CN109721527A - A kind of novel anti-PD-L1 compound, its application and the composition containing it - Google Patents
A kind of novel anti-PD-L1 compound, its application and the composition containing it Download PDFInfo
- Publication number
- CN109721527A CN109721527A CN201711025361.1A CN201711025361A CN109721527A CN 109721527 A CN109721527 A CN 109721527A CN 201711025361 A CN201711025361 A CN 201711025361A CN 109721527 A CN109721527 A CN 109721527A
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- Prior art keywords
- alkyl
- independently
- halogenated
- halogen
- ring
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000003545 alkoxy group Chemical group 0.000 claims description 58
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 38
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 34
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of novel anti-PD-L1 compound, its application and containing its composition.The present invention provides a kind of substitution biaryl compound, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrugs shown in formula I.
Description
Technical field
The invention belongs to biomedicine fields, are related to the novel anti-PD-L1 compound of one kind, its application and the combination containing it
Object.
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, developing safer, efficient novel PD-L1 inhibitor medicaments has huge social value and economic effect
Benefit, and the research hotspot of major pharmaceutical manufacturer at present.
Summary of the invention
The existing PD-1/PD-L1 monoclonal antibody medicine of the technical problems to be solved by the invention needs intravenous injection and to solid tumor
Therapeutic activity is bad, the defects such as bioavilability is low, thus, the present invention provides a kind of novel anti-PD-L1 compound, it answers
With and containing its composition, which is small molecule PD-L1 inhibitor, is presented that activity is high, bioavilability is high, drug is steady
Calmly, the advantages that Orally-administrable, and the compound can cause and enhance the autoimmune response of body.The compound is PD-
L1 inhibitor.
The present invention provides a kind of substitution biaryl compound shown in formula I, (it can anti-programmed death receptors ligand
1, that is, be used as PD-L1 inhibitor), its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite, it is three-dimensional
Isomers, its tautomer or its prodrug；
Wherein, the ring A is phenyl, thienyl, pyrrole radicals or piperidyl；
The p is 0,1 or 2；
All R1It independently is-OCH3、-OH、-OCH2CH3、-O(CH2)OCH3、-OCH2CH=CH2、-O(CH2)2CH3、-
O(CH2)2Morpholinyl or F；(when ring A is hexatomic ring, all R1Ortho position, the meta or para position of ring B can be separately located in；When
When ring A is five-membered ring, all R1Ortho position or the meta position of ring B can be separately located in；It is described when ring A is hexatomic ring and p is 2
R1The meta position and contraposition of ring B can be located at)
Alternatively, being connected to adjacent carbon atom, (when ring A is hexatomic ring, " adjacent carbon atom " can position when p is 2
In " meta position and the contraposition " or " ortho position and meta position " of ring B, but can be located at ring B " meta position and contraposition ") two R1Formation-O-
(CRcRd)q-O-；The q is 1 or 2；All RcAnd RdIt independently is hydrogen, C1-C6Alkyl (such as C1-C4Alkyl, and example
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, also such as methyl), hydroxyl, carboxyl,
Cyano, amino, C1-C6Alkoxy (such as methoxy or ethoxy), C1-C6Halogenated alkyl (number of " halogen " can
For one or more [such as 2,3 or 4]；All " halogen " can independently be fluorine, chlorine or bromine, and can be fluorine；Described
“C1-C6Halogenated alkyl " such as-CH2F、-CHF2Or-CF3) or C1-C6Halogenated alkoxy (number of " halogen " can be
One or more [such as 2,3 or 4]；All " halogen " can independently be fluorine, chlorine or bromine, and can be fluorine；Described
“C1-C6Halogenated alkoxy " such as-OCH2F、-OCHF2Or-OCF3)；
The ring B is(such as)、
(when the connection site of the group of above-mentioned ring B and other groups is in upper and lower position, the upper end [or lower end] can be with
Ring A connection, lower end [or upper end] can be with (CH2)mConnection；
When the connection site of the group of above-mentioned ring B and other groups is in left-right position, left end [or right end] can be with
Ring A connection, right end [or left end] can be with (CH2)mConnection)
All Y1、Y2And Y8It independently is-C (R4)2-、-N(R5)-,-O- ,-S (=O)wOr-C (=O)-；All w
It independently is 0,1 or 2；
All Y3、Y4、Y5、Y6And Y7It independently is CR4Or N；
All R5It independently is hydrogen, C1-C6Alkyl (such as C1-C4Alkyl, in another example methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, in another example methyl), C1-C6Halogenated alkyl (" halogen "
Number can be one or more [such as 2,3 or 4]；All " halogen " can independently be fluorine, chlorine or bromine, and can be fluorine；Institute
" the C stated1-C6Halogenated alkyl " such as trifluoromethyl, 2- fluoro ethyl or 3,3,3- trifluoro propyl), H- (C (R4)2)k- O-C (=
O)-(C(R4)2)k-、(R6R7)N-(C(R4)2)k-、HO-(C(R4)2)k- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2
)k-、H-(C(R4)2)k-O-(C(R4)2)k-、H-(C(R4)2)k- S (=O)2-(C(R4)2)k-、H-(C(R4)2)k- C (=O)-(C
(R4)2)k-、CN-(C(R4)2)k- C (=O)-, H- (C (R4)2)k- O-C (=O)-C (=O)-(C (R4)2)k-、C3-C9Heterocycle or
C1-C9Heteroaryl；
All R4It independently is hydrogen, C1-C6Alkyl (such as C1-C4Alkyl, in another example methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl), hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-C6Alkoxy (example
Such as methoxy or ethoxy), H2N-(CH2)k-、N(R6R7)-C (=O)-, aldehyde radical, H- (CH2)k- O-C (=O)-(CH2)k-、H-
