CN114573584A - DNA-PK selective inhibitor and preparation method and application thereof - Google Patents

DNA-PK selective inhibitor and preparation method and application thereof Download PDF

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Publication number
CN114573584A
CN114573584A CN202011298735.9A CN202011298735A CN114573584A CN 114573584 A CN114573584 A CN 114573584A CN 202011298735 A CN202011298735 A CN 202011298735A CN 114573584 A CN114573584 A CN 114573584A
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alkyl
methyl
dihydro
halogen
purin
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Inventor
陈曦
侯登
陈坤成
雷永珂
任仁
闵汪洋
刘志华
刘希杰
张凯
孙永亮
路畅
张苗
孙颖慧
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Capital Pharmaceutical Holdings Beijing Co ltd
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Capital Pharmaceutical Holdings Beijing Co ltd
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Priority to CN202011298735.9A priority Critical patent/CN114573584A/en
Priority to CN202180061261.2A priority patent/CN116406272A/en
Priority to PCT/CN2021/107304 priority patent/WO2022017368A1/en
Publication of CN114573584A publication Critical patent/CN114573584A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The application relates to a DNA-PK selective inhibitor shown as a formula (I) and a preparation method and application thereof. The application comprises the application of the compound shown in the formula (I) in preparing a medicament for treating diseases related to DNA-PK. During the preparation process, the compound is prepared by substitution, reduction and synthesisA series of reactions, such as cyclization and alkylation, to give the compounds of the invention.

Description

DNA-PK selective inhibitor and preparation method and application thereof
Technical Field
The present invention relates to compounds that selectively inhibit the activity of DNA-PK proteins, to methods of making these compounds and salts thereof, and to methods of using such compounds and salts for the treatment of DNA-PK mediated diseases, including cancer.
Background
DNA-dependent protein kinase (DNA-PK) is a serine, threonine protein kinase that is activated when bound to DNA. DNA-PK is a trimer formed by polymerization of a heterodimer consisting of a catalytic subunit DNA-PKcs (size 470kD) and 2 regulatory subunits Ku70 and Ku80 after contacting and breaking DNA. Wherein the DNA-PKcs is one of phosphatidylinositol-3 kinase family members, and participates in various biochemical reaction processes: repair of double-stranded DNA breaks (DSBs), signaling of programmed death, gene surveillance, maintenance of telomere structure, etc. (FASEB J, 2005, 19 (7): 704-. Sensitivity of cells to radiotherapy and chemotherapy can be increased by inhibiting the repair of these DNA lesions (Int J Hyperthermia, 2008, 24 (1): 17-29.). In DNA damage, DNA Double Strand Break (DSB) is the most fatal, and DSB repair is mainly performed by DNA-dependent protein kinase DNA-PK dominated DNA non-homologous end joining (NHEJ). (Cell Res, 2008, 18 (1): 114-. In addition to playing a major role in the repair of DSBs, DNA-PK also functions in other ways:
1) v (D) J chain rearrangements of immunoglobulin and T cell receptors, such as deletion of DNA-PKcs or Ku protein, Severe Combined Immunodeficiency (SCID) occurs in mammalian cells
2) The telomere structure is maintained to be stable, and the lack of Ku or DNA-PKcs can cause unstable genome, cell growth retardation and premature senility;
3) DNA-PKcs is a serine/threonine kinase, a member of PI-3-K (phosphine tip in to 1-3-kinase) kinase family (including A TM, A TR, etc.), and plays a role in the functions of cell signal transduction and cell cycle after DNA damage. (Int J radial Oncol Biol Phys, 2005, 61 (3): 915-.
A range of factors can induce DNA double strand breaks, including chemotherapy, radiation therapy, and PARP inhibitors such as olaparib. DNA-PK inhibitors have the potential to sensitize these therapies. A plurality of DNA-PK selective inhibitors enter a clinical stage at present all over the world, wherein two medicaments enter a clinical second stage, but no related medicament is on the market so far, and the requirements of the related medicament are not met. The DNA-PK selective inhibitor provided by the invention has high activity, strong drug resistance and small clinical side effect, can effectively enhance the sensitivity of radiotherapy and chemotherapy in tumor treatment, and has better economic value and application prospect.
Disclosure of Invention
The invention provides a DNA-PK selective inhibitor which is a compound shown as a general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof. The invention also provides a series of compounds represented by the general formula (I) and pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, pharmaceutical compositions containing the compounds, and methods of treating diseases using the compounds.
In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof
Figure BSA0000225311520000021
Wherein the content of the first and second substances,
ring A is 6-10 membered aryl or 5-12 membered heteroaryl,
ring B is C3-8Cycloalkyl or a 4-12 membered heterocyclic ring, S on the B ring may be optionally oxidized,
z is O or S, and the compound is,
X2is CR2Or the number of N is greater than the number of N,
X1is CRR4O, S, or NR6，
R1Is H, C1-6Alkyl, or C3-8Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CN, -OH, -NH2、-O-C1-6Alkyl, or-NR-C1-6Alkyl substitution;
R7and R8Each independently selected from halogen, CN, C1-6Alkyl, -O-C1-6Alkyl and-NR-C1-6Alkyl, which may optionally be substituted by halogen, -CN, -OH, -NH2、-O-C1-6Alkyl, or-NR-C1-6The substitution of the alkyl group is carried out,
m and n are each independently 0, 1, 2, or 3,
R3is R5or-X3-R5，
R4Is R6or-X3-R6，
X3Each independently is-O-, -S-, or-NR-,
R5and R6Each independently selected from H and C1-6Alkyl, or R5And R6Taken together to form- (CH)2)p-X-(CH2)q-, wherein X is a bond, -CH-, -CO-CH-, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, a 6-to 10-membered arylene, a 5-to 12-membered heteroarylene, or a 3-to 12-membered heterocycle, and- (CH-)2)p-X-(CH2)qCH in (A-C)2Optionally substituted by halogen or C1-6The substitution of the alkyl group is carried out,
p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6,
R2selected from H, halogen, CH2F、CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl, - (CH)2)1-3-OH、-CHO、-(CO)NH2- (CO) NHR, - (CO) OR and-NR-C1-6An alkyl group.
Each R is independently H or C1-6An alkyl group;
in certain embodiments, R5And R6Each independently selected from H and C1-6Alkyl, or R5And R6Taken together to form- (CH)2)p-X-(CH2)q-, wherein X is a bond, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, a 6-to 10-membered arylene, a 5-to 12-membered heteroarylene, or a 3-to 12-membered heterocycle;
in certain embodiments, when R5And R6Each independently selected from H or C1-6When alkyl, R2Selected from halogen, CH2F、CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl, or-NR-C1-6An alkyl group, which is a radical of an alkyl group,
when R is5And R6Taken together to form- (CH)2)p-X-(CH2)qWhen is, R2Selected from H, halogen, CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl and-NR-C1-6An alkyl group, a carboxyl group,
r is H or C1-6An alkyl group;
in certain embodiments, R2Selected from H, halogen, CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl, -O-C1-6Alkyl, - (CH)2)1-3-CN、-(CH2)1-3-O-C1-6Alkyl, - (CH)2)1-3-OH、-CHO、-(CO)NH2- (CO) OR and-NR-C1-6Alkyl, R is H or C1-6An alkyl group; preferably, R2Selected from H, halogen, CHF2、CF3、CN、C1-6Alkyl and- (CO) NH2(ii) a More preferably, R2Selected from halogen, CHF2、CF3、CN、C1-6Alkyl and- (CO) NH2；
In certain embodiments, when
Figure BSA0000225311520000031
Is composed of
Figure BSA0000225311520000032
Figure BSA0000225311520000033
Or
Figure BSA0000225311520000034
When R is2Selected from halogen, CH2F、CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl and-NR-C1-6An alkyl group, a carboxyl group,
r is H or C1-6An alkyl group;
in certain embodiments, R1Is C1-6Alkyl or C3-8Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CN, -OH, -NH2、-O-C1-6Alkyl, or-NR-C1-6Alkyl substituted, R is H or C1-6Alkyl, preferably said alkyl and cycloalkyl groups may be optionally substituted by halogen or-CN;
in certain embodiments, R1Is C1-6An alkyl group;
in some embodiments of the invention, the compounds of the invention are selected from:
Figure BSA0000225311520000035
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
It is noted that the compounds and salts described in this specification can exist in solvated as well as unsolvated forms; the atoms of these compounds and salts described in this specification may exist as their isotopes; furthermore, the compounds and salts described in this specification may exist in optically active or racemic forms via one or more asymmetric carbon atoms.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof. In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable excipient.
