CN110092779A - A kind of substituted phenyl compound and its application - Google Patents
A kind of substituted phenyl compound and its application Download PDFInfo
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- CN110092779A CN110092779A CN201910087329.9A CN201910087329A CN110092779A CN 110092779 A CN110092779 A CN 110092779A CN 201910087329 A CN201910087329 A CN 201910087329A CN 110092779 A CN110092779 A CN 110092779A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The invention discloses a kind of substituted phenyl compounds and its application.The present invention provides a kind of substituted phenyl compound, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrugs shown in formula I.The advantages that high activity, bioavilability height, drug substance stable, Orally-administrable is presented in compound I provided by the invention.
Description
Technical field
The invention belongs to biomedicine field, it is related to a kind of substituted phenyl compound and its application.
Background technique
PD-1/PD-L1 signal path is most popular one of the topic for the treatment of of cancer instantly and research field.Nearly 2 years granted
The immunotherapy new drug of listing leads to as the Keytruda of the Mo Shadong and Opdivo of Bristol Myers Squibb has aimed at this signal
Road prevents signal from transmitting using monoclonal antibody combination PD-1 receptor, so that the immune system of body itself be activated to attack tumour expansion
It hits.Both new drugs are granted for treating the cancers such as melanoma, while in the clinical test for being directed to some other cancer
In also show huge potentiality.The PD-L1 inhibitor of 3 macromoleculars of U.S. FDA approved lists at present, is respectively
(Tecentriq treats bladder cancer and non-small cell lung cancer to Atezolizumab, is that first PD-L1 of FDA approval inhibits
Agent), Avelumab (treatment Merck cell cancer, be FDA approval second PD-L1 inhibitor), Durvalumab (treatment urinary tract
Epithelioma is the third PD-L1 inhibitor of FDA approval).But, the half-life period that monoclonal antibody class drug is up to 15-20 days has can
It can cause side effect relevant to being immunoreacted.And PD-1/PD-L1 monoclonal antibody medicine needs to be injected intravenously at present, and to solid tumor
Therapeutic activity it is bad.
Thus, develop safer, efficient novel PD-1/PD-L1 inhibitor medicaments have huge social value and
Economic benefit, and the research hotspot of major pharmaceutical manufacturer at present.
Summary of the invention
Intravenous injection is needed the technical problem to be solved by the present invention is to existing PD-1/PD-L1 monoclonal antibody medicine and to solid
The defects such as the therapeutic activity of tumor is bad, bioavilability is low, thus, the present invention provides a kind of substituted phenyl compound and its
Using.The compound is small molecule PD-1/PD-L1 inhibitor, and active height, bioavilability height, drug substance stable, palatable is presented
The advantages that clothes administration.
The present invention provides a kind of substituted phenyl compound shown in formula I, its pharmaceutically acceptable salt, its hydrations
Object, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug；
Wherein, the R1For hydrogen ,-(CH2)nR4Or-(CH2)nAr；
The n independently is 1,2,3 or 4；
The R4For-CH3、-CF3、CN、-OH、-CO2H、C1-C3Alkoxy carbonyl ,-C (=O) NH2、C1-C3Alkoxy or
Pyrrolidone-base；
The Ar is benzdioxan base, indazolyl, isoquinolyl, isoxazolyl, naphthalene, oxadiazoles base, phenyl, pyridine
Base, pyrimidine radicals or quinolyl；Wherein, the benzdioxan base, indazolyl, the isoquinolyl, described
Isoxazolyl, the naphthalene, the oxadiazoles base, the phenyl, the pyridyl group, the pyrimidine radicals and described
Each ring of quinolyl optionally, independently replaced by one or more (such as 1,2,3 or 4) substituent groups selected from the following, when
There are when multiple substitutions, the substituent group is identical or different: C1-C4Alkoxy (such as methoxyl group), C1-C4Alkoxy carbonyl
(such as methoxycarbonyl), C1-C4Alkoxycarbonylamino (such as methoxycarbonyl amido), C1-C4Alkyl (such as methyl),
(C1-C4Alkyl) carbonyl (such as methyl carbonyl), (C1-C4Alkyl) sulfonyl (such as methyl sulphonyl), formamido groupAmino carbonylAmino carbonyl (C1-C3Alkyl) (such as amino carbonyl methyl) ,-(CH2)r(C=
O)OC1-C4Alkyl (such as-(CH2) (C=O) OCH3)、-(CH2)rOH (such as-(CH2) OH), carboxyl, cyano, formoxyl (aldehyde
Base), halogen (such as fluorine, chlorine, bromine or iodine, in another example fluorine or chlorine), halogenated C1-C4Alkyl, halogenated C1-C4Alkoxy, is appointed at nitro
Phenoxy group, phenylcarbonyl group, pyrrole radicals and the oxinane that choosing is replaced by the phenyl that a cyano replaces, optionally by a halogen
Base；The r independently is 0,1,2,3 or 4；Any substituent group can be separately located in what above-mentioned each ring was connect with methylene
Ortho position, meta or para position；
The R2For
The R1aFor
The m is 1,2 or 3；
The Y independently is-CN, C1-C3Alkyl (such as methyl) or-Cl；
The RxFor-OH or
The RqFor hydrogen, C1-C3Alkyl or benzyl；
The R3For(such as)、(such as )、
Wherein, RzFor C1-C3Alkyl (such as methyl), C1-C3Alkyl sulphonyl C1-C3Alkyl, C1-C3Alkyl sulphinyl
C1-C3Alkyl, formamido C1-C3Alkyl, amino C1-C4Alkyl (such as 4- aminobutyl), carboxyl C1-C3Alkyl, cyano C1-
C3Alkyl, carbamyl C1-C3Alkyl (such as carbamoyhnethyl), dimethylamino formoxyl C1-C3Alkyl, dimethylamino
C1-C4Alkyl, halogenated C1-C3Alkyl, hydroxyl C1-C3Alkyl (such as methylol, 2- hydroxyethyl, 1- hydroxyethyl, 1- hydroxyl-
1- Methylethyl), C1-C3Alkyl sulfenyl C1-C3Alkyl, pyridyl group C1-C3Alkyl (such as), tetrazole radical C1-C3Alkane
Base, " methyl or benzyl are substituted or unsubstituted " imidazole radicals C1-C3Alkyl, " cyano, methyl or hydroxyl are substituted or unsubstituted " benzene
Base C1-C3Alkyl or thiazolyl C1-C3Alkyl；
The R6It independently is hydrogen, benzyl or methyl；
The R6’It is each independently hydrogen or methyl；
The R7For hydrogen, C1-C3Alkyl (such as methyl) or benzyl；
The t is 1 or 2；
The X is CH or N；
The p is 0 or 1；
The RaFor hydroxyl；
The RbIt independently is hydrogen, benzyl or methyl；
Alternatively, R3And RqNitrogen-atoms connected to them is formed together ring, the ring are as follows: (such as) or
The R8For hydroxyl or-NHSO2R11；R11For trifluoromethyl, cyclopropyl, C1-C3Alkyl, dimethylamino or by
Methyl substituted imidazole radicals；
The R9For hydrogen or-CO2H；
The Q is CH2, S, O or NCH3；
The R10It independently is halogen or hydroxyl；
The s is 0 or 1；
The w is 1,2 or 3；
The R5、R5' and R5" it independently is H, C2-C4Alkenyl, C1-C3Alkyl (such as it is methyl, ethyl, n-propyl, different
Propyl, in another example methyl), cyano, methoxyl group, halogen (such as fluorine, chlorine, bromine or iodine, in another example fluorine or chlorine) or trifluoromethyl.