(CH2)k-O-(CH2)k-、CN-(CH2)k- C (=O)-, C3-C9Heterocycle, C1-C9Heteroaryl, C1-C6Halogenated alkyl it is (described
The number of " halogen " can be one or more [such as 2,3 or 4]；All " halogen " can independently be fluorine, chlorine or bromine, and can
For fluorine；" the C1-C6Halogenated alkyl " such as-CH2F、-CHF2Or-CF3)、C1-C6Halogenated alkoxy (" halogen "
Number can be one or more [such as 2,3 or 4]；All " halogen " can independently be fluorine, chlorine or bromine, and can be
Fluorine；" the C1-C6Halogenated alkoxy " such as-OCH2F、-OCHF2Or-OCF3) or C1-C6Alkylamino (such as first ammonia
Base)；
All R6And R7It independently is hydrogen, C1-C6Alkyl (such as C1-C4Alkyl, in another example methyl, ethyl, positive third
Base, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl), hydroxyl, carboxyl, amino, C1-C6Alkoxy (such as methoxy
Base or ethyoxyl), H2N-(CH2)k-、NH2- C (=O)-, aldehyde radical, H- (CH2)k- O-C (=O)-(CH2)k-、C3-C9Heterocycle,
C1-C9Heteroaryl, C1-C6Halogenated alkyl (number of " halogen " can be one or more [such as 2,3 or 4]；
All " halogen " can independently be fluorine, chlorine or bromine, and can be fluorine；" the C1-C6Halogenated alkyl " such as-CH2F、-CHF2
Or-CF3)、C1-C6Halogenated alkoxy (number of " halogen " can be one or more [such as 2,3 or 4]；Institute
" halogen " having can independently be fluorine, chlorine or bromine, and can be fluorine；" the C1-C6Halogenated alkoxy " such as-OCH2F、-
OCHF2Or-OCF3) or C1-C6Alkylamino (such as methylamino)；
All k independently are 0,1,2,3 or 4；
The ReAnd RfIt independently is hydrogen, C1-C6Alkyl (such as C1-C4Alkyl, in another example methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, also such as methyl or tert-butyl), C3-C6Naphthenic base is (in another example cyclopropyl
Base, cyclohexyl or cyclobutyl), hydroxyl, carboxyl, amino, C1-C6Alkoxy (such as C1-C4Alkoxy, in another example methoxy
Base, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, also such as methoxy
Base), C1-C6Halogenated alkyl (number of " halogen " can be one or more [such as 2,3 or 4]；All
" halogen " can independently be fluorine, chlorine or bromine, and can be fluorine；Wherein, " C1-C6Alkyl " such as C1-C4Alkyl, in another example methyl, second
Base, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, also such as methyl；" the C1-C6Alkyl halide
Base " such as-CH2F、-CHF2Or-CF3) or C1-C6Halogenated alkoxy (number of " halogen " can be one or more [examples
Such as 2,3 or 4]；All " halogen " can independently be fluorine, chlorine or bromine, and can be fluorine；" the C1-C6Haloalkoxy
Base " such as-OCH2F、-OCHF2Or-OCF3)；
The m is 1,2 or 3；
The ring C isIn, D is CH or N, and R2
And R3One of (such as R3) it is Z, another one Rb；
All RbIt independently is H, F, Cl, Br ,-CF3、-CN、CH3Or-OCH3；
All Z independently are-(CH2)n-NH-R9-1、-(CH2)n-N(Ra1)-C(Ra2Ra3)-(CH2)n-R9-2、-(CH2)n-
N(Ra1)-(CRa4Ra5)n-R9-3(such as
)、-(CH2)n-N(Ra1)-(CRa4Ra5)n- NH-C (=O)-R9-3(such as)、-(CH2)n-N(Ra1)-
(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3(such as (such asIn another example)、
All t independently are 0 or 1；
All RyIt independently is hydrogen ,-OH ,-CH3、-CH2OH、-COOH、-CH2COOH or-CONHCH2CH2OH、-CONH2
Or-NHCOCH3；
All RgIt independently is hydrogen ,-OH ,-CH3、-OCH3、-OCOCH3Or-CH2CH=CH2；
All RhIt independently is hydrogen ,-OH ,-CH3Or-COCH3；
All R9-1It independently is cyclobutyl, fluoro or unsubstituted-CH2Cyclobutyl (the number of the fluorine atom
It can be 1 or 2；The fluoro site can be in methylene or cyclobutyl), cyclopropyl, hydroxycyclopent base, cyclopenta, hexamethylene
Base, hydroxy-cyclohexyl, hydroxyl tetrahydrofuran base, N- methyl piperidine base, N-ethylpiperidine base, hydroxy tetrahydro thienyl；
All R9-2And R9-3It independently is hydrogen, carboxyl, hydroxyl, amino, C1-C6Alkyl (such as C1-C4Alkyl, again
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, in another example methyl), azetidin
Alkanone base (such as), cyclohexyl, hydroxy phenyl, pyrrolidone-base, piperidone base, piperazine ketone group, morpholinyl (such as), imidazole radicals, N- methylimidazolyl ,-C (=O)-morpholinyl, R9-2-1Substituted or unsubstituted piperazinyl is (described
R9-2-1Number can be one or more [such as 2 or 3]), pyrrolidinyl, pyridyl group, sulfur dioxide morpholinyl or methyl
Triazolyl；All R9-2-1It independently is methyl, phenyl, alkoxyl phenyl, hydroxy phenyl, pyridyl group, pyrimidine radicals or-C (=O)
OC(CH3)3；
All Ra1、Ra2、Ra3、Ra4And Ra5It independently is H ,-CH (OH) CH3、OH、-(CH2)2OH、-CH2OH、-(CH2)2NH2、-CH2CH3Or-CH3；
Alternatively, Ra2、Ra3And C is independently collectively formed in the carbon atom being connected with them4-C6Carbocyclic ring is (in another example C5Carbocyclic ring),
N- methyl piperidine ring or pyranoid ring；
Alternatively, Ra4、Ra5And C is independently collectively formed in the carbon atom being connected with them4-C6Carbocyclic ring is (in another example C5Carbocyclic ring),
N- methyl piperidine ring or pyranoid ring；
All n independently are 1,2 or 3；
When the ring B isReFor methyl, RfWhen for hydrogen, " (CH at m and Z connection site2)n" in n
It is not simultaneously 1 (for example, n is 2 or 3 when m is 1；In another example when m is 2, n 1,2 or 3；Further for example, m be 3 when, n 1,2 or
3)。
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
DescribedCan be
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The ring B can be(such as)、
(when the connection site of the group of above-mentioned ring B and other groups is in upper and lower position, the upper end [or lower end] can be with
Ring A connection, lower end [or upper end] can be with (CH2)mConnection；
When the connection site of the group of above-mentioned ring B and other groups is in left-right position, left end [or right end] can be with
Ring A connection, right end [or left end] can be with (CH2)mConnection).
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All Y1、Y2And Y8- C (R can independently be4)2-、-N(R5)-,-O- or-S-.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All R5Hydrogen, C can independently be1-C6Alkyl, C1-C6Halogenated alkyl, H- (C (R4)2)k- O-C (=O)-(C
(R4)2)k-、(R6R7)N-(C(R4)2)k-、HO-(C(R4)2)k- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)k-、H-
(C(R4)2)k-O-(C(R4)2)k-、H-(C(R4)2)k- S (=O)2-(C(R4)2)k-、H-(C(R4)2)k- C (=O)-(C (R4)2
)k-、CN-(C(R4)2)k- C (=O)-, H- (C (R4)2)k- O-C (=O)-C (=O)-(C (R4)2)k-。
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All R5It can be hydrogen.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All R4Hydrogen, C can independently be1-C6Alkyl, hydroxyl, carboxyl, amino, C1-C6Alkoxy, H2N-
(CH2)k-、N(R6R7)-C (=O)-, H- (CH2)k- O-C (=O)-(CH2)k-、H-(CH2)k-O-(CH2)k-、CN-(CH2)k-C
(=O)-, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy or C1-C6Alkylamino.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All R4It can be hydrogen.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All R6And R7Hydrogen, C can independently be1-C6Alkyl, hydroxyl, carboxyl, amino, C1-C6Alkoxy, H2N-
(CH2)k-、NH2- C (=O)-, H- (CH2)k- O-C (=O)-(CH2)k-、C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy or
C1-C6Alkylamino.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The ReAnd RfHydrogen, C can independently be1-C6Alkyl, C3-C6Naphthenic base, hydroxyl, carboxyl, amino, C1-C6Alcoxyl
Base, C1-C6Halogenated alkyl or C1-C6Halogenated alkoxy.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The ReAnd RfHydrogen, C can independently be1-C6Alkyl, C3-C6Naphthenic base, C1-C6Alkoxy or C1-C6It is halogenated
Alkyl.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The ring B is following any group:
(when the connection site of the group of above-mentioned ring B and other groups is in upper and lower position, the upper end [or lower end] can be with
Ring A connection, lower end [or upper end] can be with (CH2)mConnection；
When the connection site of the group of above-mentioned ring B and other groups is in left-right position, left end [or right end] can be with
Ring A connection, right end [or left end] can be with (CH2)mConnection).
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The m can be 1 or 2, and can be 1.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The ring C can be
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The ring C can be
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All RbH ,-CF can independently be3Or-OCH3。
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All Z can independently be-(CH2)n-N(Ra1)-(CRa4Ra5)n-R9-3(such as )、-(CH2)n-N(Ra1)-(CRa4Ra5)n- NH-C (=O)-R9-3(such as)、-(CH2)n-N(Ra1)-(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3(such as )(such asIn another example)。
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All R9-3Carboxyl, hydroxyl, amino, C can independently be1-C6Alkyl, azetidine ketone group (such as) or morpholinyl (such as)。
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All Ra1、Ra2、Ra3、Ra4And Ra5H or OH can independently be.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
All n can be 1.
In some scheme, certain groups of the compound I are defined as follows, undefined group such as it is preceding either one
Described in case:
The ring A is phenyl；
The p is 0,1 or 2；
All R1It independently is-OCH3、-OH、-OCH2CH3、-O(CH2)OCH3、-OCH2CH=CH2Or-O (CH2)2CH3；
(when ring A is hexatomic ring, all R1Ortho position, the meta or para position of ring B can be separately located in；When ring A is five-membered ring, institute
Some R1Ortho position or the meta position of ring B can be separately located in；When ring A is hexatomic ring and p is 2, the R1It can be between ring B
Position and contraposition)
Alternatively, being connected to adjacent carbon atom, (when ring A is hexatomic ring, " adjacent carbon atom " can position when p is 2
In " meta position and the contraposition " or " ortho position and meta position " of ring B, but can be located at ring B " meta position and contraposition ") two R1Formation-O-
(CRcRd)q-O-；The q is 1 or 2；All RcAnd RdIt independently is hydrogen or C1-C6Alkyl (such as C1-C4Alkyl, and example
Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, also such as methyl)；
The ring B is(such as)、
(when the connection site of the group of above-mentioned ring B and other groups is in upper and lower position, the upper end [or lower end] can be with
Ring A connection, lower end [or upper end] can be with (CH2)mConnection；
When the connection site of the group of above-mentioned ring B and other groups is in left-right position, left end [or right end] can be with
Ring A connection, right end [or left end] can be with (CH2)mConnection)
All Y1、Y2And Y8It independently is-CH2,-NH- ,-O- or-S-；
All Y3、Y4、Y5、Y6And Y7It independently is CH or N；
The ReAnd RfIt independently is hydrogen, C1-C6Alkyl (such as C1-C4Alkyl, in another example methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, also such as methyl or tert-butyl), C3-C6Naphthenic base is (in another example cyclopropyl
Base, cyclohexyl or cyclobutyl), C1-C6Alkoxy (such as C1-C4Alkoxy, in another example methoxyl group, ethyoxyl, positive third oxygen
Base, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, also such as methoxyl group) or C1-C6Alkyl halide
(number of " halogen " can be one or more [such as 2,3 or 4] to base；All " halogen " can independently be fluorine, chlorine
Or bromine, and can be fluorine；Wherein, " C1-C6Alkyl " such as C1-C4Alkyl, in another example methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, sec-butyl, isobutyl group or tert-butyl, also such as methyl；" the C1-C6Halogenated alkyl " such as-CH2F、-CHF2Or-
CF3)；
It (can be 1 or 2, and can be for 1) that the m, which is 1,2 or 3,；
The ring C isWherein, D is CH or N, and R2And R3One of (such as R3) be Z, another one is
Rb；
All RbIt independently is H ,-CF3Or-OCH3；
All Z independently are-(CH2)n-N(Ra1)-(CRa4Ra5)n-R9-3(such as )、-(CH2)n-N(Ra1)-(CRa4Ra5)n- NH-C (=O)-R9-3(such as)、-(CH2)n-N(Ra1)-(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3(such as )(such asIn another example)；
T is 0；RyFor-COOH；
All R9-3It independently is carboxyl, hydroxyl, amino, C1-C6Alkyl (such as C1-C4Alkyl, in another example first
Base, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl, in another example methyl), azetidine ketone group
(such as) or morpholinyl (such as)；
All Ra1、Ra4And Ra5It independently is H or OH；
All n independently are 1,2 or 3 (such as all n are 1)；
When the ring B isReFor methyl, RfWhen for hydrogen, " (CH at m and Z connection site2)n" in n
It is not simultaneously 1 (for example, n is 2 or 3 when m is 1；In another example when m is 2, n 1,2 or 3；Further for example, m be 3 when, n 1,2 or
3)。
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 compound I, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolite,
Its stereoisomer, its tautomer or its prodrug, including but not limited to I-1~I- described in the embodiment of the present invention
35。
In some scheme, the compound I can be following any compound:
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 (such as embodiment of CN105705489A) and condition.
If wanting to obtain the chiral purity compound of compound of formula I of the present invention, method commonly used in the art, example can be used
It is normal using this field as used chiral induction in the synthesis process, or after obtained target compound stereoisomer mixture
The chiral resolution column or chemical resolution method of rule are split, to obtain the compound of formula I of the invention of chiral purity.
Reaction dissolvent used in each reaction step of the present invention is not particularly limited, any to a certain extent
It dissolves starting material and the solvent of reaction is not inhibited to be included in the present invention.In addition, many similar changes of this field, etc.
With replacement, or it is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the present invention
Scope.
The present invention also provides a kind of pharmaceutical compositions comprising above-mentioned compound I, its pharmaceutically acceptable salt,
Its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug and pharmaceutic adjuvant.