In another aspect, the present invention provides a method of treating a DNA-PK related disease, said method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition thereof;
in another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or tautomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a DNA-PK related disease.
In some embodiments of the invention, the DNA-PK related disease is cancer; preferably, the cancer is colorectal cancer, malignant melanoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer.
Detailed Description
Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary.
It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.
Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. The use of the singular forms also includes the plural unless specifically stated otherwise. The use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
Certain chemical terms
The terms "optional", "optional" or "optionally"It is intended that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, optionally substituted groups may be unsubstituted (e.g.: CH)2CH3) Fully substituted (e.g.: -CF2CF3) Monosubstituted (e.g.: -CH2CH2F) Or any level between mono-and fully substituted (e.g.: -CH2CHF2、-CF2CH3、-CFHCHF2Etc.). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods. Unless specific definitions are set forth, the nomenclature used herein in the analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry, as well as the laboratory procedures and techniques, are those known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents as obtained when the formula is written from right to left2O-is equivalent to-OCH2-。
As used herein, the terms "group", "chemical group" or "chemical group" refer to a particular portion or functional group of a molecule. Chemical groups are often considered as chemical entities embedded in or attached to a molecule.
Some of the chemical groups named herein may be referred to by a shorthand notation for the total number of carbon atoms. E.g. C1-6Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by shorthand notation does not include carbon atoms on possible substituents.
The terms "halogen", "halo" or "halide" refer to bromine, chlorine, fluorine or iodine.
The compounds of the invention may contain one or more (e.g. one, two, three or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including1H、2H (D or deuterium) and3h (T or tritium); c may be in any isotopic form, including12C、13C and14c; o may be in any isotopic form, including16O and18o, and the like.
The terms "aromatic", "aromatic ring", "aromatic-cyclic" refer to a planar ring portion of one or more rings having a delocalized electron-conjugated system of 4n +2 electrons, where n is an integer. The aromatic ring may be formed from 5, 6, 7, 8, 9 or more atoms. The aromatic compound may be optionally substituted and may be monocyclic or fused-ring polycyclic. The term aromatic compound includes all carbocyclic rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).
The term "heteroatom" or "hetero" refers to atoms other than carbon and hydrogen. The heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
The term "fused" or "fused ring" refers to a ring structure in which two or more rings share one or more bonds.
The term "spiro" or "spirocyclic" refers to a cyclic structure in which two or more rings share one or more atoms.
The term "alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3 methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.
The term "alkenyl" refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having one or more C ═ C double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bond in these groups may be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH ═ CH)2) 1-propenyl (CH)2CH＝CH2) Isopropenyl (C (CH)3)＝CH2) Butenyl, 1, 3-butadienyl and the like. When a numerical range is present for alkenyl as defined herein, e.g. "C2-C6Alkenyl "or" C2-6The "alkenyl group" means an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified.
The term "alkynyl" refers to an optionally substituted, straight or branched chain, monovalent hydrocarbon radical having one or more C.ident.C triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. When a numerical range occurs for alkynyl as defined herein, for example "C2-C6Alkynyl "or" C2-6Alkynyl "refers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic.
The term "arylene" refers to a divalent group derived from a monovalent aromatic radical as defined above.
The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated pi-electron system. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, cyano, nitro, carbonyl, and heteroalicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.
The term "heteroarylene" refers to a divalent radical derived from a monovalent heteroaryl group as defined above.
The term "cycloalkyl" refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, possibly including fused, spiro or bridged ring systems, containing 3 to 15 ring-forming carbon atoms, preferably 3 to 10 ring-forming carbon atoms, more preferably 3 to 8 ring-forming carbon atoms, which may or may not be saturated, attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term "heterocycle" refers to an aliphatic heterocycle, where the number of carbon atoms of the heterocycle is indicated herein (e.g., C)3-6Heterocyclic ring) in which at least one non-carbon atom must be presentAnd (iii) a heteroatom. E.g. "C3-6The nomenclature of heterocyclic "relates only to the number of carbon atoms in the ring and not to the total number of atoms in the ring. The nomenclature as "4-6 membered heterocyclic ring" refers to the total number of atoms contained in the ring (i.e., a four, five or six membered ring wherein at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining 2-4 atoms are carbon atoms or heteroatoms). For heterocycles having two or more heteroatoms, the two or more heteroatoms may be the same or different from each other. Unless otherwise specified, a "heterocycle" of the present invention may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, spiro, or bridged ring systems, the nitrogen, carbon, or sulfur of which may be optionally oxidized, the nitrogen atom may be optionally quaternized, and which may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. The heterocyclic group containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atoms on the non-aromatic ring are attached to the rest of the molecule. The heterocyclic ring may be optionally substituted. As used herein, a "heterocycle" preferably contains from about 5 to about 20 or 5 to 10 or 5-8 or 5-6 backbone ring-forming atoms.
The term "polymorph" or "polymorph" refers to a compound of the invention having multiple lattice morphologies some compounds of the invention may have more than one crystal form, and the invention encompasses all polymorphs or mixtures thereof.
Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.
Unless otherwise specified, the compounds of the present invention contain olefinic double bonds including E and Z isomers.
It is understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in the R or S configuration. It will be apparent to those skilled in the art that some of the compounds of the present invention may also exhibit cis-trans isomerism. It is to be understood that the compounds of the present invention include their individual geometric and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers may be separated from their mixtures by carrying out or modifying known methods such as chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates.
The term "pharmaceutically acceptable salts" includes both acid and base salts.
"pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, and the like, which retain the biological potency and properties of the free base of the compound, which are not biologically or otherwise undesirable. "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free acid of the compound and which are not biologically or otherwise undesirable. Salts formed by reaction with an inorganic base include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, caffeine, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
Crystallization often produces solvates of the compounds of the present invention. The term "solvate" as used herein refers to a combination of one or more molecules of the compound of the present invention and one or more molecules of a solvent.
The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent may be used. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also retain water only by chance or a mixture of water and some other solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
The term "pharmaceutical composition" refers to a formulation mixed with a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human.
The term "acceptable" in relation to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.
The term "pharmaceutically acceptable" refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.
The terms "subject," "patient," "subject" or "individual" refer to an individual having a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment related to the methods and compositions provided herein, the mammal is a human.