Above-mentioned " C1-C3Alkyl " is each independently methyl, ethyl, n-propyl or isopropyl.
Above-mentioned " C1-C4Alkyl " is each independently methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, different
Butyl or tert-butyl.
Above-mentioned " C1-C3Alkoxy " is each independently methoxyl group, ethyoxyl, positive propoxy or isopropoxy.
Above-mentioned " C1-C4Alkoxy " is each independently methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth oxygen
Base, sec-butoxy, isobutoxy or tert-butoxy.
Above-mentioned " halogen " is each independently fluorine, chlorine, bromine or iodine (such as fluorine or chlorine).
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R1For-(CH2)nAr。
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
Work as R1For-(CH2)nWhen Ar, the n is 1 or 2.
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
Work as R1For-(CH2)nWhen Ar, the Ar be phenyl, pyridyl group, each ring optionally, independently by selected from the following 1
Or 2 substituent groups replace: C1-C4Alkoxy, (C1-C4Alkyl) sulfonyl, carboxyl or cyano.
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
Work as R1For-(CH2)nWhen Ar, described-(CH2)nAr is
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R2For
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R2In, the Y is-CH3。
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R2For
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The RqFor hydrogen.
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R3For
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R3ForWhen, the RzFor C1-C3Alkyl, amino C1-C4Alkyl, carbamyl C1-C3Alkyl,
Hydroxyl C1-C3Alkyl, pyridyl group C1-C3Alkyl or " cyano, methyl or hydroxyl are substituted or unsubstituted " phenyl C1-C3Alkyl.
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program: the R3ForWhen,For
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program: the R3ForWhen, R7For C1-C3Alkyl (such as methyl) or benzyl.
In some scheme, the definition of certain groups can be as described below in the compound I, the definition of unmentioned group
Described in either a program as above: the R3ForWhen,For
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program: " the R3And RqNitrogen-atoms connected to them is formed together ring " when, the ring are as follows:(such as ) or(such as)。
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R5For H or C1-C3Alkyl (such as methyl, ethyl, n-propyl, isopropyl, in another example methyl).
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R5' it is H, C1-C3Alkyl (such as methyl, ethyl, n-propyl, isopropyl, in another example methyl) or halogen
(such as fluorine, chlorine, bromine or iodine, in another example fluorine or chlorine).
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R5" it is H.
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R1For-(CH2)nAr, the n are 1 or 2, and the Ar is phenyl, pyridyl group, and each ring is optionally, independently
Ground is replaced by 1 or 2 substituent group selected from the following: C1-C4Alkoxy, (C1-C4Alkyl) sulfonyl, carboxyl or cyano；
The R2For
Work as RqWhen for H, the R3For The RzFor C1-C3Alkyl, amino C1-C4Alkyl, ammonia first
Acyl group C1-C3Alkyl, hydroxyl C1-C3Alkyl, pyridyl group C1-C3Alkyl or " cyano, methyl or hydroxyl are substituted or unsubstituted " benzene
Base C1-C3Alkyl；R7For C1-C3Alkyl (such as methyl) or benzyl；
Alternatively, R3And RqNitrogen-atoms connected to them is formed together ring, the ring are as follows:(such as) or(such as)；
The R5For H or C1-C3Alkyl (such as methyl, ethyl, n-propyl, isopropyl, in another example methyl)；
The R5' it is H, C1-C3Alkyl (such as methyl, ethyl, n-propyl, isopropyl, in another example methyl) or halogen
(such as fluorine, chlorine, bromine or iodine, in another example fluorine or chlorine)；
The R5" it independently is H.
In some scheme, the definition of certain groups can be as described below in the compound I, and unmentioned group is determined
Described in adopted as above either a program:
The R1For
The R2For
Work as RqWhen for H, the R3For(such as)、(such as)、(such as )、(such as)、(such as)、 (such as)、(such as )、(such as)、
(such as)、
Alternatively, R3And RqNitrogen-atoms connected to them is formed together ring, the ring are as follows:
The R5For H or methyl；
The R5' it is H, methyl, fluorine or chlorine；
The R5" it is H.
In some scheme, the compound I can be following any compound:
It will be understood by those skilled in the art that the application describes the structural formula of group according to convention used in the art
Used inRefer to, corresponding group is attached by the site and other segments in compound I, group.
As a result, throughout this manual, those skilled in the art can to group described in compound I and its substituent group into
Row selection, with provide stable substituted phenyl compound I, its pharmaceutically acceptable salt, its hydrate, its solvate,
Its metabolite, its stereoisomer, its tautomer or its prodrug, including but not limited to described in the embodiment of the present invention
I-1~I-28.
Compound of formula I of the present invention can be prepared according to the chemical synthesis process of this field routine, step and item
Part can refer to this field similar the step of reacting and condition.
The present invention also provides a kind of pharmaceutical compositions comprising above-mentioned substituted phenyl compound I, it pharmaceutically may be used
The salt of receiving, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug, and
Pharmaceutic adjuvant.
