CN113429440A - Prodrug of spiro compound, preparation method and application thereof in medicine - Google Patents

Prodrug of spiro compound, preparation method and application thereof in medicine Download PDF

Info

Publication number
CN113429440A
CN113429440A CN202110305777.9A CN202110305777A CN113429440A CN 113429440 A CN113429440 A CN 113429440A CN 202110305777 A CN202110305777 A CN 202110305777A CN 113429440 A CN113429440 A CN 113429440A
Authority
CN
China
Prior art keywords
group
alkyl
compound
cancer
cycloalkyl
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.)
Granted
Application number
CN202110305777.9A
Other languages
Chinese (zh)
Other versions
CN113429440B (en
Inventor
赵鹏
庄凌航
武和平
贺峰
陶维康
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.)
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical 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 Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Publication of CN113429440A publication Critical patent/CN113429440A/en
Application granted granted Critical
Publication of CN113429440B publication Critical patent/CN113429440B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Landscapes

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

Abstract

The present disclosure relates to prodrugs of spiro compounds, methods of preparation thereof, and pharmaceutical uses thereof. Specifically, the disclosure relates to a prodrug of a spiro compound represented by general formula (I), a preparation method thereof, a prodrug-containing composition, and use thereof as a therapeutic agent, in particular use thereof as a RAF inhibitor and use thereof for preparing a medicament for treating or preventing various diseases (including cancer) associated with over-expression RAF activity.

