CN110092779B - Substituted phenyl compound and application thereof - Google Patents

Substituted phenyl compound and application thereof Download PDF

Info

Publication number
CN110092779B
CN110092779B CN201910087329.9A CN201910087329A CN110092779B CN 110092779 B CN110092779 B CN 110092779B CN 201910087329 A CN201910087329 A CN 201910087329A CN 110092779 B CN110092779 B CN 110092779B
Authority
CN
China
Prior art keywords
compound
alkyl
methyl
substituted phenyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910087329.9A
Other languages
Chinese (zh)
Other versions
CN110092779A (en
Inventor
许勇
林当
黄璐
胡海
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Wellhealth Bio Pharmaceutical Co ltd
Original Assignee
Guangzhou Wellhealth Bio Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Wellhealth Bio Pharmaceutical Co ltd filed Critical Guangzhou Wellhealth Bio Pharmaceutical Co ltd
Publication of CN110092779A publication Critical patent/CN110092779A/en
Application granted granted Critical
Publication of CN110092779B publication Critical patent/CN110092779B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Abstract

The invention discloses a substituted phenyl compound and application thereof. The invention provides a substituted phenyl compound shown as a formula I, a pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite, a stereoisomer, a tautomer or a prodrug thereof. The compound I provided by the invention has the advantages of high activity, high bioavailability, stable medicine, oral administration and the like.