In the pharmaceutical composition, the substituted phenyl compound I, its pharmaceutically acceptable salt, Qi Shui
The dosage for closing object, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug can have for treatment
Effect amount.
The pharmaceutic adjuvant can be for auxiliary material those of be widely used in drug production field.Auxiliary material is mainly used for offer one
A safe and stable and functional pharmaceutical composition, can be with providing method, and active constituent is after so that subject is received administration with institute
Expected rate dissolution, or promote subject to receive active constituent after composition is administered and effectively absorbed.The pharmaceutic adjuvant
Can be inert filler, or certain function be provided, for example, stable the composition whole pH value or prevent composition active
The degradation of ingredient.The pharmaceutic adjuvant may include one of following auxiliary material or a variety of: adhesive, suspending agent, emulsifier,
Diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antitack agent, glidant, wetting agent, gelling agent, absorption
Delayed-action activator, dissolution inhibitor, reinforcing agent, adsorbent, buffer, chelating agent, preservative, colorant, corrigent and sweetener.
Pharmaceutical composition of the invention can according to disclosure using any method well known by persons skilled in the art come
Preparation.For example, conventional mixing, dissolution, granulation, emulsification, levigate, encapsulating, embedding or lyophilized technique.
Pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucous membrane, it is oral (Gu
Body and liquid preparation), sucking, eye, rectum, part or it is parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial,
It is intramuscular) administration.Pharmaceutical composition of the invention can also be controlled release or delayed release dosage forms (such as liposome or microballoon).Solid
The example of oral preparation includes but is not limited to powder, capsule, caplet, soft capsule and tablet.Oral or mucosa delivery liquid
Formulation examples include but is not limited to suspension, lotion, elixir and solution.The example of topical preparation include but is not limited to emulsion,
Gelling agent, ointment, cream, patch, paste, foaming agent, lotion, drops or serum preparation.The preparation of parenteral is real
Example including but not limited to injection solution, the dry preparation that can be dissolved or suspended in pharmaceutically acceptable carrier, injection is outstanding
Supernatant liquid and emulsion for injection.The example of other appropriate formulations of the pharmaceutical composition includes but is not limited to eye drops and other
Ophthalmic preparation；Aerosol: such as nasal mist or inhalant；Liquid dosage form suitable for parenteral；Suppository and pastille.
The present invention also provides a kind of above-mentioned substituted phenyl compound I, its pharmaceutically acceptable salt, its hydrations
Object, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug are in preparation PD-1/PD-L1 suppression
Application in preparation.
In the application, " PD-1/PD-L1 inhibitor " refers to the combination that can block PD-1 and PD-L1, blocks negative
To adjustment signal, make T cell activity recovery, to enhance the substance of immune response.
In the application, the PD-1/PD-L1 inhibitor can be used in mammalian organism；It can also be used for
In vitro, mainly as experimental use, such as: comparison is provided as standard sample or control sample, or according to this field routine side
Kit is made in method, provides quick detection for the inhibitory effect of PD-1/PD-L1.
The present invention also provides a kind of above-mentioned substituted phenyl compound I, its pharmaceutically acceptable salt, its hydrations
Object, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug are in preparing immunomodulator
Application.
The present invention also provides a kind of above-mentioned substituted phenyl compound I, its pharmaceutically acceptable salt, its hydrations
Object, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug preparation for treat and/or
Prevention with PD-1/PD-L1 interact related disease drug in application.
Unless otherwise prescribed, all technical terms and scientific terms used herein have claimed theme fields
Standard meaning.If to Mr. Yu's term, there are multiple definition, then to be defined herein as standard.
It should be understood that above-mentioned general explanation and following detailed description are merely illustrative of, to the present invention not by
This limitation.The singular being used in the present invention, as "an" or "one", including plural, unless otherwise prescribed.This
Outside, term " includes " is open limits and non-enclosed.
Unless otherwise indicated, the present invention using mass spectrum, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology or
The conventional method of pharmacology detection, each step and condition can refer to the operating procedure and condition of this field routine.
Unless otherwise specified, the present invention is using the standard name of analytical chemistry, Synthetic Organic Chemistry and medical chemistry and mark
Quasi-experiment room step and technology.In some cases, standard technique is used for chemical synthesis, chemical analysis, medicine preparation, formula
With the treatment of drug delivery and patient.
Term " pharmaceutically acceptable " as used in the present invention is for those compounds, material, composition
And/or for dosage form, within the scope of reliable medical judgment, contacting suitable for the tissue with human and animal makes for they
With without excessive toxicity, irritation, allergic reaction or other problems or complication, with reasonable interests/Hazard ratio phase
Claim.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution
It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when in the compound of the present invention containing relatively acid functional group
To pass through the side for using the alkali of sufficient amount to contact with the neutral form of this kind of compound in pure solution or suitable atent solvent
Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.
It, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group
Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition
The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus
A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include
As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid,
Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as
Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical
Salts",Journal of Pharmaceutical Science 66:1-19(1977)).Certain specificization of the invention
It closes object and contains alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.Preferably, in a usual manner
It contacts salt with alkali or acid, then separates parent compound, thus the neutral form of raw compounds again.The parent fo of compound with
The form of its various salt is the difference is that certain physical properties, such as the different solubility in polar solvent.
" pharmaceutically acceptable salt " of the invention can pass through conventional chemical by the parent compound containing acid group or base
Method synthesis.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, via
Free acid or these compounds of alkali form are reacted with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that ether, second
The non-aqueous medias such as acetoacetic ester, ethyl alcohol, isopropanol or acetonitrile.
In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.Compounds described herein
Chemical change easily occurs in physiological conditions for prodrug to be converted to the compound of the present invention.It can convert in vivo to provide
Any compound of bioactive substance (i.e. compound shown in Formulas I) is the prodrug in the scope and spirit of the present invention.For example,
Compound containing carboxyl can hydrolyzable ester on physiology, by being hydrolyzed in vivo to obtain compound sheet shown in Formulas I
Body and serve as prodrug.The prodrug is preferably administered orally, this is because hydrolysis is in many cases mainly in the influence of digestive ferment
Lower generation.When ester itself is active or hydrolysis occurs in blood, parenteral administration can be used.In addition, pro-drug can
To be switched to the compound of the present invention by chemistry or biochemical method in environment in vivo.