The term "treatment" refers to the treatment of a disease or condition associated with a mammal, particularly a human, and includes
(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has previously been exposed to the disease or condition but has not been diagnosed as having the disease or condition;
(ii) inhibiting the disease or disorder, i.e., controlling its development;
(iii) relieving the disease or condition, i.e., causing regression of the disease or condition;
(iv) relieving symptoms caused by the disease or disorder.
The terms "disease" and "condition" may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is unknown) and therefore are not to be considered as diseases but only as unwanted conditions or syndromes, some of which more or less specific symptoms have been confirmed by clinical researchers.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to the amount of at least one agent or compound that is sufficient to alleviate, to some extent, one or more of the symptoms of the disease or condition being treated upon administration. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering", and the like refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The anti-cancer treatments described herein may be useful as monotherapy or may include conventional surgery, radiotherapy or chemotherapy in addition to the administration of a compound having formula (I); or a combination of such additional therapies. Such conventional surgery, radiation therapy or chemotherapy may be administered simultaneously, sequentially or separately with the compound of formula (I) for treatment.
Preparation of the Compounds of the invention
The following reaction scheme illustrates the process for preparing the compounds of the present invention.
It will be appreciated that in the following description, combinations of substituents and/or variables of the formula are permitted only in the context of forming stable compounds.
It will also be appreciated by those skilled in the art that in the schemes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxyl groups. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butylmethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable amino, amidino and guanidine protecting groups include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include-C (O) -R '(R' represents alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed by standard techniques known to those skilled in the art.
Examples
The following non-limiting examples are illustrative only and do not limit the invention in any way.
Unless otherwise indicated, temperatures are in degrees celsius. Reagents were purchased from commercial suppliers such as the national drug group chemical reagent beijing ltd, Alfa Aesar (Alfa Aesar), or beijing lark technologies ltd, and these reagents were used directly without further purification unless otherwise specified.
Unless otherwise stated, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; the reaction bottle is provided with a rubber diaphragm so as to add the substrate and the reagent through an injector; glassware was dried and/or heat dried.
Unless otherwise stated, column chromatography purification was performed using 200-300 mesh silica gel from Qingdao oceanic plants; preparation of thin-layer chromatography silica gel precast slab (HSGF254) produced by Nicoti chemical industry research institute was used; MS is measured by a Thermo LCQ fly model (ESI) liquid chromatography-mass spectrometer; the optical rotation was measured by using an SGW-3 automatic polarimeter, Shanghai Spanish Meter, Ltd.
Nuclear magnetic data (1H NMR) was run at 400MHz using a Varian instrument. The solvent used for nuclear magnetic data is CDCl3、CD3OD、D2O, DMSO-d6, based on tetramethylsilane (0.00ppm) or based on residual solvent (CDCl)3：7.26ppm；CD3OD：3.31ppm；D2O: 4.79 ppm; d 6-DMSO: 2.50 ppm). When indicating the diversity of the peak shapes, the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If the coupling constant is given, it is given in Hertz (Hz).
Abbreviations:
Figure BSA0000225311520000091
intermediate 13: 1- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carba-nitrile
Figure BSA0000225311520000092
Step 1: 8-amino-1, 4-dioxazine [4.5] decane-8-carbonitrile
Tetraisopropyl titanate (5.68g) was added to a saturated solution of ammonia in ethanol (50mL) under nitrogen, to which was slowly added 1, 4-dioxazine [4.5] decan-8-one (1.56 g). The reaction was stirred at room temperature for 2 hours, then cooled to-5 ℃ and TMSCN (1.1g) was added. The reaction was maintained at this temperature for 3 hours, then at room temperature overnight. The reaction was quenched with water (2mL), the system was filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 1: 1 (V: V)) to give the objective compound (0.91 g).
And 2, step: 8- ((2-chloro-5-nitropyrimidin-4-yl) amino) -1, 4-dioxa [4.5] decane-8-carbonitrile
2, 4-dichloro-5-nitropyrimidine (0.97g) and triethylamine (1.01g) were dissolved in tetrahydrofuran (50mL), and 8-amino-1, 4-dioxazine [4.5] decane-8-carbonitrile (0.91g) was slowly added under an ice bath. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride (200mL), extracted with ethyl acetate (100mL), the extracts were dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 5: 1 (V: V)) to give a yellow solid (1.5 g).
And step 3: 8- ((5-amino-2-chloropyrimidin-4-yl) amino) -1, 4-dioxaspiro [4.5] decane-8-carbonitril
To a solution of 8- ((2-chloro-5-nitropyrimidin-4-yl) amino) -1, 4-dioxa [4.5] decane-8-carbonitril (1.5g) in acetic acid (50mL) was added reduced iron powder (1.8g) at room temperature, followed by stirring at room temperature for 2 hours, the reaction solution was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol 10: 1 (V: V)) to give a white solid (1.2 g).
And 4, step 4: 8- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbo-nitrile
8- ((5-amino-2-chloropyrimidin-4-yl) amino) -1, 4-dioxaspiro [4.5] decane-8-carbonitrile (1.2g) and CDI (1.4g) in step 3 were dissolved in tetrahydrofuran (30mL), heated to 65 ℃ under nitrogen protection and stirred for 2 hours, cooled to room temperature, the reaction solution was poured into water (100mL), the reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate ═ 1: 1 (V: V)) to give a white solid (1.1 g).
And 5: 8- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbonitrile
To a solution of 8- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbonitrile (1.1g) obtained in step 4 in DMF (20mL) at 0 ℃ was slowly added 60% (mineral oil) sodium hydride (210mg), and after the addition was completed, stirring was continued at 0 ℃ for 10 minutes. Methyl iodide (1.0g) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and stirred continuously, a white precipitate was generated, and the precipitate was filtered and dried to obtain the objective compound (950 mg).
Step 6: 1- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile
To a solution of 8- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1, 4-dioxa [4.5] decane-8-carbonitrile (950mg) obtained in step 5 in dioxane (20mL) was slowly added 4M hydrochloric acid (10mL) at 0 deg.C, and stirring was continued for 10 hours after the end of addition. The reaction solution was then diluted with aqueous sodium bicarbonate (100mL) and stirred continuously, a white precipitate was generated, and the solid was filtered and dried to give the objective compound (600 mg).
Intermediate 14: 2-chloro-9- ((1r, 4r) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (synthesized according to the method described in patent WO2019/238929A 1)
Figure BSA0000225311520000101
Intermediate 15: 2-chloro-9- ((1s, 4s) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (synthesized according to the method described in patent WO2019/238929A 1)
Figure BSA0000225311520000111
Intermediate 16: 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
Figure BSA0000225311520000112
Step 1: 4- ((2-chloro-5-nitropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester
2, 4-dichloro-5-nitropyrimidine (0.97g) and triethylamine (1.01g) were dissolved in tetrahydrofuran (50mL), and tert-butyl 4-amino-4-cyanopiperidine-1-carboxylate (1.13g) was slowly added under ice bath. The reaction solution was warmed to room temperature and stirred for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride (200mL), extracted with ethyl acetate (100mL), the extracts were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 5: 1 (V: V)) to give a yellow solid (1.7 g).
Step 2: 4- ((5-amino-2-chloropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester
To a solution of tert-butyl 4- ((2-chloro-5-nitropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylate (1.7g) in acetic acid (50mL) at room temperature was added reduced iron powder (1.9g), and then the reaction was stirred at room temperature for 2 hours, and the reaction liquid was filtered with celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 10: 1 (V: V)) to give a white solid (1.3 g).