Description

Prodrug of spiro compound, preparation method and application thereof in medicine
Technical Field
The present disclosure relates to prodrugs of spiro compounds having biological activity, pharmaceutical compositions comprising the prodrugs, intermediates, and synthetic methods for preparing the prodrugs, as well as uses of the prodrugs and compositions thereof in treating or preventing various diseases, particularly diseases associated with RAF overexpression activities, such as cancer.
Background
The receptor tyrosine kinase RAF, also known as rapid accelerated fibrosarcoma, is a family of serine/threonine specific protein kinases. There are three known mammalian subtypes of RAF: A. b and C-Raf (also called Raf-1). RAF kinases participate in the RAS-RAF-MEK-ERK signal transduction reaction in Mitotically Activated Protein Kinase (MAPK) cascades (Moelling K, et al, Nature.1984.312(5994): 558-61.). The Ras-Raf-MAPK channel controls various cellular physiological processes. Extensive studies have shown that RAF family kinases play a key role in regulating Cell survival, proliferation, differentiation, apoptosis and many other physiological processes through MAPK cascades (Lavoie H et al Nat Rev Mol Cell biol.2015 (5): 281-98.). Abnormalities of the Ras-Raf-MAPK channel are implicated in a variety of biological processes associated with human disease. Excessive activity of the Ras-Raf-MAPK channel component is a common mechanism of proliferative diseases (e.g., cancer) (Leicht DT, et al. Biochim Biophys acta.2007,1773(8): 1196-212.).
In view of the close correlation between RAF activity and cancer, RAF has been used as a target for drug discovery in cancer therapy and the like. Many ATP-competitive RAF inhibitors (PLX4032/Vemurafenib, Dabrafenib, Sorafenib, etc.) have been approved for the treatment of metastatic melanoma patients and have been shown to have a positive clinical efficacy in melanoma with a relapse allele of BRAFV600E (Holderfield, m., et al. nat Rev cancer.2014,14(7): 455-67). Unfortunately, resistance to these drugs is always partially acquired by mechanisms that stimulate RAF dimerization. Therefore, if a next generation RAF inhibitor could be developed to be effective against tumors carrying the BRAFV600E mutation as well as wild-type BRAF or RAS mutations, there would be a tremendous clinical outcome. See, e.g., Allgeier, m.c. et al, WO2013/134243 filed 3, 5.2013; US2014/0275003 filed on 11/3/2014 by Batsanti, p.a. et al. In some cases, it may be desirable to improve its solubility or other properties, such as its bioavailability, by a particular route of administration.
A prodrug is a drug or compound that is metabolized to a pharmacologically active drug after administration. While prodrugs can be metabolized to the active form (prodrug) in vivo, prodrugs are generally pharmacologically inactive. Prodrugs employ various physical and chemical modifications to improve the function of the active drug. Instead of directly administering the prodrug, the corresponding prodrug can be used to improve ADMET (absorption, distribution, metabolism, excretion and toxicity) properties. Prodrugs are often designed to enhance the bioavailability of a drug when the drug itself is poorly absorbed in the body. Prodrugs can be used to improve drug selectivity or to avoid off-target effects. To reduce adverse or accidental reactions of the drug. In certain treatments, such as chemotherapy, which may have serious unexpected and undesirable side effects, the use of prodrug strategies to improve patient compliance is of great interest.
There are some published FDA-approved phosphate prodrugs on the market, such as fospinytin (i) and fostamatinib (ii).
Figure BDA0002987656820000021
In WO 2017/070135, published on 27.4.2017, Purandare, a.v., a prodrug of imidazotriazine (iii) is disclosed as CK2 protein kinase inhibitor for the treatment of cancer.
In US 2007/0213300 published on 13.9.2007, Liu, c. discloses prodrugs of pyrrolotriazines (iv) to treat diseases associated with p38 kinase.
In WO 2014/198647, published 12/18/2014, Schulze, v, discloses prodrugs (v) of triazolopyridines as Mps-1 kinase inhibitors and their use in the treatment of proliferative diseases.
Figure BDA0002987656820000022
A number of prodrug strategies exist that can provide different conditions to modulate the following properties: the resulting release of the prodrug, the physical, pharmaceutical or pharmacokinetic properties of the prodrug, and the site of attachment of functional groups that can be used for modification of the prodrug. However, the prior art does not teach or suggest specific prodrugs of the present disclosure. Finding and identifying prodrugs with desirable properties is often difficult and tortuous.
Disclosure of Invention
In one aspect of the present disclosure, there is provided a compound of formula (I),
Figure BDA0002987656820000031
or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof,
wherein:
G1selected from O, S, C (═ O), C (═ O) NH and NR6、CR7R8And S (═ O)2；
Ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
X1and X2Are the same or different and are each independently a hydrogen atom or L-R0(ii) a Provided that X is1And X2Not being hydrogen atoms at the same time;
l is selected from-CH2-、-C(＝O)O(CQ1Q2)n-and-C (═ O) S (CQ)1Q2)n-；
R0Selected from-OP (═ O) (OH)2、-OP(＝O)(OH)-OP(＝O)(OH)2、-OC(＝O)Q3、-OC(＝O)OQ3、-OC(＝O)NHQ3、-OP(＝O)(OQ4)2、-O-C(＝O)(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)(CQ1Q2)n-Cy-OP(＝O)(OH)2、-OC(＝O)CH＝CHC(＝O)OH、-O-C(＝O)-O-(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)-NH-(CQ1Q2)n-OP(＝O)(OH)2、-OC(＝O)CH(Q5)-NQ6Q7and-NQ6Q7；
Cy is aryl or heteroaryl, each independently optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Q1、Q2、Q3and Q5Are identical or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group and-C (═ O) R9Wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Q4selected from alkyl, -CH2OC(＝O)R9and-CH2-OC(＝O)OR9；
Q6And Q7Are identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (═ O) R9Cycloalkyl, heterocyclyl, aryl and heteroaryl;
R1are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, carboxyl, amino, or amino, or amino, or amino, or amino, or amino, or amino, or amino, or amino, or amino,Nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, each of which is independently optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2aand R2The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R3the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R4and R5The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R6selected from the group consisting of hydrogen atom, alkyl group, haloalkyl group, hydroxyl group, hydroxyalkyl group, amino group, cycloalkyl group, heterocyclic group, C (O) OR10、C(O)R11Aryl and heteroaryl;
R7and R8Are the same OR different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, C (O) OR10Aryl and heteroaryl;
or R7And R8Together form a cycloalkyl or heterocyclyl group;
R9is alkyl, optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkoxy, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R10selected from hydrogenAtoms, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R11selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
n is an integer of 1 to 6;
r is 0, 1,2 or 3;
s is 0, 1,2, 3 or 4; and is
q is 0, 1,2, 3 or 4.
In some embodiments of the present disclosure, a compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein G is1Is an O atom.
In some embodiments of the present disclosure, a compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R is2aIs C1-6Alkyl, preferably methyl.
In some embodiments of the present disclosure, a compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R is4And R5Is a hydrogen atom.
In some embodiments of the present disclosure, a compound of formula (I), which is a compound of formula (II) or formula (III), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof,
Figure BDA0002987656820000051
wherein:
ring A, X1、X2、R1、R2、R3S, r and q are as defined in formula (I).
In some embodiments of the present disclosure, the compounds of formula (I) and formula (II), or tautomers, cis-or trans-isomers, meso-isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein X is1And X2Are the same or different and are each independently selected from the group consisting of a hydrogen atom, -CH2-R0and-C (═ O) O (CQ)1Q2)n-R0(ii) a Provided that X is1And X2Not being hydrogen atoms at the same time; r0、Q1、Q2And n is as defined in formula (I).
In some embodiments of the present disclosure, the compounds of formula (I) and formula (II), or tautomers, cis-or trans-isomers, meso-isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein X is1And X2Are the same or different and are each independently selected from the group consisting of a hydrogen atom, -CH2OC(＝O)CH3、-CH2OC(＝O)OCH3、-CH2OC(＝O)NHCH3、-CH2OP(＝O)(OH)2、-CH2OP(＝O)(OH)OP(＝O)(OH)2、-CH2OP(＝O)(OQ4)2、-C(＝O)OCH2OC(＝O)C(CH3)3、-C(＝O)OCH2OP(＝O)(OH)2、-C(＝O)OCH2CH2OP(＝O)(OH)2、-C(＝O)OCH2OC(＝O)CH＝CHCOOH、
Figure BDA0002987656820000052
Figure BDA0002987656820000053
Provided that X is1And X2Is not simultaneousIs a hydrogen atom; q4As defined in formula (I); preferably, X1is-CH2OP(＝O)(OH)2(ii) a And X2Is a hydrogen atom; or, X1Is a hydrogen atom; and X2is-CH2OP(＝O)(OH)2。
In some embodiments of the present disclosure, the compounds of formula (I) and formula (II), which are compounds of formula (III) or formula (IV), or tautomers, cis or trans isomers, meso forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof,
Figure BDA0002987656820000061
wherein:
L1and L2Are the same or different and are each independently selected from-CH2-、-C(＝O)O(CQ1Q2)n-and-C (═ O) S (CQ)1Q2)n-; preferably, L1And L2Are the same or different and are each independently-CH2-；
RaAnd RbAre identical or different and are each independently selected from the group consisting of-OP (═ O) (OH)2、-OP(＝O)(OH)-OP(＝O)(OH)2、-OC(＝O)Q3、-OC(＝O)OQ3、-OC(＝O)NHQ3、-OP(＝O)(OQ4)2、-O-C(＝O)(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)(CQ1Q2)n-Cy-OP(＝O)(OH)2,-OC(＝O)CH＝CHC(＝O)OH、-O-C(＝O)-O-(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)-NH-(CQ1Q2)n-OP(＝O)(OH)2、-OC(＝O)CH(Q5)-NQ6Q7and-NQ6Q7(ii) a preferably-OP (═ O) (OH)2。
Ring A, R1、R2、R3、Cy、Q1～Q7S, r, q and n are as defined in formula (I).
In some embodiments of the present disclosure, the compounds of formula (I), formula (II), formula (III), and formula (IV), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein ring a is a 5-or 6-membered heteroaryl; pyridyl, pyridazinyl and pyrimidinyl are preferred.
In some embodiments of the present disclosure, the compounds of formula (I), formula (II), formula (III) and formula (IV), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein
Figure BDA0002987656820000062
Selected from:
Figure BDA0002987656820000063
Figure BDA0002987656820000064
R1and s is as defined in formula (I).
In some embodiments of the present disclosure, the compounds of formula (I), formula (II), formula (III) and formula (IV), or tautomers, cis or trans isomers, meso forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein R is1Selected from the group consisting of hydrogen atoms, haloalkyl groups and haloalkoxy groups; preferably selected from hydrogen atoms, halogenated C1-6Alkyl or halo C1-6An alkoxy group.
In some embodiments of the disclosure, the compounds of formula (I), formula (II), formula (III), and formula (IV), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers, or mixtures thereofA form of matter, or a pharmaceutically acceptable salt or solvate thereof, wherein R1Is haloalkyl or haloalkoxy; preferably a halogen atom1-6Alkyl or halo C1-6An alkoxy group.
In some embodiments of the present disclosure, the compounds of formula (I), formula (II), formula (III) and formula (IV), or tautomers, cis or trans isomers, meso forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein R is2And R3Is a hydrogen atom.
In some embodiments of the present disclosure, the compounds of formula (I), formula (II), formula (III), and formula (IV), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein s is 0 or 1.
In some embodiments of the present disclosure, the compounds of formula (I), formula (II), formula (III), and formula (IV), or tautomers, cis or trans isomers, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein q is 0 or 1.