The compound of the present invention can include the original of unnatural proportions on one or more atoms for constituting the compound
Daughter isotope.For example, radioisotope labeled compound can be used, such as tritium (3H), iodine-125 (125I) or C-14 (14C).This
The transformation of all isotopics of the compound of invention, no matter radioactivity whether, be included within the scope of the present invention.
Small molecule PD-1/PD-L1 inhibitor of the present invention may be used as single dose, or for example with other therapeutic agents
Atezolizumab or Avelumab or Durvalumab combination, to enhance the effect of these therapeutic agents.
Term " active constituent ", " therapeutic agent " or " active material " refers to a kind of chemical entities, it can be effectively treated
Target disorder, disease or illness.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise
Content.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: the substituted phenyl compound of the present invention as immunomodulator is
The advantages that small molecule PD-1/PD-L1 inhibitor, presentation activity height, bioavilability height, drug substance stable, Orally-administrable.Separately
Outside, compound preparation is convenient, production cost is low.
Specific embodiment
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that following
Embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Particular technique or item are not specified in embodiment
Part, it described technology or conditions or is carried out according to the literature in the art according to product description.Agents useful for same or instrument
Production firm person is not specified in device, and being can be with conventional products that are commercially available.
The embodiment provides phenyl compound substituted shown in Formulas I, the method for preparing it and intermediate and
Its application in medicine preparation.
The preparation of 1 compound I-2 of embodiment
(1) preparation of compound I-2-2
The fluoro- two ring 2.2.2 octane of Isosorbide-5-Nitrae-diazotising of compound I-2-1 (4.3g, 31.13mmol), 1- chloromethyl -4- is double
(tetrafluoro boric acid) salt (15g, 42.34mmol) is added in 250mL single port bottle, will after acetonitrile (60mL) room temperature reaction being added 5 days
Reaction system is spin-dried for, and column chromatographs to obtain compound I-2-2, the amount of obtaining 2.8g, yield 28.8%.
1H NMR(500MHz,CDCl3): δ=11.22 (s, 1H), 9.66 (s, 1H), 7.24 (d, J=5.0Hz, 1H),
6.58 (d, J=5.0Hz, 1H)
(2) preparation of compound I-2-4
Compound I-2-3 (2.0g, 14.91mmol) is added in 50mL single port bottle, addition thionyl chloride (6.5mL),
After methylene chloride (20mL) reacts at room temperature 3h, TLC detects fully reacting, and reaction system is spin-dried for, and oil pump drawing is dry to obtain compound
I-2-4, the amount of obtaining 1.8g, yield 79.4%.
(3) preparation of compound I-2-7
By compound I-2-5 (3.5g, 19.45mmol), compound I-2-6 (2.61g, 12.97mmol), Pd (dppf)
Cl2·CH2Cl2(120mg, 1.30mmol) is added in 250mL there-necked flask, and toluene (19mL), ethyl alcohol (6.35mL) is added, sets
Change N2Three times, NaHCO is added3After (19mL, 2M, 38.92mmol) reacts at room temperature 3h, TLC detects fully reacting, by reaction system
It is spin-dried for, is dissolved with ethyl acetate, wash, be spin-dried for organic phase, column chromatography obtains compound I-2-7, the amount of obtaining 3.1g, yield
93.2%.
1H NMR(500MHz,CDCl3): δ=7.36 (d, J=7.0Hz, 1H), 7.23 (t, J=7.5Hz, 1H), 7.17-
7.19 (m, 1H), 6.90 (d, J=8.5Hz, 1H), 6.81 (d, J=2.0Hz, 1H), 6.76 (dd, J1=2.0Hz, J2=
8.5Hz,1H),4.76(s,2H),4.30(s,4H).
(4) preparation of compound I-2-8
By compound I-2-7 (720mg, 2.81mmol), compound I-2-2 (1.1g, 7.03mmol), PPh3(2.2g,
It 8.43mmol) is added in 50mL single port bottle, is added THF (20mL, Dry), diethyl azodiformate is added dropwise under ice bath
(DEAD) after THF (10mL) the solution room temperature reaction 1.5h of (1.3mL, 8.43mmol), TLC detects fully reacting, by reactant
System is spin-dried for, and is dissolved with ethyl acetate, and washing is spin-dried for organic phase, column chromatography obtains compound I-2-8, the amount of obtaining 230mg, yield
20.78%.
1H NMR(500MHz,CDCl3): δ=11.39 (s, 1H), 9.68 (s, 1H), 7.39 (t, J=4.5Hz, 1H),
7.22-7.25 (m, 3H), 6.91 (d, J=8.0Hz, 1H), 6.83 (d, J=2.0Hz, 1H), 6.76 (dd, J1=2.0Hz, J2=
8.0Hz, 1H), 6.64 (d, J=7.0Hz, 1H), 5.19 (s, 2H), 4.31 (s, 4H), 2.26 (s, 3H)
(5) preparation of compound I-2-9
By compound I-2-8 (230mg, 0.58mmol), compound I-2-4 (90mg, 0.58mmol), CsCO3(230mg,
0.70mmol), NaI (9mg, 0.06mmol) is added in 25mL single port bottle, is added DMF (6mL, Dry), 70 DEG C of reactions 3h, TLC
Fully reacting is monitored, reaction system is spin-dried for, is dissolved with ethyl acetate, filters, is spin-dried for, column chromatography obtains compound I-2-9,
230mg, yield 77.25% must be measured.
1H NMR(500MHz,CDCl3): δ=10.30 (d, J=3.0Hz, 1H), 8.90 (d, J=7.5Hz, 2H), 8.07-
8.08 (m, 1H), 7.63 (d, J=11.0Hz, 1H), 7.35-7.37 (m, 1H), 7.25-7.27 (m, 2H), 6.92 (d, J=
8.5Hz, 1H), 6.82 (d, J=2.0Hz, 1H), 6.77 (dd, J1=2.0Hz, J2=8.5Hz, 1H), 6.67 (d, J=6.0Hz,
1H),5.25(s,2H),5.19(s,2H),4.31(s,4H),2.29(s,2H).
(6) preparation of compound I-2-10
By compound I-2-9 (100mg, 0.20mmol), KH2PO4(8mg, 0.06mmol) is added in 10mL single port bottle,
Acetonitrile/H is added2O (2mL/0.4mL) is stirred and H is added under ice bath2O2After stirring 3min, NaClO is added in (0.3mL)2(38mg,
Aqueous solution (0.3mL) 0.4mmol) reacts 3h, and TLC monitors fully reacting, and saturation solution of sodium bisulfite 0.5mL is added and quenches
It goes out reaction, stirs 5min, 50mL ethyl acetate, 20mL saturated salt solution are added into solution, liquid separation is collected organic phase, then used
Ethyl acetate extracts three times (30mL × 3), organic phase is spin-dried for, column chromatography obtains compound I-2-10, the amount of obtaining 64mg, yield
62.06%, directly progress the next step.
(7) preparation of compound I-2-12
By compound I-2-10 (64mg, 0.12mmol), compound I-2-11 (43mg, 0.16mmol), 1- (3- diformazan ammonia
Base propyl) -3- ethyl-carbodiimide hydrochloride (EDCl) (40mg, 0.21), I-hydroxybenzotriazole (HOBT) (28mg,
0.21mmol), n,N-diisopropylethylamine (DIPEA) (0.05mL, 0.3mmol) is added in 10mL single port bottle, and DMF is added
(2mL, Dry), overnight, TLC monitors fully reacting for room temperature reaction, is spin-dried for reaction system, and ethyl acetate dissolution is washed, and liquid separation is received
Collect organic phase, is spin-dried for, column chromatography obtains compound I-2-12, the amount of obtaining 90mg, yield 100%.
1H NMR(500MHz,CDCl3): δ=8.86 (s, 1H), 8.85 (s, 1H), 8.33 (t, J=2.5Hz, 1H), 8.22
(d, J=8.0Hz, 1H), 7.95 (d, J=12.5Hz, 1H), 7.35-7.37 (m, 1H), 7.24-7.25 (m, 1H), 6.91 (d, J
=8.0Hz, 1H), 6.82 (d, J=2.0Hz, 1H), 6.77 (dd, J1=2.0Hz, J2=8.0Hz, 1H), 6.68 (d, J=
7.5Hz,1H),5.17-5.27(m,4H),4.64(dd,J1=2.0Hz, J2=8.5Hz, 1H), 4.31 (s, 4H), 4.16-4.20
(m, 1H), 3.90 (t, J=5.8Hz, 0.5H), 3.13 (d, J=4.5Hz, 0.5H), 2.29 (s, 3H), 1.47 (s, 9H), 1.12
(d, J=6.5Hz, 3H), 1.05 (s, 9H)
(8) preparation of compound I-2
It by compound I-2-12 (90mg, 0.12mmol), is added in 25mL single port bottle, methylene chloride (2mL), three is added
Fluoroacetic acid (0.15mL), overnight, next day TLC monitors fully reacting for room temperature reaction, and reaction system is spin-dried for, ethyl acetate dissolution,
It is spin-dried for, column chromatography obtains compound I-2, the amount of obtaining 65mg, yield 61.23%.
1H NMR(500MHz,CD3OD): δ=8.96 (s, 1H), 8.87 (s, 1H), 8.45 (t, J=2.0Hz, 1H), 7.78
(d, J=12.0Hz, 1H), 7.41 (d, J=12.0Hz, 1H), 7.19-7.25 (m, 2H), 7.15 (d, J=7.0Hz, 1H),
(6.88 d, J=8.5Hz, 1H), 6.73-6.76 (m, 2H), 5.42 (s, 2H), 5.34 (s, 2H), 4.53-4.54 (m, 1H),
4.28-4.31 (m, 5H), 2.28 (s, 3H), 1.11 (d, J=6.5Hz, 3H)
The general synthetic method of compound I-1, I-3~I-28 is the same as embodiment 1.
1 biological characteristis of effect example
Purpose
Using the PD1/PD-L1 binding assay kit of Cisbio company, homogeneous phase time discrimination fluorescence (HTRF) skill is used
The ability of compound combination PD1/PD-L1 shown in art measurement research formula I.
Background
In this report, we use in CN105705489A in embodiment 202 target compound as reference compound,
28 compounds have been screened on PD-L1 by HTRF Assay.Since 10 μM, 3 times dilute, are continuous compound initial concentration
Dilution 10 times, each test is done twice.
Material: (Sigma is public by PD1/PD-L1 binding assay kit (Cisbio company #63ADK000CPDPEC), DMSO
Department, Cat.No.D2650), 384 hole assay plates (Corning company, Cat.No.4513).
Experimental method
I. prepare the compound for analysis
1. serial diluted compound
1) by 100 times of diluted chemical compound to ultimate density, with 100% in Echo plate (Labcyte, P-05525)
DMSO reaction.For example, being 10 μM if necessary to highest inhibitor concentration, then the DMSO for preparing 1mM compound in this step is molten
Liquid.
2) by 30% 100%DMSO that 15 μ l are transferred in next hole come 3 times of diluted compounds, it is continuous dilute
Release 10 dilutions.
3) 30 μ l 100%DMSO are added as no compound control and not enzyme control.Plate is designated as source plate.
2. preparing detection plate
200nl is dissolved in the compound in DMSO and is transferred to Echo analysis plates.
II. measurement reaction
1. preparing 2 × (i.e. 2 times) PD-L1 enzyme solutions
2. preparing 2 × PD1 solution
3. 2 × PD-L1 enzyme solutions are transferred in assay plate
Analysis plates are containing the compound of 200nl.
The 2xPD-L1 enzyme solutions of 5 μ L are added into each hole of 384 hole assay plates.
It is incubated at room temperature 10 minutes.
4. 2 × PD1 solution is transferred in assay plate
The 2xPD1 solution of 5 μ l is added into each hole of 384 hole assay plates.
5.PD1/PD-L1 is combined
It is incubated for 60 minutes at 25 DEG C.
6. preparing detection mixture
Anti-tag1-Eu and Anti-tag2-XL665 is added in detection buffer
7. adding detection combination
384 orifice plates of 10 μ L detection mixture are added,
It is incubated for 60 minutes at 25 DEG C
III.Envision reading
With HTRF method, read by Envision.
IV. curve matching
From Envision program copy data.
Conversion values are converted into inhibiting value.
Suppression percentage=(maximum value-conversion values)/(maximum value-minimum value) × 100%.
" maximum value " represents DMSO control；" minimum value " represents the control of not enzyme activity.
Fitting data obtains IC in XLfit excel plug-in version 5.4.0.850Value.