And step 3: 4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester 4- ((5-amino-2-chloropyrimidin-4-yl) amino) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.3g) and CDI (1.5g) in step 2 are dissolved in tetrahydrofuran (50mL), heating to 65 ℃ under the protection of nitrogen, stirring for 2 hours, cooling to room temperature, pouring the reaction solution into water (100mL), the reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 1: 1 (V: V)) to obtain a white solid (1.2 g).
And 4, step 4: 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester
To a solution of tert-butyl 4- (2-chloro-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylate (1.2g) obtained in step 3 in DMF (20mL) at 0 ℃ was slowly added 60% (mineral oil) sodium hydride (200mg), and after completion of addition stirring was continued at 0 ℃ for 10 minutes. Methyl iodide (1.0g) was then slowly added to the reaction solution, and after 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and stirred continuously, and a white precipitate was generated, which was filtered and dried to obtain the objective compound (990 mg).
And 5: 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbo-nitrile
To a solution of tert-butyl 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-cyanopiperidine-1-carboxylate (990mg) obtained in step 4 in dioxane (20mL) was slowly added 4M hydrochloric acid (20mL) at 0 ℃ and stirring was continued for 10 hours after the addition was completed. The reaction solution was then neutralized with saturated aqueous sodium hydrogencarbonate solution to pH 8, a white precipitate was generated, and the solid was filtered and dried to give the objective compound (500 mg).
Example 86: (E) -27，47-dimethyl-28，29-dihydro-27H-3-aza-2 (9, 2) -purine-4 (6, 3) - [1, 2, 4]]Triazole [4, 3-a ]]Pyridine-1 (4, 1) -piperidinylcyclohexane-286-diketones
Figure BSA0000225311520000121
Step 1: 2- (7-methyl-6-nitro- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetic acid methyl ester
2-hydrazino-4-methyl-5-nitropyridine (1.68g) and monomethyl malonate (1.18g) were dissolved in toluene (50mL) at room temperature, phosphorus oxychloride (3.1g) was added thereto, and the reaction mixture was stirred at 90 ℃ for 12 hours. The reaction was cooled to room temperature, quenched by addition of methanol, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol 50: 1 (V: V)) to give the title compound (1.2 g).
Step 2: 2- (7-methyl-6-nitro- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetic acid
Methyl 2- (7-methyl-6-nitro- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetate (1.2g) was dissolved in MeOH (30mL) at room temperature, to which was added 1M aqueous lithium hydroxide (30 mL). The reaction mixture was stirred at room temperature for 2 hours, and the pH of the system was adjusted to 4 with 1M dilute aqueous hydrochloric acid, whereby a precipitate was generated. The solid was filtered and dried to give the title compound (900 mg).
And step 3: 2-chloro-7-methyl-9- (1- (2- (7-methyl-6-nitro- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one
2- (7-methyl-6-nitro- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetic acid (900mg), intermediate 62-chloro-7-methyl-9- (piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (1.1g), HATU (2.9g) were dissolved in DMF (30mL) at 0 deg.C, DIEA (1.5mL) was added thereto, the reaction mixture was stirred at room temperature for 12 hours, then poured into water (100mL) and stirred constantly, and the resulting precipitate was collected and filtered to give the title compound (1.5 g).
And 4, step 4: 9- (1- (2- (6-amino-7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-7-methyl-9- (1- (2- (7-methyl-6-nitro- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -7, 9-dihydro-8H-purin-8-one (1.5g) in acetic acid (50mL) was added reduced iron powder (1.6g) at room temperature, the reaction was stirred at room temperature for 2 hours, the reaction solution was filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol 10: 1 (V: V)) to give a white solid (1.21 g).
And 5: (E) -27，47-dimethyl-28，29-dihydro-27H-3-aza-2 (9, 2) -purine-4 (6, 3) - [1, 2, 4]]Triazole [4, 3-a ]]Pyridine-1 (4, 1) -piperidinylcyclohexane-286-diketones
9- (1- (2- (6-amino-7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-3-yl) acetyl) piperidin-4-yl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (46mg), RuPhos Pd G3(9mg), and cesium carbonate (65mg) were dissolved in dioxane (20mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (16 mg).
1H NMR(400MHz，DMSO-d6)8.93(s，1H)，8.72(s，1H)，7.98(s，1H)，7.54(s，1H)，4.28-4.70(m，2H)，3.93-4.13(m，2H)，3.73(d，J＝16.0Hz，1H)，3.15-3.24(m，4H)，2.74-2.88(m，1H)，2.25(s，3H)，1.38-1.59(m，2H)，0.79-0.90(m，2H)。
Example 87: 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxylic acid
Figure BSA0000225311520000131
Example 784- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxamide (50mg) was dissolved at room temperature in dioxane (5mL), 2M aqueous KOH (1mL) was added and heated to 90 ℃ with stirring for 12 hours, cooled to room temperature, the system pH was adjusted to 5 with 1M dilute aqueous hydrochloric acid, then the reaction solution was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (10 mg).
1H NMR(400MHz，DMSO-d6)8.96(s，1H)，8.67(s，1H)，8.36(s，1H)，8.13(s，1H)，7.68(s，1H)，3.60-3.67(m，2H)，3.48-3.55(m，2H)，3.27(s，3H)，2.92-3.01(m，2H)，2.32(s，3H)，2.01-2.09(m，2H)。
Example 88: (E) -27，47-dimethyl-28，29-dihydro-27H-3-aza-2 (9, 2) -purine-4 (6, 3) - [1, 2, 4]]Triazole [4, 3-a ]]Pyridine-1 (4, 1) -piperidine cycloheptane-287-diketones
Figure BSA0000225311520000141
This compound was synthesized by following the synthesis procedure of example 86 using monomethyl succinate as starting material.
MS(ESI)m/z 434.17(M+H)+
Example 89: (11r，14r)-44-chloro-27，46-dimethyl-28，29-dihydro-27H-5, 8-dioxo-3-aza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -Cyclohexanetriane-28-ketones
Figure BSA0000225311520000142
Step 1: 2- ((1r, 4r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) oxy) acetic acid ethyl ester
2-chloro-9- ((1r, 4r) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (283mg) and dimeric rhodium acetate (9mg) were dissolved in dichloromethane (20mL) at room temperature, ethyl diazoacetate (8mL, 15% in toluene) was added thereto, and the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (50mL), extracted with dichloromethane, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 30: 1 (V: V)) to give the title compound (184 mg).
Step 2: 2-chloro-9- ((1r, 4r) -4- (2-hydroxyethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
Ethyl acetate ethyl 2- ((1r, 4r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) oxy) acetate (184mg) was dissolved in toluene (20mL) at-78 deg.C, to which was added 1M DIBAL-H toluene solution (3 mL). The reaction mixture was warmed to room temperature and stirred for 12 hours, the reaction solution was poured into water, the system pH was adjusted to 3 with 1M dilute aqueous hydrochloric acid, ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the title compound (114 mg).
And step 3: 2-chloro-9- ((1r, 4r) -4- (2- (2, 4-dimethyl-5-nitrophenoxy) ethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
DIAD (140mg) was slowly added dropwise to a solution of 2-chloro-9- ((1r, 4r) -4- (2-hydroxyethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (114mg), 2-chloro-4-methyl-5-nitrophenol (65mg), and triphenylphosphine (190mg) in toluene (20mL) at 0 deg.C, and after the addition was complete, it was warmed to room temperature and stirring was continued for 12 hours. Methanol (2mL) was added to the reaction mixture and stirred for 1 hour, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 1: 1 (V: V)) to give a pale yellow solid (140 mg).
And 4, step 4: 9- ((1r, 4r) -4- (2- (5-amino-2, 4-dimethylphenoxy) ethoxy) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of 2-chloro-9- ((1r, 4r) -4- (2- (2, 4-dimethyl-5-nitrophenoxy) ethoxy) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (140mg) in acetic acid (10mL) was added reduced iron powder (150mg) at room temperature, followed by stirring at room temperature for 2 hours, filtration with celite and collection of the filtrate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol 10: 1 (V: V)) to give a white solid (100 mg).
And 5: (11r，14r)-44-chloro-27，46-dimethyl-28，29-dihydro-27H-5, 8-dioxo-3-aza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -Cyclohexanetriane-28-ketones
9- ((1r, 4r) -4- (2- (5-amino-2, 4-dimethylphenoxy) ethoxy) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (44mg), RuPhos Pd G3(9mg) and cesium carbonate (65mg) were dissolved in dioxane (10mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (26 mg).
MS(ESI)m/z 430.15(M+H)+
Example 90: (S) -44-chloro-27，467-trimethyl-28，29-dihydro-27H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-28-ketones
Figure BSA0000225311520000151
This compound was synthesized following the synthetic procedure of example 89 using intermediate 6 and the appropriate halogenated aliphatic alcohol as starting materials.
1H NMR(400MHz，DMSO-d6)8.38-8.44(m，1H)，7.88-7.91(m，1H)，7.14(s，1H)，6.92-6.96(m，1H)，4.31-4.62(m，2H)，3.61-3.82(m，1H)，3.41(s，1.5H)，3.40(s，1.5H)，2.42-3.23(m，5H)，2.26(s，3H)，1.50-1.68(m，3.5H)，0.98-1.25(m，3.5H)。
Example 91: 9- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure BSA0000225311520000152
Figure BSA0000225311520000161
4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carboxylic acid (42mg) was dissolved in THF (10mL) at-78 deg.C, and LAH (15mg) was added thereto. The reaction mixture was warmed to room temperature and stirred for 2 hours, the reaction solution was poured into water, the system pH was adjusted to 3 with 1M dilute aqueous hydrochloric acid, ethyl acetate was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 15: 1 (V: V)), to give the objective compound (12 mg).
1H NMR(400MHz，DMSO-d6)9.48(s，1H)，8.24(s，1H)，7.89(s，1H)，7.56(s，1H)，6.63(s，1H)，4.11(s，2H)，3.76-3.81(m，4H)，3.38(s，3H)，3.26-3.34(m，2H)，2.47(s，3H)，1.85-1.92(m，2H)。
Example 92: (11r，14r)-27，47-dimethyl-28，29-dihydro-27H-5, 8-dioxo-3-aza-4 (6, 4) -quinoline-2 (9, 2) -purine-1 (1, 4) -cyclohexasicyclooctane-28-ketones
Figure BSA0000225311520000162
This compound was synthesized following the synthetic procedure of example 89 using intermediate 13 and the appropriate nitrophenols as starting materials.
1H NMR(400MHz，DMSO-d6)8.44-8.58(m，1H)，8.35(s，1H)，8.20(s，1H)，7.98(s，1H)，7.80(s，1H)，6.86-6.98(m，1H)，4.15-4.50(m，4H)，3.74-4.02(m，2H)，3.30(s，3H)，2.56-2.73(m，2H)，2.53(s，3H)，1.88-2.04(m，2H)，1.68-1.83(m，2H)，1.10-1.38(m，2H)。
Example 93: 4- (2- ((4-amino-7-methylquinazolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure BSA0000225311520000163
Figure BSA0000225311520000171
Step 1: 2-amino-4-methyl-5-nitrobenzonitrile
2-fluoro-4-methyl-5-nitrobenzonitrile (300mg) and a saturated solution of ammonia in ethanol (10mL) were placed in a sealed tube, heated to 80 ℃ and stirred for 3 hours. After cooling to room temperature, the reaction mixture was poured into water (30mL) to cause precipitation. The solid was filtered and dried to give the title compound (180 mg).
Step 2: 7-methyl-6-nitroquinazolin-4-amine
A solution of 2-amino-4-methyl-5-nitrobenzonitrile (180mg) in formamide (10mL) was heated to 180 ℃ and stirred for 8 hours. After cooling to room temperature, the reaction solution was poured into water to cause precipitation. The solid was filtered and dried to give the title compound (120 mg).
And step 3: 7-methyl quinazoline-4, 6-diamine
To a solution of 7-methyl-6-nitroquinazolin-4-amine (120mg) in acetic acid (10mL) at room temperature was added reduced iron powder (250mg), the reaction was stirred at room temperature for 12 hours, the reaction solution was filtered through celite, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol 10: 1 (V: V)) to give a white solid (100 mg).
And 4, step 4: 4- (2- ((4-amino-7-methylquinazolin-6-yl) amino) -7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
The intermediates 14- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile (59mg), 7-methyl quinazoline-4, 6-diamine (35mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were sequentially added to a flask charged with dioxane (20mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100 ℃ with stirring for 2 hours. Cooled to room temperature, filtered, the filter cake was washed with dichloromethane, the filtrates were combined and concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the title compound (23 mg).
1H NMR(400MHz，DMSO-d6)8.82(s，1H)，8.27(s，1H)，8.22(s，1H)，8.18(s，1H)，7.53(s，2H)，7.49(s，1H)，3.78-3.85(m，2H)，3.46-3.55(m，2H)，3.29(s，3H)，2.56-2.70(m，4H)，2.36(s，3H)。
Example 94: 7- (methyl-d)3) -2- ((6-methyl- [1, 2, 4)]Triazole [1, 5-a ]]Pyridin-7-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure BSA0000225311520000172
Figure BSA0000225311520000181
Analogously to example 71, a CD was used3I (deuterated iodomethane) instead of CH3The target compound (33mg) is synthesized by 2 steps by taking the I as a substitute raw material.
1H NMR(400MHz，DMSO-d6)8.71(s，1H)，8.54(s，1H)，8.40(s，1H)，8.21-8.25(m，2H)，4.39-4.49(m，1H)，3.95(dd，J＝11.6Hz，4.0Hz，2H)，3.40(t，J＝11.6Hz，2H)，2.44-5.57(m，2H)，2.36(s，3H)，1.63-1.71(m，2H)。
Example 95: (11r，14r)-44-chloro-27，46-dimethyl-28，29-dihydro-27H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanoctadecane-28-ketones
Figure BSA0000225311520000182
Step 1: 2-chloro-7-methyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one
2-chloro-9- ((1r, 4r) -4-hydroxycyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (566mg) was dissolved in dichloromethane (20mL) at room temperature, Dess-Martin oxidant (900mg) was slowly added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (50mL), extracted with dichloromethane (100mL), the organic phase was separated, dried and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 30: 1 (V: V)) to give the title compound (530 mg).
