CN、-C(O)OCH 3 and-S (O) 2 CH 3 Or, the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, epoxyhexenyl and piperazinyl groups are each independently optionally substituted with one or more substituents selected from-CH 3 、-CD 3 、-CH(CH 3 ) 2 Or substituents of cyclopropylSubstitution;
preferably, R 1 Selected from the group consisting ofAlternatively, R 1 Selected from the group consisting of
9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 1 Selected from-C 1-3 Alkyl, said-C 1-3 Alkyl is optionally substituted with one or more groups selected from F, cl, -OH, -OCH 3 、-NH 2 、-N(CH 3 ) 2 、-CH 3 -halomethyl, -halomethoxy, -CH 2 OH、-C 1-3 alkylene-N (CH) 3 ) 2 、-CN、-C(O)OCH 3 、-CD 3 、-CH(CH 3 ) 2 Cyclopropyl and-S (O) 2 CH 3 Is substituted by a substituent of (a);
preferably, R 1 Selected from the group consisting of
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 1 -L 1 -is selected from
Preferably, R 1 -L 1 -is selected from
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 2 Each independently selected from H, F, cl, hydroxy, -C 1-3 Alkyl, -OC 1-3 Alkyl, said C 1-3 Alkyl optionally substituted with one or more substituents selected from F, cl, hydroxy and-CN;
Or any two adjacent R 2 Together with the atoms to which they are attached, form a five membered heteroaryl group and a five membered heterocyclyl group; the five membered heterocyclyl and five membered heteroaryl are each optionally substituted with one or more groups selected from F, cl, -OH, -CN, -NH 2 、-CH 3 Is substituted by a substituent of (a);
preferably, R 2 Selected from H, F, cl, -CH 3 、-OCH 3 and-CH 2 OH; or any two adjacent R 2 Together with the atoms to which they are attached form pyrazolyl and pyrrolyl; alternatively, R 2 Selected from-CHF 2 、-OCHF 2 、-CF 3 and-CN;
preferably, R 2 Is H or R 2 Selected from-CHF 2 、-OCHF 2 -CN and-CH 2 OH。
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 3 Selected from-CH 3 、-CH 2 CH 3 Cyclopropyl, isopropyl, allyl,Propargyl, -CH 2 -cyclopropyl and-CH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, R 3 Selected from allyl, or R 3 Selected from isopropyl groups.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein R 4 Selected from-C 1-6 Alkyl, -C 3-6 Cycloalkyl, -O-C 1-6 Alkyl, -S-C 1-6 Alkyl and-n=s (O) (CH 3 ) 2 The C is 1-6 Alkyl and-C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from halogen, oxo, hydroxy, -CN, -NH 2 、-C 1-6 Alkyl, -C 1-3 alkylene-OH, -C 1-3 alkylene-OC 1-3 Alkyl, -C 1-3 alkylene-CN, -halo C 1-6 Alkyl, -S (O) 2 C 1-6 Alkyl and-C 1-3 alkylene-S (O) 2 C 1-3 Substituent substitution of alkyl;
preferably, R 4 Selected from-C 1-3 Alkyl and-C 3-6 Cycloalkyl group, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from F, cl, oxo, hydroxy, -CN, -NH 2 、-Me、-CH 2 OH、-CH 2 OMe、-CH 2 -CN、-CF 3 、-CH 2 CF 3 、-S(O) 2 CH 3 、-CH 2 S(O) 2 CH 3 Is substituted by a substituent of (a);
more preferably, R 4 Selected from the group consisting ofAlternatively, R 4 Selected from->
14. According to any one of claims 1-12A compound of claim, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, wherein any two adjacent R 4 To which atoms are attached to form C 5-6 Cycloalkyl and 5-6 membered heterocyclyl; the C is 5-6 Cycloalkyl and 5-6 membered heterocyclyl are each optionally substituted with one or more groups selected from F, cl, hydroxy, -CN, -NH 2 、-CH 3 、-CH 2 CH 3 、-CH 2 OH、-CH 2 CN、-CHF 2 、-CH 2 F and-CF 3 Is substituted by a substituent of (a);
preferably, any two adjacent R 4 The atoms to which they are attached form cyclopentane; the cyclopentane is optionally substituted with one or more groups selected from hydroxy, -CH 3 、-CH 2 CH 3 and-CN.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable form thereof, having a structure represented by formula (IIa):
wherein,
L 1 as defined in claim 1 or 5;
Z 1 、Z 2 、Z 3 each independently selected from N and CH;
ring a is as defined in claim 1 or 2;
R 1 as defined in claim 1 or 8;
R 2 as defined in claim 1 or 11;
R 3 as defined in claim 1 or 12;
R 4 as defined in claim 1, 13 or 14;
m, n are each independently selected from 0, 1, 2, 3 and 4;
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable form thereof, having a compound of formula (IIa-1):
wherein,
L 1 as defined in claim 1 or 5;
R 1 as defined in claim 1 or 8;
R 2 as defined in claim 1 or 11;
R 3 as defined in claim 1 or 12;
R 4 as defined in claim 1, 13 or 14;
n is selected from 0, 1, 2 and 3.
17. The compound according to any one of claims 1-15, or a pharmaceutically acceptable form thereof, having a compound of formula (IIa-1A):
wherein,
L 1 selected from-C 2-4 Alkenylene-, -C 2-4 Alkynylene-, -C (O) -C 2-4 Alkynylene-, -C (O) NH-, -NHC (O) NH-, -S (O) 2 -、-S(O) 2 NH-and-NHS (O) 2 -; the C is 2-4 Alkenylene, C 2-4 Alkynylene optionally being substituted with one or more groups selected from halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halo C 1-6 Alkyl, oxo, hydroxy, -CN, -NH 2 Is substituted by a substituent of (a); preferably L 1 Selected from ethynylene, -CH 2 -ethynylene-, -C (O) NH-and-NHC (O) -;
R 1 selected from-C 1-3 Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl; the-C 1-3 Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl are each independently optionally substituted with one or more groups selected from F, cl, -OH, -OCH 3 、-NH 2 、-N(CH 3 ) 2 、-CH 3 -halomethyl, -halomethoxy, -CH 2 OH、-C 1-3 alkylene-N (CH) 3 ) 2 、-CN、-C(O)OCH 3 、-CD 3 、-CH(CH 3 ) 2 Cyclopropyl, isopropyl and-S (O) 2 CH 3 Is substituted by a substituent of (a); preferably, the-C 1-3 Alkyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl are each independently optionally substituted with one or more groups selected from-N (CH 3 ) 2 、-C 1-3 alkylene-N (CH) 3 ) 2 、-OH、-CH 3 、-CD 3 Cyclopropyl, isopropyl;
R 2 each independently selected from H, F, cl, hydroxy, -CN, -C 1-3 Alkyl, -OC 1-3 Alkyl, said C 1-3 Alkyl optionally substituted with one or more substituents selected from F, cl, hydroxy and-CN;
R 3 selected from allyl;
R 4 selected from-C 1-3 Alkyl and-C 3-6 Cycloalkyl group, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups are each optionally substituted with one or more groups selected from F, cl, oxo, hydroxy, -CN, -NH 2 、-Me、-CH 2 OH、-CH 2 OMe、-CH 2 -CN、-CF 3 、-CH 2 CF 3 、-S(O) 2 CH 3 、-CH 2 S(O) 2 CH 3 Is substituted by a substituent of (a); preferably, the C 1-3 Alkyl and C 3-6 Cycloalkyl groups each optionally being one or moreSelected from hydroxyl groups;
n is selected from 0, 1, 2 and 3;
m is selected from 0, 1, 2 and 3;
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, nitrogen oxides, isotopic labels, metabolites or prodrugs.
18. A compound of the formula or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof:
19. a pharmaceutical composition comprising a compound of any one of claims 1-18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotopic label, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
20. Use of a compound according to any one of claims 1-18 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotopic label, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the prevention and/or treatment of a Wee1 kinase-associated disease; preferably, the Wee1 kinase-associated disease is a cancer-like disorder.
CN202310679246.5A 2022-07-05 2023-06-08 Pyrazolopyrimidinone compound, preparation method and application thereof Pending CN117343062A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2022107938510 2022-07-05
CN202210793851 2022-07-05
CN202211669529 2022-12-23
CN2022116695293 2022-12-23

