CN110790780B - Boron-containing azetidine derivatives - Google Patents

Boron-containing azetidine derivatives Download PDF

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CN110790780B
CN110790780B CN201910709470.8A CN201910709470A CN110790780B CN 110790780 B CN110790780 B CN 110790780B CN 201910709470 A CN201910709470 A CN 201910709470A CN 110790780 B CN110790780 B CN 110790780B
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pharmaceutically acceptable
acceptable salt
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tautomer
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CN110790780A (en
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熊剑
谢程
徐雄彬
陈新海
黎健
陈曙辉
张爱明
张喜全
田心
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

This applicationDisclosed is a boron-containing azetidine derivative, specifically a compound represented by formula (I) or a pharmaceutically acceptable salt, a tautomer, a stereoisomer or a geometric isomer thereof, and use thereof for preparing a medicament for treating or preventing multiple myeloma.

Description

Boron-containing azetidine derivatives
Technical Field
The present application relates to boron-containing azetidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases associated with multiple myeloma.
Background
Multiple Myeloma (MM) is a malignant proliferative disease of plasma cells characterized by abnormal proliferation of clonal plasma cells in the bone marrow, destruction of hematopoietic function, stimulation of osteolytic lesions in the skeleton, detection of monoclonal immunoglobulins or fragments thereof (M protein) in serum and/or urine, and clinical manifestations of bone pain, anemia, hypercalcemia, renal dysfunction, infection, and hemorrhage. Bortezomib is a reversible proteasome inhibitor that achieves the goal of treating multiple myeloma by promoting apoptosis of myeloma cells. However, resistance to bortezomib has developed in some of the multiple myeloma patients during long-term treatment. Therefore, there remains a need for new and safe drugs for the treatment of multiple myeloma.
Detailed Description
In one aspect, the present application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof,
Figure BDA0002153225620000011
wherein the content of the first and second substances,
ring A is selected from phenyl or 5-10 membered heteroaryl;
each R 1 Independently selected from halogen, OH, NH 2 、CN、C 1-3 Alkyl or C 1-3 Heteroalkyl group wherein said C 1-3 Alkyl or C 1-3 Heteroalkyl is optionally substituted by one or more substituents selected from halogen, OH or NH 2 Substituted with a group of (1);
n is selected from 0, 1,2,3,4 or 5;
R 2 and R 3 Each independently selected from H, halogen, OH, NH 2 、CN、C 1-6 Alkyl radical, C 1-6 Heteroalkyl group, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 Alkyl-, wherein said C 1-6 Alkyl radical, C 1-6 Heteroalkyl group, C 3-6 Cycloalkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 Alkyl-optionally substituted by one or more groups selected from halogen, OH, me, NH 2 、-NH(C 1-3 Alkyl) or-N (C) 1-3 Alkyl radical) 2 Substituted with a group of (1);
R 4 is selected from C 1-6 An alkyl group;
R 5 is selected from H or C 1-3 An alkyl group.
In some embodiments, ring a is selected from phenyl or 5-6 membered heteroaryl; in some embodiments, ring a is selected from phenyl.
In some casesIn embodiments, each R is 1 Independently selected from halogen, OH, NH 2 、CN、C 1-3 Alkyl or C 1-3 A heteroalkyl group; in some embodiments, each R is 1 Independently selected from fluorine, chlorine, bromine, iodine, OH, NH 2 、CN、C 1-3 Alkyl or C 1-3 An alkoxy group; in some embodiments, each R is 1 Independently selected from fluorine, chlorine, bromine, iodine, OH, NH 2 Or a methyl group; in some embodiments, each R is 1 Independently selected from fluorine, chlorine, bromine or iodine; in some embodiments, each R is 1 Independently selected from fluorine or chlorine.
In some embodiments, n is selected from 0, 1 or 2; in some embodiments, n is selected from 1 or 2.