In some embodiments of the present disclosure, the compounds of formula (I), formula (II), formula (III), and formula (IV), or tautomers, cis or trans isomers, meso forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts or solvates thereof, wherein r is 0 or 1.
In some embodiments of the present disclosure, a compound of formula (II), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure BDA0002987656820000071
Selected from:
Figure BDA0002987656820000072
Figure BDA0002987656820000073
R1selected from the group consisting of hydrogen atoms, haloalkyl groups and haloalkoxy groups; preferably selected from hydrogen atoms, halogenated C1-6Alkyl or halo C1-6An alkoxy group; x1is-CH2OP(＝O)(OH)2(ii) a And X2Is a hydrogen atom; or, X1Is a hydrogen atom; and X2is-CH2OP(＝O)(OH)2；R2And R3Is a hydrogen atom; s is 0 or 1.
Table a exemplary prodrug compounds of the present disclosure include, but are not limited to:
Figure BDA0002987656820000074
Figure BDA0002987656820000081
Figure BDA0002987656820000091
other exemplary prodrug compounds of the present disclosure include, but are not limited to:
Figure BDA0002987656820000092
Figure BDA0002987656820000101
Figure BDA0002987656820000102
preference is given to
Figure BDA0002987656820000103
In another aspect of the present disclosure, there is provided a compound represented by formula (IIIA) or (IVA):
Figure BDA0002987656820000104
or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein:
Rwis-SCH3Or an iodine atom;
ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
L1and L2Are the same or different and are each independently selected from-CH2-、-C(＝O)O(CQ1Q2)n-and-C (═ O) S (CQ)1Q2)n-; preferably, L1And L2Are the same or different and are each independently-CH2-；
Q1And Q2Are identical or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group and-C (═ O) R9Wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R9is alkyl, optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkoxy, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R1the same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from the group consisting ofOptionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R2the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R3the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
n is an integer of 1 to 6;
r is 0, 1,2 or 3;
s is 0, 1,2, 3 or 4; and is
q is 0, 1,2, 3 or 4. Which is an intermediate for the preparation of formula (III) or formula (IV).
Exemplary intermediates of the present disclosure include, but are not limited to:
Figure BDA0002987656820000111
Figure BDA0002987656820000121
in another aspect of the present disclosure, there is provided a process for preparing a prodrug compound of formula (III) or formula (IV), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, the process comprising:
Figure BDA0002987656820000131
formula (IIIA) formulaCompound and Ra-H reaction to give a compound of general formula (III);
compounds of the general formula (IVA) and Rb-H reaction to give a compound of general formula (IV);
wherein:
Rwis-SCH3；
Ring A, R1、R2、R3、L1、L2、Ra、RbS, r and q are as defined for compounds of formula (III) or formula (IV).
The present disclosure provides a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present disclosure provides for the use of a compound of formula (I), formula (II), formula (III), formula (IV) and shown in table a, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting RAF.
The present disclosure provides the use of a compound of formula (I), formula (II), formula (III), formula (IV) and shown in table a, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment of a RAF mediated disease or disorder. Preferably, the RAF mediated disease or disorder is a tumor, more preferably, the RAF mediated disease or disorder is cancer. Wherein the tumor (preferably cancer) is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.
The present disclosure provides a method of inhibiting RAF comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same.
The present disclosure provides a method of treating a RAF mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same. Preferably, the RAF mediated disease or disorder is a tumor, more preferably, the RAF mediated disease or disorder is cancer. Wherein the tumor (preferably cancer) is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.
Another aspect of the present disclosure provides a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
Another aspect of the present disclosure provides a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting RAF.
Another aspect of the present disclosure provides a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, for use in the treatment of a RAF mediated disease or disorder. Preferably, the RAF mediated disease or disorder is a tumor, more preferably, the RAF mediated disease or disorder is cancer. Wherein the tumor (preferably cancer) is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.
The tumors occurring in the above cancers are malignant tumors.
The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the invention by conventional means. Thus, the active compounds of the present invention may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present invention may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
The dosage of the compound or composition used in the methods of treatment of the present invention will generally vary with the severity of the disease, the weight of the patient and the relative efficacy of the compound. However, as a general guide, the active compound is preferably in unit dosage form, or in such a way that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the invention may be expressed in the form of a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid. A suitable unit dose may be 0.1 to 1000 mg.
The pharmaceutical compositions of the invention may contain, in addition to the active compound, one or more adjuvants selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.
The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Term part
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1,2, 3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle, cycloalkylthio, heterocyclylthio, and oxo.
The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. For example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Preferably 2 to 20 carbon atoms, more preferably 2 to 12 (e.g., 2,3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, most preferably 2 to 6 carbon atoms, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, alkoxy, alkynyl, alkylthio, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle, cycloalkylthio, heterocyclylthio, and oxo.
The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like. Preferably 2 to 20 carbon atoms, more preferably 2 to 12 (e.g. 2,3, 4,5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, most preferably 2 to 6 carbon atoms. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkenyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycle, alkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.
The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing from 1 to 20 carbon atoms, preferably from 1 to 12 (e.g., 1,2, 3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably from 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)2-), 1-ethylidene (-CH (CH)3) -), 1, 2-ethylene (-CH)2CH2) -, 1-propylene (-CH (CH)2CH3) -), 1, 2-propylene (-CH)2CH(CH3) -), 1, 3-propylene (-CH)2CH2CH2-) 1, 4-butylene (-CH2CH2CH2CH2-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more independently selected from the group consisting of alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.
The term "alkenylene" refers to an alkylene compound containing a carbon-carbon double bond in the molecule, wherein the alkylene isThe radicals are as defined above. Preferably 2 to 20 carbon atoms, more preferably 2 to 12 (e.g. 2,3, 4,5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, most preferably 2 to 6 carbon atoms. Non-limiting examples of alkenylene include, but are not limited to, ethenylene (-CH-), propenylene (-CH-CHCH)2-, 1-butenylene (-CH ═ CHCH)2CH2-, 2-butenylene (-CH)2CH＝CHCH2-) and the like. Alkenylene may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms (e.g., 3, 4,5, 6, 7, or 8) or 3 to 6 (3, 4,5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g. 7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0002987656820000181
the term "fused cyclic alkyl" refers to a5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g. 7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0002987656820000182
the term "bridged cycloalkyl" refers to a5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g. 7, 8, 9 or 10). They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0002987656820000191
such cycloalkyl rings include those wherein the above cycloalkyl is fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, halo, alkoxy, alkenyl, alkynyl, alkylthio, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio and oxo.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g. 3, 4,5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g. 1,2, 3 or 4) are heteroatoms; more preferably 3 to 10 ring atoms (e.g., 3, 4,5, 6, 7, 8, 9 or 10), of which 1-3 are heteroatoms; more preferably 6 to 10 ring atoms (e.g., 6, 7, 8, 9 or 10), with 1-3 being heteroatoms; most preferably 5 to 6 ring atoms, of which 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14) and more preferably 7 to 10 (e.g. 7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0002987656820000192
the term "fused heterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain oneOr a plurality of double bonds, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g. 7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0002987656820000201
the term "bridged heterocyclyl" refers to 5 to 14 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered), polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g. 7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0002987656820000202
such heterocyclyl rings include those wherein the heterocyclyl group described above is fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:
Figure BDA0002987656820000203
Figure BDA0002987656820000204
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio.
The term "aryl" refers to a6 to 14 membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. Such aryl rings include those wherein the above-described aryl group is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0002987656820000211
the aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1,2, 3, and 4) heteroatoms, 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 membered) ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10), more preferably 5 or 6 membered, e.g. thiadiazole, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. Such heteroaryl rings include those wherein the heteroaryl group described above is fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0002987656820000212
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more, in some cases preferably 1 to 5 (e.g., 1,2, 3, 4 and 5), in some cases more preferably 1 to 3, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.
The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived by removing one hydrogen atom from the parent ring atom, or those derived by removing two hydrogen atoms from the parent ring atom or from two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".
The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.
The term "bond" refers to a covalent bond of the symbol "-".
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.
The term "hydroxy" refers to-OH.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "oxo" refers to ═ O.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art will be able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in the body of a mammal and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bonding includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
By "prodrug" is meant a compound that can be converted in vivo under physiological conditions, for example, by hydrolysis in blood, to yield the active parent compound.