Publications (1)

Publication Number Publication Date
CN117343062A true CN117343062A (en) 2024-01-05

Family

ID=89369852

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310679246.5A Pending CN117343062A (en) 2022-07-05 2023-06-08 Pyrazolopyrimidinone compound, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN117343062A (en)

Similar Documents

Publication Publication Date Title
CN114127053B (en) Substituted pyrazine compound, preparation method and application thereof
CN111153899B (en) Substituted pyridine compound, preparation method and application thereof
EP2875001B1 (en) Nitrogenous heterocyclic derivatives and their application in drugs
EP2253625B1 (en) Pyridazinones, the preparation and the use thereof
DK2495243T3 (en) NEW 5-FLUOROURACIL DERIVATE
KR20200024777A (en) Use of Rheto-associated protein kinase inhibitors, pharmaceutical compositions containing Rheto-associated protein kinase inhibitors, methods of manufacture and uses of pharmaceutical compositions
CN111484491B (en) Substituted pyrido-cyclic compounds, process for their preparation and their use
EP3997070A1 (en) Heterocyclic compounds as bet inhibitors
WO2022161222A1 (en) Heterocyclic shp2 inhibitor, preparation method therefor, and use thereof
FR2943669A1 (en) NICOTINAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
AU2019372121A1 (en) Heterocyclic compounds as BET inhibitors
CN109180681B (en) DNA toxic dimer compound
AU2022265301A1 (en) Compounds and their uses as cd38 inhibitors
KR20200094730A (en) Aromatic compounds, pharmaceutical compositions and uses thereof
CN117343062A (en) Pyrazolopyrimidinone compound, preparation method and application thereof
EP2496704A1 (en) Therapeutic compounds
CN117917415A (en) Substituted heteropolycyclic compound, preparation method and application thereof
TW202404977A (en) Pyrimido-five-membered heterocyclic compound, and preparation method therefor and use thereof
CN112480100B (en) Pyrrolidone derivatives
CN107474024B (en) Glutaminase inhibitor and composition and application thereof
US20240208942A1 (en) Metap-2 inhibitors, pharmaceutical compositions and therapeutic methods thereof
WO2023057371A1 (en) 1,2,4-oxadiazol-5-one derivatives for the treatment of cancer
WO2024113194A1 (en) Shp2 inhibitors, compositions and methods thereof
WO2023061263A1 (en) Shp2 inhibitor, pharmaceutical composition comprising same, and use thereof
CN114907189A (en) Polyphenol-substituted 3-aryl-2-aryl methacrylic compound and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication