CN109721527B - Novel anti-PD-L1 compound, application thereof and composition containing same - Google Patents

Novel anti-PD-L1 compound, application thereof and composition containing same Download PDF

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CN109721527B
CN109721527B CN201711025361.1A CN201711025361A CN109721527B CN 109721527 B CN109721527 B CN 109721527B CN 201711025361 A CN201711025361 A CN 201711025361A CN 109721527 B CN109721527 B CN 109721527B
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ring
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CN109721527A (en
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许勇
黄璐
林当
胡海
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Guangzhou Wellhealth Bio Pharmaceutical Co ltd
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Guangzhou Wellhealth Bio Pharmaceutical Co ltd
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Abstract

The invention discloses a novel anti-PD-L1 compound, application thereof and a composition containing the same. The invention provides a substituted biaryl compound shown in a formula I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, metabolites thereof, stereoisomers thereof, tautomers thereof or prodrugs thereof.

Description

Novel anti-PD-L1 compound, application thereof and composition containing same
Technical Field
The invention belongs to the field of biological medicine, and relates to a novel anti-PD-L1 compound, application thereof and a composition containing the same.
Background
The PD-1/PD-L1 signaling pathway is one of the most popular topics in the current cancer treatment and research fields. New immunotherapeutic drugs, such as Keystuda from moxadong and Opdivo from Bai Shi Guibao, have been marketed in batches over the last two years, which aim at this signaling pathway, and monoclonal antibodies are used to bind to the PD-1 receptor to prevent signaling, thereby activating the immune system of the body itself to attack tumor development. These two new drugs have been approved for the treatment of cancers such as melanoma and the like, and have also shown great potential in clinical trials against some other cancers. Currently 3 large molecule PD-L1 inhibitors are marketed by the U.S. FDA as Atezolizumab (tecentiq, the first FDA-approved PD-L1 inhibitor for the treatment of bladder cancer and non-small cell lung cancer), avelumab (the second FDA-approved PD-L1 inhibitor for the treatment of merck cell cancer), durvalumab (the third FDA-approved PD-L1 inhibitor for the treatment of urothelial cancer), respectively. However, monoclonal antibodies have a half-life as long as 15-20 days, which 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 therapeutic activity on solid tumors.
Therefore, the development of safer and more efficient novel PD-L1 inhibitor drugs has great social value and economic benefit, and is also a research hotspot of various large medicine enterprises at present.
Disclosure of Invention
The invention aims to solve the technical problems that the existing PD-1/PD-L1 monoclonal antibody needs intravenous injection, has poor therapeutic activity on solid tumors, has low bioavailability and the like, and therefore, the invention provides a novel anti-PD-L1 compound, application thereof and a composition containing the compound, wherein the compound is a small molecule PD-L1 inhibitor, has the advantages of high activity, high bioavailability, stable medicine, capability of oral administration and the like, and can cause and enhance autoimmune response of organisms. The compounds are PD-L1 inhibitors.
The invention provides a substituted biaryl compound (which can resist programmed death receptor ligand 1, namely, is used as a PD-L1 inhibitor), pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer, tautomer or prodrug thereof shown in a formula I;
wherein ring a is phenyl, thienyl, pyrrolyl or piperidinyl;
p is 0, 1 or 2;
all R 1 Is independently-OCH 3 、-OH、-OCH 2 CH 3 、-O(CH 2 )OCH 3 、-OCH 2 CH＝CH 2 、-O(CH 2 ) 2 CH 3 、-O(CH 2 ) 2 -morpholinyl or F; (when ring A is a six-membered ring, all R' s 1 Can be independently positioned at the ortho, meta or para position of the ring B; when ring A is a five-membered ring, all R 1 Can be independently located in the ortho or meta position of ring B; when ring A is a six-membered ring and p is 2, said R 1 Can be positioned in meta-position and para-position of ring B)
Alternatively, when p is 2, two R's attached to adjacent carbon atoms (where ring A is a six-membered ring, the "adjacent carbon atoms" may be located "meta-and para-or" ortho-and meta-to "and may be located" meta-and para-to "to ring B) 1 Formation of-O- (CR) c R d ) q -O-; q is 1 or 2; all R c And R is d Independently hydrogen, C 1 -C 6 Alkyl (e.g. C) 1 -C 4 Alkyl radicals of (2), in addition to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also for example, methyl), hydroxy, carboxyl, cyano, amino, C 1 -C 6 Alkoxy (e.g. methoxy or ethoxy), C 1 -C 6 The number of "halo" groups (the number of "halo" groups may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkyl "such as-CH 2 F、-CHF 2 or-CF 3 ) Or C 1 -C 6 The number of haloalkoxy groups (the "halogen" may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkoxy "of (e.g. -OCH) 2 F、-OCHF 2 or-OCF 3 )；
The ring B is(e.g.)>)、/>
(when the linking site of the group of the above ring B with other groups is in the upper and lower positions, the upper end [ or the lower end ]]Can be connected with ring A, lower end [ or upper end ]]Can be combined with (CH) 2 ) m Connecting;
when the linking site of the group of the above ring B with other groups is in the left-right position, the left end [ or the right end ]]Can be connected with ring A, right end [ or left end ]]Can be combined with (CH) 2 ) m Connection
All Y 1 、Y 2 And Y 8 independently-C (R) 4 ) 2 -、-N(R 5 )-、-O-、-S(＝O) w -or-C (=o) -; all w are independently 0, 1 or 2;
all Y 3 、Y 4 、Y 5 、Y 6 And Y 7 Independently CR 4 Or N;
all R 5 Independently hydrogen, C 1 -C 6 Alkyl (e.g. C) 1 -C 4 Alkyl radicals of (2), in addition to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, in addition to, for example, methyl), C 1 -C 6 The number of "halo" groups (the number of "halo" groups may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkyl "such as trifluoromethyl, 2-fluoroethyl or 3, 3-trifluoropropyl), H- (C (R) 4 ) 2 ) k -O-C(＝O)-(C(R 4 ) 2 ) k -、(R 6 R 7 )N-(C(R 4 ) 2 ) k -、HO-(C(R 4 ) 2 ) k -C(＝O)-、N(R 6 R 7 )-C(＝O)-、HO-(C(R 4 ) 2 ) k -、H-(C(R 4 ) 2 ) k -O-(C(R 4 ) 2 ) k -、H-(C(R 4 ) 2 ) k -S(＝O) 2 -(C(R 4 ) 2 ) k -、H-(C(R 4 ) 2 ) k -C(＝O)-(C(R 4 ) 2 ) k -、CN-(C(R 4 ) 2 ) k -C(＝O)-、H-(C(R 4 ) 2 ) k -O-C(＝O)-C(＝O)-(C(R 4 ) 2 ) k -、C 3 -C 9 Heterocyclyl or C 1 -C 9 Heteroaryl;
all R 4 Independently hydrogen, C 1 -C 6 Alkyl (e.g. C) 1 -C 4 Alkyl radicals of (2), in turn for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl), hydroxy, fluoro, chloro, bromo, carboxyl, amino, C 1 -C 6 Alkoxy (e.g. methoxy or ethoxy), H 2 N-(CH 2 ) k -、N(R 6 R 7 ) -C (=o) -, aldehyde group, H- (CH) 2 ) k -O-C(＝O)-(CH 2 ) k -、H-(CH 2 ) k -O-(CH 2 ) k -、CN-(CH 2 ) k -C(＝O)-、C 3 -C 9 Heterocyclyl, C 1 -C 9 Heteroaryl, C 1 -C 6 The number of "halo" groups (the number of "halo" groups may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkyl "such as-CH 2 F、-CHF 2 or-CF 3 )、C 1 -C 6 The number of haloalkoxy groups (the "halogen" may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkoxy "of (e.g. -OCH) 2 F、-OCHF 2 or-OCF 3 ) Or C 1 -C 6 Alkylamino (e.g., methylamino);
all R 6 And R is 7 Independently hydrogen, C 1 -C 6 Alkyl (e.g. C) 1 -C 4 Alkyl radicals of (2), in turn for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl), hydroxy, carboxyl, amino, C 1 -C 6 Alkoxy (e.g. methoxy or ethoxy), H 2 N-(CH 2 ) k -、NH 2 -C (=o) -, aldehyde group, H- (CH) 2 ) k -O-C(＝O)-(CH 2 ) k -、C 3 -C 9 Heterocyclyl, C 1 -C 9 Heteroaryl, C 1 -C 6 The number of "halo" groups (the number of "halo" groups may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkyl "such as-CH 2 F、-CHF 2 or-CF 3 )、C 1 -C 6 The number of haloalkoxy groups (the "halogen" may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkoxy "of (e.g. -OCH) 2 F、-OCHF 2 or-OCF 3 ) Or C 1 -C 6 Alkylamino (e.g., methylamino);
all k are independently 0, 1, 2, 3 or 4;
the R is e And R is f Independently hydrogen, C 1 -C 6 Alkyl (e.g. C 1 -C 4 Alkyl radicals of (2), in addition to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also, for example, methyl or tert-butyl), C 3 -C 6 Cycloalkyl (again e.g. cyclopropyl, cyclohexyl or cyclobutyl), hydroxy, carboxy, amino, C 1 -C 6 Alkoxy (e.g. C 1 -C 4 Alkoxy radicals of (2), such as the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy radical, and also such as the methoxy radical),C 1 -C 6 The number of "halo" groups (the number of "halo" groups may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; wherein "C 1 -C 6 Alkyl "such as C 1 -C 4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also such as methyl; the said "C 1 -C 6 Haloalkyl "such as-CH 2 F、-CHF 2 or-CF 3 ) Or C 1 -C 6 The number of haloalkoxy groups (the "halogen" may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; the said "C 1 -C 6 Haloalkoxy "of (e.g. -OCH) 2 F、-OCHF 2 or-OCF 3 )；
M is 1, 2 or 3;
the ring C isWherein D is CH or N, and R 2 And R is 3 One of (e.g. R 3 ) Z and the other R b ；
All R b H, F, cl, br, -CF independently 3 、-CN、CH 3 or-OCH 3 ；
All Z are independently- (CH) 2 ) n -NH-R 9-1 、-(CH 2 ) n -N(R a1 )-C(R a2 R a3 )-(CH 2 ) n -R 9-2 、-(CH 2 ) n -N(R a1 )-(CR a4 R a5 ) n -R 9-3 (e.g. )、-(CH 2 ) n -N(R a1 )-(CR a4 R a5 ) n -NH-C(＝O)-R 9-3 (e.g.)>)、-(CH 2 ) n -N(R a1 )-(CR a4 R a5 ) n -O-(CR a4 R a5 ) n -O-(CR a4 R a5 ) n -R 9-3 (e.g. (e.g.)>Also for example->)、/>
All t are independently 0 or 1;
all R y Independently hydrogen, -OH, -CH 3 、-CH 2 OH、-COOH、-CH 2 COOH or-CONHCH 2 CH 2 OH、-CONH 2 or-NHCOCH 3 ；
All R g Independently hydrogen, -OH, -CH 3 、-OCH 3 、-OCOCH 3 or-CH 2 CH＝CH 2 ；
All R h Independently hydrogen, -OH, -CH 3 or-COCH 3 ；
All R 9-1 Independently cyclobutyl, fluoro or unsubstituted-CH 2 Cyclobutyl (the number of fluorine atoms may be 1 or 2; the fluoro site may be methylene or cyclobutyl), cyclopropyl,Hydroxycyclopentyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxytetrahydrofuranyl, N-methylpiperidinyl, N-ethylpiperidinyl, hydroxytetrahydrothienyl;
all R 9-2 And R is 9-3 Independently hydrogen, carboxyl, hydroxyl, amino, C 1 -C 6 Alkyl (e.g. C) 1 -C 4 In turn, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, in turn, for example, methyl), azetidinone groups (for example) Cyclohexyl, hydroxyphenyl, pyrrolidone, piperidone, piperazinone, morpholinone (e.g.)) Imidazolyl, N-methylimidazolyl, -C (=o) -morpholinyl, R 9-2-1 Substituted or unsubstituted piperazinyl (said R 9-2-1 May be one or more [ e.g. 2 or 3 ]]) Pyrrolidinyl, pyridinyl, thiomorpholinyl, or methyltriazolyl; all R 9-2-1 Independently methyl, phenyl, alkoxyphenyl, hydroxyphenyl, pyridyl, pyrimidinyl or-C (=o) OC (CH) 3 ) 3 ；
All R a1 、R a2 、R a3 、R a4 And R is a5 Is independently H, -CH (OH) CH 3 、OH、-(CH 2 ) 2 OH、-CH 2 OH、-(CH 2 ) 2 NH 2 、-CH 2 CH 3 or-CH 3 ；
Alternatively, R a2 、R a3 And the carbon atoms to which they are attached are independently taken together to form C 4 -C 6 Carbocycles (again e.g. C 5 Carbocycle), N-methylpiperidine ring or pyran ring;
alternatively, R a4 、R a5 And the carbon atoms to which they are attached are independently taken together to form C 4 -C 6 Carbocycles (again e.g. C 5 Carbocycle), N-methylpiperidine ring or pyran ring;
all n are independently 1, 2 or 3;
when said ring B isR e Is methyl, R f In the case of hydrogen, m, and at the Z junction site "(CH) 2 ) n "n is not 1 at the same time (e.g., n is 2 or 3 when m is 1; e.g., n is 1, 2 or 3 when m is 2; e.g., n is 1, 2 or 3 when m is 3).