Step 2: 2-chloro-9- ((1r, 4r) -4- ((2-hydroxyethyl) amino) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one
2-chloro-7-methyl-9- (4-oxocyclohexyl) -7, 9-dihydro-8H-purin-8-one (530mg) and ethanolamine (250mg) were dissolved in methylene chloride (30mL) at 0 ℃ and acetic acid (200mg) and sodium triacetoxyborohydride (900mg) were added thereto in this order. The reaction mixture was warmed to room temperature and stirred for 12 hours, the reaction solution was poured into water, dichloromethane was added for extraction, the organic phase was separated and concentrated under reduced pressure, and after evaporation to dryness, the residue was purified by column chromatography (eluent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the title compound (200mg) and its isomer (190 mg).
And step 3: tert-butyl ((1r, 4r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2-hydroxyethyl) carbamate
To a solution of 2-chloro-9- ((1r, 4r) -4- ((2-hydroxyethyl) amino) cyclohexyl) -7-methyl-7, 9-dihydro-8H-purin-8-one (200mg) in dichloromethane (20mL) was slowly added dropwise (Boc) at 0 deg.C2O (200mg), after the addition was complete, the temperature was raised to room temperature and stirring was continued for 12 hours. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 1: 1 (V: V)) to give the title compound (170 mg).
And 4, step 4: tert-butyl ((1r, 4r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2- (2, 4-dimethyl-5-nitrophenoxy) ethyl) carbamate
DIAD (200mg) was slowly added dropwise to a solution of tert-butyl ((1r, 4r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2-hydroxyethyl) carbamate (170mg), 2-chloro-4-methyl-5-nitrophenol (100mg), and triphenylphosphine (263mg) in toluene (20mL) at 0 deg.C, and after the addition was complete, it was warmed to room temperature and stirring was continued for 12 hours. Methanol (2mL) was added to the reaction mixture and stirred for 1 hour, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 1: 1 (V: V)) to give a pale yellow solid (150 mg).
And 5: 9- ((1r, 4r) -4- ((2- (5-amino-2, 4-dimethylphenoxy) ethyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one
To a solution of tert-butyl ((1r, 4r) -4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexyl) (2- (2, 4-dimethyl-5-nitrophenoxy) ethyl) carbamate (150mg) in acetic acid (15mL) was added reduced iron powder (200mg) at room temperature, followed by stirring at room temperature for 12 hours, the reaction solution was filtered through celite and the filtrate was collected. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol-10: 1 (V: V)) to give a white solid (90 mg).
Step 6: (11r，14r)-44-chloro-27，46-dimethyl-28，29-dihydro-27H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanoctadecane-28-ketones
9- ((1r, 4r) -4- ((2- (5-amino-2, 4-dimethylphenoxy) ethyl) amino) cyclohexyl) -2-chloro-7-methyl-7, 9-dihydro-8H-purin-8-one (45mg), RuPhos Pd G3(9mg) and cesium carbonate (65mg) were dissolved in dioxane (10mL) under nitrogen, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (11 mg).
1H NMR(400MHz，CDCl3)8.50(s，1H)，7.90(s，1H)，7.12(s，1H)，6.96(s，1H)，4.71-4.78(m，2H)，4.53-4.65(m，1H)，3.72-3.80(m，1H)，3.48-3.55(m，2H)，3.40(s，3H)，2.74-2.86(m，2H)，2.42-2.52(m，2H)，2.28(s，3H)，2.03-2.13(m，2H)，1.80-1.94(m，2H)。
Example 96: (11s，14s)-44-chloro-27，46-dimethyl-28，29-dihydro-27H-5-oxa-3, 8-diaza-2 (9, 2) -purine-4 (1, 3) -benzo-1 (1, 4) -cyclohexanoctadecane-28-ketones
Figure BSA0000225311520000191
This compound (21mg) was synthesized using the isomer obtained in the second step of the synthesis method of example 95.
1H NMR(400MHz，CDCl3)8.43(s，1H)，7.88(s，1H)，7.13(s，1H)，6.86(s，1H)，4.31-4.42(m，3H)，3.41(s，3H)，2.95-3.07(m，3H)，2.80-2.93(m，2H)，2.26(s，3H)，1.94-2.08(m，2H)，1.54-1.71(m，4H)。
Example 97: 7- (methyl-d 3) -2- ((7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) amino) -9- (tetrahydro-2H-pyran-4-yl) -7, 9-dihydro-8H-purin-8-one
Figure BSA0000225311520000201
The title compound (43mg) was synthesized in analogy to example 94, using 7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-amine.
1H NMR(400MHz，DMSO-d6)9.09(s，1H)，8.81(s，1H)，8.58(s，1H)，8.05(s，1H)，7.60(s，1H)，4.34-4.44(m，1H)，3.94(dd，J＝11.6Hz，3.6Hz，2H)，3.39(t，J＝11.6Hz，2H)，2.42-2.55(m，2H)，2.309s，3H)，1.60-1.67(m，2H)。
Example 98: (R) -44-chloro-27，466-trimethyl-28，29-dihydro-27H-5-oxa-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocycloheptane-28-ketones
Figure BSA0000225311520000202
This compound was synthesized following the synthetic procedure of example 89 using intermediate 6 and the appropriate halogenated aliphatic alcohol as starting materials.
1H NMR(400MHz，CDCl3)8.26(s，1H)，7.91(s，1H)，7.16(s，1H)，6.98(s，1H)，4.44-4.66(m，2H)，3.60-4.02(m，2H)，3.41(s，3H)，2.50-3.32(m，8H)，2.27(s，3H)，1.65(d，J＝5.2Hz，3H)。
Example 99: (E) -44-chloro-27，46-dimethyl-28，29-dihydro-27H-5-oxo-3-aza-2 (9, 2) -purine-1 (4, 1) -piperidine-4 (1, 3) -benzocyclononane-7-en-289-diketones
Figure BSA0000225311520000203
This compound was synthesized following the synthetic procedure of example 89 using intermediate 6 and 4-bromocrotonic acid as starting materials.
1H NMR(400MHz，DMSO-d6)8.42(s，1H)，8.17(s，1H)，7.88(s，1H)，7.21(s，1H)，6.43(d，J＝6.4Hz，1H)，5.14-5.20(m，1H)，4.32-4.44(m，2H)，3.85-3.94(m，1H)，3.30(s，3H)，3.07(d，J＝7.6Hz，2H)，2.50-2.59(m，1H)，2.27-2.44(m，2H)，2.17-2.27(m，4H)，1.68-1.76(m，1H)，1.52-1.59(m，1H)。
Example 100: 1-methyl-4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
Figure BSA0000225311520000211
Step 1: 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1-methylpiperidine-4-carba nitrile
To a solution of 4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbo-nitrile (292mg) in DMF (10mL) at 0 ℃ was slowly added 60% (mineral oil) sodium hydride (80mg), and after the addition was complete stirring was continued at 0 ℃ for 10 min. Methyl iodide (0.15g) was then slowly added to the reaction solution at 0 ℃ and stirred at room temperature for 1 hour, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol 15: 1 (V: V)) to give the objective compound (90 mg).
Step 2: 1-methyl-4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) piperidine-4-carbonitrile
4- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -1-methylpiperidine-4-carbonitrile (62mg), 7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were successively added to a flask containing dioxane (20mL) under nitrogen, the reaction flask was replaced three times with nitrogen and heated to 100 ℃ for 2 hours with stirring. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (53 mg).