In the pharmaceutical composition, the compound I, its pharmaceutically acceptable salt, its hydrate, its solvent
The dosage of compound, its metabolite, its stereoisomer, its tautomer or its prodrug can be therapeutically effective 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 compound I, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug are preparing the application in PD-L1 inhibitor.
The PD-L1 inhibitor can be used in mammalian organism；PD-L1 inhibitor of the present invention also can be used
In in vitro, mainly as experimental use, such as: comparison is provided as standard sample or control sample, or according to this field routine
Kit is made in method, provides quick detection for the inhibitory effect of PD-L1.
The present invention also provides a kind of above-mentioned compound I, its pharmaceutically acceptable salt, its hydrate, its solvation
Object, its metabolite, its stereoisomer, its tautomer or its prodrug, in preparation for treating and/or preventing and PD-
Application in the drug of the related disease of L1 activity.
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.When Referral URL or other identifier or
Address, it should be appreciated that such identifier can change, and the specific information on internet can change, but mutual by search
Networking can find same information.Reference this type of information can get and open propagate.
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 " used in the present invention belongs to the derivative of the compounds of this invention, wherein by with acid
The parent compound is modified at the mode of salt at salt or with alkali.The example of pharmaceutically acceptable salt includes but is not limited to: alkali
The inorganic acid of base such as amine or the alkali metal of acylate, acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt
Quaternary ammonium salt including conventional avirulent salt or parent compound, such as nontoxic inorganic acid or organic acid are formed by salt.
Conventional avirulent salt includes but is not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid
Selected from Aspirin, 2- ethylenehydrinsulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid,
Citric acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid,
Hydrochloric acid, hydriodate, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, methane
Sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, sub- acetic acid, succinic acid, ammonia
Base sulfonic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
" 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.
Certain compounds of the invention can exist with nonsolvated forms or solvation form, including hydrate form.
In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.Of the invention is certain
Compound can exist with polycrystalline or amorphous form.
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, such as tritium (3H), iodine-125 (125I) or C-14 (14C) can be used.
The transformation of all isotopics of the compound of the present invention, no matter radioactivity whether, be included within the scope of the present invention.
In some embodiments, compound described in the invention exists as stereoisomer, wherein in the presence of not right
Title or chiral centre.Stereoisomer is named as R or S according to the substituent group configuration around asymmetric carbon atom.It is used herein
Term R and S are IUPAC 1974Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl.Chem, (1976), configuration defined in 45:13-30, by reference to by its content simultaneously
Enter herein.The embodiments described herein particularly including various stereoisomers and its mixture.Stereoisomer includes mapping
The mixture of isomers, diastereoisomer and enantiomer or diastereomer.In some embodiments, chemical combination
Each stereoisomer of object is synthetically prepared from the commercial materials containing asymmetric or chiral centre, or passes through preparation racemic mixing
Then object splits and prepares.Method for splitting is for example: (1) by the mixture of enantiomter in conjunction with chiral auxiliary, by tying again
The non-enantiomer mixture that brilliant or chromatographic isolation obtains, discharges optically pure product from auxiliary agent；Or (2) in chiral chromatogram
The mixture of optical enantiomorphs is directly separated on column.
Small molecule PD-L1 inhibitor of the present invention may be used as single dose, or be combined with other therapeutic agents, to enhance this
The effect of a little therapeutic agents.
Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, it can have
The therapeutic purpose disorder of effect ground, disease or illness.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise
Content.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: the compound of the present invention is small molecule PD-L1 inhibitor, and activity is presented
The advantages that height, bioavilability height, drug substance stable, Orally-administrable, and the compound can cause and enhance itself of body
Immune response.The compound is PD-L1 inhibitor.In addition, compound preparation is convenient, production cost is low, production cost is only
It is the 10% of monoclonal antibody class macromolecular PD-L1 inhibitor.
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 compound shown in Formulas I, the method for preparing it and intermediate, containing its composition,
And its application in medicine preparation.
The preparation of 1 compound I-1 of embodiment
By compound I-1a (43mg, 0.1mmol), S- piperidines -2- carboxylic acid (13.6mg, 0.105mmol) and triacetyl
Oxygroup sodium borohydride (21.2mg, 0.25mmol) is added in 10mL dichloromethane solution, stirs 1 hour at 80~85 DEG C, will
Crude product is purified through preparative LC/MS, and assessing its purity through lcms analysis is 98%.
The preparation of 2 compound I-14 of embodiment
By compound I-14a (39mg, 0.1mmol), piperidines -2- carboxylic acid (13.6mg, 0.105mmol) and triacetyl
Oxygroup sodium borohydride (21.2mg, 0.25mmol) is added in 10mL dichloromethane solution, stirs 45 minutes at 80~85 DEG C, will
Crude product is purified through preparative LC/MS, and assessing its purity through lcms analysis is 97%.
The preparation of 3 compound I-20 of embodiment
By compound I-20a (35mg, 0.1mmol), piperidines -2- carboxylic acid (13.6mg, 0.105mmol) and triacetyl
Oxygroup sodium borohydride (21.2mg, 0.25mmol) is added in 10mL dichloromethane solution, stirs 50 minutes at 80~85 DEG C, will
Crude product is purified through preparative LC/MS, and assessing its purity through lcms analysis is 98%.
The preparation of 4 compound I-35 of embodiment
By compound I-35a (40.4mg, 0.1mmol), piperidines -2- carboxylic acid (13.6mg, 0.105mmol) and three second
Triacetoxyborohydride (21.2mg, 0.25mmol) is added in 10mL dichloromethane solution, stirs 60 minutes at 80~85 DEG C,
Crude product is purified through preparative LC/MS, and assessing its purity through lcms analysis is 98%.
Compound I-2~I-13, I-15~I-19, I-21~I-34 general synthetic method with embodiment 1-4.
The appraising datum of compound I-1~I-35 is as shown in the table:
1 biological characteristis of effect example
Use PD-1/PD-L1 homogeneous phase time discrimination fluorescence (HTRF) binding assay research formula (I) compound combination PD-L1
Ability.