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the said processCan be->
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the ring B may be(e.g.)>)、/>
(when the linking site of the group of the above ring B with other groups is in the upper and lower positions, the upper end [ or the lower end ]]Can be connected with ring A, lower end [ or upper end ]]Can be combined with (CH) 2 ) m Connecting;
when the connection site of the group of the ring B and other groups is at a left-right positionIts left end [ or right end ]]Can be connected with ring A, right end [ or left end ]]Can be combined with (CH) 2 ) m Connection).
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all Y 1 、Y 2 And Y 8 Can be independently-C (R) 4 ) 2 -、-N(R 5 ) -, -O-or-S-.
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R 5 Can be independently hydrogen, C 1 -C 6 Alkyl, C of (2) 1 -C 6 Haloalkyl, H- (C (R) 4 ) 2 ) k -O-C(＝O)-(C(R 4 ) 2 ) k -、(R 6 R 7 )N-(C(R 4 ) 2 ) k -、HO-(C(R 4 ) 2 ) k -C(＝O)-、N(R 6 R 7 )-C(＝O)-、HO-(C(R 4 ) 2 ) k -、H-(C(R 4 ) 2 ) k -O-(C(R 4 ) 2 ) k -、H-(C(R 4 ) 2 ) k -S(＝O) 2 -(C(R 4 ) 2 ) k -、H-(C(R 4 ) 2 ) k -C(＝O)-(C(R 4 ) 2 ) k -、CN-(C(R 4 ) 2 ) k -C(＝O)-、H-(C(R 4 ) 2 ) k -O-C(＝O)-C(＝O)-(C(R 4 ) 2 ) k -。
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R 5 May be hydrogen.
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R 4 Can be independently hydrogen, C 1 -C 6 Alkyl, hydroxy, carboxyAmino, C 1 -C 6 Alkoxy, H 2 N-(CH 2 ) k -、N(R 6 R 7 )-C(＝O)-、H-(CH 2 ) k -O-C(＝O)-(CH 2 ) k -、H-(CH 2 ) k -O-(CH 2 ) k -、CN-(CH 2 ) k -C(＝O)-、C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 An alkylamino group of (a).
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R 4 May be hydrogen.
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R 6 And R is 7 Can be independently hydrogen, C 1 -C 6 Alkyl, hydroxy, carboxy, amino, C 1 -C 6 Alkoxy, H 2 N-(CH 2 ) k -、NH 2 -C(＝O)-、H-(CH 2 ) k -O-C(＝O)-(CH 2 ) k -、C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 An alkylamino group of (a).
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the R is e And R is f Can be independently hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, hydroxy, carboxyl, amino, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl or C of (C) 1 -C 6 Is a halogenated alkoxy group of (a).
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the R is e And R is f Can be independently hydrogen,C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy or C of (2) 1 -C 6 Is a haloalkyl group of (2).
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the ring B is any one of the following groups:
(when the linking site of the group of the above ring B with other groups is in the upper and lower positions, the upper end [ or the lower end ]]Can be connected with ring A, lower end [ or upper end ]]Can be combined with (CH) 2 ) m Connecting;
when the linking site of the group of the above ring B with other groups is in the left-right position, the left end [ or the right end ]]Can be connected with ring A, right end [ or left end ]]Can be combined with (CH) 2 ) m Connection).
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the m can be 1 or 2, and can also be 1.