In some embodiments, the structural units of the compounds of formula (I)
Figure BDA0002153225620000021
Is selected from
Figure BDA0002153225620000022
In some embodiments, the structural units of the compounds of formula (I)
Figure BDA0002153225620000023
Is selected from
Figure BDA0002153225620000024
Figure BDA0002153225620000025
In some embodiments, the structural units of the compounds of formula (I)
Figure BDA0002153225620000026
Is selected from
Figure BDA0002153225620000027
Figure BDA0002153225620000028
In some embodiments, R 2 And R 3 Each independently selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 Alkyl-, wherein said C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 Alkyl-optionally substituted by one or more groups selected from halogen, OH, me, NH 2 、-NH(C 1-3 Alkyl) or-N (C) 1-3 Alkyl radical) 2 Substituted with a group of (1); in some embodiments, R 2 And R 3 Each independently selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-3 Alkyl-or phenyl-C 1-3 Alkyl-; in some embodiments, R 2 And R 3 Each independently selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-CH 2 -or phenyl-CH 2 -; in some embodiments, R 2 And R 3 Each independently selected from H,
Figure BDA0002153225620000029
In some embodiments, R 2 And R 3 One selected from H and the other selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 Alkyl-, wherein said C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 Alkyl-optionally substituted by one or more groups selected from halogen, OH, me, NH 2 、NH(C 1-3 Alkyl) or N (C) 1-3 Alkyl radical) 2 Substituted with a group of (1); in some embodiments, R 2 And R 3 One selected from H and the other selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-3 Alkyl-or phenyl-C 1-3 Alkyl-; in some embodiments, R 2 And R 3 One selected from H and the other selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-CH 2 -or phenyl-CH 2 -; in some embodiments, R 2 And R 3 One is selected from H and the other is selected from H,
Figure BDA00021532256200000210
Figure BDA00021532256200000211
In some embodiments, R 4 Is selected from C 3-5 An alkyl group; in some embodiments, R 4 Is selected from C 4 An alkyl group; in some embodiments, R 4 Is selected from
Figure BDA0002153225620000031
In some embodiments, R 5 Is selected from H.
In another aspect, the present application also provides a compound of formula (I-a), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof,
Figure BDA0002153225620000032
wherein, ring A, n, R 1 、R 2 、R 3 、R 4 And R 5 As defined above for the compounds of formula (I).
In some embodiments, a building block
Figure BDA0002153225620000033
As defined for the compounds of formula (I).
In another aspect, the present application also provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof,
Figure BDA0002153225620000034
wherein, ring A, n, R 1 、R 2 And R 3 As defined for the compounds of formula (I).
In some embodiments, a building block
Figure BDA0002153225620000035
As defined for the compounds of formula (I).
In another aspect, the present application also provides a compound of formula (II-a) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof,
Figure BDA0002153225620000036
wherein, ring A, n, R 1 、R 2 And R 3 Definition of (2), and structural units
Figure BDA0002153225620000037
As defined for the compounds of formula (II).
In another aspect, the present application also provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof,
Figure BDA0002153225620000041
wherein n and R 1 And R 2 As defined for the compounds of formula (I).
In some embodiments, a building block
Figure BDA0002153225620000042
Is selected from
Figure BDA0002153225620000043
In some embodiments, a building block
Figure BDA0002153225620000044
Is selected from
Figure BDA0002153225620000045
In another aspect, the present application also provides a compound of formula (III-a), or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof,
Figure BDA0002153225620000046
wherein n and R 1 And R 2 Definition of (2), and structural units
Figure BDA0002153225620000047
As defined for the compounds of formula (III).
In another aspect, the present application also provides a compound selected from the following structural formulae:
Figure BDA0002153225620000048
Figure BDA0002153225620000049
or a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof.
In another aspect, the present application also provides a compound selected from the following structural formulae:
Figure BDA0002153225620000051
Figure BDA0002153225620000052
or a pharmaceutically acceptable salt thereof, a tautomer thereof, or a geometric isomer thereof.
In another aspect, the present application also provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable adjuvant, carrier, or diluent.
In another aspect, the present application also provides a method of treating multiple myeloma in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof, or a pharmaceutical composition thereof.
In another aspect, the present application also provides a use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating multiple myeloma.
In another aspect, the present application also provides the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof, or a pharmaceutical composition thereof, in the prevention or treatment of multiple myeloma.
In another aspect, the present application also provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, or a geometric isomer thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of multiple myeloma.
The compound provided by the application has a weak inhibition degree on CYP isozyme; certain permeability is shown in a membrane permeation test of cells; the in vitro liver microsome has certain stability; better oral bioavailability; the compound has obvious antitumor activity in vivo, better safety and dose-effect dependence trend.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as indefinite or unclear unless it is specifically defined, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The dashed line (- - - - -) in the structural units or groups in this application represents a covalent bond.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e = O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The terms "optionally" or "optionally" mean 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, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH) 2 CH 3 ) Monosubstituted (e.g. CH) 2 CH 2 F) Polysubstituted (e.g. CHFCH) 2 F、CH 2 CHF 2 Etc.) or completely substituted (CF) 2 CF 3 ). 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. Herein C m-n It is the moiety that has an integer number of carbon atoms in the given range. E.g. "C 1-6 By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then each R has independent options; as another example, the structural unit
Figure BDA0002153225620000061
Each R in (1) 1 Are independent and may be the same or different. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "amino" refers to-NH 2 A group.
The term "alkyl" refers to a group of formula C n H 2n+1 A hydrocarbon group of (2). The alkyl group may be linear or branched. For example, the term "C 1-6 Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above.
The term "alkoxy" refers to-O-alkyl.
The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.
The term "aryl" refers to an aromatic cyclic group that is an all-carbon monocyclic or fused polycyclic ring having a conjugated pi-electron system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, and the like.
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S with the remaining ring atoms being C and having at least one aromatic ring. Preferred heteroaryls have a single 4-to 8-membered ring, especially a 5-to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
Unless otherwise specified, C 3-6 Cycloalkyl- (CH) 2 ) 1-3 -comprises C 3-6 cycloalkyl-CH 2 -、C 3-6 Cycloalkyl- (C)H 2 ) 2 -and C 3-6 Cycloalkyl- (CH) 2 ) 3 -; likewise, phenyl- (CH) 2 ) 1-3 -comprises phenyl-CH 2 -, phenyl- (CH) 2 ) 2 -and phenyl- (CH) 2 ) 3 -。
The term "heteroalkyl" is a straight or branched alkyl group preferably having from 1 to 14 carbons, more preferably from 1 to 10 carbons, even more preferably from 1 to 6 carbons, and most preferably from 1 to 3 carbons in the chain, wherein one or more carbons are substituted with a heteroatom selected from S, O and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkyl amines, amides, thioethers (alkyl sulfides), and the like, including alkoxy, alkylthio, alkylamino; unless otherwise specified, C 1-6 The heteroalkyl radical including C 1 、C 2 、C 3 、C 4 、C 5 And C 6 Heteroalkyl of (e.g. C) 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 An alkylamino group.
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is predisposed to the disease condition but has not yet been diagnosed as having it;
(ii) Inhibiting the disease or disease state, i.e., arresting its development;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art, in view of their own knowledge and this disclosure.
The term "pharmaceutically acceptable" is intended to refer 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 human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The word "comprise" or "comprises" and variations thereof such as "comprises" or "comprising", will be understood in an open, non-exclusive sense, i.e., "including but not limited to".
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.
Using wedge and dashed bonds, unless otherwise indicated
Figure BDA0002153225620000071
Indicating the absolute configuration of the stereocenter. When the compounds of the present application contain olefinic double bonds or other centers of geometric asymmetry, they include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present application.
The compounds of the present application may exist in specific geometric isomeric or stereoisomeric forms. The present application contemplates all such compounds, including tautomers, cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present application.
The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labeled compounds of the present application (e.g., with 3 H and 14 c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation) 3 H) And carbon-14 (i.e. the 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and 18 f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, heavier isotopes are used (such as deuterium (i.e., deuterium) 2 H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.
The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of general formula (I) described herein, the daily dose is from 0.01 to 200mg/kg body weight, in single or divided doses.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes herein and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
An important consideration in the art of synthetic route planning is the selection of suitable protecting Groups for reactive functional Groups (such as amino Groups in the present application), for example, reference may be made to Greene's Protective Groups in Organic Synthesis (4 th Ed.) Hoboken, new Jersey: john Wiley & Sons, inc. all references cited herein are incorporated herein in their entirety.
In some embodiments, the compounds of formula (I) herein may be prepared by one skilled in the art by the following general routes and using methods known in the art:
Figure BDA0002153225620000091
the following abbreviations are used in this application:
TBTU represents O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate; TFA represents trifluoroacetic acid; DEA stands for diethylamine; RLU stands for relative light units; me represents a methyl group.
For clarity, the invention is further illustrated by examples, which do not limit the scope of the application. All reagents used herein were commercially available and used without further purification.
Detailed description of the preferred embodiments
EXAMPLE 1 Synthesis of Compound I-1
Figure BDA0002153225620000092
Figure BDA0002153225620000101
Step 1: synthesis of Compound 3-3
N, N-diisopropylethylamine (22.02 g) was added to an acetonitrile (200 mL) solution containing compound 3-1 (10 g) and compound 3-2 (20.13 g) at room temperature. The reaction mixture was stirred at 100 ℃ for 16 hours, then cooled to room temperature, and then added to ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to remove the solvent, and the residue was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10). MS (ESI) m/z:227.9[ 2], [ M +1].
Step 2: synthesis of Compound 3-4
To a mixed solution of Compound 3-3 (7.2 g) in methanol (20 mL), tetrahydrofuran (20 mL) and water (10 mL) at 0 ℃ was added LiOH. H 2 O (6.65 g). The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure and diluted with water and ethyl acetate, and the organic phase was separated. The aqueous layer was adjusted to pH =6 with 1mol/L hydrochloric acid, and then extracted with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to remove the solvent to give compound 3-4, which was used directly in the next reaction. MS (ESI) m/z 213.9[ 2], [ M ] +1]。
And step 3: synthesis of Compounds 3 to 5
To a solution of compound 3-4 (1.5 g) in dichloromethane (50 mL) was added glycine methyl ester hydrochloride (1.06 g), TBTU (2.71 g) and N, N-diisopropylethylamine (3.64 g) at-10 ℃. The reaction mixture was stirred at-10 ℃ to 0 ℃ for 3 hours, then diluted with water (40 mL) and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to remove the solvent, and the residue was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 5:1) to give compound 3-5.MS (ESI) m/z:284.9[ 2], [ M +1].
And 4, step 4: synthesis of Compounds 3-6:
to a mixed solution of 3-5 (0.5 g) of tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) at 0 ℃ was added LiOH. H 2 O (369.03 mg). The reaction mixture was stirred at 0 ℃ to 20 ℃ for 2 hours, then concentrated and diluted with water (3 mL) and the organic phase was separated. The aqueous layer was adjusted to pH =6 with 1mol/L hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to remove the solvent to give compounds 3-6, which were used directly in the next reaction. MS (ESI) m/z:270.9[M+1]。
and 5: synthesis of Compounds 3 to 8
To a solution of compound 3-6 (0.26 g), compound 3-7 (437.84 mg), and TBTU (370.71 mg) in dichloromethane (10 mL) at-10 deg.C was added N, N-diisopropylethylamine (273.56 mg). The reaction mixture was slowly warmed to room temperature and stirred for an additional 2 hours, then the reaction mixture was diluted by addition to water (10 mL) and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to remove the solvent, and the residue was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:1) to give compounds 3-8.MS (ESI) m/z:518.2[ 2], [ M +1].