Description

Substituted phenyl compound and application thereof
Technical Field
The invention belongs to the field of biological medicine, and relates to a substituted phenyl compound and application thereof.
Background
The PD-1/PD-L1 signaling pathway is one of the most topical topics in the current field of cancer therapy and research. New immunotherapeutic drugs, such as Keytruda in Sanshadong and Opdivo in Baishimaibao, have been marketed in recent two years and have aimed at this signaling pathway, using monoclonal antibodies that bind to PD-1 receptors to prevent signaling and thus activate the body's own immune system to spread the attack on tumors. The two new medicines are already approved for treating cancers such as melanoma, and simultaneously show great potential in clinical trials aiming at other cancers. Currently, 3-macromolecule FDA approved PD-L1 inhibitors in the united states are marketed as Atezolizumab (tecentiq, the first PD-L1 inhibitor approved by the FDA for the treatment of bladder cancer and non-small cell lung cancer), Avelumab (the second PD-L1 inhibitor approved by the FDA for the treatment of merck cell carcinoma), and Durvalumab (the third PD-L1 inhibitor approved by the FDA for the treatment of urothelial cancer). However, the half-life of monoclonal antibodies as long as 15-20 days may cause side effects associated with immune responses. In addition, the current PD-1/PD-L1 monoclonal antibody medicine needs intravenous injection, and has poor curative activity on solid tumors.
Therefore, the development of safer and more efficient novel PD-1/PD-L1 inhibitor medicaments has great social value and economic benefit, and is also a research hotspot of various large pharmaceutical enterprises at present.
Disclosure of Invention
The technical problems to be solved by the invention are that the existing PD-1/PD-L1 monoclonal antibody medicine needs intravenous injection, and has the defects of poor curative activity on solid tumors, low bioavailability and the like, so the invention provides a substituted phenyl compound and application thereof. The compound is a micromolecular PD-1/PD-L1 inhibitor, and has the advantages of high activity, high bioavailability, stable medicine, oral administration and the like.
The invention provides a substituted phenyl compound shown as a formula I, pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof;
Figure BDA0001962207440000021
wherein, R is1Is hydrogen, - (CH)2)nR4Or- (CH)2)nAr；
N is independently 1, 2, 3 or 4;
the R is4is-CH3、-CF3、CN、-OH、-CO2H、C1-C3Alkoxycarbonyl, -C (═ O) NH2、C1-C3Alkoxy, or pyrrolidinonyl;
ar is benzodioxanyl, indazolyl, isoquinolyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridyl, pyrimidyl or quinolyl; wherein each ring of said benzodioxanyl, said indazolyl, said isoquinolyl, said isoxazolyl, said naphthyl, said oxadiazolyl, said phenyl, said pyridyl, said pyrimidyl and said quinolyl is optionally, independently substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of: c 1-C4Alkoxy (e.g. methoxy), C1-C4Alkoxycarbonyl (e.g. methyl)Oxycarbonyl) group C1-C4Alkoxycarbonylamino group (e.g. methoxycarbonylamino group), C1-C4Alkyl (e.g. methyl), (C)1-C4Alkyl) carbonyl (e.g. methylcarbonyl), (C)1-C4Alkyl) sulphonyl (e.g. methylsulfonyl), carboxamido
Figure BDA0001962207440000031
Aminocarbonyl group
Figure BDA0001962207440000032
Aminocarbonyl group (C)1-C3Alkyl) (e.g. aminocarbonylmethyl), - (CH)2)r(C＝O)OC1-C4Alkyl (e.g., - (CH)2)(C＝O)OCH3)、-(CH2)rOH (e.g., - (CH)2) OH), carboxyl, cyano, formyl (aldehyde group), halogen (e.g. fluorine, chlorine, bromine or iodine, also e.g. fluorine or chlorine), halogeno C1-C4Alkyl, halo C1-C4Alkoxy, nitro, phenyl optionally substituted with one cyano, phenoxy optionally substituted with one halogen, phenylcarbonyl, pyrrolyl, and tetrahydropyranyl; r is independently 0, 1, 2, 3 or 4; any substituent can be independently positioned at ortho, meta or para positions of the connection between each ring and the methylene;
the R is2Is composed of
Figure BDA0001962207440000033
Figure BDA0001962207440000034
The R is1aIs composed of
Figure BDA0001962207440000035
M is 1, 2 or 3;
y is independently-CN, C1-C3Alkyl (e.g., methyl), or-Cl;
the R isxis-OH,Or
Figure BDA0001962207440000036
The R isqIs hydrogen, C1-C3Alkyl, or benzyl;
the R is3Is composed of
Figure BDA0001962207440000041
(e.g. in
Figure BDA0001962207440000042
)、
Figure BDA0001962207440000043
(e.g. in
Figure BDA0001962207440000044
Figure BDA0001962207440000045
)、
Figure BDA0001962207440000046
Figure BDA0001962207440000047
Wherein R iszIs C1-C3Alkyl (e.g. methyl), C1-C3Alkylsulfonyl radical C 1-C3Alkyl radical, C1-C3Alkylsulfinyl radical C1-C3Alkyl, carboxamido C1-C3Alkyl, amino C1-C4Alkyl (e.g. 4-aminobutyl), carboxy C1-C3Alkyl, cyano C1-C3Alkyl, carbamoyl C1-C3Alkyl (e.g. carbamoylmethyl), dimethylcarbamoyl C1-C3Alkyl, dimethylamino C1-C4Alkyl, halo C1-C3Alkyl, hydroxy C1-C3Alkyl (e.g. hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl)1-methylethyl radical), C1-C3Alkylthio radical C1-C3Alkyl, pyridyl C1-C3Alkyl (for example)
Figure BDA0001962207440000048
) Tetrazolyl group C1-C3Alkyl, "methyl or benzyl substituted or unsubstituted" imidazolyl C1-C3Alkyl, "cyano, methyl or hydroxy substituted or unsubstituted" phenyl C1-C3Alkyl, or thiazolyl C1-C3An alkyl group;
said R6Independently hydrogen, benzyl or methyl;
said R6’Each independently hydrogen or methyl;
said R7Is hydrogen, C1-C3Alkyl (e.g., methyl) or benzyl;
t is 1 or 2;
x is CH or N;
p is 0 or 1;
said RaIs a hydroxyl group;
said RbIndependently hydrogen, benzyl or methyl;
or, R3And RqTogether with the nitrogen atom to which they are attached form a ring which is:
Figure BDA0001962207440000051
Figure BDA0001962207440000052
(e.g. in
Figure BDA0001962207440000053
) Or are each
Figure BDA0001962207440000054
Said R8Is hydroxy or-NHSO2R11；R11Is trifluoromethyl, cyclopropyl, C 1-C3Alkyl, dimethylamino, or imidazolyl substituted with methyl;
said R9Is hydrogen or-CO2H；
Q is CH2S, O or NCH3；
R is as described10Independently halogen or hydroxy;
s is 0 or 1;
w is 1, 2 or 3;
said R5、R5' and R5"independently is H, C2-C4Alkenyl radical, C1-C3Alkyl (for example methyl, ethyl, n-propyl, isopropyl, and also for example methyl), cyano, methoxy, halogen (for example fluorine, chlorine, bromine or iodine, and also for example fluorine or chlorine), or trifluoromethyl.