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the ring C may be
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the ring C may be
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R b Can be independently H, -CF 3 or-OCH 3 。
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all Z's can independently be- (CH) 2 ) n -N(R a1 )-(CR a4 R a5 ) n -R 9-3 (e.g. )、-(CH 2 ) n -N(R a1 )-(CR a4 R a5 ) n -NH-C(＝O)-R 9-3 (e.g.)、-(CH 2 ) n -N(R a1 )-(CR a4 R a5 ) n -O-(CR a4 R a5 ) n -O-(CR a4 R a5 ) n -R 9-3 (e.g.)> )/>(e.g.)>Also for example->)。
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R 9-3 Can be independently carboxyl, hydroxyl, amino or C 1 -C 6 Alkyl, azetidinonyl (e.g.)) Or morpholinyl (e.g.)>)。
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all R a1 、R a2 、R a3 、R a4 And R is a5 And may independently be H or OH.
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
all n may be 1.
In one embodiment, certain groups of compound I are defined as follows, undefined groups are as described in any of the previous embodiments:
the ring A is phenyl;
p is 0, 1 or 2;
all R 1 Is independently-OCH 3 、-OH、-OCH 2 CH 3 、-O(CH 2 )OCH 3 、-OCH 2 CH＝CH 2 or-O (CH) 2 ) 2 CH 3 The method comprises the steps of carrying out a first treatment on the surface of the (when ring A is a six-membered ring, all R' s 1 Can be independently positioned at the ortho, meta or para position of the ring B; when ring A is a five-membered ring, all R 1 Can be independently located in the ortho or meta position of ring B; when ring A is a six-membered ring and p is 2, said R 1 Can be positioned in meta-position and para-position of ring B)
Alternatively, when p is 2, it is attached toTwo R's of adjacent carbon atoms (where ring A is a six-membered ring, the "adjacent carbon atoms" may be located "meta-and para-or" ortho-and meta-to "or" meta-and para-to "to ring B) 1 Formation of-O- (CR) c R d ) q -O-; q is 1 or 2; all R c And R is d Independently hydrogen or C 1 -C 6 Alkyl (e.g. C) 1 -C 4 Further for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, further for example methyl);
the ring B is(e.g.)>)、/>
(when the linking site of the group of the above ring B with other groups is in the upper and lower positions, the upper end [ or the lower end ]]Can be connected with ring A, lower end [ or upper end ]]Can be combined with (CH) 2 ) m Connecting;
when the linking site of the group of the above ring B with other groups is in the left-right position, the left end [ or the right end ]]Can be connected with ring A, right end [ or left end ]]Can be combined with (CH) 2 ) m Connection
All Y 1 、Y 2 And Y 8 independently-CH 2 -, -NH-; -O-or-S-;
all Y 3 、Y 4 、Y 5 、Y 6 And Y 7 Independently CH or N;
the R is e And R is f Independently hydrogen, C 1 -C 6 Alkyl (e.g. C 1 -C 4 Alkyl radicals of (2), in addition to methyl, ethyl, n-propyl, isopropylRadical, n-butyl, sec-butyl, isobutyl or tert-butyl, also for example methyl or tert-butyl), C 3 -C 6 Cycloalkyl (again e.g. cyclopropyl, cyclohexyl or cyclobutyl), C 1 -C 6 Alkoxy (e.g. C 1 -C 4 Alkoxy radicals of (2), such as the methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy radical, also such as the methoxy radical), or C 1 -C 6 The number of "halo" groups (the number of "halo" groups may be one or more [ e.g. 2, 3 or 4 ]]The method comprises the steps of carrying out a first treatment on the surface of the All "halogen" can independently be fluorine, chlorine or bromine, and can also be fluorine; wherein "C 1 -C 6 Alkyl "such as C 1 -C 4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also such as methyl; the said "C 1 -C 6 Haloalkyl "such as-CH 2 F、-CHF 2 or-CF 3 )；
M is 1, 2 or 3 (which may be 1 or 2, or may be 1);
the ring C isWherein D is CH or N, and R 2 And R is 3 One of (e.g. R 3 ) Z and the other R b ；
All R b Independently H, -CF 3 or-OCH 3 ；
All Z are independently- (CH) 2 ) n -N(R a1 )-(CR a4 R a5 ) n -R 9-3 (e.g. )、-(CH 2 ) n -N(R a1 )-(CR a4 R a5 ) n -NH-C(＝O)-R 9-3 (e.g.)、-(CH 2 )n-N(R a1 )-(CR a4 R a5 ) n -O-(CR a4 R a5 ) n -O-(CR a4 R a5 ) n -R 9-3 (e.g. )/>(e.g.)>Also e.g. as)；
t is 0; r is R y -COOH;
all R 9-3 Independently is carboxyl, hydroxyl, amino, C 1 -C 6 Alkyl (e.g. C) 1 -C 4 In turn, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, in turn, for example, methyl), azetidinone groups (for example) Or morpholinyl (e.g.)>)；
All R a1 、R a4 And R is a5 Independently H or OH;
all n are independently 1, 2 or 3 (e.g., all n are 1);
when said ring B isR e Is methyl, R f In the case of hydrogen, m, and at the Z junction site "(CH) 2 ) n "n is not 1 at the same time (e.g., n is 2 or 3 when m is 1; e.g., n is 1, 2 or 3 when m is 2; e.g., n is 1, 2 or 3 when m is 3).
Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used inIt means that the corresponding group is linked to other fragments, groups in compound I through this site.
Thus, throughout this specification, one skilled in the art may select groups and substituents thereof as described in compound I to provide stable compound 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-35 as described in the examples of the invention.
In one embodiment, the compound I may be any one of the following compounds:
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the compounds of formula I according to the present invention may be prepared according to chemical synthesis methods conventional in the art, and reference may be made to procedures and conditions for similar reactions in the art (e.g. examples of CN105705489 a).
If a chiral pure compound of the formula I according to the present invention is desired, it may be obtained by a method commonly used in the art, for example, by chiral induction during synthesis or by resolution using a chiral resolution column or chemical resolution method commonly used in the art after preparing a stereoisomer mixture of the target compound, thereby obtaining a chiral pure compound of the formula I according to the present invention.
The reaction solvent used in each of the reaction steps described in the present invention is not particularly limited, and any solvent which dissolves the starting materials to some extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention.
The invention also provides a pharmaceutical composition which comprises the compound I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, metabolites thereof, stereoisomers thereof, tautomers thereof or prodrugs thereof, and pharmaceutical excipients.
In the pharmaceutical composition, the compound I, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a metabolite thereof, a stereoisomer thereof, a tautomer thereof or a prodrug thereof may be used in a therapeutically effective amount.
The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. 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 can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill 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, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (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 formulations which may 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; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The invention also provides application of the compound I, pharmaceutically acceptable salts thereof, hydrates thereof, solvates thereof, metabolites thereof, stereoisomers thereof, tautomers thereof or prodrugs thereof in preparing PD-L1 inhibitors.
The PD-L1 inhibitor can be used in a mammalian organism; the PD-L1 inhibitors of the invention may also be used in vitro, mainly as experimental uses, for example: the kit can be used as a standard sample or a control sample for comparison or prepared according to a conventional method in the field to provide rapid detection for the inhibition effect of PD-L1.
The invention also provides application of the compound I, pharmaceutically acceptable salts, hydrates, solvates, metabolites, stereoisomers, tautomers or prodrugs thereof in preparing medicaments for treating and/or preventing diseases related to PD-L1 activity.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control. When referring to a URL or other identification or address, it should be understood that such an identifier may change, specific information on the internet may change, but equivalent information may be found by searching the internet. The references demonstrate that such information is available and publicly disseminated.
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 defined as open and not closed.
Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques or pharmacological detection, and reference is made to procedures and conditions conventional in the art.
The present invention employs, unless otherwise indicated, standard nomenclature of analytical chemistry, organic synthetic chemistry, and medicinal chemistry, and 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 salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure 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 the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure 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 organic acid salts including acids such 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, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids such as arginine and the like, 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 basic and acidic functionalities that can be converted to either base or acid addition salts. Preferably, the salt is contacted with a base or acid in a conventional manner to isolate the parent compound, thereby regenerating the neutral form of the compound. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the invention wherein the parent compound is modified by salt formation with an acid or by salt formation with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannins, tartaric acid, and p-toluenesulfonic acid.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of 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 both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the 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 invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily 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 by chemical or biochemical methods in an in vivo environment.
Certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds such as tritium (3H), iodine-125 (125I) or C-14 (14C) may be labeled with a radioisotope. 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.