The formula used is:
The bottom Y=reading+(top reading-bottom reading)/(1+ (IC50/X)×HillSlope。
Experimental result shows that substituted phenyl compound shown in formula I has the IC of 0.01nM-500nM range50
Value, wherein part of compounds shows the IC with 0.01nM-10nM range50Value, part of compounds, which is shown, to be had
10.01nM-500nM the IC of range50Value, is specifically shown in the following table 1.
Table 1
Therefore, small molecule of the compound shown in Formulas I of the present invention as a kind of inhibition PD-1/PD-L1 interaction
Object is closed, there is the activity as the PD-1/PD-L1 inhibitor to interact, and therefore can be used for treating with PD-1/PD-L1's
Interact relevant disease, by the interaction for inhibiting PD-1/PD-L1.
The test of 2 metabolic stability in vitro of effect example
Clearance rate of the metabolic stability in vitro Experimental Evaluation compound in phase metabolism, and can predict its in liver cell and
Intracorporal intrinsic clearance.We stablize experimental evaluation part of compounds of the present invention in people and rat by In vitro metabolism
The metabolic stability of hepatomicrosome.Wherein describedization that control compound is 1001 from CN106536515A embodiment number
Close object.
Concrete operation step bibliography (Tang Minghai, Wang Hairong, Wang Chunyan, Ye Haoyu antitumorization of this experimental method
It closes In vitro metabolism of the object E7 in different genera hepatomicrosome enzyme and studies [J] CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2016 the 9th phases, 1739-
Page 1743) described in measuring method.
Experimental result is shown, numbers the compound for being 1001 relative to above-mentioned CN106536515A embodiment:Part of compounds of the present invention is in people and rat liver microsomes
More excellent metabolic stability is shown, provides important evidence for further preclinical study.
The test of 3 pharmacokinetics experiment of effect example
SD rat single dose intravenous and oral the compounds of this invention is given respectively and CN106536515A embodiment number is
1250 control compound:(number CPD1250).
Research purpose: single intravenous injection (IV) and oral (PO) give compound shown in ICR mouse formula I, with
And CPD1250, blood sample is acquired with trace blood mode in different time points, LC-MS/MS measures tested material in ICR mice plasma
Concentration and calculate relevant parameter, investigate the Pharmacokinetic Characteristics of each tested material in vivo.
Test material: test sample is the particular compound I-2 of compound shown in formula I.
Test sample preparation:
It is prepared to drug solns: each compound being first directly dissolved in DMSO (accurate weighing) respectively, is configured to respectively
The stock solution of 10mg/mL.Then compound stock solution shown in desired amount of CPD1250, Formulas I -2 is calculated and measured, is added 5%
Solutol and water for injection further dissolve, and are made into the uniform solution of required 0.5mg/mL respectively, give for oral or intravenous
Medicine, remaining stock solution are used for bioanalysis.
Dosage and administration mode:
Selected male ICR mouse is for testing, according to the form below administration.Oral group is administered first fasting about 14 hours, about 4 after administration
Restore feed after hour.
Table 2: administration table
Sample collection and processing: vein group 0.083h, 0.25h, 0.5h upon administration, 1h, 2h, 6h and for 24 hours, oral group exists
0.25h after administration, 0.5h, 1h, 2h, 4h, 8h and for 24 hours take a blood sample about 30 μ L through vein under jaw or other suitable methods, and heparin sodium is anti-
Solidifying, Blood specimen collection is placed on ice, centrifugal separation plasma (centrifugal condition: 8000 revs/min, 6 minutes, 4 DEG C).It collects
Ultra low temperature freezer is deposited in front of plasma analysis.
Data analysis: when carrying out plasma drug level-time graph drafting, BLQ is denoted as 0.
When carrying out medicine for parameter calculating, CmaxBLQ (including " No peak ") before is calculated according to 0；CmaxOccur later
BLQ (including " No peak ") is not involved in calculating without exception.
7.0 software of Phoenix WinNonlin calculates following pharmacokinetic parameter: AUC(0-t)、AUC(0-∞)、T1/2、
MRT(0-∞)、Cmax、Tmax、F。
Animal disposition: it is euthanized after being grouped remaining animal acquisition blank blood；Animal for test is in acquisition last blood
It is euthanized after sample.The processing of all animals is recorded in experimental record.
Detailed clinical observation: each time point does not observe obvious abnormal symptom before administration and after administration.
Pharmacokinetic parameter result:
ICR mouse vein and oral gives the medicine generation after the part particular compound of compound shown in formula I respectively
Kinetic parameter are as follows:
Under this experimental condition, ICR mouse vein gives the average C after 1mg/kg CPD1250maxFor 187.33ng/mL,
Average AUC(0-t)For 604.55h*ng/mL；ICR Mouse oral gives the average C after 5mg/kgCPD1250maxFor 220.18ng/
ML, average AUC(0-t)For 1266.55h*ng/mL, CPD1250 is 22.90% in the mean bioavailability of mouse.
Under this experimental condition, ICR mouse vein gives the average C after the compound I-2 of 1mg/kg respectivelymaxFor
330.20ng/mL average AUC(0-t)For 1145.78h*ng/mL；ICR Mouse oral is given flat after the compound I-2 of 5mg/kg
Equal CmaxFor 690.35ng/mL, average AUC(0-t)For 7624.22h*ng/mL, mean bioavailability of the compound I-2 in mouse
It is 75.50%.
Pharmacokinetic study results show that compound of the present invention is shown preferably relative to control compound
Pharmacokinetic Characteristics, oral administration biaavailability is high, provides important evidence for further preclinical study.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example
It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are different
Surely identical embodiment or example is referred to.Moreover, particular features, structures, materials, or characteristics described can be any
It can be combined in any suitable manner in one or more embodiment or examples.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective
In the case where can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention.