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to show a meaningful benefit to the patient, e.g., a sustained reduction in viral load. When an active ingredient is given alone, the term refers to that ingredient alone. When administered in combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sequentially or simultaneously.
The term "treatment" or similar expressions refer to: (i) inhibiting, i.e., arresting the development of, a disease, disorder, or condition; (ii) ameliorating the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition. In addition, the compounds of the present disclosure may be used to prevent the prophylactic effect of a disease, disorder, or condition in a subject that may be predisposed to the disease, disorder, and/or condition, but has not yet been diagnosed as having the disease.
As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.
When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be understood by those skilled in the art, when a parameter is not a critical parameter, a number is typically given for illustrative purposes only and is not limited to that number.
Inhibitors of protein kinases are widely sought and many small molecules capable of modulating protein kinases have been reported. We have recently found that prodrugs of a class of spiro compounds are potent inhibitors of protein kinases, particularly RAF kinase. These novel spiro compounds possess desirable stability, bioavailability, therapeutic index and toxicity data, which are important to ensure their drugability.
These prodrugs typically comprise a biologically active spiro compound, and the spiro compound is substituted at the nitrogen atom of one or more amide groups with a substituent X1Or X2Substituted, the group X1Or X2Can be metabolized or otherwise converted under conditions to produce an active spiro compound. Without being bound to any relevant practice or theory, it is believed that the phosphate-containing groups enhance the solubility of the biologically active spiro compounds and thus increase oral bioavailability. Phosphoric acid group X1，X2Are found to be metabolized by phosphatases in the digestive tract, thereby forming potentially active parent drugs that are absorbed.
It has been found that biologically active spiro compounds are shown below (see compound 1), when made to contain X (e.g., X)1Or X2) Group (-CH)2-OP(＝O)(OH)2) I.e. introduction of X groups (e.g. X) at the superscript asterisk on the amide N1Or X2(see compound A below),
Figure BDA0002987656820000241
the water solubility and the oral bioavailability are obviously improved. This increased water solubility contributes to better dissolution in the intestinal tract, thereby facilitating oral absorption. Similar improvements in water solubility and oral bioavailability are expected for other active spiro compounds with similarly poor water solubility when formulated as phosphate prodrugs.
Synthesis of the Compounds of the disclosure
For the purpose of the present disclosure, the following technical solutions are adopted in the present disclosure, but the synthesis method of the present disclosure is not limited to the following synthesis methods:
the preparation method of the compound shown in the general formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof comprises the following steps:
Figure BDA0002987656820000242
a compound of the formula (IIIA) and Ra-H reaction to give general formula (III);
wherein:
Rwis-SCH3Or an iodine atom;
ring A, R1、R2、R3、L1、RaS, r and q are as defined for the compounds of the general formula (III).
The preparation method of the compound shown in the general formula (IV) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof comprises the following steps:
Figure BDA0002987656820000251
compounds of the general formula (IVA) and Rb-H reaction to give a compound of general formula (IV);
wherein:
Rwis-SCH3Or an iodine atom;
ring A, R1、R2、R3、L2、RbS, r and q are as defined for the compounds of formula (IV).
The above reaction is preferably carried out in a solvent including, but not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide and mixtures thereof.
Detailed Description
Examples
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure. If specific conditions for the experimental methods are not specified in the examples of the present disclosure, they are generally according to conventional conditions or recommended by the manufacturers of raw materials and products. No indication is made that the reagents of particular origin are commercially available conventional reagents.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using Bruker AVANCE-300, AVANCE-400 or AVANCE-500 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d) as the solvent6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD)。
Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column), Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column), or Shimadzu UFLC (Xbridge C185 um 150X 4.6mm column) for High Performance Liquid Chromatography (HPLC) measurements.
Chiral HPLC analytical determination using LC-10A (Shimadzu) or SFC-analytical (Berger Instruments Inc.) or Waters-UPC 2.
MS was measured by using SHIMADZU (ESI) LC-MS (Shimadzu, model: LC-20AD, LCMS-2020), Waters UPLC-QDa (ACQUITY)
Figure BDA0002987656820000252
BEH, 2.1 × 50mm 1.7um chromatography column), Agilent6120(Xbridge C185 um 50 × 4.6mm chromatography column).
Average inhibition rate of kinase and IC50The values were measured using a Microplate reader (BMG, Germany).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The CombiFlash rapid preparation machine used Teledyne ISCO or Agela Technologies.
Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of the Parr 3916EKX type and a hydrogen generator of the QL-500 type or a hydrogenation apparatus of the HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the solvent is adjusted according to the polarity of the compound. The elution system for column chromatography, thin layer chromatography and CombiFlash flash rapid prep of purified compounds comprises: a: dichloromethane and methanol, B: hexane and ethyl acetate. The volume ratio of the solvent may be adjusted depending on the polarity of the compound, and a small amount of a basic agent such as ammonia or an acidic agent such as acetic acid may be added in some cases.
The final compound was purified by Shimadzu (LC-20AD, SPD20A) preparative HPLC (Phenomenex Gemini-NX 5uM C1821.2X 100mm column), Waters 2767(Sunfire Pre C1810 uM 19X 250mm column), or Waters 2767-QDa (Xbridge Pre C1810 uM 19X 250mm column) in water/MeOH or water/CH3Purification in CN elution System and optional additives such as HCOOH, TFA and NH4HCO3。
The following abbreviations are used in the examples:
DIPEA is N, N-diisopropylethylamine,
HATU is 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate,
the DCM is the methylene chloride, and the DCM is the methylene chloride,
DMF is N, N-dimethylformamide,
the DMSO is dimethyl sulfoxide, and the DMSO is dimethyl sulfoxide,
the EtOAc is ethyl acetate which is the mixture of the ethyl acetate,
prep HPLC for preparative high performance liquid chromatography,
NMR is the nuclear magnetic resonance of a proton,
MS is mass spectrometry, where (+) refers to positive mode, typically giving M +1 (or M + H) absorption, where M ═ molecular weight.
General reaction scheme
1
Figure BDA0002987656820000271
General reaction scheme
2
Figure BDA0002987656820000272
General reaction scheme
3
Figure BDA0002987656820000273
General reaction scheme
4
Figure BDA0002987656820000281
Example 1
N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide 1
Figure BDA0002987656820000282
First step of
7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one 1c
Pyrrolidine (1.81g, 2.12mL, 25.4mmol) was added to a solution of 1- (4-bromo-2-hydroxyphenyl) ethan-1-one 1a (10.9g, 50.7mmol) and tetrahydro-4H-pyran-4-one 1b (6.60g, 65.9mmol) in methanol (100mL) at room temperature. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated, and to the resulting residue were added water (20mL), a hydrochloric acid solution (1N, 40mL) and ethyl acetate (200 mL). The organic phase was washed with water (25 mL. times.2), dried, filtered, and concentrated under reduced pressure to give the title compound 1c (11.8g, yield: 78.1%) which was used without purification.
1HNMR(400MHz,CDCl3)δ1.77-1.83(m,2H),1.97-2.01(m,2H),2.76(s,2H),3.82-3.88(m,4H),7.17(d,1H),7.27(s,1H),7.74(d,1H)。
Second step of
(Z) -7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one oxime 1d
To a solution of compound 1c (9g, 30.29mmol) in ethanol (90mL) were added hydroxylamine hydrochloride (6.31g, 90.87mmol) and sodium acetate (7.45g, 90.87mmol), and the reaction was heated to reflux and stirred for 2 hours. The reaction solution was diluted with saturated sodium chloride solution (150mL), extracted with ethyl acetate (100 mL. times.2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound 1d as a crude product (9g, yield: 95%).
MS m/z(ESI):312.1[M+H]+
The third step
(Z) -7-bromo-2 ',3',5',6' -tetrahydrospiro [ chromane-2, 4' -pyran ] -4-one O-p-toluenesulfonyl oxime 1e
To a solution of compound 1d (2g, 8.64mmol) in dichloromethane (100mL) was added triethylamine (4.72g, 46.61mmol) and p-toluenesulfonic anhydride (12.17g, 37.29 mmol). The reaction was stirred at room temperature for 2 hours. Then, water (150mL) and methylene chloride (150mL) were added for extraction, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane ═ 0:1 to 1:10, 200 to 300 mesh silica gel) to obtain the title compound 1e (9g, yield: 62%).
1H NMR(400MHz,DMSO):δ7.91(d,2H),7.57(d,1H),7.50(d,2H),7.29(d,1H),7.18(dd,1H),3.61(d,4H),3.02(s,2H),2.41(s,3H),1.72-1.57(m,4H)。
MS m/z(ESI):465.9[M+H]+
The fourth step
8-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one 1f
To a solution of compound 1e (8.8g, 18.87mmol) in dichloromethane (100mL) at 0 deg.C was added aluminum trichloride (10.06g, 75.48mmol), and the mixture was stirred at 0-10 deg.C for 2 hours. Saturated sodium bicarbonate solution was added for dilution (100mL) and concentrated HCl was added to adjust the pH to 1. The mixture was extracted with dichloromethane (150mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residuePurification by silica gel column chromatography (ethyl acetate: hexane ═ 0:1 to 9:1, 200 to 300 mesh silica gel) gave the title compound 1f (3g, yield: 51%).1HNMR(400MHz,CDCl3),δ7.61(s,1H),7.30(s,1H),7.23(s,1H),6.90(d,1H),3.98-3.85(m,4H),2.57(s,2H),2.03-2.00(m,2H),1.88-1.81(m,2H)。
MS m/z(ESI):312.0[M+H]+
The fifth step
8- (5-amino-2-methylphenyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -4(5H) -one 1g
To a solution of compound 1f (1.5g, 4.81mmol) in 1, 4-dioxane (20mL) were added water (10mL), sodium carbonate (1.02g, 9.61mmol), 1-bis (diphenylphosphino) ferrocene palladium dichloride (350.00mg, 478.14umol) and 4-methyl-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -aniline (1.34g, 5.77mmol), and the reaction was stirred under nitrogen at 90 ℃ for 4 hours. The reaction was cooled and extracted with ethyl acetate (30mL), the organic phase was collected, washed with water (10mL × 3) and saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to obtain 1g of the title compound (1.6g, yield 98%).
1H NMR(400MHz,CDCl3):δ7.64(s,1H),7.08-7.01(m,4H),6.64(dd,1H),6.58(d,1H),3.95-3.92(m,2H),3.85-3.77(m,2H),3.62(brs,2H),2.59(s,2H),2.15(s,3H),2.04-2.00(m,2H),1.87-1.79(m,2H)。
MS m/z(ESI):339.1[M+H]+
The sixth step
N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide 1
Compound 1g (140mg, 413.71umol), 5- (trifluoromethyl) pyridazine-3-carboxylic acid (70mg, 64.48umol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (235.96mg, 620.57umol) and triethylamine (125.59mg, 1.24mmol) were added to N, N-dimethylformamide (5mL), respectively, and the mixture was stirred at room temperature for 12 hours. The completion of the reaction was monitored by LC-MS. Extraction with ethyl acetate (20mL) collected the organic phase, washed with saturated sodium chloride solution, dried and concentrated to give the crude product which was prepared by thin layer chromatography to give the title compound 1(93mg, 44% yield).