In some embodiments, the compounds described herein exist as stereoisomers, wherein asymmetric or chiral centers are present. Stereoisomers are designated R or S depending on the configuration of substituents around the chiral carbon atom. The terms R and S as used herein are IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem, (1976), configurations defined in 45:13-30, the contents of which are incorporated herein by reference. Embodiments described herein include, inter alia, various stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. In some embodiments, each stereoisomer of a compound is prepared synthetically from commercial starting materials containing asymmetric or chiral centers or by preparing racemic mixtures followed by resolution. The splitting method is as follows: (1) Combining the mixture of enantiomers with a chiral auxiliary, and releasing the optically pure product from the auxiliary by recrystallisation or chromatographic separation of the resulting mixture of diastereomers; or (2) directly separating the mixture of optical enantiomers on a chiral chromatographic column.
The small molecule PD-L1 inhibitors of the invention may be used as single agents, or in combination with other therapeutic agents, to enhance the efficacy of these therapeutic agents.
The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the compound disclosed by the invention is a small-molecule PD-L1 inhibitor, has the advantages of high activity, high bioavailability, stable medicine, capability of oral administration and the like, and can cause and enhance autoimmune response of organisms. The compounds are PD-L1 inhibitors. In addition, the compound is convenient to prepare and low in production cost, and the production cost is only 10% of that of the monoclonal antibody macromolecular PD-L1 inhibitor.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Embodiments of the present invention provide compounds of formula I, methods and intermediates for preparing them, compositions containing them, and their use in preparing medicaments.
EXAMPLE 1 preparation of Compound I-1
Compound I-1a (43 mg,0.1 mmol), S-piperidine-2-carboxylic acid (13.6 mg,0.105 mmol), and sodium triacetoxyborohydride (21.2 mg,0.25 mmol) were added to a 10mL dichloromethane solution, stirred at 80-85℃for 1 hour, and the crude product was purified by preparative LC/MS and evaluated for 98% purity by LCMS analysis.
EXAMPLE 2 preparation of Compound I-14
Compound I-14a (39 mg,0.1 mmol), piperidine-2-carboxylic acid (13.6 mg,0.105 mmol), and sodium triacetoxyborohydride (21.2 mg,0.25 mmol) were added to a 10mL dichloromethane solution and stirred at 80-85℃for 45 min, the crude product was purified by preparative LC/MS and its purity was 97% as assessed by LCMS analysis.
EXAMPLE 3 preparation of Compound I-20
Compound I-20a (35 mg,0.1 mmol), piperidine-2-carboxylic acid (13.6 mg,0.105 mmol), and sodium triacetoxyborohydride (21.2 mg,0.25 mmol) were added to a 10mL dichloromethane solution and stirred at 80-85℃for 50 min, the crude product was purified by preparative LC/MS and its purity was 98% as assessed by LCMS analysis.
EXAMPLE 4 preparation of Compound I-35
Compound I-35a (40.4 mg,0.1 mmol), piperidine-2-carboxylic acid (13.6 mg,0.105 mmol), and sodium triacetoxyborohydride (21.2 mg,0.25 mmol) were added to a 10mL dichloromethane solution, stirred at 80-85℃for 60 min, and the crude product was purified by preparative LC/MS and evaluated for 98% purity by LCMS analysis.
General synthetic methods for the compounds I-2 to I-13, I-15 to I-19, I-21 to I-34 were the same as in examples 1 to 4.
The identification data for compounds I-1 to I-35 are shown in the following table:
effect example 1 biological assay
The ability of compounds of formula (I) to bind PD-L1 was studied using a PD-1/PD-L1 Homogeneous Time Resolved Fluorescence (HTRF) binding assay.