Claims (10)
1. a kind of substituted phenyl compound shown in formula I, its pharmaceutically acceptable salt, its hydrate, its solvate,
Its metabolite, its stereoisomer, its tautomer or its prodrug:
Wherein, the R1For hydrogen ,-(CH2)nR4Or-(CH2)nAr；
The n independently is 1,2,3 or 4；
The R4For-CH3、-CF3、CN、-OH、-CO2H、C1-C3Alkoxy carbonyl ,-C (=O) NH2、C1-C3Alkoxy or pyrroles
Alkanone base；
The Ar be benzdioxan base, indazolyl, isoquinolyl, isoxazolyl, naphthalene, oxadiazoles base, phenyl, pyridyl group,
Pyrimidine radicals or quinolyl；Wherein, the benzdioxan base, the indazolyl, the isoquinolyl, the different evil
Oxazolyl, the naphthalene, the oxadiazoles base, the phenyl, the pyridyl group, the pyrimidine radicals and the quinoline
Each ring of quinoline base optionally, is independently replaced by one or more substituent groups selected from the following: C1-C4Alkoxy, C1-C4Alkoxy
Carbonyl, C1-C4Alkoxycarbonyl amino, C1-C4Alkyl, (C1-C4Alkyl) carbonyl, (C1-C4Alkyl) sulfonyl, formamido group, ammonia
Base carbonyl, amino carbonyl (C1-C3Alkyl) ,-(CH2)r(C=O) O C1-C4Alkyl ,-(CH2)rOH, carboxyl, cyano, aldehyde radical, halogen
Plain, halogenated C1-C4Alkyl, halogenated C1-C4Alkoxy, nitro, the phenyl optionally replaced by a cyano, optionally by a halogen
Substituted phenoxy group, phenylcarbonyl group, pyrrole radicals or THP trtrahydropyranyl；The r independently is 0,1,2,3 or 4；
The R2For
The R1aFor
The m is 1,2 or 3；
The Y is each independently-CN, C1-C3Alkyl or-Cl；
The RxFor-OH or
The RqFor hydrogen, C1-C3Alkyl or benzyl；
The R3For
Wherein RzFor C1-C3Alkyl, C1-C3Alkyl sulphonyl C1-C3Alkyl, C1-C3Alkyl sulphinyl C1-C3Alkyl, formamide
Base C1-C3Alkyl, amino C1-C4Alkyl, carboxyl C1-C3Alkyl, cyano C1-C3Alkyl, carbamyl C1-C3Alkyl, dimethylamino
Formoxyl C1-C3Alkyl, dimethylamino C1-C4Alkyl, halogenated C1-C3Alkyl, hydroxyl C1-C3Alkyl, C1-C3Alkyl sulfenyl C1-
C3Alkyl, pyridyl group C1-C3Alkyl, tetrazole radical C1-C3Alkyl, " methyl or benzyl are substituted or unsubstituted " imidazole radicals C1-C3Alkane
Base, " cyano, methyl or hydroxyl are substituted or unsubstituted " phenyl C1-C3Alkyl or thiazolyl C1-C3Alkyl；
The R6It is each independently hydrogen, benzyl or methyl；
The R6’It is each independently hydrogen or methyl；
The R7For hydrogen, C1-C3Alkyl or benzyl；
The t is 1 or 2；
The X is CH or N；
The p is 0 or 1；
The RaFor hydroxyl；
The RbIt independently is hydrogen, benzyl or methyl；
Or R3And RqNitrogen-atoms connected to them is formed together ring, the ring are as follows:
The R8For hydroxyl or-NHSO2R11；The R11For trifluoromethyl, cyclopropyl, C1-C3Alkyl, dimethylamino or
By methyl substituted imidazole radicals；
The R9For hydrogen or-CO2H；
The Q is CH2, S, O or NCH3；
The R10It independently is halogen or hydroxyl；
The s is 0 or 1；
The w is 1,2 or 3；
The R5、R5' and R5" it is each independently H, C2-C4Alkenyl, C1-C3Alkyl, cyano, methoxyl group, halogen or fluoroform
Base.
2. the phenyl compound I replaced as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug, which is characterized in that work as R1For-(CH2)nR4When,
The n is 1 or 2；
And/or work as R1For-(CH2)nR4When, the R4In, the C1-C3Alkoxy carbonyl is methoxycarbonyl；
And/or work as R1For-(CH2)nR4When, the R4In, the C1-C3Alkoxy is methoxyl group；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, when there are multiple substitutions, the substituent group is identical or not
Together；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, when there are multiple substitutions, described being substituted by is taken by 2 or 3
Replace for base；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the C1-C4Alkoxy is methoxyl group；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the C1-C4Alkoxy carbonyl is methoxycarbonyl；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the C1-C4Alkoxycarbonylamino is methoxycarbonyl amine
Base；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the C1-C4Alkyl is methyl；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, (the C1-C4Alkyl) carbonyl be methyl carbonyl；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, (the C1-C4Alkyl) sulfonyl be mesyl；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the amino carbonyl (C1-C3Alkyl) it is amino carbonyl methyl；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, described-(CH2)r(C=O) OC1-C4Alkyl is-(CH2) (C=
O)OCH3；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, described-(CH2)qOH is-(CH2)OH；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the halogen is fluorine or chlorine；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the halogenated C1-C4Alkyl be the methyl that fluorine or chlorine replace or
Ethyl；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the halogenated C1-C4Alkoxy is the methoxy that fluorine or chlorine replace
Base or ethyoxyl；
And/or work as R1For-(CH2)nWhen Ar, in the Ar, the n is 1 or 2；
And/or work as R1For-(CH2)nWhen Ar, the n is 1 or 2；
And/or the RqFor hydrogen；
And/or the R2In, the Y is-CH3；
And/or the R2For
And/or work as R3ForWhen, the RzIn, the C1-C3Alkyl is methyl；
And/or work as R3ForWhen, the RzIn, the C1-C3Alkyl sulphonyl C1-C3Alkyl is mesyl
Methyl；
And/or work as R3ForWhen, the RzIn, the C1-C3Alkyl sulphinyl C1-C3Alkyl is that methyl is sub-
Sulfonvlmethvl；
And/or work as R3ForWhen, the RzIn, the formamido C1-C3Alkyl is amide methyl；
And/or work as R3ForWhen, the RzIn, the amino C1-C4Alkyl is 4- aminobutyl；
And/or work as R3ForWhen, the RzIn, the carboxyl C1-C3Alkyl is carboxymethyl group；
And/or work as R3ForWhen, the RzIn, the cyano C1-C3Alkyl is cyano methyl；
And/or work as R3ForWhen, the RzIn, the carbamyl C1-C3Alkyl is carbamoyhnethyl；
And/or work as R3ForWhen, the RzIn, the dimethylcarbamoyl C1-C3Alkyl is dimethyl carbamyl
Ylmethyl；
And/or work as R3ForWhen, the RzIn, the dimethylamino C1-C4Alkyl is dimethylamino first
Base；
And/or work as R3ForWhen, the RzIn, the halogenated C1-C3Alkyl be the methyl that fluorine or chlorine replace or
Ethyl；
And/or work as R3ForWhen, the RzIn, the hydroxyl C1-C3Alkyl be methylol, 2- hydroxyethyl,
1- hydroxyethyl, 2- hydroxy-2-methyl ethyl；
And/or work as R3ForWhen, the RzIn, the C1-C3Alkyl sulfenyl C1-C3Alkyl is methyl mercapto first
Base；
And/or work as R3ForWhen, the RzIn, the pyridyl group C1-C3Alkyl is pyridylmethyl；
And/or work as R3ForWhen, the RzIn, the tetrazole radical C1-C3Alkyl is tetrazolium ylmethyl；
And/or work as R3ForWhen, the RzIn, the imidazole radicals C1-C3Alkyl is imidazolyl methyl；
And/or work as R3ForWhen, the RzIn, the phenyl C1-C3Alkyl is benzyl；
And/or work as R3ForWhen, the RzIn, the thiazolyl C1-C3Alkyl is benzothiazolylmethyl；
And/or " the R3And RqNitrogen-atoms connected to them is formed together ring " in, the ring are as follows:
And/or " the R3And RqNitrogen-atoms connected to them is formed together ring " in, the Q is CH2；
And/or " the R3And RqNitrogen-atoms connected to them is formed together ring " in, the R10For hydroxyl；
And/or the R5、R5' and R5" described in C1-C3Alkyl is methyl；
And/or the R5、R5' and R5" described in halogen be fluorine or chlorine.