And 6: synthesis of Compounds 3-9
To a mixed solution of compounds 3 to 8 (0.17 g) in methanol (4 mL) and n-hexane (6 mL) was added isobutylboronic acid (234.45 mg) and 1mol/L aqueous hydrochloric acid (1.31 mL) at 0 ℃. The reaction mixture was slowly warmed to room temperature and stirred for an additional 12 hours, then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give compound 3-9.MS (ESI) m/z of 366.1[ 2] M-17].
And 7: synthesis of Compound I-1
To a solution of compound 3-9 (0.38 g) in methanol (4 mL) was slowly added dropwise an aqueous hydrochloric acid solution (1M, 3.97mL) at 0 ℃. The reaction was stirred at 30 ℃ for 19 hours. Concentrating under reduced pressure, purifying the concentrate by preparative HPLC, and separating by SFC to obtain compound I-1. 1 H NMR(400MHz,METHANOL-d 4 )δ6.78-6.86(m,1H),6.71-6.78(m,2H),4.53-4.63(m,3H),3.94-4.18(m,2H),2.72(br t,J＝7.28Hz,1H),2.28-2.40(m,1H),2.11-2.24(m,1H),1.58-1.70(m,1H),1.28-1.37(m,2H),0.90(d,J＝6.53Hz,6H)。MS(ESI)m/z:402.1[M+1].
Preparative HPLC separation method:
and (3) chromatographic column: xtimate C18 150 x 25mm x 5um
Mobile phase: water (0.225% FA) -MeOH
Elution gradient: b% is 61% -91%,
the retention time of the compound I-1 in the high performance liquid phase column was 9.5min.
Preparation of SFC separation method:
a chromatographic column: AD (250mm 30mm, 5um)
Mobile phase: a: carbon dioxide; b: ethanol
Elution gradient: 25% -25% of B
Flow rate: 60mL/min
The second peak is shown in the high-efficiency chiral liquid phase column of the compound I-1.
Compounds I-2,I-3 and I-4 were synthesized in a similar manner to example 1, as shown in Table 1 below:
TABLE 1
Figure BDA0002153225620000111
Figure BDA0002153225620000121
Test example 1: in vitro antiproliferative assays for MM1.S cells
This experiment investigated the effect of compounds on inhibiting cell proliferation by determining their effect on cell activity in vitro in the tumor cell line mm1. S.
MM1.S cells were seeded into black 96-well cell culture plates at a density of 7,000 cells per well, and the plates were then assayed at 37 ℃,5% CO 2 And incubated overnight in an incubator at 100% relative humidity. Test compounds were added to the cell culture wells at a concentration (0.3-2000 nM) and the plates were then returned to the incubator with vehicle control (DMSO added, no compound) and blank control. The plates were incubated at 37 ℃ and 5% CO 2 And culturing in an incubator with 100% relative humidity for 2 days. The samples were processed using the Promega CellTiter-Glo luminescence cell activity assay kit (Promega-G7571) standard method and the luminescence signal was detected on a SpectraMax i3x of Molecular Devices plate reader. The inhibition rate of the test compound was calculated using the following formula:
Figure BDA0002153225620000131
the results are shown in Table 2.
TABLE 2
Compound numbering IC 50 (μM)
I-1 0.0096
I-2 0.0130
I-3 0.0139
I-4 0.1018
。
Test example 2: human liver microsome CYP inhibition assay
The objective of the study project was to evaluate the inhibition of human liver microsomal cytochrome P450 isozymes (CYP 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3 A4) by the test samples using the 5-in-1 probe substrate of the CYP isozyme.
Mixed Human Liver Microsomes (HLM) were purchased from Corning Inc. (Steuben, new York, USA) or XenoTech, LLC. (Lenexa, KS, USA) and stored at less than-70 ℃ prior to use.