Homogeneous phase time discrimination fluorescence (HTRF) binding assay
All bindings carry out in HTRF measurement buffer, and the buffer is by being supplemented with 0.1% (withv) cow's serum
The dPBS of albumin and 0.05% (v/v) Tween-20 composition.For PD-1-Ig/PD-L1-His binding assay, by inhibitor
15m is cultivated in advance in 4 μ l measurement buffer with PD-L1-His (10nM is final), is then added in 1 μ l measurement buffer
PD-1-Ig (20nM is final) simultaneously further cultivates 15m.Use the PD-L1 from people, dog or mouse.Use europium cryptate-
The anti-His (20nM is final) of anti-Ig (1nM is final) and allophycocyanin (APC) label of label completes HTRF detection.By antibody
It is diluted in HTRF detection buffer and 5 μ l is allocated in the top of association reaction mixture.Reaction mixture is balanced 30 minutes
And signal (665nm/620nm ratio) is obtained using EnVision fluorimeter.In PD-1-Ig/PD-L2-His (respectively 20&
5nM), between CD80-His/PD-L1-Ig (respectively 100&10nM) and CD80-His/CTLA4-Ig (respectively 10&5nM) into
The additional binding assay of row.The following progress of competition research between biotinylation SEQIDNO:71 and human PD-L 1-His.It will inhibit
Agent and PD-L1-His (10nM is final) cultivate 60m in 4 μ l measurement buffer in advance, are then added in 1 μ l measurement buffer
Biotinylated SEQIDNO:71 (0.5nM is final).In conjunction with balance 30m, the europium in 5 μ l HTRF buffers is then added
The anti-His of cryptate-label Streptavidin (2.5pM is final) and APC- label (20nM is final).Reaction is mixed
Object balance 30m simultaneously obtains signal (665nm/620nm ratio) using EnVision fluorimeter.
Following table lists the present invention such as measured in PD-1/PD-L1 homogeneous phase time discrimination fluorescence (HTRF) binding assay
Compound I-1~I-35 IC50.Formula I compound represented shows the IC with following range50Value: A=
4nM-100nM；B=101nM-300nM；C=301nM-1 μM；D=1.001-10 μM.
So compound shown in Formulas I of the present invention has the work of the inhibitor of the interaction as PD-1/PD-L1
Property, and therefore can be used for treating disease relevant to the interaction of PD-1/PD-L1.Pass through the mutual of inhibition PD-1/PD-L1
Effect.
The test of 2 dynamic solubility of effect example:
The test of dynamic solubility is commonly used in the high flux screening of drug in the drug discovery stage.In dynamic analysis
In, a good solubility should help to create reliable data in vitro and in vivo.Since dynamic solubility is
PH dependence, what the pH value of water phase was always specified, usually measurement is 7.4 (physiological ph of body fluid) in pH value.
Test method: weigh quantitative combination object sample be dissolved in pure DMSO, final concentration of 10mM, by test-compound with
Control compound (10mM DMSO mother liquor, every 10 μ L of hole) is added in 96 orifice plates containing every 490 μ L buffer of hole.It is vortexed 2 minutes
Afterwards, sample panel on the oscillator at room temperature (22 ± 2 DEG C) be incubated for 24 hours.Then 200 μ L samples are shifted to MultiScreen mistake
Filter plate (polycarbonate membrane) is filtered with micropore vacuum manifold (millipore vacuum manifold) and collects filtrate.With
HPLC-UV measures the concentration of compound in filtrate.The UV standard solution and solubility test sample of 3 various concentrations are first laggard
Sample.Each sample inserting needle 2 times brings standard curve into and calculates concentration, averages.
Experimental result shows that compound of the present invention has good water-soluble property, and is better than control compound (source
The compound described in CN105705489A embodiment 1 is also a kind of small molecule compound suppression of PD-1/PD-L1 interaction
Preparation, IC50For 6-100nM).
The test of 3 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 control compound is from compound described in CN105705489A embodiment 1.
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 shows that it is steady to show more excellent metabolism relative to control compound for compound of the present invention
It is qualitative, important evidence is provided 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 substitution biaryl compound shown in formula I, its pharmaceutically acceptable salt, its hydrate, its solvate,
Its metabolite, its stereoisomer, its tautomer or its prodrug,
Wherein, the ring A is phenyl, thienyl, pyrrole radicals or piperidyl；
The p is 0,1 or 2；
All R1It independently is-OCH3、-OH、-OCH2CH3、-O(CH2)OCH3、-OCH2CH=CH2、-O(CH2)2CH3、-O
(CH2)2Morpholinyl or F；
Alternatively, being connected to two R of adjacent carbon atom when p is 21Formation-O- (CRcRd)q-O-；The q is 1 or 2；All
RcAnd RdIt independently is hydrogen, C1-C6Alkyl, hydroxyl, carboxyl, cyano, amino, C1-C6Alkoxy, C1-C6Halogenated alkyl or
C1-C6Halogenated alkoxy；
The ring B is
All Y1、Y2And Y8It independently is-C (R4)2-、-N(R5)-,-O- ,-S (=O)wOr-C (=O)-；All w are independent
Ground is 0,1 or 2；
All Y3、Y4、Y5、Y6And Y7It independently is CR4Or N；
All R5It independently is hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl, H- (C (R4)2)k- O-C (=O)-(C (R4)2
)k-、(R6R7)N-(C(R4)2)k-、HO-(C(R4)2)k- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)k-、H-(C
(R4)2)k-O-(C(R4)2)k-、H-(C(R4)2)k- S (=O)2-(C(R4)2)k-、H-(C(R4)2)k- C (=O)-(C (R4)2)k-、
CN-(C(R4)2)k- C (=O)-, H- (C (R4)2)k- O-C (=O)-C (=O)-(C (R4)2)k-、C3-C9Heterocycle or C1-C9It is miscellaneous
Aryl；
All R4It independently is hydrogen, C1-C6Alkyl, hydroxyl, fluorine, chlorine, bromine, carboxyl, amino, C1-C6Alkoxy, H2N-
(CH2)k-、N(R6R7)-C (=O)-, aldehyde radical, H- (CH2)k- O-C (=O)-(CH2)k-、H-(CH2)k-O-(CH2)k-、CN-
(CH2)k- C (=O)-, C3-C9Heterocycle, C1-C9Heteroaryl, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy or C1-C6's
Alkylamino；
All R6And R7It independently is hydrogen, C1-C6Alkyl, hydroxyl, carboxyl, amino, C1-C6Alkoxy, H2N-(CH2)k-、
NH2- C (=O)-, aldehyde radical, H- (CH2)k- O-C (=O)-(CH2)k-、C3-C9Heterocycle, C1-C9Heteroaryl, C1-C6Alkyl halide
Base, C1-C6Halogenated alkoxy or C1-C6Alkylamino；
All k independently are 0,1,2,3 or 4；
The ReAnd RfIt independently is hydrogen, C1-C6Alkyl, C3-C6Naphthenic base, hydroxyl, carboxyl, amino, C1-C6Alkoxy, C1-C6
Halogenated alkyl or C1-C6Halogenated alkoxy；
The m is 1,2 or 3；
The ring C isIn, D is CH or N, and R2And R3In
One of be Z, another one Rb；
All RbIt independently is H, F, Cl, Br ,-CF3、-CN、CH3Or-OCH3；
All Z independently are-(CH2)n-NH-R9-1、-(CH2)n-N(Ra1)-C(Ra2Ra3)-(CH2)n-R9-2、-(CH2)n-N
(Ra1)-(CRa4Ra5)n-R9-3、-(CH2)n-N(Ra1)-(CRa4Ra5)n- NH-C (=O)-R9-3、-(CH2)n-N(Ra1)-
(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3、
All t independently are 0 or 1；
All RyIt independently is hydrogen ,-OH ,-CH3、-CH2OH、-COOH、-CH2COOH or-CONHCH2CH2OH、-CONH2Or-
NHCOCH3；
All RgIt independently is hydrogen ,-OH ,-CH3、-OCH3、-OCOCH3Or-CH2CH=CH2；
All RhIt independently is hydrogen ,-OH ,-CH3Or-COCH3；
All R9-1It independently is cyclobutyl, fluoro or unsubstituted-CH2Cyclobutyl, cyclopropyl, hydroxycyclopent base, ring penta
Base, cyclohexyl, hydroxy-cyclohexyl, hydroxyl tetrahydrofuran base, N- methyl piperidine base, N-ethylpiperidine base, hydroxy tetrahydro thienyl；
All R9-2And R9-3It independently is hydrogen, carboxyl, hydroxyl, amino, C1-C6Alkyl, azetidine ketone group, cyclohexyl,