The above-mentioned "C1-C3Alkyl "is each independently methyl, ethyl, n-propyl or isopropyl.
The above-mentioned "C1-C4Alkyl "is each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
The above-mentioned "C1-C3Alkoxy "is each independently methoxy, ethoxy, n-propoxy or isopropoxy.
The above-mentioned "C1-C4Alkoxy "is each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy.
The "halo" s mentioned above are each independently fluorine, chlorine, bromine or iodine (e.g. fluorine or chlorine).
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
The R is1Is- (CH)2)nAr。
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
when R is1Is- (CH)2)nIn Ar, n is 1 or 2.
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
when R is1Is- (CH)2)nAr is phenyl or pyridyl, each ring being optionally and independently substituted with 1 or 2 substituents selected from the group consisting of: c1-C4Alkoxy group, (C)1-C4Alkyl) sulfonyl, carboxyl, or cyano.
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
when R is1Is- (CH)2)nAr is- (CH) of2)nAr is
Figure BDA0001962207440000071
Figure BDA0001962207440000072
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
the R is2Is composed of
Figure BDA0001962207440000073
Figure BDA0001962207440000074
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
said R2In (A), the Y is-CH3。
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
The R is2Is composed of
Figure BDA0001962207440000081
Figure BDA0001962207440000082
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
the R isqIs hydrogen.
In one embodiment, certain groups of compound I are defined as follows, and non-recited groups are defined as in any of the above embodiments:
r is as described3Is composed of
Figure BDA0001962207440000083
Figure BDA0001962207440000084
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
the R is3Is composed of
Figure BDA0001962207440000085
When R is saidzIs C1-C3Alkyl, amino C1-C4Alkyl, carbamoyl C1-C3Alkyl, hydroxy C1-C3Alkyl, pyridyl C1-C3Alkyl, or "cyano, methyl or hydroxy substituted or unsubstituted" phenyl C1-C3An alkyl group.
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments: the R is3Is composed of
Figure BDA0001962207440000086
When the utility model is used, the water is discharged,
Figure BDA0001962207440000087
is composed of
Figure BDA0001962207440000091
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments: the R is3Is composed of
Figure BDA0001962207440000092
When R is7Is C1-C3Alkyl (e.g., methyl) or benzyl.
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments: the R is 3Is composed of
Figure BDA0001962207440000093
When the temperature of the water is higher than the set temperature,
Figure BDA0001962207440000094
is composed of
Figure BDA0001962207440000095
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments: said "R3And RqWhen taken together with the nitrogen atom to which they are attached to form a ring ", the ring is:
Figure BDA0001962207440000096
(e.g. in
Figure BDA0001962207440000097
Figure BDA0001962207440000101
) Or is
Figure BDA0001962207440000102
(e.g. in
Figure BDA0001962207440000103
)。
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
said R5Is H, or C1-C3Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, and also, for example, methyl).
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
said R5' is H, C1-C3Alkyl (for example methyl, ethyl, n-propyl, isopropyl, again for example methyl), or halogen (for example fluorine, chlorine, bromine or iodine, again for example fluorine or chlorine).
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
said R5"is H.
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
The R is1Is- (CH)2)nAr, wherein n is 1 or 2, Ar is phenyl or pyridyl, and each ring is optionally and independently substituted by 1 or 2 substituents selected from the group consisting of: c1-C4Alkoxy group, (C)1-C4Alkyl) sulfonyl, carboxyl, or cyano;
the R is2Is composed of
Figure BDA0001962207440000104
Figure BDA0001962207440000111
When R isqWhen is H, said R3Is composed of
Figure BDA0001962207440000112
Figure BDA0001962207440000113
Said RzIs C1-C3Alkyl, amino C1-C4Alkyl, carbamoyl C1-C3Alkyl, hydroxy C1-C3Alkyl, pyridyl C1-C3Alkyl, or "cyano, methyl or hydroxy substituted or unsubstituted" phenyl C1-C3An alkyl group; r7Is C1-C3Alkyl (e.g., methyl) or benzyl;
or, R3And RqTogether with the nitrogen atom to which they are attached form a ring which is:
Figure BDA0001962207440000114
(e.g. in
Figure BDA0001962207440000115
) Or is
Figure BDA0001962207440000116
(e.g. in
Figure BDA0001962207440000117
)；
Said R5Is H, or C1-C3Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, and also, for example, methyl);
said R5' is H, C1-C3Alkyl (such as methyl, ethyl, n-propyl, isopropyl, and also for example methyl), or halogen (such as fluorine, chlorine, bromine, or iodine, and also for example fluorine or chlorine);
said R5"is independently H.
In one embodiment, certain groups of compound I are defined as follows, and groups not mentioned are defined as in any of the above embodiments:
the R is1Is composed of
Figure BDA0001962207440000121
Figure BDA0001962207440000122
The R is2Is composed of
Figure BDA0001962207440000123
Figure BDA0001962207440000124
When R isqWhen is H, said R 3Is composed of
Figure BDA0001962207440000125
(e.g. in
Figure BDA0001962207440000126
)、
Figure BDA0001962207440000127
(e.g. in
Figure BDA0001962207440000128
)、
Figure BDA0001962207440000129
(e.g. in
Figure BDA00019622074400001210
Figure BDA00019622074400001211
)、
Figure BDA00019622074400001212
(e.g. in the case of
Figure BDA00019622074400001213
)、
Figure BDA00019622074400001214
(e.g. in
Figure BDA00019622074400001215
)、
Figure BDA00019622074400001216
Figure BDA0001962207440000131
(e.g. in
Figure BDA0001962207440000132
)、
Figure BDA0001962207440000133
(e.g. in
Figure BDA0001962207440000134
Figure BDA0001962207440000135
)、
Figure BDA0001962207440000136
(e.g. in
Figure BDA0001962207440000137
)、
Figure BDA0001962207440000138
(e.g. in
Figure BDA0001962207440000139
)、
Figure BDA00019622074400001310
Or, R3And RqTogether with the nitrogen atom to which they are attached form a ring which is:
Figure BDA00019622074400001311
Figure BDA00019622074400001312
said R5Is H, or methyl;
said R5' is H, methyl, fluoro or chloro;
said R5"is H.
In one embodiment, the compound I can be any one of the following compounds:
Figure BDA0001962207440000141
Figure BDA0001962207440000151
Figure BDA0001962207440000161
Figure BDA0001962207440000171
it will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in the radicals described herein
Figure BDA0001962207440000172
Means that the corresponding group is linked to other fragments, groups in compound I via this site.
Thus, throughout this specification, the groups and substituents thereof described in compound I may be selected by one skilled in the art to provide stable substituted phenyl compounds I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, metabolites thereof, stereoisomers thereof, tautomers thereof or prodrugs thereof, including but not limited to I-1 to I-28 as described in the examples of the present invention.
The compound of formula I of the invention can be prepared according to conventional chemical synthesis methods in the field, and the steps and conditions thereof can refer to the steps and conditions of similar reactions in the field.
The invention also provides a pharmaceutical composition, which comprises the substituted phenyl compound I, pharmaceutically acceptable salts, hydrates, solvates, metabolites, stereoisomers, tautomers or prodrugs thereof and pharmaceutic adjuvants.
In the pharmaceutical composition, the substituted phenyl compound I, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer, or its prodrug may be used in a therapeutically effective amount.
The pharmaceutical excipients may be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories, and lozenges.
The invention also provides application of the substituted phenyl compound I, the pharmaceutically acceptable salt, the hydrate, the solvate, the metabolite, the stereoisomer, the tautomer or the prodrug thereof in preparation of PD-1/PD-L1 inhibitors.
In the application, the PD-1/PD-L1 inhibitor is a substance which can block the combination of PD-1 and PD-L1, block negative regulation signals and restore the activity of T cells so as to enhance the immune response.
In the use, the PD-1/PD-L1 inhibitor is useful in a mammalian organism; also can be used in vitro, mainly for experimental purposes, for example: the antibody can be used as a standard sample or a control sample for comparison, or can be prepared into a kit according to the conventional method in the field, so as to provide rapid detection for the inhibition effect of PD-1/PD-L1.
The invention also provides application of the substituted phenyl compound I, the pharmaceutically acceptable salt, the hydrate, the solvate, the metabolite, the stereoisomer, the tautomer or the prodrug thereof in preparing an immunomodulator.
The invention also provides application of the substituted phenyl compound I, the pharmaceutically acceptable salt, the hydrate, the solvate, the metabolite, the stereoisomer, the tautomer or the prodrug thereof in preparation of medicines for treating and/or preventing diseases related to PD-1/PD-L1 interaction.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is standard in the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Furthermore, the term "comprising" is open-ended and not closed-ended.
The present invention employs, unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques or pharmacological detection, and the various steps and conditions may be referred to those conventional in the art.
Unless otherwise indicated, the present invention employs standard nomenclature for analytical chemistry, organic synthetic chemistry, and medicinal chemistry, as well as standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, drug preparation, formulation and drug delivery, and treatment of patients.
The term "pharmaceutically acceptable" as used herein 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.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are Salts of amino acids (e.g., arginine, etc.), and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (tritium) (III)3H) Iodine-125 (I)125I) Or C-14(14C) .1. the All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The small molecule PD-1/PD-L1 inhibitors described herein can be used as a single agent or in combination with other therapeutic agents such as Atezolizumab, or Avelumab, or Durvalumab to enhance the effect of these therapeutic agents.
The term "active ingredient", "therapeutic agent", or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the substituted phenyl compound used as the immunomodulator is a small-molecule PD-1/PD-L1 inhibitor, and has the advantages of high activity, high bioavailability, stable medicine, oral administration and the like. In addition, the compound is convenient to prepare and low in production cost.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The embodiment of the invention provides a substituted phenyl compound shown as a formula I, a preparation method and an intermediate thereof, and application thereof in preparing medicines.
Figure BDA0001962207440000221
EXAMPLE 1 preparation of Compound I-2
Figure BDA0001962207440000231
(1) Preparation of Compound I-2-2
Figure BDA0001962207440000232
Adding the compound I-2-1(4.3g, 31.13mmol) and 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroborate) salt (15g, 42.34mmol) into a 250mL single-neck bottle, adding acetonitrile (60mL) into the bottle, reacting for 5 days at room temperature, then carrying out spin drying on a reaction system, and carrying out column chromatography to obtain the compound I-2-2, wherein the yield is 2.8g and 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
Figure BDA0001962207440000233
Adding the compound I-2-3(2.0g,14.91mmol) into a 50mL single-neck bottle, adding thionyl chloride (6.5mL) and dichloromethane (20mL) to react at room temperature for 3h, detecting by TLC that the reaction is complete, spin-drying the reaction system, and oil-pumping to obtain the compound I-2-4, wherein the yield is 1.8g and 79.4%.
(3) Preparation of Compound I-2-7
Figure BDA0001962207440000241