Adding the diluted working solution of the test sample with serial concentrations (100, 30.0, 10.0, 3.00, 1.00, 0.300, 0.100 and 0.0300 μ M) into an incubation system containing human liver microsomes, probe substrate and cofactor of a circulation system, and adding solvent without the test sample as enzyme activitySexual control (100%). The concentration of the metabolite produced by the probe substrate in the sample is determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The mean percent activity versus concentration of the test samples was analyzed by nonlinear regression using SigmaPlot (v.11). Calculating IC by three-parameter or four-parameter sigmoidal logarithmic equation 50 The value is obtained. The test results are shown in table 3:
TABLE 3 inhibition of CYP isozymes by Compounds
Figure BDA0002153225620000132
Test example 3 cell Membrane Permeability test of Compounds
The test compounds were evaluated for cell membrane permeability on MDR1-MDCK II cells.
Test compounds (10 mM compound in DMSO) were diluted with transfer buffer (Hank's balanced salt solution with 10mM hydroxyethylpiperazine Qin Yi thiosulfonic acid, pH = 7.4) to make up samples at ase:Sub>A final concentration of 2 μ M, and then administered bilaterally (B-ase:Sub>A and ase:Sub>A-B). After administration, the cell plate is left at 37 ℃ and contains 5% CO 2 And incubation in a suitably saturated incubator for 150 minutes. After the 150-minute incubation, samples were collected and the concentration in the test compound transport samples was semi-quantitatively determined using the LC/MS/MS method. The results of the cell membrane permeability tests for the test compounds are shown in table 4.
Table 4 cell membrane permeability test results for test compounds
Figure BDA0002153225620000141
Note: papp a to B indicates the rate of entry of the compound into the cell; papp B to a indicates the rate at which the cell removes efflux of the compound; exclusion ratio = Papp B to a/Papp a to B.
Test example 4 hepatic microsome stability test of Compounds
Stability evaluation of compounds was performed by incubating test compounds with CD-1 mice, SD rats, and human liver microsomes.
Preparation of test compound solution samples: a10 mM DMSO solution (5. Mu.L) of the compound of example was added to a mixed solvent of DMSO (45. Mu.L) and methanol and water (450. Mu.L, volume ratio of methanol and water 1:1) to prepare a 100. Mu.M test compound solution; 50. Mu.L of a 100. Mu.M test compound solution was added to 450. Mu.L of a 100mM potassium phosphate buffer to obtain a 10. Mu.M test compound solution.
After pre-incubating 10 μ M of the test compound solution with three species of microsomes for 10 minutes, reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) regeneration system working solution was then added to the incubation plate at each time point to initiate the reaction, and finally stop solution (100% acetonitrile) was added to the reaction plate to stop the reaction at 0,5, 10, 20, 30 and 60 minutes, respectively. The test compounds and the control compounds were assayed by LC-MS/MS. The results of the liver microsome stability test for the test compounds are shown in table 5:
table 5 results of liver microsome stability test of test compounds
Compound (I) Hepatic microsomal stability (T) 1/2 ,min)
I-1 44.7(H)，27.0(R)，24.1(M)
I-3 12.7(H)，13.0(R)，11.7(M)
I-4 15.4(H)，13.3(R)，12.7(M)
Note: h stands for human, R stands for rat, and M stands for mouse.
Test example 5: compound pharmacokinetic evaluation
Purpose of the experiment: test Compounds pharmacokinetics in CD-1 mice
Experimental materials: CD-1 mouse (Male)
And (3) experimental operation: rodent pharmacokinetic characteristics of the compound after intravenous injection and oral administration are tested by a standard scheme, and the candidate compound is prepared into a clear solution in an experiment and is given to a mouse for single intravenous injection and oral administration. The intravenous injection and oral administration solvent is ethanol and polyethylene glycol-15 hydroxystearate aqueous solution in a certain proportion. Collecting whole blood sample within 24 hours, centrifuging for 15 minutes at 3000g, separating supernatant to obtain plasma sample, adding 4 times volume of acetonitrile solution containing internal standard to precipitate protein, centrifuging to obtain supernatant, adding equal volume of water, centrifuging to obtain supernatant, sampling, quantitatively analyzing blood concentration by LC-MS/MS analysis method, and calculating drug substitution parameters, wherein the results are shown in Table 6:
TABLE 6 pharmacokinetic test results
Figure BDA0002153225620000142
* Data of 20mg/kg of drug for oral gavage of mice;
* Data of 14mg/kg drug orally administered to mice;
* Data for mice receiving 5mg/kg of drug via oral gavage.