1H NMR(400MHz,DMSO-d6):δ11.26(s,1H),9.96(d,1H),9.82(s,1H),8.57(d,1H),7.88(d,1H),7.86(s,1H),7.31(d,1H),7.17-7.09(m,2H),7.05(d,1H),3.81-3.78(m,2H),3.72-3.68(m,2H),2.50(s,2H),2.25(s,3H),1.87-1.74(m,4H)。
19F NMR(376.5MHz,DMSO-d6):δ-63.08。
MS m/z(ESI):513.2[M+H]+
Examples 2 to 7 were prepared using the foregoing method and general procedure described in example 1, but substituting the appropriate aryl carboxylic acid in step 6 as described in the foregoing schemes and examples. The required starting materials are either commercially available, described in the literature, or readily synthesized by those skilled in the art from commercial reagents using routine reactions without undue experimentation.
Example 2
N-4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) isonicotinamide 2
Figure BDA0002987656820000301
1HNMR(400MHz,CD3OD),δ8.92(d,1H),8.32(s,1H),8.14(d,1H),7.66(s,1H),7.64(d,1H),7.33(d,1H),7.15(s,2H),7.10(s,1H),3.98(t,2H),3.84-3.82(m,2H),2.60(s,2H),2.30(s,3H),2.03-2.00(m,2H),1.89-1.84(m,2H).
MS m/z(ESI):512.0[M+1]+
Example 3
Figure BDA0002987656820000311
N-4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -2- (trifluoromethyl) pyrimidine-5-carboxamide 3
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.83(s,1H),9.50(s,2H),7.78–7.59(m,2H),7.40–7.28(m,1H),7.17–7.07(m,2H),7.04(d,1H),3.87–3.63(m,4H),2.62(s,2H),2.25(s,3H),1.92–1.69(dt,4H).
LCMS:MS m/z(ESI):513.0[M+H]+.
Example 4
Figure BDA0002987656820000312
2- (difluoromethoxy) -N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin 2,4' -pyran ] -8-yl) phenyl) isonicotinamide 4
1H NMR(400MHz,DMSO-d6):δ10.51(s,1H),9.82(s,1H),8.46(d,1H),7.78-7.56(m,5H),7.30(d,1H),7.11-7.08(m,2H),7.03(s,1H),3.83-3.60(m,4H),2.50(s,2H),2.23(s,3H),1.86-1.76(m,4H).
19F NMR(376.5MHz,DMSO-d6):δ-87.37(s,2F).
MS m/z(ESI):510.2[M+H]+
Example 5
Figure BDA0002987656820000313
N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) 2- (trifluoromethoxy) isonicotinamide 5
1H NMR(400MHz,DMSO-d6):δ10.56(s,1H),9.82(s,1H),8.58(d,1H),7.90(d,1H),7.75(s,1H),7.70(d,1H),7.65(s,1H),7.30(d,1H),7.14-7.09(m,2H),7.03(s,1H),3.83-3.68(m,4H),2.50(s,2H),2.23(s,3H),1.86-1.72(m,4H).
19F NMR(376.5MHz,DMSO-d6):δ-55.14(s).
MS m/z(ESI):528.2[M+H]+
Example 6
Figure BDA0002987656820000321
N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -6- (trifluoromethyl) pyridazine-3-carboxamide 6
1H NMR(400MHz,DMSO):δ11.22(s,1H),9.82(s,1H),8.58-8.50(m,2H),7.87-7.84(m,2H),7.32(d,1H),7.17-7.09(m,2H),7.05(d,1H),3.84-3.77(m,2H),3.72-3.67(m,2H),2.50(s,2H),2.25(s,3H),1.87-1.73(m,4H).
19F NMR(376.5MHz,DMSO-d6):δ-65.67
LCMS:MS m/z(ESI):513.1[M+H]+
Example 7
Figure BDA0002987656820000322
N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -6- (trifluoromethoxy) nicotinamide 7
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.82(s,1H),8.90(d,1H),8.50(dd,1H),7.76–7.59(m,2H),7.52–7.39(m,1H),7.30(d,1H),7.22–7.09(m,2H),7.03(d,1H),3.91–3.76(m,2H),3.73-3.65(dt,2H),2.62(s,2H),2.24(s,3H),1.90–1.73(m,4H).
LCMS:MS m/z(ESI):528.0[M+H]+.
Example A1
(8- (2-methyl-5- (5- (trifluoromethyl) pyridazin-3-carboxamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A1
Figure BDA0002987656820000323
Figure BDA0002987656820000331
First step of
N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide A1c
To a solution of 4-methyl-3- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenylamine A1a (613mg, 2.63mmol) in N, N-dimethylformamide (12mL) were added 5- (trifluoromethyl) pyridazine-3-carboxylic acid A1b (500mg, 2.63mmol) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.02g, 2.68mmol), followed by addition of N, N-diisopropylethylamine (1.5mL, 9.07mmol) at 0 ℃. The resulting mixture was stirred at room temperature for 1 hour. Ethyl acetate (150mL) was added and the organic phase was washed successively with saturated ammonium chloride solution (40mL), saturated sodium bicarbonate solution (40mL) and saturated sodium chloride solution (40 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate as eluent) to give the title compound A1c (873mg, yield: 82%).
MS m/z(ESI):408.3[M+H]+
Second step of
8-bromo-5- ((methylthio) methyl) -2',3',5',6' -tetrahydro-3H-spiro [ benzo [ b ] [1,4] -oxazepin-2, 4' -pyran-4 (5H) -one A1d
To a reaction flask were added compound 1f (31mg, 0.10mmol) and N, N-dimethylformamide (0.5 mL). The mixture was cooled to 0 ℃ and sodium hydride (5mg, 0.125mmol) was added and stirred for 30 min. Chloromethyl methyl sulfide (12mg, 0.125mmol) and tetrabutylammonium iodide (48mg, 0.15mmol) were added thereto. The mixture was stirred at room temperature for 1 hour and reacted at 45 ℃ for 18 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2X 5 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (ethyl acetate: hexane ═ 0 to 30:100) to give the title compound A1d (25mg, yield 67.2%).
MS m/z(ESI):373.0[M+1]+
The third step
N- (4-methyl-3- (5- ((methylthio) methyl) -4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamide A1e
A reaction flask was charged with A1d (330mg, 0.81mmol), compound A1c (361mg, 0.97mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (59mg, 0.081mmol) and cesium carbonate (528mg, 1.62mmol), and reacted under an argon atmosphere. To the reaction mixture was added a solution of 1, 4-dioxane (10 mL)/water (2mL) and stirred at 105 ℃ for 3 hours. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate (3X 25 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (ethyl acetate: dichloromethane: 0:100 to 65:100) to obtain the title compound A1e (250mg, yield: 54%).
MS m/z(ESI):573.2[M+1]+
The fourth step (8- (2-methyl-5- (5- (trifluoromethyl) pyridazin-3-carboxamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A1
A mixture of Compound A1e (200mg, 0.35mmol), phosphoric acid (1.37g, 14.0mmol) and 3A molecular sieves (200mg) in tetrahydrofuran (6mL) was stirred at room temperature for 15 minutes and cooled to 0 ℃. N-iodosuccinimide (158mg, 0.7mmol) was added and reacted at 0 ℃ for 30 minutes and at room temperature for 1 hour, respectively. The reaction mixture was filtered to remove solids. The filtrate was diluted with methanol and cooled to 0 ℃. The resulting mixture was quenched with saturated sodium thiosulfate solution, adjusted to pH7 with 2N sodium hydroxide, filtered through celite, washed with methanol, and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (0-50% acetonitrile in water + 0.2% ammonium hydrogencarbonate) to give the title compound A1(141mg, yield: 65%).
1H NMR(400MHz,CH3OH-d4)δ9.63(d,1H),8.54(d,1H),7.73(d,1H),7.67(d,2H),7.24(d,1H),7.18(dd,1H) 6.97(d,1H),5.45(s,2H),3.86(td,2H),3.70(dt,2H),2.51(s,2H),2.20(s,3H),1.87(d,2H),1.73(ddd, 2H). In CH3OH-d4No two-OH groups and NH on the phosphoric acid were observed.
31P NMR(400MHz,CH3OH-d4)δ-1.53(s)。
MS m/z(ESI):623.0[M+1]+
Examples a 2-a 7 were prepared using the above-described method and general procedure described in example a1, but replacing the appropriate arylboronic acid ester in step 3 as described in the foregoing schemes and examples. The required starting materials are either commercially available, described in the literature, or readily synthesized by those skilled in the art from commercial reagents using routine reactions without undue experimentation.
Example A2
(8- (2-methyl-5- (2- (trifluoromethyl) isonicotinamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A2
Figure BDA0002987656820000351
Example a2 was prepared using the foregoing method and the general method described in example a1, but substituting the appropriate arylboronic acid ester in step 3 as described in the foregoing schemes and examples. The necessary starting materials are either commercially available or obtained as described in the literature or synthesized by one skilled in the art of organic synthesis from commercially available reagents using conventional reactions.
1H NMR(400MHz,CH3OH-d4) δ 8.81(d,1H),8.21(s,1H),8.03(dd,1H),7.72(d,1H),7.59(dd,1H),7.50(d,1H),7.22(d,1H),7.16(dd,1H),6.96(d,1H),5.45(d,2H), 3.93-3.77 (m,2H),3.70(dt,2H),2.51(s,2H),2.19(s,3H),1.87(d,2H),1.73(ddd, 2H). In CH3No two-OH groups and NH on phosphoric acid were observed in OH-d 4.
31P NMR(400MHz,CH3OH-d4)δ-1.40(s)
MS m/z(ESI):622.0[M+H]+
Example A3
(8- (2-methyl-5- (2- (trifluoromethyl) pyrimidine-5-carboxamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A3
Figure BDA0002987656820000352
1H NMR(400MHz,CH3OH-d4) Δ 9.43(s,2H),8.06(d,1H),7.71(dd,1H),7.55(d,1H),7.31(d,1H),7.24(dd,1H),7.00(d,1H),5.50(brs,2H),3.98-3.92(m,2H),3.82-3.76(m,2H),2.58(s,2H),2.28(s,3H),1.98-1.93(m,2H),1.85-1.78(m,2H) in CH3No two-OH groups and NH on phosphoric acid were observed in OH-d 4.
19F NMR(376.5MHz,CH3OH-d4):δ-71.98.
LCMS:MS m/z(ESI):621.0[M-H]-
Example A4
(8- (5- (2- (difluoromethoxy) isonicotinamido) -2-methylphenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepin-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A4
Figure BDA0002987656820000361
1H NMR(400MHz,CH3OH-d4) Δ 8.37(d,1H),8.00(d,1H),7.69-7.64(m,2H),7.60(t,1H),7.54(d,1H),7.44(s,1H),7.29(d,1H),7.24(d,1H),7.01(d,1H),5.50(brs,2H),3.98-3.91(m,2H),3.81-3.76(m,2H),2.58(s,2H),2.27(s,3H),1.98-1.94(m,2H),1.85-1.77(m,2H) in CH3No two-OH groups and NH on phosphoric acid were observed in OH-d 4.
19F NMR(376.5MHz,CH3OH-d4):δ-90.49.
LCMS:MS m/z(ESI):618.0[M-H]-
Example A5
(8- (2-methyl-5- (2- (trifluoromethoxy) isonicotinamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A5
Figure BDA0002987656820000362
1H NMR(400MHz,CH3OH-d4) Δ:8.48(d,1H),7.0(d,2H),7.67(dd,1H),7.61(s,1H),7.56(d,1H),7.31(d,1H),7.25(dd,1H),7.05(d,1H),5.55(brs,2H),3.98-3.92(m,2H),3.81-3.77(m,2H),2.59(s,2H),2.27(s,3H),1.98-1.93(m,2H),1.86-1.77(m,2H) in CH3No two-OH groups and NH on phosphoric acid were observed in OH-d44.
31P NMR(162.0MHz,CH3OH-d4):δ:-1.62
19F NMR(376.5MHz,CH3OH-d4):δ:-58.03
LCMS:MS m/z(ESI):636.0[M-H]-.
Example A6
(8- (2-methyl-5- (6- (trifluoromethyl) pyridazin-3-carboxamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] [1,4] oxazepine-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A6
Figure BDA0002987656820000371
1H NMR(400MHz,CH3OH-d4) Δ 8.60(d,1H),8.34(d,1H),8.06(d,1H),7.78-7.73(m,2H),7.33(d,1H),7.27(dd,1H),7.03(d,1H),5.50(brs,2H),3.99-3.92(m,2H),3.81-3.77(m,2H),2.59(s,2H),2.29(s,3H),1.99-1.95(m,2H),1.86-1.77(m,2H) in CH3No two-OH groups and NH on phosphoric acid were observed in OH-d 4.
19F NMR(376.5MHz,CH3OH-d4):δ-68.55.
LCMS:MS m/z(ESI):621.0[M-H]-
Example A7
(8- (2-methyl-5- (6- (trifluoromethoxy) nicotinamido) phenyl) -4-oxo-2 ',3,3',4,5',6' -hexahydro-5H-spiro [ benzo [ b ] ] [1,4] oxazepine-2, 4' -pyran ] -5-yl) dihydrogenphosphate methyl ester A7
Figure BDA0002987656820000372
1H NMR(400MHz,CH3OH-d4) Δ 8.86(d,1H),8.45(dd,1H),7.89(d,1H),7.67(dd,1H),7.53(d,1H),7.31-7.23(m,3H),7.03(d,1H),5.53(brs,2H),3.98-3.92(m,2H),3.81-3.76(m,2H),2.59(s,2H),2.27(s,3H),1.98-1.93(m,2H),1.85-1.77(m,2H) in CH3No two-OH groups and NH on phosphoric acid were observed in OH-d 4.
19F NMR(376.5MHz,CH3OH-d4):δ:-58.05
31P NMR(162.0MHz,CH3OH-d4):δ:0.04
LCMS:MS m/z(ESI):636.0[M-1]-.
Example B1
(N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ B ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamido) dihydrogenphosphate methyl ester B1
Figure BDA0002987656820000381
First step of
N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -N- ((methylthio) methyl) -5- (trifluoromethyl) pyridazine-3-carboxamide B1a
Compound A1c (500mg, 1.23mmol) and N, N-dimethylformamide (10mL) were added to the reaction flask. The reaction mixture was cooled to 0 deg.C, sodium hydride (74mg, 1.85mmol) was added, and stirred for 30 minutes. Chloromethyl methyl sulfide (236mg, 2.46mmol) and tetrabutylammonium iodide (1.19g, 3.69mmol) were added thereto. The mixture was stirred at room temperature for 1 hour and reacted at 45 ℃ for 18 hours. After cooling, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2 × 50 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate: hexane: 0-30:100) to give the title compound B1a (112mg, yield: 20%).
MS m/z(ESI):468.0[M+1]+
Second step of
N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ B ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -N- ((methylthio) methyl) -5- (trifluoromethyl) pyridazine-3-carboxamide B1B