Mixing compound I-2-5(3.5g, 19.45mmol), compound I-2-6(2.61g, 12.97mmol), Pd (dppf) Cl2·CH2Cl2(120mg, 1.30mmol) was put into a 250mL three-necked flask, and toluene (19mL) and ethanol (6.35mL) were added to replace N2Three times, NaHCO is added3(19mL, 2M and 38.92mmol) is reacted for 3 hours at room temperature, TLC detection shows that the reaction is complete, the reaction system is dried in a spinning mode, ethyl acetate is used for dissolving, water washing is carried out, an organic phase is dried in a spinning mode, and a column chromatography method is carried out to obtain a compound I-2-7, wherein the yield is 3.1g and 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
Figure BDA0001962207440000242
Mixing compound I-2-7(720mg, 2.81mmol), compound I-2-2(1.1g, 7.03mmol), PPh3(2.2g, 8.43mmol) was added to a 50mL single neck flask, THF (20mL, Dry) was added, and diethyl azodicarboxylate was added dropwise under ice bathAfter ester (DEAD) (1.3mL, 8.43mmol) in THF (10mL) was reacted for 1.5h at room temperature, TLC checked for completion of the reaction, the reaction system was spun dry, dissolved in ethyl acetate, washed with water, the organic phase was spun dry, and column chromatography was performed to obtain compound I-2-8 in 230mg, 20.78% yield.
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
Figure BDA0001962207440000251
Mixing compound I-2-8(230mg, 0.58mmol), compound I-2-4(90mg, 0.58mmol), CsCO3(230mg, 0.70mmol) and NaI (9mg, 0.06mmol) are added into a 25mL single-neck bottle, DMF (6mL, Dry) is added, the reaction is carried out for 3h at 70 ℃, TLC is used for monitoring the reaction completion, the reaction system is dried in a spinning mode, ethyl acetate is used for dissolving, filtering and drying are carried out, and the compound I-2-9 is obtained through column chromatography, the yield is 230mg, and the yield is 77.25%.
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
Figure BDA0001962207440000261
Mixing compound I-2-9(100mg,0.20mmol) and KH2PO4(8mg,0.06mmol) was added to a 10mL single neck flask and acetonitrile/H was added2O (2mL/0.4mL), H was added with stirring in an ice bath2O2(0.3mL), stir for 3minThen, NaClO is added2(38mg,0.4mmol) in water (0.3mL), reacting for 3h, monitoring the reaction by TLC, adding saturated sodium bisulfite solution 0.5mL to quench the reaction, stirring for 5min, adding 50mL ethyl acetate and 20mL saturated saline solution into the solution, separating, collecting the organic phase, extracting three times with ethyl acetate (30 mL. times.3), spin-drying the organic phase, and performing column chromatography to obtain compound I-2-10 with yield of 64mg and yield of 62.06%, wherein the next step of reaction is directly performed.
(7) Preparation of Compound I-2-12
Figure BDA0001962207440000262
Adding compound I-2-10(64mg, 0.12mmol), compound I-2-11(43mg, 0.16mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl) (40mg, 0.21mmol), 1-Hydroxybenzotriazole (HOBT) (28mg, 0.21mmol), N-Diisopropylethylamine (DIPEA) (0.05mL, 0.3mmol) into a 10mL single-neck flask, adding DMF (2mL, Dry), reacting at room temperature overnight, monitoring by TLC for complete reaction, spin-drying the reaction system, dissolving ethyl acetate, washing with water, collecting organic phase by liquid separation, and performing spin-column chromatography to obtain compound I-2-12 with the yield of 90 mg.
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
Figure BDA0001962207440000271
Adding the compound I-2-12(90mg, 0.12mmol) into a 25mL single-neck bottle, adding dichloromethane (2mL) and trifluoroacetic acid (0.15mL), reacting overnight at room temperature, monitoring the reaction completion by TLC the next day, spin-drying the reaction system, dissolving with ethyl acetate, spin-drying, and performing column chromatography to obtain the compound I-2 with the yield of 65mg and 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 synthesis of compounds I-1, I-3 to I-28 is as in example 1.
Effect example 1 biological assay
Purpose(s) to
The ability of the compounds of formula I of the present invention to bind to PD1/PD-L1 was investigated using the PD1/PD-L1 binding assay kit from Cisbio using a homogeneous time-resolved fluorescence (HTRF) technique.
Background
In this report, we screened 28 compounds on PD-L1 by HTRF Assay using the target compound in example 202 in CN105705489A as a reference compound. Compound starting concentration was started at 10 μ M, 3 fold diluted, 10 serial dilutions, and two times for each test.
Materials: PD1/PD-L1 binding assay kit (Cisbio #63ADK000CPDPEC), DMSO (Sigma, Cat. No. D2650), 384-well assay plate (Corning, Cat. No. 4513).
Experimental methods
I. Preparation of Compounds for analysis
1. Serial dilution compounds
1) Compounds were diluted 100-fold of the final concentration and reacted with 100% DMSO in an Echo plate (Labcyte, P-05525). For example, if a maximum inhibitor concentration of 10. mu.M is desired, a DMSO solution of 1mM compound is prepared at this step.
2) Compounds were diluted 3-fold by transferring 15 μ Ι into 30% 100% DMSO in the next well, 10 dilutions were serially diluted.
3) 30 μ l of 100% DMSO was added as a no compound control and no enzyme control. The plate is labeled as the source plate.
2. Preparing a test board
200nl of compound dissolved in DMSO were transferred to an Echo assay plate.
Measurement reaction
1. A2X (i.e., 2-fold) PD-L1 enzyme solution was prepared
2. Preparation of 2XPD1 solution
3. Transfer of 2XPD-L1 enzyme solution to assay plate
The assay plate already contained 200nl of compound.
Add 5. mu.L of 2xPD-L1 enzyme solution to each well of a 384 well assay plate.
Incubate at room temperature for 10 minutes.
4. Transfer of 2XPD1 solution to assay plate
Add 5 μ l of 2xPD1 solution to each well of 384 well assay plates.
PD1/PD-L1 binding
Incubate at 25 ℃ for 60 minutes.
6. Preparing a detection mixture
Adding Anti-tag1-Eu and Anti-tag2-XL665 to detection buffer
7. Add detection combination
A 384 well plate to which 10 μ L of the assay mixture was added,
Incubation at 25 ℃ for 60 min
Envision reading
Readings were taken by Envision using HTRF method.
Curve fitting
Data is copied from the Envision program.
The conversion value is converted into an inhibition value.
Percent inhibition ═ (max-conversion)/(max-min) × 100%.