Test example 6: in vivo pharmacodynamic study of compound in human myeloma MM.1S cell subcutaneous xenograft tumor CB-17SCID model
Cell culture: in vitro monolayer culture of human myeloma MM.1S cells under conditions of adding 10% fetal bovine serum to RPMI-1640 medium at 37 deg.C 5% 2 And (5) culturing in an incubator. Passage was performed twice a week with conventional digestion treatment with pancreatin-EDTA. When the saturation degree of the cells is 80-90% and the quantity reaches the requirement, collecting the cells, counting and inoculating.
Animals: CB-17SCID mice, female, 6-8 weeks old, weight 17-20 g.
Each mouse was implanted with mm.1s tumor cells in the right back for tumor growth. When the average tumor volume reaches 100-150mm 3 Administration is started. Seven days are a dosing cycle, and the test compound is administered orally on the first and fourth days of each cycle, respectively, for a total of three cycles. The dose administered was 5mg/kg and 7mg/kg. Tumor volume was measured twice weekly using a two-dimensional caliper, and the volume was measured in cubic millimeters and calculated by the following formula: v =0.5a × b 2 Wherein a and b are the major and minor diameters of the tumor, respectively. The anti-tumor efficacy was determined by dividing the mean tumor gain volume of compound-treated animals by the mean tumor gain volume of untreated animals, while the safety of the compounds was determined by the change in body weight of compound-treated animals. The test results are shown in Table 7.
TABLE 7 test results of Compounds tested in the CB-17SCID model of human myeloma MM.1S cell subcutaneous xenograft tumor
Figure BDA0002153225620000151
And (3) TGI: tumor Growth Inhibition (Tumor Growth Inhibition rate). TGI (%) = [1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the time of administration of the treatment group)/(average tumor volume at the end of treatment of the solvent control group-average tumor volume at the start of treatment of the solvent control group) ] × 100%.

Claims (32)

1. A compound of formula (I) or a pharmaceutically acceptable salt, or tautomer thereof,
Figure FDA0003877932620000011
wherein the content of the first and second substances,
ring A is selected from phenyl or 5-10 membered heteroaryl;
each R 1 Independently selected from halogen, OH, NH 2 、CN、C 1-3 Alkyl or C 1-3 Alkoxy, wherein said C 1-3 Alkyl or C 1-3 Alkoxy is optionally substituted by one or more groups selected from halogen, OH or NH 2 Substituted with a group of (1);
n is selected from 0, 1,2,3 or 4;
R 2 and R 3 Each independently selected from H, halogen, OH, NH 2 、CN、C 1-6 Alkyl radical, C 3-6 Cycloalkyl, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 Alkyl-;
R 4 is selected from C 1-6 An alkyl group;
R 5 is selected from H or C 1-3 An alkyl group.
2. A compound of formula (i), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 1, wherein ring a is selected from phenyl or 5-6 membered heteroaryl.
3. A compound of formula (i), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 2, wherein ring a is selected from phenyl.
4. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, or tautomer thereof, wherein each R 1 Independently selected from fluorine, chlorine, bromine, iodine, OH, NH 2 、CN、C 1-3 Alkyl or C 1-3 An alkoxy group.
5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a tautomer thereof, according to claim 4, wherein each R 1 Independently selected from fluorine, chlorine, bromine, iodine, OH, NH 2 Or a methyl group.
6. A compound of formula (I), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 5, wherein each R is 1 Independently selected from fluorine, chlorine, bromine or iodine.
7. A compound of formula (i) as claimed in claim 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereofTautomers, wherein each R 1 Independently selected from fluorine or chlorine.