Hydroxy phenyl, pyrrolidone-base, piperidone base, piperazine ketone group, morpholinyl, imidazole radicals, N- methylimidazolyl ,-C (=O)-morpholine
Base, R9-2-1Substituted or unsubstituted piperazinyl, pyrrolidinyl, pyridyl group, sulfur dioxide morpholinyl or methyl-triazole base；All
R9-2-1It independently is methyl, phenyl, alkoxyl phenyl, hydroxy phenyl, pyridyl group, pyrimidine radicals or-C (=O) OC (CH3)3；
All Ra1、Ra2、Ra3、Ra4And Ra5It independently is H ,-CH (OH) CH3、OH、-(CH2)2OH、-CH2OH、-(CH2)2NH2、-
CH2CH3Or-CH3；
Alternatively, Ra2、Ra3And C is independently collectively formed in the carbon atom being connected with them4-C6Carbocyclic ring, N- methyl piperidine ring or pyrans
Ring；
Alternatively, Ra4、Ra5And C is independently collectively formed in the carbon atom being connected with them4-C6Carbocyclic ring, N- methyl piperidine ring or pyrans
Ring；
All n independently are 1,2 or 3；
When the ring B isReFor methyl, RfWhen for hydrogen, " (CH at m and Z connection site2)n" in n it is different
When be 1.
2. compound I as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolism
Product, its stereoisomer, its tautomer or its prodrug, which is characterized in that work as R1It independently is-OCH3、-OH、-
OCH2CH3、-O(CH2)OCH3、-OCH2CH=CH2、-O(CH2)2CH3、-O(CH2)2When morpholinyl or F, ring A are hexatomic ring, institute
Some R1It is separately located in ortho position, the meta or para position of ring B
And/or work as R1It independently is-OCH3、-OH、-OCH2CH3、-O(CH2)OCH3、-OCH2CH=CH2、-O(CH2)2CH3、-O
(CH2)2When morpholinyl or F, ring A are five-membered ring, all R1It is separately located in ortho position or the meta position of ring B；
And/or as two R for being connected to adjacent carbon atom1Formation-O- (CRcRd)qWhen-O-, ring A are hexatomic ring, " the phase
Adjacent carbon atom " is located at " meta position and the contraposition " or " ortho position and meta position " of ring B；
And/or as any RcFor C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any RcFor C1-C6Alkoxy when, the C1-C6Alkoxy be methoxy or ethoxy；
And/or as any RcFor C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any RcFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any RcFor C1-C6Halogenated alkoxy when, the number of " halogen " is one or more；
And/or as any RcFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any RdFor C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any RdFor C1-C6Alkoxy when, the C1-C6Alkoxy be methoxy or ethoxy；
And/or as any RdFor C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any RdFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any RdFor C1-C6Halogenated alkoxy when, the number of " halogen " is one or more；
And/or as any RdFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine, chlorine or bromine；
And/or when the connection site of the group of the ring B and other groups is in upper and lower position, the upper end and ring A connect
It connects, lower end and (CH2)mConnection, alternatively, its lower end is connect with ring A, upper end and (CH2)mConnection；
And/or when the connection site of the group of the ring B and other groups is in left-right position, left end and ring A connect
It connects, right end and (CH2)mConnection, alternatively, its right end is connect with ring A, left end and (CH2)mConnection；
And/or when any ring B isWhen, it is describedFor
And/or as any R5For C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any R5For C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any R5For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R4For C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any R4For C1-C6Alkoxy when, the C1-C6Alkoxy be methoxy or ethoxy；
And/or as any R4For C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any R4For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R4For C1-C6Halogenated alkoxy when, the number of " halogen " is one or more；
And/or as any R4For C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R4For C1-C6Alkylamino when, the C1-C6Alkylamino be methylamino；
And/or as any R6For C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any R6For C1-C6Alkoxy when, the C1-C6Alkoxy be methoxy or ethoxy；
And/or as any R6For C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any R6For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R6For C1-C6Halogenated alkoxy when, the number of " halogen " is one or more；
And/or as any R6For C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R6For C1-C6Alkylamino when, the C1-C6Alkylamino be methylamino；
And/or as any R7For C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any R7For C1-C6Alkoxy when, the C1-C6Alkoxy be methoxy or ethoxy；
And/or as any R7For C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any R7For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R7For C1-C6Halogenated alkoxy when, the number of " halogen " is one or more；
And/or as any R7For C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R7For C1-C6Alkylamino when, the C1-C6Alkylamino be methylamino；
And/or as any ReFor C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any ReFor C3-C6When naphthenic base, the C3-C6Naphthenic base is cyclopropyl, cyclohexyl or ring fourth
Base；
And/or as any ReFor C1-C6Alkoxy when, the C1-C6Alkoxy be methoxy or ethoxy；
And/or as any ReFor C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any ReFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any ReFor C1-C6Halogenated alkoxy when, the number of " halogen " is one or more；
And/or as any ReFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any RfFor C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any RfFor C3-C6When naphthenic base, the C3-C6Naphthenic base is cyclopropyl, cyclohexyl or ring fourth
Base；
And/or as any RfFor C1-C6Alkoxy when, the C1-C6Alkoxy be methoxy or ethoxy；
And/or as any RfFor C1-C6Halogenated alkyl when, the number of " halogen " is one or more；
And/or as any RfFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any RfFor C1-C6Halogenated alkoxy when, the number of " halogen " is one or more；
And/or as any RfFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine, chlorine or bromine；
And/or as any R9-1For fluoro or unsubstituted-CH2When cyclobutyl, the number of the fluorine atom is 1
Or 2；
And/or as any R9-1For fluoro or unsubstituted-CH2When cyclobutyl, the fluoro site is in methylene
Or cyclobutyl；
And/or as any R9-2For C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any R9-2When for azetidine ketone group, the azetidine ketone group is
And/or as any R9-2When for morpholinyl, the morpholinyl is
And/or as any R9-2For R9-2-1When substituted piperazinyl, the R9-2-1Number be one or more；
And/or as any R9-3For C1-C6Alkyl when, the C1-C6Alkyl be C1-C4Alkyl；
And/or as any R9-3When for azetidine ketone group, the azetidine ketone group is
And/or as any R9-3When for morpholinyl, the morpholinyl is
And/or as any R9-3For R9-2-1When substituted piperazinyl, the R9-2-1Number be one or more；
And/or as the Ra2、Ra3And C is independently collectively formed in the carbon atom being connected with them4-C6When carbocyclic ring, the C4-
C6Carbocyclic ring is C5Carbocyclic ring；
And/or as the Ra4、Ra5And C is independently collectively formed in the carbon atom being connected with them4-C6When carbocyclic ring, the C4-
C6Carbocyclic ring is C5Carbocyclic ring；
And/or m be 1 when, n be 2 or 3；Or, when m is 2, n 1,2 or 3；Or, when m is 3, n 1,2 or 3.