"maximum" represents DMSO control; "minimum" represents a control with no enzyme activity.
Fitting data acquisition IC in XLFit excel plug-in version 5.4.0.850The value is obtained.
The formula used is:
y ═ bottom reading + (top reading-bottom reading)/(1 + (IC)50/X)×HillSlope。
The experimental results show that the substituted phenyl compounds shown in the formula I have IC in the range of 0.01nM-500nM50Values, where some compounds show IC's with ranges of 0.01nM-10nM50Values, some of the compounds showed IC's with a range of 10.01nM-500nM50The values are shown in Table 1 below.
TABLE 1
Figure BDA0001962207440000301
Figure BDA0001962207440000311
Therefore, the compound shown in the formula I as a small molecule compound for inhibiting the interaction of PD-1/PD-L1 has the activity of being an inhibitor of the interaction of PD-1/PD-L1, and can be used for treating diseases related to the interaction of PD-1/PD-L1 by inhibiting the interaction of PD-1/PD-L1.
Effect example 2 in vitro metabolic stability test
In vitro metabolic stability experiments assess the clearance of a compound in one phase of metabolism and can predict its intrinsic clearance in hepatocytes and in vivo. We evaluated the metabolic stability of some compounds of the invention in human and rat liver microsomes by in vitro metabolic stability experiments. Wherein the control compound is derived from the compound of CN106536515A example number 1001.
The specific operation steps of the experimental method refer to the determination method described in the literature (Tangminghai, Wang Haishun, Wang Chunhui, Yehaoyu. anti-tumor compound E7 in vitro metabolism study of liver microsome enzymes of different species [ J ]. Chinese medicine J2016, 9 th stage 2016, page 1739-1743).
The experimental results show thatThe CN106536515A example is a compound with the number of 1001:
Figure BDA0001962207440000312
the partial compound of the invention shows better metabolic stability in human and rat liver microsomes, and provides important basis for further preclinical research.
Effect example 3 pharmacokinetic experiment test
SD rats were administered a single intravenous and oral administration of a compound of the invention and a control compound numbered 1250 from CN106536515A example, respectively:
Figure BDA0001962207440000321
(accession number CPD 1250).
The research purpose is as follows: the compound shown in the formula I and CPD1250 are administered to ICR mice by single intravenous Injection (IV) and oral administration (PO), blood samples are collected by micro-blood collection at different time points, LC-MS/MS is used for measuring the concentration of a test object in the plasma of the ICR mice and calculating related parameters, and the pharmacokinetic characteristics of each test object in vivo are examined.
Test materials: the test sample is a specific compound I-2 of the compound shown in the formula I.
Preparing a test sample:
preparation of a dosing solution: each compound was first dissolved directly in DMSO (accurately weighed) to prepare 10mg/mL stock solutions. And then calculating and measuring the required dosage of CPD1250 and the compound stock solution shown in the formula I-2, adding 5% Solutol and water for injection for further dissolution, respectively preparing the required 0.5mg/mL uniform solution for oral administration or intravenous administration, and using the residual stock solution for biological analysis.
Administration dose and administration mode:
male ICR mice were selected for the experiments and dosed as follows. The oral group fasted for about 14 hours before administration and the diet was restored after about 4 hours after administration.
Table 2: administration table
Figure BDA0001962207440000331
Sample collection and processing: intravenous group at 0.083h, 0.25h, 0.5h, 1h, 2h, 6h and 24h after administration, oral group at 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration, collecting blood by submaxillary vein or other suitable means about 30 μ L, heparin sodium anticoagulation, blood sample collection placed on ice, and separating plasma by centrifugation (centrifugation conditions: 8000 rpm, 6 min, 4 ℃). The collected plasma was stored in an ultra-low temperature refrigerator before analysis.
And (3) data analysis: when plasma drug concentration-time curves were plotted, BLQ was recorded as 0.
When calculating the drug substitution parameters, CmaxThe previous BLQ (including "No peak") is calculated as 0; cmaxBLQ (including "No peak") appearing later does not participate in the calculation uniformly.
The Phoenix WinNonlin 7.0 software calculated the following pharmacokinetic parameters: AUC(0-t)、AUC(0-∞)、T1/2、MRT(0-∞)、Cmax、Tmax、F。
Animal treatment: grouping the rest animals, collecting blank blood, and euthanizing; animals used for the test were euthanized after the last blood sample was taken. Treatment of all animals was recorded in the experimental records.
Detailed clinical observations: no significant abnormal symptoms were observed at each time point before and after administration.
Pharmacokinetic parameter results:
the pharmacokinetic parameters after intravenous and oral administration of some specific compounds of the compounds of formula I according to the invention in ICR mice were:
under the conditions of this experiment, ICR mice had an average C after intravenous administration of 1mg/kg CPD1250max187.33ng/mL, mean AUC(0-t)604.55h ng/mL; average C after oral administration of 5mg/kg CPD1250 in ICR micemax220.18ng/mL, mean AUC(0-t)1266.55h ng/mL, the mean bioavailability of CPD1250 in mice was 22.90%.
Under the conditions of this test, the ICR mice were administered 1mg/kg of Compound I-2 intravenously, respectivelyAverage C ofmax330.20ng/mL, mean AUC(0-t)1145.78h ng/mL; average C after oral administration of 5mg/kg of Compound I-2 to ICR mice max690.35ng/mL, mean AUC(0-t)7624.22h ng/mL, the mean bioavailability of compound I-2 in mice was 75.50%.
The pharmacokinetic research result shows that the compound of the invention has better pharmacokinetic characteristics and high oral bioavailability compared with a control compound, and provides an important basis for further preclinical research.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.