3. the phenyl compound I replaced as claimed in claim 2, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug, which is characterized in that
R1For-(CH2)nWhen Ar, described-(CH2)nAr is
And/or the R2For
And/or the R3ForWhen, it is describedFor
And/or the R3ForWhen, it is describedFor
And/or as the " R3And RqNitrogen-atoms connected to them is formed together ring " when, it is describedAre as follows:
And/or as the " R3And RqNitrogen-atoms connected to them is formed together ring " when, it is describedFor
Or
And/or the R5For H or methyl；
And/or the R5' it is H, methyl, fluorine or chlorine；
And/or the R5" it is H.
4. the phenyl compound I replaced as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug, which is characterized in that
The R1For-(CH2)nAr, the n be 1 or 2, the Ar be phenyl, pyridyl group, each ring optionally, independently by
1 or 2 substituent group selected from the following replaces: C1-C4Alkoxy, (C1-C4Alkyl) sulfonyl, carboxyl or cyano；
And/or the R2For
And/or work as RqWhen for H, the R3For The RzFor C1-C3Alkyl, amino C1-C4Alkyl, ammonia first
Acyl group C1-C3Alkyl, hydroxyl C1-C3Alkyl, pyridyl group C1-C3Alkyl or " cyano, methyl or hydroxyl are substituted or unsubstituted " benzene
Base C1-C3Alkyl；R7For C1-C3Alkyl or benzyl；
And/or alternatively, R3And RqNitrogen-atoms connected to them is formed together ring, the ring are as follows:
And/or the R5For H or C1-C3Alkyl；
And/or the R5' it is H, C1-C3Alkyl or halogen；
And/or the R5" it independently is H.
5. the phenyl compound I replaced as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug, which is characterized in that
The R1For-(CH2)nAr, the n be 1 or 2, the Ar be phenyl, pyridyl group, each ring optionally, independently by
1 or 2 substituent group selected from the following replaces: C1-C4Alkoxy, (C1-C4Alkyl) sulfonyl, carboxyl or cyano；
The R2For
Work as RqWhen for H, the R3For The RzFor C1-C3Alkyl, amino C1-C4Alkyl, ammonia first
Acyl group C1-C3Alkyl, hydroxyl C1-C3Alkyl, pyridyl group C1-C3Alkyl or " cyano, methyl or hydroxyl are substituted or unsubstituted " benzene
Base C1-C3Alkyl；R7For C1-C3Alkyl or benzyl；
Alternatively, R3And RqNitrogen-atoms connected to them is formed together ring, the ring are as follows:
The R5For H or C1-C3Alkyl；
The R5' it is H, C1-C3Alkyl or halogen；
The R5" it independently is H.
6. the phenyl compound I replaced as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug, which is characterized in that the R1For
The R2For
Work as RqWhen for H, the R3For
Alternatively, R3And RqNitrogen-atoms connected to them is formed together ring, the ring are as follows:
The R5For H or methyl；
The R5' it is H, methyl, fluorine or chlorine；
The R5" it is H.
7. the phenyl compound I replaced as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug, which is characterized in that the compound I is such as
Under any compound:
8. a kind of pharmaceutical composition comprising such as substituted phenyl compound I according to any one of claims 1 to 7, its medicine
Acceptable salt on, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its before
Medicine and pharmaceutic adjuvant.
9. it is a kind of as substituted phenyl compound I according to any one of claims 1 to 7, its pharmaceutically acceptable salt, its
Hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug are in preparation for treating
And/or prevention and PD-1/PD-L1 interact the drug of related disease.
10. it is a kind of as substituted phenyl compound I according to any one of claims 1 to 6, its pharmaceutically acceptable salt,
Its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug are in preparation PD-1/
PD-L1 inhibitor, or preparing the application in immunomodulator.
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| WO2020192570A1 (en) * | 2019-03-22 | 2020-10-01 | 上海再极医药科技有限公司 | Small-molecule inhibitor of pd-1/pd-l1, pharmaceutical composition thereof with pd-l1 antibody, and application of same |
| WO2021052386A1 (en) * | 2019-09-17 | 2021-03-25 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Combination of small molecule inhibitor of the pd-1/pd-l1 interaction and anti-pd-1 antibody for treating cancer |
| CN112574183A (en) * | 2019-09-29 | 2021-03-30 | 南京华威医药科技集团有限公司 | PD-1 inhibitor and preparation method and application thereof |
| CN112587666A (en) * | 2019-09-17 | 2021-04-02 | 广州再极医药科技有限公司 | Combination of a small molecule inhibitor of the PD-1/PD-L1 interaction and an anti-PD-1 antibody for the treatment of cancer |
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