3. compound I as claimed in claim 2, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolism
Product, its stereoisomer, its tautomer or its prodrug, which is characterized in that work as R1It independently is-OCH3、-OH、-
OCH2CH3、-O(CH2)OCH3、-OCH2CH=CH2、-O(CH2)2CH3、-O(CH2)2Morpholinyl or F, ring A are hexatomic ring and p is
When 2, the R1Positioned at the meta position and contraposition of ring B；
And/or as two R for being connected to adjacent carbon atom1Formation-O- (CRcRd)qWhen-O-, ring A are hexatomic ring, " the phase
Adjacent carbon atom " is located at " meta position and the contraposition " of ring B；
And/or as any RcFor C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any RcFor C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any RcFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any RcFor C1-C6Halogenated alkoxy, " halogen " number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any RcFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine；
And/or as any RdFor C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any RdFor C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any RdFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any RdFor C1-C6Halogenated alkoxy, " halogen " number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any RdFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine；
And/or as any R5For C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any R5For C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any R5For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any R4For C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any R4For C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any R4For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any R4For C1-C6Halogenated alkoxy, " halogen " number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any R4For C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine；
And/or as any R6For C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any R6For C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any R6For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any R6For C1-C6Halogenated alkoxy, " halogen " number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any R6For C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine；
And/or as any R7For C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any R7For C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any R7For C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any R7For C1-C6Halogenated alkoxy, " halogen " number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any R7For C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine；
And/or as any ReFor C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any ReFor C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any ReFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any ReFor C1-C6Halogenated alkoxy, " halogen " number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any ReFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine；
And/or as any RfFor C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any RfFor C1-C6Halogenated alkyl, " halogen " number be it is multiple when, described is multiple
It is 2,3 or 4；
And/or as any RfFor C1-C6Halogenated alkyl when, all " halogen " independently is fluorine；
And/or as any RfFor C1-C6Halogenated alkoxy, " halogen " number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any RfFor C1-C6Halogenated alkoxy when, all " halogen " independently is fluorine；
And/or as any R9-2For C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any R9-2For R9-2-1Substituted piperazinyl, the R9-2-1Number be it is multiple when, described is more
A is 2,3 or 4；
And/or as any R9-3For C1-C6Alkyl when, the C1-C6Alkyl be methyl, it is ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl；
And/or as any R9-3For R9-2-1Substituted or unsubstituted piperazinyl, the R9-2-1Number be it is multiple when,
It is described it is multiple be 2,3 or 4.
4. compound I as claimed in claim 3, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolism
Product, its stereoisomer, its tautomer or its prodrug, which is characterized in that as any RcFor C1-C6Alkyl
When, the C1-C6Alkyl be methyl；
And/or as any RcFor C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be-CH2F、-CHF2
Or-CF3；
And/or as any RcFor C1-C6Halogenated alkoxy when, " the C1-C6Halogenated alkoxy " be-
OCH2F、-OCHF2Or-OCF3；
And/or as any RdFor C1-C6Alkyl when, the C1-C6Alkyl be methyl；
And/or as any RdFor C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be-CH2F、-CHF2
Or-CF3；
And/or as any RdFor C1-C6Halogenated alkoxy when, " the C1-C6Halogenated alkoxy " be-
OCH2F、-OCHF2Or-OCF3；
And/or as any R5For C1-C6Alkyl when, the C1-C6Alkyl be methyl；
And/or as any R5For C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be trifluoromethyl,
2- fluoro ethyl or 3,3,3- trifluoro propyl；
And/or as any R4For C1-C6Alkyl when, the C1-C6Alkyl be methyl；
And/or as any R4For C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be-CH2F、-CHF2
Or-CF3；
And/or as any R4For C1-C6Halogenated alkoxy when, " the C1-C6Halogenated alkoxy " be-
OCH2F、-OCHF2Or-OCF3；
And/or as any R6For C1-C6Alkyl when, the C1-C6Alkyl be methyl；
And/or as any R6For C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be-CH2F、-CHF2
Or-CF3；
And/or as any R6For C1-C6Halogenated alkoxy when, " the C1-C6Halogenated alkoxy " be-
OCH2F、-OCHF2Or-OCF3；
And/or as any R7For C1-C6Alkyl when, the C1-C6Alkyl be methyl；
And/or as any R7For C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be-CH2F、-CHF2
Or-CF3；
And/or as any R7For C1-C6Halogenated alkoxy when, " the C1-C6Halogenated alkoxy " be-
OCH2F、-OCHF2Or-OCF3；
And/or as any ReFor C1-C6Alkyl when, the C1-C6Alkyl be methyl or tert-butyl；
And/or as any ReFor C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be-CH2F、-CHF2
Or-CF3；
And/or as any ReFor C1-C6Halogenated alkoxy when, " the C1-C6Halogenated alkoxy " be-
OCH2F、-OCHF2Or-OCF3；
And/or as any RfFor C1-C6Alkyl when, the C1-C6Alkyl be methyl or tert-butyl；
And/or as any RfFor C1-C6Halogenated alkyl when, " the C1-C6Halogenated alkyl " be-CH2F、-CHF2
Or-CF3；
And/or as any RfFor C1-C6Halogenated alkoxy when, " the C1-C6Halogenated alkoxy " be-
OCH2F、-OCHF2Or-OCF3；
And/or as any R9-2For C1-C6Alkyl when, the C1-C6Alkyl be methyl；
And/or as any R9-2For R9-2-1Substituted piperazinyl, the R9-2-1Number be it is multiple when, described is more
A is 2 or 3；
And/or as any R9-3For C1-C6Alkyl when, the C1-C6Alkyl be methyl；
And/or as any R9-3For R9-2-1Substituted or unsubstituted piperazinyl, the R9-2-1Number be it is multiple when,
It is described it is multiple be 2 or 3.