Claims (11)

1. A substituted phenyl compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
Figure FDA0003611290280000011
wherein, R is1Is- (CH)2)nAr；
N is independently 1;
ar is phenyl or pyridyl; wherein said phenyl and said pyridyl are independently substituted with one substituent selected from the group consisting of: c1-C4Alkoxy group, (C)1-C4Alkyl) sulfonyl, carboxyl or cyano;
the R is2Is composed of
Figure FDA0003611290280000012
Y is independently C1-C3An alkyl group;
the R isxis-OH or
Figure FDA0003611290280000013
The R isqIs hydrogen;
the R is3Is composed of
Figure FDA0003611290280000014
Wherein R iszIs carbamoyl group C1-C3An alkyl group;
or R3And RqTogether with the nitrogen atom to which they are attached form a ring which is:
Figure FDA0003611290280000015
Figure FDA0003611290280000016
r is as described8Is a hydroxyl group;
said R9Is hydrogen;
q is CH2；
Said R10Independently is a hydroxyl group;
s is 1;
w is 2;
said R5Is H or C1-C3An alkyl group;
the above-mentionedR of (A)5 ’Is H, C1-C3Alkyl or halogen;
r is as described5"is H.
2. A substituted phenyl compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
Figure FDA0003611290280000021
wherein, R is1Is- (CH)2)nAr；
N is independently 1;
ar is phenyl or pyridyl; wherein said phenyl and said pyridyl are independently substituted with one substituent selected from the group consisting of: c 1-C4Alkoxy group, (C)1-C4Alkyl) sulfonyl, carboxyl or cyano;
y is independently C1-C3An alkyl group;
the R is2Is composed of
Figure FDA0003611290280000022
The R isxIs composed of
Figure FDA0003611290280000031
The R isqIs hydrogen;
the R is3Is composed of
Figure FDA0003611290280000032
Wherein R iszIs carbamoyl radical C1-C3An alkyl group;
or R3And RqTogether with the nitrogen atom to which they are attached form a ring of
Figure FDA0003611290280000033
Said R10Independently is a hydroxyl group;
s is 1;
w is 2;
said R5Is H or C1-C3An alkyl group;
said R5' is H, C1-C3Alkyl or halogen;
r is as described5"is H.
3. The substituted phenyl compound I, its pharmaceutically acceptable salt, or its stereoisomer of claim 1 or 2,
in said Ar, said C1-C4Alkoxy is methoxy, said (C)1-C4Alkyl) sulfonyl is methanesulfonyl;
and/or, said R2In which Y is-CH3；
And/or when R3Is composed of
Figure FDA0003611290280000034
When R is saidzIn (1), carbamoyl group C1-C3Alkyl is carbamoylmethyl;
and/or, said R5In (b), the C1-C3Alkyl is methyl;
and/or, said R5' of the above, C1-C3The alkyl is methyl, and the halogen is fluorine or chlorine.
4. The substituted phenyl compound I, its pharmaceutically acceptable salt, or its stereoisomer of claim 1,
The- (CH)2)nAr is
Figure FDA0003611290280000041
Figure FDA0003611290280000042
And/or, said R2Is composed of
Figure FDA0003611290280000043
And/or, when said R is3Is composed of
Figure FDA0003611290280000044
When it is used, the
Figure FDA0003611290280000045
Is composed of
Figure FDA0003611290280000046
When said "R" is3And RqWhen they form a ring together with the nitrogen atom to which they are attached ″, said
Figure FDA0003611290280000047
Is composed of
Figure FDA0003611290280000048
And/or, said R5Is H or methyl;
and/or, said R5' is H, methyl, fluorine or chlorine.
5. The substituted phenyl compound I, its pharmaceutically acceptable salt, or its stereoisomer of claim 2,
the- (CH)2)nAr is
Figure FDA0003611290280000049
Figure FDA00036112902800000410
And/or, said R2Is composed of
Figure FDA0003611290280000051
And/or, when said R is3Is composed of
Figure FDA0003611290280000052
When it is used, the
Figure FDA0003611290280000053
Is composed of
Figure FDA0003611290280000054
When said "R" is3And RqWhen they form a ring together with the nitrogen atom to which they are attached, said
Figure FDA0003611290280000055
Is composed of
Figure FDA0003611290280000056
And/or, said R5Is H or methyl;
and/or, said R5' is H, methyl, fluorine or chlorine.
6. The substituted phenyl compound of claim 1, wherein R is selected from the group consisting of1Is composed of
Figure FDA0003611290280000057
Figure FDA0003611290280000058
Said R2Is composed of
Figure FDA0003611290280000059
Said R3Is composed of
Figure FDA00036112902800000510
Or, R3And RqTogether with the nitrogen atom to which they are attached form a ring which is:
Figure FDA0003611290280000061
Figure FDA0003611290280000062
r is as described5Is H or methyl;
r is as described5' is H, methyl, fluoro or chloro;
said R5"is H.
7. The substituted phenyl compound I, its pharmaceutically acceptable salt, or its stereoisomer of claim 2, wherein R is 1Is composed of
Figure FDA0003611290280000063
Figure FDA0003611290280000064
Said R2Is composed of
Figure FDA0003611290280000065
Said R3Is composed of
Figure FDA0003611290280000066
Or, R3And RqTogether with the nitrogen atom to which they are attached form a ring of
Figure FDA0003611290280000067
Said R5Is H or methyl;
said R5' is H, methyl, fluoro or chloro;
said R5"is H.
8. A substituted phenyl compound I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the compound I is any one of the following compounds:
Figure FDA0003611290280000071
Figure FDA0003611290280000081
Figure FDA0003611290280000091
9. a pharmaceutical composition comprising a substituted phenyl compound I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 8, and a pharmaceutical excipient.
10. Use of a substituted phenyl compound I according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a stereoisomer thereof for the preparation of a medicament for the treatment and/or prevention of diseases associated with PD-1/PD-L1 interactions.
11. Use of the substituted phenyl compound I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof according to any one of claims 1 to 8 for the preparation of a PD-1/PD-L1 inhibitor, or for the preparation of an immunomodulator.
CN201910087329.9A 2018-01-29 2019-01-29 Substituted phenyl compound and application thereof Active CN110092779B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2018100843674 2018-01-29
CN201810084367 2018-01-29