Homogeneous Time Resolved Fluorescence (HTRF) binding assays
All binding studies were performed in HTRF assay buffer consisting of dPBS supplemented with 0.1% (wt v) bovine serum albumin and 0.05% (v/v) Tween-20. For the PD-1-Ig/PD-L1-His binding assay, inhibitors were pre-incubated with PD-L1-His (10 nM final) for 15m in 4. Mu.l assay buffer, followed by addition of PD-1-Ig (20 nM final) in 1. Mu.l assay buffer and further incubation for 15m. PD-L1 from human, dog or mouse was used. HTRF detection was accomplished using europium cryptate-labeled anti-Ig (1 nM final) and Allophycocyanin (APC) -labeled anti-His (20 nM final). The antibodies were diluted in HTRF detection buffer and 5 μl was dispensed over the binding reaction mixture. The reaction mixture was equilibrated for 30 minutes and a signal (665 nm/620nm ratio) was obtained using an EnVision fluorometer. Additional binding assays were performed between PD-1-Ig/PD-L2-His (20 &5nM, respectively), CD80-His/PD-L1-Ig (100 &10nM, respectively) and CD80-His/CTLA4-Ig (10 &5nM, respectively). Competition studies between biotinylated SEQ ID NO:71 and human PD-L1-His were performed as follows. The inhibitor was pre-incubated with PD-L1-His (10 nM final) for 60m in 4. Mu.l assay buffer followed by the addition of biotinylated SEQ ID NO:71 (0.5 nM final) in 1. Mu.l assay buffer. Binding was equilibrated for 30m, followed by the addition of europium cryptate-labeled streptavidin (2.5 pM final) and APC-labeled anti-His (20 nM final) in 5. Mu.l HTRF buffer. The reaction mixture was equilibrated for 30m and a signal (665 nm/620nm ratio) was obtained using an EnVision fluorometer.
The following table lists the IC's for compounds I-1 to I-35 of the present invention as measured in the PD-1/PD-L1 Homogeneous Time Resolved Fluorescence (HTRF) binding assay 50 . The compounds of formula I of the present invention exhibit an IC having the following range 50 Value: a=4 nM-100nM; b=101 nM-300nM; c=301 nM-1 μm; d=1.001-10 μm.
Thus, the compounds of formula I of the present invention have activity as inhibitors of PD-1/PD-L1 interactions and are therefore useful in the treatment of diseases associated with PD-1/PD-L1 interactions. By inhibiting the interaction of PD-1/PD-L1.
Effect example 2 kinetic solubility test:
kinetic solubility testing is commonly used for high throughput screening of drugs during the drug discovery phase. In kinetic analysis, a good solubility should help to generate reliable in vitro and in vivo data. Since the kinetic solubility is pH-dependent, the pH of the aqueous phase is always specified, typically measured at pH 7.4 (physiological pH of body fluids).
The testing method comprises the following steps: quantitative compound samples were weighed and dissolved in pure DMSO to a final concentration of 10mM, and test compound and control compound (10 mM DMSO stock solution, 10. Mu.L per well) were added to 96-well plates containing 490. Mu.L buffer per well. After vortexing for 2 minutes, the sample plates were incubated on a shaker at room temperature (22.+ -. 2 ℃) for 24 hours. Then transfer 200 μl of sample to a MultiScreen filter plate (polycarbonate membrane), filter with a microporous vacuum manifold (millipore vacuum manifold) and collect the filtrate. The concentration of the compounds in the filtrate was determined by HPLC-UV. The 3 UV standard substance solutions with different concentrations are sampled sequentially with the solubility test sample. Each sample was spiked 2 times and the concentration was calculated by taking the standard curve and averaging.
Experimental results show that the compound of the invention has good water solubility and is superior to a control compound (the compound from CN105705489A, example 1, which is also a small molecule inhibitor of PD-1/PD-L1 interaction, IC) 50 6-100 nM).
Effect example 3 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 of the compounds of the invention in human and rat liver microsomes by in vitro metabolic stability experiments. Wherein the control compound was derived from the compound described in example 1 of CN105705489 a.
The specific procedure for this experimental procedure is described in the references (Shang Minghai, wang Hairong, wang Chunyan, sheyu. In vitro metabolism of antitumor compound E7 in liver microsomal enzymes of different species [ J ]. J. Chinese traditional medicine, 2016, 9 th edition, pages 1739-1743).
Experimental results show that compared with a control compound, the compound provided by the invention has better metabolic stability, and provides important basis for further preclinical research.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means 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 present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. 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 will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives, and variations may be made in the above embodiments by those skilled in the art without departing from the spirit and principles of the invention.

Claims (3)

1. A substituted biaryl compound or a pharmaceutically acceptable salt thereof, wherein the substituted biaryl compound is:
2. a pharmaceutical composition comprising the substituted biaryl compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.
3. Use of a substituted biaryl compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a PD-L1 inhibitor or in the preparation of a medicament for the treatment and/or prophylaxis of a disease associated with PD-L1 activity.
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