Compound 1f (231mg, 0.74mmol), B1a (265mg, 0.57mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (44mg, 0.06mmol) and cesium carbonate (372mg, 1.14mmol) were added to a reaction flask and reacted under argon. 1, 4-dioxane (66 mL)/water (1.2mL) was added to the reaction mixture and stirred at 105 ℃ for 3 hours. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate (3X 25 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (ethyl acetate: dichloromethane: 0:100 to 75:100) to obtain the title compound B1B (190mg, yield: 58%).
MS m/z(ESI):573.0[M+1]+
The third step
(N- (4-methyl-3- (4-oxo-2 ',3',4,5,5',6' -hexahydro-3H-spiro [ benzo [ B ] [1,4] oxazepin-2, 4' -pyran ] -8-yl) phenyl) -5- (trifluoromethyl) pyridazine-3-carboxamido) dihydrogenphosphate methyl ester B1
A mixture of compound B1B (155mg, 0.27mmol), phosphoric acid (1.06g, 10.8mmol) and 3A molecular sieves (80mg) in tetrahydrofuran (5mL) was stirred at room temperature for 15 minutes and then cooled to 0 ℃. N-iodosuccinimide (122mg, 0.54mmol) was added and reacted at 0 ℃ for 30 minutes and at room temperature for 1 hour, respectively. The reaction mixture was filtered to remove solids. The filtrate was diluted with methanol and then cooled to 0 ℃. The resulting mixture was quenched with saturated sodium thiosulfate solution, adjusted to pH7 with 2N NaOH, filtered through celite, washed with methanol, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (0-50% acetonitrile in water + 0.2% ammonium hydrogencarbonate) to give the title compound B1(130mg, yield: 77%).
1H NMR(400MHz,CH3OH-d4) δ 9.33(s,1H),8.13(s,1H), 7.16-6.94 (m,4H),6.84(d,1H),6.76(s,1H),5.61(s,2H),3.86(td,2H),3.71(dt,2H),2.45(s,2H),2.05(s,3H),1.87(d,2H),1.73(ddd, 2H). In CH3No two-OH groups on the phosphoric acid were observed in OH-d 4.
31P NMR(400MHz,CH3OH-d4)δ-1.28(s)。
MS m/z(ESI):623.0[M+1]+
Test example 1 pharmacokinetic testing of Compounds of the disclosure
The instrument comprises the following steps:
API4000 triple quadrupole tandem mass spectrometer, applied biosystems, usa;
shimadzu LC-30AD ultra performance liquid chromatography system, Shimadzu, japan.
Chromatographic conditions are as follows:
a chromatographic column: welch Xtimate C181.8 μm 30x2.1mm
Mobile phase A: aqueous solution containing 0.5% formic acid, 5mM ammonium acetate (gradient elution)
Mobile phase B: 0.5% formic acid, 5mM ammonium acetate in 95% acetonitrile/water (gradient elution)
Column temperature: 35 deg.C
Preparation of test samples
Mu.l of plasma sample was mixed with 50. mu.L of internal standard solution (100ng/mL) and 200. mu.L of CH3CN precipitant was mixed and the solution was vortexed and stirred for 5 minutes, then centrifuged for 10 minutes (4000 rpm). 8 μ L of supernatant was sampled for LC/MS/MS analysis.
The process is as follows:
in the PK study in SD rats, animals of each group (N ═ 4, male 2, female 2) were fasted overnight. The intragastric administration (ig) group was administered by intragastric gavage. Blood samples (0.2ml) were collected from the orbit at time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours, placed in an ethidene-diaminediacetic acid tetrapotassium (K2 EDTA) anticoagulated blood collection tube, and then centrifuged at 4 deg.C (10,000rpm) for 1 minute to obtain plasma. Plasma samples were separated over 1 hour and stored at-20 ℃ until analyzed by liquid chromatography-tandem mass spectrometry (LC/MS). The whole process from blood collection to centrifugation was performed under ice bath conditions. Rats were fed 2 hours after dosing.
Data analysis
Pharmacokinetic parameters were derived by non-compartmental analysis of plasma concentrations (determined by LC/MS) versus time point data. Peak concentrations (Cmax) and Cmax times were recorded directly from experimental observations. Calculating the area under the curve from time zero to the last sample time (AUC) using a combination of linear and logarithmic trapezoidal summations0-t)。
As a result:
in rat gavage (ig) dosing experiments, the prodrug compound a1 in formulation a was dosed at 20mpk and 100mpk (× for a1, dose 1 equivalent of the parent drug). Plasma exposure levels indicated that only prodrug compound 1 was detected and prodrug compound a1 was not found. AUC at 20mpk0-t 19922ng/ml × h; AUC at 100mpk0-t 132780ng/ml × h (table 1).
In sharp contrast, also in the rat gavage (ig) dosing experiment, the original drug compound 1 was tried in different formulations using different doses, the best AUC of which0T can only reach around 22000ng/ml h (Table 1). Prodrug compound a1 of the present disclosure showed significant AUC compared to the original drug compound 10-t is improved.
A similar trend was also observed in compound B1: in rat gavage experiments (ig), prodrug compound B1 was also administered at doses of 20mpk and 100mpk (× for B1, dose 1 equivalent of the parent drug). Plasma exposure levels indicated that only prodrug compound 1 was detected and prodrug compound B1 was not found. AUC at 20mpk0-t 20736ng/ml h; AUC at 100mpk0-t 102170ng/ml × h (table 1). Compared to the original drug compound 1, the present disclosureProdrug compound B1 also showed significant AUC0-t is improved.
Table 1 pharmacokinetic data for the compounds of the disclosure.
Figure BDA0002987656820000401
Note that for prodrug compounds a1 and B1, the dose is 1 equivalent of the parent drug compound.
Formulation a 5% dimethyl sulfoxide + 20% PEG400+ 70% (10% TPGS) + 5% (1% HPMC K100LV)
Formulation b, 5% dimethyl sulfoxide, 40% PEG400, 5% ethanol and 50% propylene glycol
Formulation c, 5% dimethyl sulfoxide + 25% PEG400+ 35% RH40+ 35% water
Abbreviations:
Cmaxmaximum plasma concentration
PEG400 polyethylene glycol 400
HPMC K100LV hydroxypropyl methylcellulose (HPMC) K100LV
TPGS D-alpha-tocopheryl polyethylene glycol 1000 succinate
RH40:
Figure BDA0002987656820000411
RH40
Test example 2:
biological evaluation
cRAF kinase Activity inhibition assay
The ability of a compound to inhibit cRAF kinase activity was tested in vitro using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay, and assayed according to kit instructions. Briefly, human recombinant cRAF protein kinase (BPS Bioscience, catalog No. 40008) was first diluted to 0.027 ng/. mu.l using 1-fold kinase buffer a (Life Tech, catalog No. PV6135, 5-fold original concentration, diluted 1-fold with water); fluorescein-labeled MAP2K1(Life Tech, catalog number PV4812) was diluted to 0.5 μ M; ATP (Life Tech, Cat # PV3227) was diluted to 20. mu.M; 2.5ul of each of the diluted reagents described above was then added to a 384 well plate (Perkinelmer, ProxiPlate-384 Plus, Cat. No. 60)08280) Mixing, and mixing; add 2.5 μ L of the compound after gradient dilution to the above mixture (blank for the same volume of dilution without compound); then, 10. mu.l of 400-fold diluted LanthaScreen Tb-pMAP2K1(pSer217/221) antibody (Life Tech, Cat. No. PV4817) was added and incubated at room temperature for 1 hour. Data were read on PHERAStar FSX, percent inhibition of kinase activity by compound was calculated (blank 0% inhibition, no kinase control 100% inhibition), dose response curves were generated using GraphPad Prism software, and median Inhibitory Concentration (IC) was calculated by non-linear regression analysis50)。
BRAFWTInhibition of kinase Activity
Detection of compound vs BRAF in vitro using time-resolved fluorescence resonance energy transfer (TR-FRET) assayWTThe inhibitory capacity of kinase activity was determined according to the kit instructions. Briefly, human recombinant BRAF was first diluted 1-fold with 1-fold kinase buffer a (Life Tech, catalog No. PV6135, 5-fold original concentration, 1-fold diluted with water)WTProtein kinase (BPS Bioscience, catalog number 40065) diluted to 0.027 ng/. mu.L; fluorescein-labeled MAP2K1(Life Tech, catalog number PV4812) was diluted to 0.5 μ M; ATP (Life Tech, Cat # PV3227) was diluted to 20. mu.M; 2.5ul of each of the diluted reagents described above was added to a 384 well plate (Perkinelmer, ProxiPlate-384 Plus, cat. No. 6008280) and mixed well; add 2.5 μ L of the compound after gradient dilution to the above mixture (blank for the same volume of dilution without compound); then, 10. mu.l of 400-fold diluted LanthaScreen Tb-pMAP2K1(pSer217/221) antibody (Life Tech, Cat. No. PV4817) was added and incubated at room temperature for 1 hour. Data were read on PHERAStar FSX, percent inhibition of kinase activity by compound was calculated (blank 0% inhibition, no kinase control 100% inhibition), dose response curves were generated using GraphPad Prism software, and median Inhibitory Concentration (IC) was calculated by non-linear regression analysis50)。
BRAFV600EInhibition of kinase Activity
Detection of compound vs BRAF in vitro using time-resolved fluorescence resonance energy transfer (TR-FRET) assayV600EInhibitory Activity of kinaseThe assay was performed according to the kit instructions. Briefly, human recombinant BRAFV600E protein kinase (BPS Bioscience, catalog No. 40533) was first diluted to 0.027 ng/. mu.l using 1-fold kinase buffer a (Life Tech, catalog No. PV6135, 5-fold original concentration, diluted 1-fold with water); fluorescein-labeled MAP2K1(Life Tech, catalog number PV4812) was diluted to 0.5 μ M; ATP (Life Tech, Cat # PV3227) was diluted to 20. mu.M; 2.5ul of each of the diluted reagents described above was added to a 384 well plate (Perkinelmer, ProxiPlate-384 Plus, cat. No. 6008280) and mixed well; add 2.5 μ L of the compound after gradient dilution to the above mixture (blank for the same volume of dilution without compound); then, 10. mu.L of 400-fold diluted LanthaScreen Tb-pMAP2K1(pSer217/221) antibody (Life Tech, Cat. No. PV4817) was added and incubated at room temperature for 1 hour. Data were read on PHERAStar FSX, percent inhibition of kinase activity by compound was calculated (blank 0% inhibition, no kinase control 100% inhibition), dose response curves were generated using GraphPad Prism software, and median Inhibitory Concentration (IC) was calculated by non-linear regression analysis50)。
Figure BDA0002987656820000421
And (4) conclusion: the disclosed compounds are potential inhibitors of RAF.
Test example 3 solubility testing of compounds of the present disclosure in PBS7.4 and Fassif
3.1 preparation of reference solution:
a 10 μ L stock solution of a sample to be tested (concentration 10mM, dissolved in DMSO) and 990 μ L of an organic mixed solvent (usually DMSO: acetonitrile: ethanol ═ 1:1:1) were precisely measured in a 2mL sample bottle and mixed well to obtain a clear 100 μ M sample solution as a reference solution.
3.2 preparation of compound PBS7.4 solution:
weighing a proper amount of a test compound, and adding DMSO or DMSO: acetonitrile: ethanol 1:1:1 was dissolved to prepare a 10mM stock solution of the test compound. Precisely measuring 10 mu L of stock solution of the compound to be detected and 990 mu L of PBS solution with pH7.4 in a 2mL sample bottle, and uniformly mixing, wherein the final DMSO concentration of the solution is 1% (v/v). The solution was prepared in two portions in parallel, shaken on a flat bed at room temperature for 24 hours, centrifuged at 5000rpm for 20min, and the supernatant was transferred to a liquid chromatograph for analysis.
3.3 preparation of compound Fassif solution:
dissolving 1mg of sample to be detected into 900 mu L of Fassif solution, strongly mixing, and preparing two solutions in parallel; after shaking in a 37 ℃ water bath for 24 hours, the mixture was centrifuged at 4000rpm for 30min, and the supernatant was transferred to liquid chromatography as a sample solution.
3.4. Data processing
Solubility (μ M) — peak area of sample/peak area of reference — (μ M) — (dilution of sample solution). The final solubility was taken as the average of the two measurements.
TABLE 3 solubility testing of Compounds of the present disclosure
Figure BDA0002987656820000431
And (4) conclusion: prodrug molecule example a1 is able to significantly improve solubility over the parent compound example 1. The other prodrug molecules A3, a4, a5 and a6 all have good solubility.
The foregoing embodiments and examples are provided for illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art based upon this disclosure, and such changes and modifications may be made without departing from the spirit and scope of the invention. All documents cited are incorporated herein by reference in their entirety without admission that they are prior art.