Publications (2)

Publication Number Publication Date
CN110092779A CN110092779A (en) 2019-08-06
CN110092779B true CN110092779B (en) 2022-07-12

Family

ID=67443800

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910087329.9A Active CN110092779B (en) 2018-01-29 2019-01-29 Substituted phenyl compound and application thereof

Country Status (1)

Country Link
CN (1) CN110092779B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111714628B (en) * 2019-03-22 2024-03-22 上海再极医药科技有限公司 Small molecule PD-1/PD-L1 inhibitor, pharmaceutical composition of small molecule PD-1/PD-L1 inhibitor and PD-L1 antibody and application of small molecule PD-1/PD-L1 inhibitor
EP4031129A4 (en) * 2019-09-17 2023-08-09 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
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
CN112574183B (en) * 2019-09-29 2022-07-08 南京华威医药科技集团有限公司 PD-1 inhibitor and preparation method and application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (en) * 2013-09-04 2016-06-22 百时美施贵宝公司 Compounds useful as immunomodulators
CN105777756A (en) * 2014-07-02 2016-07-20 广东东阳光药业有限公司 Heteroaryl compound and application thereof in medicines
CN106536515A (en) * 2014-04-14 2017-03-22 百时美施贵宝公司 Compounds useful as immunomodulators
WO2017066227A1 (en) * 2015-10-15 2017-04-20 Bristol-Myers Squibb Company Compounds useful as immunomodulators
CN107573332A (en) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (en) * 2013-09-04 2016-06-22 百时美施贵宝公司 Compounds useful as immunomodulators
CN106536515A (en) * 2014-04-14 2017-03-22 百时美施贵宝公司 Compounds useful as immunomodulators
CN105777756A (en) * 2014-07-02 2016-07-20 广东东阳光药业有限公司 Heteroaryl compound and application thereof in medicines
WO2017066227A1 (en) * 2015-10-15 2017-04-20 Bristol-Myers Squibb Company Compounds useful as immunomodulators
CN107573332A (en) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application

Also Published As

Publication number Publication date
CN110092779A (en) 2019-08-06

Similar Documents

Publication Publication Date Title
CN110092779B (en) Substituted phenyl compound and application thereof
CN109721527B (en) Novel anti-PD-L1 compound, application thereof and composition containing same
CN103097340B (en) Therapeutic activity composition and its application method
CN110092745B (en) Compound containing aromatic ring and application thereof
CN108395443B (en) Cyclic compounds inhibiting programmed death receptor ligand 1 and uses thereof
CN109563060B (en) IDO1 inhibitor and preparation method and application thereof
RU2720810C2 (en) Salts of a quinazoline derivative and a method for production thereof
EP3983384B1 (en) N-(phenyl)-indole-3-sulfonamide derivatives and related compounds as gpr17 modulators for treating cns disorders such as multiple sclerosis
CN110759908B (en) N-benzenesulfonyl benzamide compound for inhibiting Bcl-2 protein and composition and application thereof
CN110092740B (en) Fused ring compound and application thereof
US20160229848A1 (en) Benzazepine Ketone Compounds as Glycogen Phosphorylase Inhibitor, Preparation Method therefor, and Medical Uses
JP2021519828A (en) Diaryl macrocycles, pharmaceutical compositions and their uses
WO2021238328A1 (en) Compound containing hydroxamic acid, and preparation method therefor and use thereof
CN113072484B (en) Succinate-containing sulfanilamide benzamide compound and preparation method and application thereof
CN109096219B (en) Novel anti-PD-L1 compound, application thereof and composition containing same
CN111499591A (en) ROR gamma modulators
CN115504963A (en) C-Myc protein degradation agent
CN112898286A (en) Benzothiophene compound or pharmaceutically acceptable salt and isomer thereof, and preparation method, pharmaceutical composition and application thereof
CN108794517A (en) A kind of arginase inhibitor and preparation method thereof and purposes
JPWO2019235553A1 (en) Azetidine derivatives and their prodrugs
CN108623528A (en) A kind of substituted pyrimidine trione compound and the composition and application thereof comprising the compound
CN114149386A (en) Aryl pentadiene amide aldehyde dehydrogenase inhibitor, and synthesis method and application thereof
EP4223757A1 (en) Fxr small-molecule agonist, and preparation method therefor and use thereof
CN110092799B (en) Cyclic compound, preparation method and application thereof
CN111057069B (en) Cyclic compound, application and composition thereof

Legal Events

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