1H NMR(400MHz，DMSO-d6)9.06(s，1H)，8.75(s，1H)，8.35(s，1H)，8.17(s，1H)，7.67(s，1H)，3.27(s，3H)，2.73-2.82(m，2H)，2.58-2.71(m，4H)，2.35(s，3H)，2.10-2.25(m，5H)。
Example 101: 1- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbanitrile
Figure BSA0000225311520000212
Intermediate 131- (2-chloro-7-methyl-8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbonitrile (61mg), 7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-amine (30mg), RuPhos Pd G3(9mg), and cesium carbonate (130mg) were added in that order to a flask containing dioxane (20mL) under nitrogen, the reaction flask was replaced with nitrogen three times, heated to 100 ℃ and stirred for 2 hours. Cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 15: 1 (V: V)) to give the objective compound (43 mg).
1H NMR(400MHz，DMSO-d6)9.05(s，1H)，8.79(s，1H)，8.35(s，1H)，8.20(s，1H)，7.68(s，1H)，3.30(s，3H)，3.18-3.27(m，2H)，2.71-2.81(m，2H)，2.36-2.45(m，4H)，2.34(s，3H)。
Example 102: 4-amino-1- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexane-1-carbonitrile
Figure BSA0000225311520000221
1- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbo-nitrile (42mg) and ammonium formate (30mg) were dissolved in tetrahydrofuran (20mL), to which was added sodium cyanoborohydride (30mg) and stirred for 12 hours. The reaction solution was poured into water and extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to obtain the objective compound (23 mg).
1H NMR(400MHz，DMSO-d6)9.09(s，0.6H)，9.04(s，0.4H)，8.77(s，0.4H)，8.75(s，0.6H)，8.35(s，0.4H)，8.34(s，0.6H)，8.20(s，0.4H)，8.18(s，0.6H)，7.68(s，0.4H)，7.67(s，0.6H)，3.28(s，3H)，3.22-3.27(m，1H)，2.97-3.05(m，0.6H)，2.62-2.80(m，1.4H)，2.40-2.52(m，1H)，2.36(s，1.8H)，2.35(s，1.2H)，2.10-2.21(m，1H)，1.85-1.93(m，1H)，1.65-1.74(m，1H)，1.38-1.52(m，2H)。
Example 103: (1s, 4s) -4-hydroxy-1- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexane-1-carbonitrile
Figure BSA0000225311520000222
1- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) -4-oxocyclohexane-1-carbo-nitrile (42mg) was dissolved in methanol (5mL), to which was added sodium borohydride (20mg) and stirred for 1 hour. The reaction solution was poured into water and extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 10: 1 (V: V)) to give the objective compound (17mg) and its isomer.
1H NMR(400MHz，DMSO-d6)9.05(s，1H)，8.73(s，1H)，8.34(s，1H)，8.16(s，1H)，7.67(s，1H)，4.60(s，1H)，3.74-3.82(m，1H)，3.28(s，3H)，2.80-2.82(m，2H)，2.30-2.42(m，5H)，1.59-1.75(m，4H)。
Example 104: (1s, 4s) -4-hydroxy-1- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) cyclohexane-1-carbonitrile
Figure BSA0000225311520000231
The title compound was the isomer of example 103 (14 mg).
1H NMR(400MHz，DMSO-d6)9.08(s，1H)，8.74(s，1H)，8.35(s，1H)，8.17(s，1H)，7.67(s，1H)，4.80(d，J＝5.2Hz，1H)，3.33-3.47(m，1H)，3.27(s，3H)，2.57-2.65(m，2H)，2.48-2.56(m，2H)，2.35(s，3H)，1.83-1.92(m，2H)，1.39-1.52(m，2H)。
Example 105: 4- (7- (methyl-d 3) -2- ((7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbonitrile
Figure BSA0000225311520000232
Following example 71, 7-methyl- [1, 2, 4] triazolo [4, 3-a ] pyridin-6-amine was used as a surrogate amine to perform a catalytic coupling reaction to give the title compound (34 mg).
1H NMR(400MHz，CDCl3)9.38(s，1H)，8.80(s，1H)，8.00(s，1H)，7.59(s，1H)，6.74(s，1H)，4.07-4.13(m，2H)，3.83-3.92(m，2H)，2.84-2.92(m，2H)，2.62-2.69(m，2H)，2.46(s，3H)。
Example 106: 9- (4-Ethyltetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure BSA0000225311520000233
Step 1: 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbaldehyde
Example 919- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one (82mg) was dissolved in dichloromethane (20mL) at room temperature, Dess-Martin oxidant (100mg) was slowly added thereto, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (50mL), extracted with dichloromethane (100mL), the organic phase was separated, dried and concentrated under reduced pressure, and the crude product was used in the next step without purification (60 mg).
Step 2: 9- (4-ethyltetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Dimethyl (1-diazo-2-oxopropyl) phosphonate (40mg) was dissolved in methanol (10mL) at 0 ℃ and potassium carbonate (70mg) and 4- (7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -8-oxo-7, 8-dihydro-9H-purin-9-yl) tetrahydro-2H-pyran-4-carbaldehyde (60mg) were added successively thereto. The reaction mixture was warmed to room temperature and stirred for 12 hours, and the reaction mixture was concentrated under reduced pressure, evaporated to dryness, and the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol 10: 1 (V: V)) to give the objective compound (14 mg).
1H NMR(400MHz，CDCl3)9.83(s，1H)，8.31(s，1H)，7.76-8.02(m，2H)，6.76(s，1H)，3.89-4.02(m，4H)，3.39(s，3H)，2.77-2.83(m，3H)，2.62-2.72(m，2H)，2.52(s，3H)。
Example 107: 9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Figure BSA0000225311520000241
Step 1: tert-butyl (7- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -5-methyl-6-oxo-6, 7-dihydro-5H-pyrrolo [3, 2-d ] pyrimidin-2-yl) (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) carbamate
9- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one (82mg) of example 91 was dissolved in methylene chloride (20mL) at room temperature, di-tert-butyl dicarbonate (100mg), triethylamine (100mg) and DMAP (10mg) were successively and slowly added to the solution, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (50mL), extracted with dichloromethane (100mL), the organic phase was separated, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 30: 1 (V: V)) to give the objective compound (100 mg).
Step 2: tert-butyl (9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl) (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) carbamate
Tert-butyl (7- (4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) -5-methyl-6-oxo-6, 7-dihydro-5H-pyrrolo [3, 2-d ] pyrimidin-2-yl) (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) carbamate (100mg) was dissolved in THF (15mL) at 0 deg.C, and diethylaminosulfur trifluoride (150mg) was added thereto. The reaction mixture was warmed to 50 ℃ and stirred for 12 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50mL), extracted with dichloromethane (100mL), the organic phase was separated, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 30: 1 (V: V)) to give the objective compound (60 mg).
And step 3: 9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-2- ((7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) amino) -7, 9-dihydro-8H-purin-8-one
Tert-butyl (9- (4- (fluoromethyl) tetrahydro-2H-pyran-4-yl) -7-methyl-8-oxo-8, 9-dihydro-7H-purin-2-yl) (7-methyl- [1, 2, 4] triazolo [1, 5-a ] pyridin-6-yl) carbamate (60mg) was dissolved in dichloromethane (10mL) at 0 deg.C, to which trifluoroacetic acid (1.5mL) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (100mL), extracted with dichloromethane (100mL), the organic phase was separated, dried and concentrated under reduced pressure, the reaction solution was concentrated under reduced pressure in vacuo, and after evaporation, the residue was purified by thin layer chromatography (developing solvent: dichloromethane: methanol ═ 20: 1 (V: V)) to give the objective compound (33 mg).