5. compound I as claimed in claim 4, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolism
Product, its stereoisomer, its tautomer or its prodrug, which is characterized in that describedFor
And/or the ring B is following any group:
And/or when the ring C isWhen, it is describedFor
And/or when any Z is-(CH2)n-N(Ra1)-(CRa4Ra5)n-R9-3When, described-(CH2)n-N(Ra1)-
(CRa4Ra5)n-R9-3For
And/or when any Z is-(CH2)n-N(Ra1)-(CRa4Ra5)n- NH-C (=O)-R9-3When, described-(CH2)n-
N(Ra1)-(CRa4Ra5)n- NH-C (=O)-R9-3For
And/or when any Z is-(CH2)n-N(Ra1)-(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3When,
Described-(CH2)n-N(Ra1)-(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3For
And/or when any Z isWhen, it is describedForSuch as
6. compound I as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolism
Product, its stereoisomer, its tautomer or its prodrug, which is characterized in that the p is 0 or 2；When p is 2, it is connected to
Two R of adjacent carbon atom1Formation-O- (CRcRd)q-O-；All RcAnd RdIt independently is hydrogen or C1-C6Alkyl；
And/or the ring B is
And/or all Y1、Y2And Y8It independently is-C (R4)2-、-N(R5)-,-O- or-S-；
And/or all R5It independently is hydrogen, C1-C6Alkyl, C1-C6Halogenated alkyl, H- (C (R4)2)k- O-C (=O)-(C
(R4)2)k-、(R6R7)N-(C(R4)2)k-、HO-(C(R4)2)k- C (=O)-, N (R6R7)-C (=O)-, HO- (C (R4)2)k-、H-
(C(R4)2)k-O-(C(R4)2)k-、H-(C(R4)2)k- S (=O)2-(C(R4)2)k-、H-(C(R4)2)k- C (=O)-(C (R4)2
)k-、CN-(C(R4)2)k- C (=O)-, H- (C (R4)2)k- O-C (=O)-C (=O)-(C (R4)2)k-；
And/or all R4It independently is hydrogen, C1-C6Alkyl, hydroxyl, carboxyl, amino, C1-C6Alkoxy, H2N-
(CH2)k-、N(R6R7)-C (=O)-, H- (CH2)k- O-C (=O)-(CH2)k-、H-(CH2)k-O-(CH2)k-、CN-(CH2)k-C
(=O)-, C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy or C1-C6Alkylamino；
And/or all R6And R7It independently is hydrogen, C1-C6Alkyl, hydroxyl, carboxyl, amino, C1-C6Alkoxy, H2N-
(CH2)k-、NH2- C (=O)-, H- (CH2)k- O-C (=O)-(CH2)k-、C1-C6Halogenated alkyl, C1-C6Halogenated alkoxy or
C1-C6Alkylamino；
And/or the ReAnd RfIt independently is hydrogen, C1-C6Alkyl, C3-C6Naphthenic base, hydroxyl, carboxyl, amino, C1-C6Alcoxyl
Base, C1-C6Halogenated alkyl or C1-C6Halogenated alkoxy；
And/or the m is 1 or 2；
And/or the ring C is
And/or all RbIt independently is H ,-CF3Or-OCH3；
And/or all Z independently are-(CH2)n-N(Ra1)-(CRa4Ra5)n-R9-3、-(CH2)n-N(Ra1)-(CRa4Ra5)n-
NH-C (=O)-R9-3、-(CH2)n-N(Ra1)-(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3Or
And/or all R9-3It independently is carboxyl, hydroxyl, amino, C1-C6Alkyl, azetidine ketone group or morpholinyl；
And/or all Ra1、Ra2、Ra3、Ra4And Ra5It independently is H or OH；
And/or all n are 1.
7. compound I as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolism
Product, its stereoisomer, its tautomer or its prodrug, which is characterized in that the ring A is phenyl；
The p is 0,1 or 2；
All R1It independently is-OCH3、-OH、-OCH2CH3、-O(CH2)OCH3、-OCH2CH=CH2Or-O (CH2)2CH3；
Alternatively, being connected to two R of adjacent carbon atom when p is 21Formation-O- (CRcRd)q-O-；The q is 1 or 2；All
RcAnd RdIt independently is hydrogen or C1-C6Alkyl；
The ring B is
All Y1、Y2And Y8It independently is-CH2,-NH- ,-O- or-S-；
All Y3、Y4、Y5、Y6And Y7It independently is CH or N；
The ReAnd RfIt independently is hydrogen, C1-C6Alkyl, C3-C6Naphthenic base, C1-C6Alkoxy or C1-C6Halogenated alkyl；
The m is 1,2 or 3；
The ring C isWherein, D is CH or N, and R2And R3One of be Z, another one Rb；
All RbIt independently is H ,-CF3Or-OCH3；
All Z independently are-(CH2)n-N(Ra1)-(CRa4Ra5)n-R9-3、-(CH2)n-N(Ra1)-(CRa4Ra5)n- NH-C (=
O)-R9-3、-(CH2)n-N(Ra1)-(CRa4Ra5)n-O-(CRa4Ra5)n-O-(CRa4Ra5)n-R9-3Or
T is 0；RyFor-COOH；
All R9-3It independently is carboxyl, hydroxyl, amino, C1-C6Alkyl, azetidine ketone group or morpholinyl；
All Ra1、Ra4And Ra5It independently is H or OH；
All n independently are 1,2 or 3；
When the ring B isReFor methyl, RfWhen for hydrogen, " (CH at m and Z connection site2)n" in n it is different
When be 1.
8. compound I as described in claim 1, its pharmaceutically acceptable salt, its hydrate, its solvate, its metabolism
Product, its stereoisomer, its tautomer or its prodrug, which is characterized in that the compound I is following any chemical combination
Object:
9. a kind of pharmaceutical composition comprising such as compound I according to any one of claims 1 to 8, its is pharmaceutically acceptable
Salt, its hydrate, its solvate, its metabolite, its stereoisomer, its tautomer or its prodrug and medicinal
Auxiliary material.
10. it is a kind of as compound I according to any one of claims 1 to 8, its pharmaceutically acceptable salt, its hydrate, its
Solvate, its metabolite, its stereoisomer, its tautomer or its prodrug preparation PD-L1 inhibitor or
For treating and/or preventing the application with PD-L1 activity in the drug of related disease.
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| US11130740B2 (en) | 2017-04-25 | 2021-09-28 | Arbutus Biopharma Corporation | Substituted 2,3-dihydro-1H-indene analogs and methods using same |
| US11135210B2 (en) | 2018-02-22 | 2021-10-05 | Chemocentryx, Inc. | Indane-amines as PD-L1 antagonists |
| WO2022033303A1 (en) * | 2020-08-11 | 2022-02-17 | 中国人民解放军军事科学院军事医学研究院 | Benzylamine derivative, preparation method therefor and use thereof |
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