8. A compound of formula (i), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 1, wherein n is selected from 0, 1 or 2.
9. A compound of formula (i), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 8, wherein n is selected from 1 or 2.
10. A compound of formula (I) as claimed in claim 1, wherein R is R, or a pharmaceutically acceptable salt or tautomer thereof 2 And R 3 Each independently selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 An alkyl group-.
11. A compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt, or tautomer thereof, wherein R is 2 And R 3 Each independently selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-3 Alkyl-or phenyl-C 1-3 An alkyl radical.
12. A compound of formula (I) according to claim 11 or a pharmaceutically acceptable salt, or tautomer thereof, wherein R is 2 And R 3 Each independently selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-CH 2 -or phenyl-CH 2 -。
13. A compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt, or tautomer thereof, wherein R is 2 And R 3 Each independently selected from H,
Figure FDA0003877932620000012
14. A compound of formula (I) as claimed in claim 1 or a pharmaceutical preparation thereofA pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 2 And R 3 One selected from H and the other selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-6 Alkyl-or phenyl-C 1-6 An alkyl group-.
15. A compound of formula (I) according to claim 14 or a pharmaceutically acceptable salt, or tautomer thereof, wherein R is 2 And R 3 One selected from H and the other selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-C 1-3 Alkyl-or phenyl-C 1-3 An alkyl group.
16. A compound of formula (I) according to claim 15, or a pharmaceutically acceptable salt, or tautomer thereof, wherein R is 2 And R 3 One selected from H and the other selected from H, C 1-6 Alkyl radical, C 3-6 cycloalkyl-CH 2 -or phenyl-CH 2 -。
17. A compound of formula (I) according to claim 16 or a pharmaceutically acceptable salt, or tautomer thereof, wherein R is 2 And R 3 One is selected from H and the other is selected from H,
Figure FDA0003877932620000021
18. A compound of formula (I) as claimed in claim 1, wherein R is R, or a pharmaceutically acceptable salt or tautomer thereof 4 Is selected from C 3-5 An alkyl group.
19. A compound of formula (I), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 18, wherein R is 4 Is selected from C 4 An alkyl group.
20. A compound of formula (I) according to claim 19 or a pharmaceutically acceptable salt, or tautomer thereof, wherein R is 4 Is selected from
Figure FDA0003877932620000022
21. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt, or tautomer thereof, wherein R 5 Is selected from H.
22. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or a tautomer thereof selected from a compound of formula (I-a) or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
Figure FDA0003877932620000023
23. a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a tautomer thereof, as claimed in claim 1, selected from a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
Figure FDA0003877932620000024
24. a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof selected from a compound of formula (II-a), or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
Figure FDA0003877932620000025
25. a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a tautomer thereof, according to claim 1, selected from a compound of formula (III), or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
Figure FDA0003877932620000031
26. a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, or a tautomer thereof selected from a compound of formula (III-a) or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
Figure FDA0003877932620000032
27. a compound of formula (I), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 25 or 26, wherein the structural elements are
Figure FDA0003877932620000033
Is selected from
Figure FDA0003877932620000034
28. A compound of formula (i), or a pharmaceutically acceptable salt, or tautomer thereof, as claimed in claim 27, wherein the structural elements are
Figure FDA0003877932620000035
Is selected from
Figure FDA0003877932620000036
29. A compound of the formula:
Figure FDA0003877932620000037
Figure FDA0003877932620000038
or a pharmaceutically acceptable salt thereof, or a tautomer thereof.
30. A compound of the formula:
Figure FDA0003877932620000041
Figure FDA0003877932620000042
or a pharmaceutically acceptable salt thereof, or a tautomer thereof.
31. A pharmaceutical composition comprising a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or a tautomer thereof.
32. Use of a compound of any one of claims 1-30, a pharmaceutically acceptable salt thereof, or a tautomer thereof, or a pharmaceutical composition of claim 31, in the manufacture of a medicament for the treatment of multiple myeloma.
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