1H NMR(400MHz，CDCl3)9.60(s，1H)，8.33(s，1H)，7.80-7.97(m，2H)，6.64(s，1H)，4.71(d，J＝47.2Hz，2H)，3.87-3.93(m，2H)，3.62-3.68(m，2H)，3.34-3.42(m，5H)，2.50(s，3H)，1.94-2.02(m，2H)。
Biological Activity assay
DNA-PK compound bioactivity test method
1. Determination of proliferative Activity of Compounds in MDA-MB-468 cells
The invention relates to a detection method for cell proliferation inhibition, which is established under the condition of combining a DNA-PK inhibitor established in human breast cancer cells MDA-MB-468 with a chemotherapeutic drug Doxorubicin. The specific method comprises the following steps: human breast cancer cells MDA-MB-468 cells were cultured in RPMI-1640 medium (purchased from Biological Industries, BI) supplemented with 10% fetal bovine serum (FBS, purchased from Hyclone) and 1% penicillin/streptomycin double antibody (P/S, purchased from Life Techology) under the conditions of (37 ℃, 5% CO 2). The day before compound detection, MDA-MB-468 cells were plated in 96-well plates (#3917, purchased from Corning) at a concentration of 1000 cells/190. mu.L/well. After 24 hours Doxorubicin was added to a final concentration of 10nM (DMSO final concentration 0.1%), the test compound was diluted 3-fold in 100% DMSO starting at 10mM (10 concentrations in total), then 2. mu.L of each concentration was added to 48. mu.L of RPMI-1640 medium, and 5. mu.L of each diluted test compound was added to the plated cell suspension. After incubation of the compounds with cells in a Cell incubator for 120h (5 days), the medium was aspirated and incubated again for 5-10 min with 25. mu.L of Cell-Titer Glo (G7570, purchased from Promega) reagent. Fluorescence values were then read on a CLARIO starPlus (purchased from BMG) plate reader and the data were calculated using GraphPad Prism software to obtain IC50 values for inhibition of cell proliferation by this compound.
Partial examples cellular Activity data
Compound numbering Active IC in MDA-MB-468 cells50(nM)
Example 90 158.3
Example 92 47.3
Example 93 39.4
Example 106 128
2. Pharmacokinetic data for compounds:
male SD rats are from Beijing Wittingle laboratory animal technology, Inc., the rats are divided into groups of 3 rats, and suspension of samples to be tested (5mg/kg, suspension is 0.5% HPMC, 0.1% Tween 80 in H) is orally administrated2O). Animals were fasted overnight prior to the experiment, with the fasting time ranging from 10 hours prior to dosing to 4 hours post-dosing. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose, respectively, after isoflurane anesthesia using a small animal anesthesia machine, 0.3mL of whole blood was collected through the fundus venous plexus, placed in a heparin anticoagulation tube, the sample was centrifuged at 4 ℃ for 5 minutes at 4000rpm, the plasma was transferred to a centrifuge tube and stored at-80 ℃ until analysis, the sample in the plasma was extracted using protein precipitation, and the extract was analyzed by LC/MS.
Figure BSA0000225311520000261
Industrial applicability
The invention provides a DNA-PK selective inhibitor and preparation and application thereof. The invention also provides a series of compounds represented by the general formula (I) and pharmaceutically acceptable salts, solvates, polymorphs or isomers thereof, pharmaceutical compositions containing the compounds, and methods of treating diseases using the compounds. The DNA-PK selective inhibitor provided by the invention has high activity, strong drug resistance and small clinical side effect, can effectively enhance the sensitivity of radiotherapy and chemotherapy in tumor treatment, and has better economic value and application prospect.

Claims (9)

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,
Figure FSA0000225311510000011
wherein the content of the first and second substances,
ring A is 6-10 membered aryl or 5-12 membered heteroaryl,
ring B is C3-8Cycloalkyl or a 4-12 membered heterocyclic ring, S on the B ring may optionally be oxidized,
z is O or S, and the compound is a linear or branched compound,
X2is CR2Or the number of N is greater than the number of N,
X1is CRR4O, S, or NR6，
R1Is H, C1-6Alkyl, or C3-8Cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen, -CN, -OH, -NH2、-O-C1-6Alkyl, or-NR-C1-6The substitution of the alkyl group is carried out,
R7and R8Each independently selected from halogen, CN, C1-6Alkyl, -O-C1-6Alkyl and-NR-C1-6Alkyl, which may optionally be substituted by halogen, -CN, -OH, -NH2、-O-C1-6Alkyl, or-NR-C1-6The substitution of the alkyl group is carried out,
m and n are each independently 0, 1, 2, or 3,
R3is R5or-X3-R5，
R4Is R6or-X3-R6，
X3Each independently is-O-, -S-, or-NR-,
R5and R6Each independently selected from H and C1-6Alkyl, or R5And R6Taken together to form- (CH)2)p-X-(CH2)q-, wherein X is a bond, -CH-, -CO-CH-, -O-, -S, -N (R) -, -CO-, -C (O) NR-, -C (O) O-, a 6-to 10-membered arylene, a 5-to 12-membered heteroarylene, or a 3-to 12-membered heterocycle, and- (CH-)2)p-X-(CH2)qCH in (E)2Optionally substituted by halogen or C1-6The substitution of the alkyl group is carried out,
p and q are each independently 0, 1, 2, 3, or 4, and p + q is 1, 2, 3, 4, 5, or 6,
R2selected from H, halogen, CH2F、CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl, - (CH)2)1-3-OH、-CHO、-(CO)NH2- (CO) NHR, - (CO) OR and-NR-C1-6An alkyl group.
R is H or C1-6An alkyl group.
2. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein
When R is5And R6Each independently selected from H or C1-6When alkyl, R2Selected from halogen, CH2F、CH2F、CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl, or-NR-C1-6An alkyl group, a carboxyl group,
when R is5And R6Taken together to form- (CH)2)p-X-(CH2)qWhen is, R2Selected from H, halogen, CH2F、CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl and-NR-C1-6An alkyl group, a carboxyl group,
r is H or C1-6An alkyl group.
3. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph or thereofIsomers of the compounds, wherein
Figure FSA0000225311510000025
Is composed of
Figure FSA0000225311510000021
Figure FSA0000225311510000022
Or
Figure FSA0000225311510000023
When R is2Selected from halogen, CH2F、CH2F、CHF2、CF3、-OH、-NH2、CN、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, -O-C1-6Alkyl, - (CH)2)1-6-CN、-(CH2)1-6-O-C1-6Alkyl and-NR-C1-6An alkyl group, a carboxyl group,
r is H or C1-6An alkyl group.
4. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R1Is C1-6Alkyl, which may optionally be substituted by halogen, -CN, -OH, -NH2、-O-C1-6Alkyl, or-NR-C1-6Alkyl substituted, R is H or C1-6An alkyl group.
5. The following compounds:
Figure FSA0000225311510000024
or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.
6. A pharmaceutical composition comprising a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof.
7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment of DNA-PK related diseases.
8. The use of claim 7, wherein the DNA-PK related disease is cancer.
9. The use of claim 7, wherein the DNA-PK associated disease is colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer.
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Publication number Priority date Publication date Assignee Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023036156A1 (en) * 2021-09-07 2023-03-16 首药控股(北京)股份有限公司 Dna-pk selective inhibitor, and preparation method therefor and use thereof

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