Claims (20)

1. A compound of the general formula (I),
Figure FDA0002987656810000011
or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof,
wherein:
G1selected from O, S, C (═ O), C (═ O) NH and NR6、CR7R8And S (═ O)2；
Ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
X1and X2Are the same or different and are each independently a hydrogen atom or L-R0(ii) a Provided that X is1And X2Not being hydrogen atoms at the same time;
l is selected from-CH2-、-C(＝O)O(CQ1Q2)n-and-C (═ O) S (CQ)1Q2)n-；
R0Selected from-OP (═ O) (OH)2、-OP(＝O)(OH)-OP(＝O)(OH)2、-OC(＝O)Q3、-OC(＝O)OQ3、-OC(＝O)NHQ3、-OP(＝O)(OQ4)2、-O-C(＝O)(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)(CQ1Q2)n-Cy-OP(＝O)(OH)2、-OC(＝O)CH＝CHC(＝O)OH、-O-C(＝O)-O-(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)-NH-(CQ1Q2)n-OP(＝O)(OH)2、-OC(＝O)CH(Q5)-NQ6Q7and-NQ6Q7；
Cy is aryl or heteroaryl, each independently optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Q1、Q2、Q3and Q5Are identical or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group and-C (═ O) R9Wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitroAlkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Q4selected from alkyl, -CH2OC(＝O)R9and-CH2-OC(＝O)OR9；
Q6And Q7Are identical or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, -C (═ O) R9Cycloalkyl, heterocyclyl, aryl and heteroaryl;
R1the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R2aand R2The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R3the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R4and R5The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R6selected from the group consisting of hydrogen atom, alkyl group, haloalkyl group, hydroxyl group, hydroxyalkyl group, amino group, cycloalkyl group, heterocyclic group, C (O) OR10、C(O)R11Aryl and heteroaryl;
R7and R8Are the same OR different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, C (O) OR10Aryl and heteroaryl;
or R7And R8Together form a cycloalkyl or heterocyclyl group;
R9is alkyl, optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkoxy, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R10selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R11selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
n is an integer of 1 to 6;
r is 0, 1,2 or 3;
s is 0, 1,2, 3 or 4; and is
q is 0, 1,2, 3 or 4.
2. The compound of claim 1, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein G is1Is an O atom.
3. The compound according to claim 1 or 2, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R is2aIs C1-6Alkyl, preferably methyl.
4. A compound according to any one of claims 1 to 3, or a tautomer thereofA isomer, cis or trans, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R4And R5Is a hydrogen atom.
5. The compound according to any one of claims 1 to 4, which is a compound represented by the general formula (II), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof,
Figure FDA0002987656810000031
wherein:
ring A, X1、X2、R1、R2、R3S, r and q are as defined in claim 1.
6. The compound of any one of claims 1 to 5, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein X is1And X2Are the same or different and are each independently selected from the group consisting of a hydrogen atom, -CH2-R0and-C (═ O) O (CQ)1Q2)n-R0(ii) a Provided that X is1And X2Not being hydrogen atoms at the same time; r0、Q1、Q2And n is as defined in claim 1.
7. The compound of any one of claims 1 to 5, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein X is1And X2Are the same or different and are each independently selected from the group consisting of a hydrogen atom, -CH2OC(＝O)CH3、-CH2OC(＝O)OCH3、-CH2OC(＝O)NHCH3、-CH2OP(＝O)(OH)2、-CH2OP(＝O)(OH)OP(＝O)(OH)2、-CH2OP(＝O)(OQ4)2、-C(＝O)OCH2OC(＝O)C(CH3)3、-C(＝O)OCH2OP(＝O)(OH)2、-C(＝O)OCH2CH2OP(＝O)(OH)2、-C(＝O)OCH2OC(＝O)CH＝CHCOOH、
Figure FDA0002987656810000032
Figure FDA0002987656810000033
Provided that X is1And X2Not being hydrogen atoms at the same time; q4As defined in claim 1.
8. The compound of claim 1, which is a compound of formula (III) or formula (IV), or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof,
Figure FDA0002987656810000041
wherein:
L1and L2Are the same or different and are each independently selected from-CH2-、-C(＝O)O(CQ1Q2)n-and-C (═ O) S (CQ)1Q2)n-; preferably, L1And L2Are the same or different and are each independently-CH2-；
RaAnd RbAre identical or different and are each independently selected from the group consisting of-OP (═ O) (OH)2、-OP(＝O)(OH)-OP(＝O)(OH)2、-OC(＝O)Q3、-OC(＝O)OQ3、-OC(＝O)NHQ3、-OP(＝O)(OQ4)2、-O-C(＝O)(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)(CQ1Q2)n-Cy-OP(＝O)(OH)2,-OC(＝O)CH＝CHC(＝O)OH、-O-C(＝O)-O-(CQ1Q2)n-OP(＝O)(OH)2、-O-C(＝O)-NH-(CQ1Q2)n-OP(＝O)(OH)2、-OC(＝O)CH(Q5)-NQ6Q7and-NQ6Q7(ii) a preferably-OP (═ O) (OH)2。
Ring A, R1、R2、R3、Cy、Q1～Q7S, r, q and n are as defined in claim 1.
9. The compound of any one of claims 1 to 8, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein ring a is a 5-or 6-membered heteroaryl; pyridyl, pyridazinyl and pyrimidinyl are preferred.
10. The compound according to any one of claims 1 to 9, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure FDA0002987656810000042
Selected from:
Figure FDA0002987656810000043
Figure FDA0002987656810000044
R1and s is as defined in claim 1。
11. The compound according to any one of claims 1 to 10, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R is1Is haloalkyl or haloalkoxy; preferably a halogen atom1-6Alkyl or halo C1-6An alkoxy group.
12. The compound according to any one of claims 1 to 11, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R is2And R3Is a hydrogen atom.
13. The compound according to any one of claims 1 to 12, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, which is selected from the group consisting of:
Figure FDA0002987656810000051
Figure FDA0002987656810000061
Figure FDA0002987656810000062
preference is given to
Figure FDA0002987656810000063
14. A compound of formula (IIIA) or (IVA):
Figure FDA0002987656810000064
or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof,
wherein:
Rwis-SCH3Or an iodine atom;
ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
L1and L2Are the same or different and are each independently selected from-CH2-、-C(＝O)O(CQ1Q2)n-and-C (═ O) S (CQ)1Q2)n-; preferably, L1And L2Are the same or different and are each independently-CH2-；
Q1And Q2Are identical or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group and-C (═ O) R9Wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R9is alkyl, optionally substituted with one or more substituents selected from the group consisting of alkoxy, halo, haloalkoxy, hydroxy, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R1the same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroarylIs substituted with one or more substituents of (1);
R2the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R3the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
n is an integer of 1 to 6;
r is 0, 1,2 or 3;
s is 0, 1,2, 3 or 4; and is
q is 0, 1,2, 3 or 4.
15. The compound of claim 14, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of:
Figure FDA0002987656810000071
Figure FDA0002987656810000081
16. a process for preparing a compound of formula (III) or formula (IV) according to claim 8, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, comprising:
Figure FDA0002987656810000082
a compound of the formula (IIIA) and Ra-H reaction to give a compound of general formula (III);
compounds of the general formula (IVA) and Rb-H reaction to give a compound of general formula (IV);
wherein:
Rwis-SCH3；
Ring A, R1、R2、R3、L1、L2、Ra、RbS, r and q are as defined in claim 8.
17. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 13, or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
18. Use of a compound of general formula (I) according to any one of claims 1 to 13 or a tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 17, for the manufacture of a medicament for the inhibition of RAF.
19. Use of a compound of general formula (I) according to any one of claims 1 to 13 or a tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition according to claim 17, for the manufacture of a medicament for the treatment of a RAF mediated disease or disorder; preferably, the RAF mediated disease or disorder is cancer.
20. The use of claim 19, wherein the cancer is selected from the group consisting of lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck cancer, and myeloma; lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdomyosarcoma, synovial sarcoma, and mesothelioma are preferred.
CN202110305777.9A 2020-03-23 2021-03-23 Prodrug of spiro compound, preparation method and application thereof in medicine Active CN113429440B (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202010208470 2020-03-23
CN2020102084702 2020-03-23
CN2021101849519 2021-02-10
CN202110184951 2021-02-10

Publications (2)

Publication Number Publication Date
CN113429440A true CN113429440A (en) 2021-09-24
CN113429440B CN113429440B (en) 2023-05-12

Family

ID=77752896

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110305777.9A Active CN113429440B (en) 2020-03-23 2021-03-23 Prodrug of spiro compound, preparation method and application thereof in medicine

Country Status (1)

Country Link
CN (1) CN113429440B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264945A (en) * 2020-02-17 2021-08-17 江苏恒瑞医药股份有限公司 Spiro derivative, preparation method and medical application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014207648A1 (en) * 2013-06-24 2014-12-31 Lupin Limited Chromane and chromene derivatives and their use as crac modulators
CN108699065A (en) * 2015-12-18 2018-10-23 诺华股份有限公司 Tricyclic compounds and composition as kinase inhibitor
CN109963845A (en) * 2017-05-23 2019-07-02 江苏恒瑞医药股份有限公司 Loop coil carboxamides derivatives, preparation method and its application in medicine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014207648A1 (en) * 2013-06-24 2014-12-31 Lupin Limited Chromane and chromene derivatives and their use as crac modulators
CN108699065A (en) * 2015-12-18 2018-10-23 诺华股份有限公司 Tricyclic compounds and composition as kinase inhibitor
CN109963845A (en) * 2017-05-23 2019-07-02 江苏恒瑞医药股份有限公司 Loop coil carboxamides derivatives, preparation method and its application in medicine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264945A (en) * 2020-02-17 2021-08-17 江苏恒瑞医药股份有限公司 Spiro derivative, preparation method and medical application thereof

Also Published As

Publication number Publication date
CN113429440B (en) 2023-05-12

Similar Documents

Publication Publication Date Title
JP7211959B2 (en) Amide derivative inhibitor and its production method and use
WO2020156311A1 (en) Pyridazine derivative inhibitor, and preparation method and application thereof
CN111107848B (en) Pharmaceutical composition containing amide derivatives, and preparation method and application thereof
TW202115076A (en) Pyrimidine five-membered nitrogen heterocyclic derivatives, a preparation method thereof and pharmaceutical use thereof
CN107033097B (en) Oxadiazole derivative, preparation method and medical application thereof
KR20210150491A (en) Phosphatidylinositol 3-kinase inhibitor
TW202016120A (en) Tricyclic derivatives inhibitor, preparation method, and applications thereof
RU2742770C1 (en) Indole derivative and formamide, method for production thereof and use in medicine
US20210355107A1 (en) Multi-substituted pyridone derivatives and medical use thereof
WO2022105771A1 (en) Nitrogen-containing heterocyclic derivative, and preparation method therefor and medical application thereof
TW201917129A (en) Triacyclic derivatives containing pyrazole, their preparation methods and applications thereof
CN117597341A (en) Sulfonamide derivative, preparation method and application thereof in medicine
CN115594695A (en) Macrocyclic compound, preparation method and medical application thereof
WO2022089389A1 (en) Heterocyclic compound, preparation method therefor, pharmaceutical composition thereof and application thereof
CN113429440B (en) Prodrug of spiro compound, preparation method and application thereof in medicine
EP4039674A1 (en) Sulfo-substituted biaryl compound or salt thereof, preparation method therefor, and use thereof
TW202325298A (en) A nitrogen-containing tetracyclic compound, a preparation method and medical use thereof
CN112996783B (en) 2-aminopyrimidine derivatives, preparation method and application thereof in medicines
TW201817726A (en) 3,4-dipyridinyl pyrazole derivatives, a preparation method thereof and pharmaceutical use thereof
CN109535132B (en) 2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof
CN113912608B (en) Pyrimidopyrimidinone derivatives, preparation method thereof and application thereof in medicines
CN110964034B (en) Pyrimidothiophene derivative, preparation method and medical application thereof
WO2024041613A1 (en) Heterocyclic compound, method for preparing same, and pharmaceutical use thereof
WO2022166810A1 (en) Fused azatricyclic derivative, preparation method therefor, and application thereof in medicine
WO2022161447A1 (en) Dicarboxamide compound, preparation method therefor, and pharmaceutical use thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant