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CN111808086B - Heterocyclic substituted styryl-4-phenylpyridine derivative, preparation method and medical application thereof - Google Patents

Heterocyclic substituted styryl-4-phenylpyridine derivative, preparation method and medical application thereof Download PDF

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CN111808086B
CN111808086B CN202010518455.8A CN202010518455A CN111808086B CN 111808086 B CN111808086 B CN 111808086B CN 202010518455 A CN202010518455 A CN 202010518455A CN 111808086 B CN111808086 B CN 111808086B
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pharmaceutically acceptable
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hydrogen
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CN111808086A (en
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刘力锋
朱卫星
陈永刚
黄栋
关慧平
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Abstract

The invention relates to a heterocycle substituted styryl-4-phenylpyridine derivative, a preparation method thereof and application thereof as a PD-1/PD-L1 inhibitor. Specifically, the invention discloses a compound of formula (I) or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, and a preparation method and application thereof, wherein the definition of each group in the formula is shown in the specification and the claims.

Description

Heterocyclic substituted styryl-4-phenylpyridine derivative, preparation method and medical application thereof
Technical Field
The invention belongs to the technical field of medicines. In particular, the invention relates to a heterocyclic substituted styryl-4-phenylpyridine derivative, a preparation method thereof, an application of the heterocyclic substituted styryl-4-phenylpyridine derivative as a PD-1/PD-L1 inhibitor, and a pharmaceutical composition prepared from the heterocyclic substituted styryl-4-phenylpyridine derivative.
Background
Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers a negative signal when interacting with two other ligands, PD-L1 or PD-L2. PD-1 and its ligands are widely expressed and exert a wider range of immunomodulatory effects in T cell activation and tolerance than other members of CD 28. PD-1 and its ligands are involved in attenuating infectious and tumor immunity and promoting chronic infection and tumor progression. The biological importance of PD-1 and its ligands suggests the possibility of manipulation of the PD-1 pathway for the treatment of various human diseases (Ariel Pedoeem et al, Curr Top Microbiol Immunol (2011); 350: 17-37).
T cell activation and dysfunction depend on direct and regulated receptors. Based on their functional outcome, co-signal transduction molecules can be divided into co-stimulators and co-inhibitors, which positively and negatively control the initiation, growth, differentiation and functional maturation of T cell responses (Li Shi, et al, Journal of Hematology & Oncology 2013, 6: 74).
Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway prevent T cell down-regulation and promote immune responses against cancer. Various PD-1 pathway inhibitors have shown strong activity at various stages of Clinical trials (RDHarvey, Clinical Pharmacology & Therapeutics (2014); 962, 214-223).
Programmed death-1 (PD-1) is a co-receptor that is predominantly expressed by T cells. The binding of PD-1 to its ligand, PD-L1 or PD-L2, is essential for the physiological regulation of the immune system. The main functional role of the PD-1 signaling pathway is to suppress self-reactive T cells, which are used to protect against autoimmune diseases. Thus, elimination of the PD-1 pathway can lead to the disruption of immune tolerance, which can ultimately lead to the development of pathological autoimmunity. In contrast, tumor cells can sometimes specify that the PD-1 pathway escapes immune surveillance mechanisms. Therefore, blocking the PD-1 pathway has become an attractive target for cancer therapy. Current methods include six agents, which are neutralizing antibodies or fusion proteins that target PD-1 and PD-L1. More than forty Clinical trials are underway to better define the role of PD-1 blockade in multiple tumor types (Hyun-Tak Jin et al, Clinical Immunology (Amsterdam, Netherlands) (2014), 153(1), 145-152).
International applications WO 01/14557, WO 02/079499, WO 2002/086083, WO 03/042402, WO 2004/004771, WO 2004/056875, WO2006121168, WO2008156712, WO2010077634, WO2011066389, WO2014055897, WO2014059173, WO2014100079 and US patent US08735553 report PD-1 or PD-L1 inhibitory antibodies or fusion proteins.
Furthermore, international applications WO2011161699, WO2012/168944, WO2013144704 and WO2013132317 report peptides or peptidic compounds capable of suppressing and/or inhibiting the programmed cell death 1(PD1) signaling pathway.
However, there remains a need for more potent, better and/or selective immunomodulators of the PD-1 pathway. The present invention provides heterocycle-substituted styryl-4-phenylpyridine derivatives that are capable of suppressing and/or inhibiting the programmed cell death 1(PD1) signaling pathway.
Disclosure of Invention
The invention aims to provide a compound which has a novel structure and can be used as a PD-1/PD-L1 inhibitor.
The invention provides a compound shown as a formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, a solvate or a prodrug thereof in a first aspect:
Figure BDA0002531043340000021
in the formula (I), the compound is shown in the specification,
Z1is N or CR1；Z2Is N or CR2；Z3Is N or CR3；Z4Is N or CR4；
RAIs C6-10Aryl, 5 or 6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, 8 to 10 membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; said C is6-10Aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl are unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: halogen, cyano, acetyl, hydroxy, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxy, C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, -CONRa0Rb0、-C(O)C1-3Alkyl, -SO2C1-3Alkyl, -SO2 NRa0Rb0(ii) a Wherein R isa0、Rb0Each independently is hydrogen or C1-3An alkyl group;
R1、R2、R3、R4、R5、R6、R7each independently hydrogen, halogen, cyano, acetyl, hydroxy, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxy, C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, -CONRa1Rb1、-C(O)C1-3Alkyl, -SO2C1-3Alkyl, -SO2NRa1Rb1(ii) a Wherein R isa1、Rb1Each independently is hydrogen or C1-3An alkyl group;
Rc、Rdeach independently of the others is hydrogen, hydroxy, cyano, halogen, C1-3Alkyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxymethyl;
Rais C3-6Cycloalkyl or- (CR)a2Rb2)m-R0；RbIs hydrogen or C1-3An alkyl group;
or Ra、RbIs linked to the linking nitrogen atom to form a 5 or 6 membered saturated mono-heterocyclic ring; said 5 or 6 membered saturated mono-heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; said 5 or 6 membered saturated mono-heterocyclic ring being unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: carboxy, hydroxy, cyano, halogen, C1-3Alkyl, halo C1-3Alkyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxymethyl;
Ra2、Rb2each independently is hydrogen, hydroxy, carboxy or C1-3An alkyl group;
R0is C1-3Alkyl, hydroxy, carboxy, -NHC (O) CH3Pyrrolidonyl, - (OCH)2CH2)p-NH2；
m is 1,2 or 3; p is 1,2 or 3;
l is a bond, NH, O, S (O) or S (O)2；
n is 1,2 or 3;
Re、Rfthe same or different, each independently hydrogen, halogen, hydroxy, cyano, carboxy, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl or C1-3An alkyl group;
RBis a 4 to 6 membered saturated mono-heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; a 5 or 6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, an 8 to 10 membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur; the 4 to 6 membered saturated monocyclic heterocycle, 5 or 6 membered monocyclic heteroaryl, 8 to 10 membered bicyclic heteroaryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group S, the group S substituents being selected from: halogen, cyano, acetyl, hydroxy, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxy, C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, -CONRa3Rb3、-C(O)C1-3Alkyl, -SO2C1-3Alkyl, -SO2NRa3Rb3(ii) a Wherein R isa3、Rb3Each independently is hydrogen or C1-3An alkyl group.
In another preferred embodiment, the substituents of group S are selected from: fluorine, chlorine, bromine, iodine, cyano, acetyl, hydroxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, -CONH2、-CONHCH3、-CON(CH3)2、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)CH3、-SO2CH3、-SO2CH2CH3、-SO2CH2CH2CH3、-SO2CH(CH3)CH3、-SO2NH2、-SO2NHCH3、-SO2N(CH3)2。
In another preferred embodiment, RBWherein said 4 to 6 membered saturated mono-heterocyclic ring is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran.
In another preferred embodiment, RBWherein said 5 or 6 membered monocyclic heteroaryl is selected from: thiophene, N-alkylcyclopyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, oxadiazole derivative, and pharmaceutically acceptable salts thereof,1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In another preferred embodiment, RBThe 8-to 10-membered bicyclic heteroaryl group in (1) is selected from: benzo [ d ] carbonyl]Isoxazoles, 1H-indoles, isoindoles, 1H-benzo [ d ]]Imidazole, benzo [ d ]]Isothiazole, 1H-benzo [ d ]][1,2,3]Triazole, benzo [ d ]]Oxazole, benzo [ d ]]Thiazoles, indazoles, benzofurans, benzols [ b ]]Thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido [3,2-d ]]Pyrimidine, pyrido [2,3-d ]]Pyrimidine, pyrido [3,4-d ]]Pyrimidine, pyrido [4,3-d ]]Pyrimidine, 1, 8-naphthyridine, 1, 7-naphthyridine, 1, 6-naphthyridine and 1, 5-naphthyridine.
In another preferred embodiment, RBIs azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, or pyridine, said azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, pyridine being unsubstituted or substituted with 1,2, or 3 substituents independently selected from the group consisting of: cyano radicals, halogeno radicals C1-3Alkyl, -CONRa3Rb3(ii) a Wherein R isa3、Rb3Each independently is hydrogen or C1-3An alkyl group.
In another preferred embodiment, RBIs azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, or pyridine, said azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, pyridine being unsubstituted or substituted with 1,2, or 3 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, cyano, acetyl, hydroxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, hydroxyethyl, hydroxypropyl, beta-,Difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, -CONH2、-CONHCH3、-CON(CH3)2、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)CH3、-SO2CH3、-SO2CH2CH3、-SO2CH2CH2CH3、-SO2CH(CH3)CH3、-SO2NH2、-SO2NHCH3、-SO2N(CH3)2。
In another preferred embodiment, RBIs azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, or pyridine, said azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, pyridine being unsubstituted or substituted with 1,2, or 3 substituents independently selected from the group consisting of: cyano, trifluoromethyl, -CONH2、-CONHCH3、-CON(CH3)2。
In another preferred embodiment, RBIs oxetane, morpholine or pyridine, said oxetane, morpholine or pyridine being unsubstituted or substituted with 1 substituent independently selected from the group consisting of: cyano, trifluoromethyl, -CONH2。
In another preferred embodiment, Z1Is CR1；Z2Is CR2；Z3Is CR3；Z4Is N.
In another preferred embodiment, R1、R2And R3One of which is cyano.
In another preferred embodiment, R1Is cyano or C1-3An alkyl group; r2、R3Is hydrogen.
In another preferred embodiment, R1Is halogen, cyano, acetyl, hydroxy, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxy, C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, -CONRa1Rb1、-C(O)C1-3Alkyl, -SO2C1-3Alkyl, -SO2NRa1Rb1(ii) a Wherein R isa1、Rb1Each independently is hydrogen or C1-3An alkyl group; r2、R3Is hydrogen.
In another preferred embodiment, R1、R2、R3Each independently of the others hydrogen, fluorine, chlorine, bromine, iodine, cyano, acetyl, hydroxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, -CONH2、-CONHCH3、-CON(CH3)2、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)CH3、-SO2CH3、-SO2CH2CH3、-SO2CH2CH2CH3、-SO2CH(CH3)CH3、-SO2NH2、-SO2NHCH3、-SO2N(CH3)2。
In another preferred embodiment, R1Is fluorine, chlorine, bromine, iodine, cyano, acetyl, hydroxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, dichloromethyl, trichloromethyl, monochloro methylEthyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -CONH2、-CONHCH3、-CON(CH3)2、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)CH3、-SO2CH3、-SO2CH2CH3、-SO2CH2CH2CH3、-SO2CH(CH3)CH3、-SO2NH2、-SO2NHCH3、-SO2N(CH3)2；R2、R3Is hydrogen.
In another preferred embodiment, R1Is cyano or methyl; r2、R3Is hydrogen.
In another preferred embodiment, RAIs phenyl or a 5 or 6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the phenyl, 5 or 6 membered monocyclic heteroaryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: fluorine, chlorine, bromine, iodine, cyano, acetyl, hydroxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, -CONH2、-CONHCH3、-CON(CH3)2、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)CH3、-SO2CH3、-SO2CH2CH3、-SO2CH2CH2CH3、-SO2CH(CH3)CH3、-SO2NH2、-SO2NHCH3、-SO2N(CH3)2。
In another preferred embodiment, RAWherein the 5 or 6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur is selected from: thiophene, N-alkyl cyclic pyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 5-triazole, 1,3, 4-triazole, tetrazole, isoxazole, oxadiazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, 1,2, 5-oxadiazole, 1,3, 4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
In another preferred embodiment, RAThe 8 to 10 membered bicyclic heteroaryl having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur of (a) is selected from: benzo [ d ] carbonyl]Isoxazoles, 1H-indoles, isoindoles, 1H-benzo [ d ]]Imidazole, benzo [ d ]]Isothiazole, 1H-benzo [ d ]][1,2,3]Triazole, benzo [ d ]]Oxazole, benzo [ d ]]Thiazoles, indazoles, benzofurans, benzols [ b ]]Thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido [3,2-d ]]Pyrimidine, pyrido [2,3-d ]]Pyrimidine, pyrido [3,4-d ]]Pyrimidine, pyrido [4,3-d ]]Pyrimidine, 1, 8-naphthyridine, 1, 7-naphthyridine, 1, 6-naphthyridine and 1, 5-naphthyridine.
In another preferred embodiment, RAIs unsubstituted phenyl.
In another preferred embodiment, R6Is halogen, cyano, acetyl, hydroxy, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxy, C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, halo C1-3Alkoxy radical, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, -CONRa1Rb1、-C(O)C1-3Alkyl, -SO2C1-3Alkyl radical、-SO2NRa1Rb1(ii) a Wherein R isa1、Rb1Each independently is hydrogen or C1-3An alkyl group; r5、R7Is hydrogen.
In another preferred embodiment, R5、R6And R7In which one is halogen or halogeno C1-3An alkyl group.
In another preferred embodiment, R6Is halogen or halogeno C1-3An alkyl group; r5、R7Is hydrogen.
In another preferred embodiment, R5、R6、R7Each independently of the others hydrogen, fluorine, chlorine, bromine, iodine, cyano, acetyl, hydroxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, -CONH2、-CONHCH3、-CON(CH3)2、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)CH3、-SO2CH3、-SO2CH2CH3、-SO2CH2CH2CH3、-SO2CH(CH3)CH3、-SO2NH2、-SO2NHCH3、-SO2N(CH3)2。
In another preferred embodiment, R6Is fluorine, chlorine, bromine, iodine, cyano, acetyl, hydroxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxyChloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, -CONH2、-CONHCH3、-CON(CH3)2、-C(O)CH3、-C(O)CH2CH3、-C(O)CH2CH2CH3、-C(O)CH(CH3)CH3、-SO2CH3、-SO2CH2CH3、-SO2CH2CH2CH3、-SO2CH(CH3)CH3、-SO2NH2、-SO2NHCH3、-SO2N(CH3)2；R5、R7Is hydrogen.
In another preferred embodiment, R6Is fluorine, chlorine or trifluoromethyl; r5、R7Is hydrogen.
In another preferred embodiment, R6Is chloro or trifluoromethyl; r5、R7Is hydrogen.
In another preferred embodiment, Rc、RdIs hydrogen.
In another preferred embodiment, Ra、RbThe 5 or 6 membered saturated mono-heterocyclic ring formed in conjunction with the linking nitrogen atom is selected from: tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine-1, 1-dioxide; said 5 or 6 membered saturated mono-heterocyclic ring being unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: carboxyl, hydroxyl, cyano, halogen, methyl, ethyl, n-propyl, isopropyl, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, carboxymethyl.
In another preferred embodiment, Ra、RbThe 5 or 6 membered saturated mono-heterocyclic ring which is formed by linking with the linking nitrogen atom is piperidine; the 5 or 6 membered saturated mono-heterocyclic ring is unsubstituted or substituted with 1 carboxy group.
In another preferred embodiment, Ra、RbThe 5 or 6 membered saturated mono-heterocyclic ring formed by attachment to the linking nitrogen atom is selected from the following structures:
Figure BDA0002531043340000061
in a further preferred embodiment of the method,
Figure BDA0002531043340000071
selected from:
Figure BDA0002531043340000072
in a further preferred embodiment of the method,
Figure BDA0002531043340000073
selected from:
Figure BDA0002531043340000074
in another preferred embodiment, L is a bond or O; n is 1,2 or 3. In another preferred embodiment, Re、RfThe same or different, each independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, carboxyl, cyanomethyl, cyanoethyl, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl or isopropyl. In another preferred embodiment, Re、RfThe same or different, each independently is hydrogen or methyl.
In another preferred embodiment, n is 1 and R ise、RfThe same or different, each independently is hydrogen or methyl.
In another preferred embodiment, n is 2 or 3, n ReAnd n RfAre all H.
Understandably, "Re、RfThe same or different "is to be understood as including (1) ReAnd RfAre the same or different from each other; (2) when there are more than one ReWhen a plurality of ReThe same or different from each other; (3) when there are more than one RfWhen a plurality of RfThe same or different, etc.
In another preferred embodiment, the compound is selected from the following group of structures:
Figure BDA0002531043340000081
Figure BDA0002531043340000091
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and at least one other agent, wherein the other agent is an anti-cancer agent, a chemotherapeutic agent, or an anti-proliferative compound.
In a fourth aspect, the present invention provides the use of a compound according to the first aspect of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second or third aspects of the present invention, for the manufacture of a medicament for the treatment of cancer or an infectious disease.
In another preferred embodiment, the cancer is selected from: bone cancer, cancer of the head or neck, pancreatic cancer, skin cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, non-hodgkin's lymphoma, carcinoma of the esophagus, carcinoma of the small intestine, cancer of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, chronic lymphoid leukemia, childhood solid tumors, lymphocytic lymphomas, cancer of the bladder, carcinoma of the kidney or ureter, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, including asbestos-induced cancer, and combinations of said cancers.
In another preferred embodiment, the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease.
In a fifth aspect, the present invention provides a method of modulating an immune response in a subject mediated by the PD-1 signalling pathway, said method comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second or third aspect of the present invention.
In a sixth aspect, the present invention provides a method of inhibiting growth and/or migration of tumour cells in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second or third aspect of the present invention.
In another preferred embodiment, the tumor cell is a cancer selected from the group consisting of: breast, colon, lung, melanoma, prostate and kidney cancers.
In another preferred example, the tumor cell is a cancer selected from the list consisting of: bone cancer, cancer of the head or neck, pancreatic cancer, skin cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, non-hodgkin's lymphoma, carcinoma of the esophagus, carcinoma of the small intestine, cancer of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, chronic lymphoid leukemia, childhood solid tumors, lymphocytic lymphomas, cancer of the bladder, carcinoma of the kidney or ureter, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, including asbestos-induced cancer, and combinations of said cancers.
In a seventh aspect, the present invention provides a method of treating an infectious disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second or third aspect of the present invention.
In an eighth aspect, the present invention provides a method of treating bacterial, viral and fungal infections in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound according to the first aspect of the present invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second or third aspect of the present invention.
In another preferred example, infectious diseases include, but are not limited to, HIV, influenza, herpes, Giardia, malaria, Leishmania, pathogenic infections caused by hepatitis virus (A, B, & C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, EB (Epstein Barr) virus), adenovirus, influenza virus, arbovirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum virus, poliovirus, rabies virus, JC virus and arbovirus encephalitis virus, pathogenic infections caused by bacterial chlamydia, rickettsia bacteria, mycobacteria, staphylococci, streptococcus, Pneumococcus (pneumonococci), meningococci and conocci, klebsiella, proteus, serratia, pseudomonas, escherichia coli, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and lyme disease bacteria, pathogenic infections caused by the following fungi: candida (candida albicans, candida krusei (krusei), candida glabrata (glabrata), candida tropicalis (tropicalis), etc.), cryptococcus neoformans, aspergillus (aspergillus fumigatus), aspergillus niger (niger), etc.), mucor (mucor, humicola, rhizopus (rhizopus), trichosporon, Blastomyces dermatitidis (Blastomyces dermatitidis), Paracoccidioides brasiliensis (Paracoccidioides brasiliensis), coccidioidomycosis immitis (coccoidis capsulitis), and Histoplasma (Histoplasma capsulim), and pathogenic infections caused by: endophytic species of dysentery (Entamoeba histolytica), Baphicacanthi cubensis (Ballantidia coli), Fowler-Nordheim (Naegleriafarleri), Acanthamoeba (Acanthamoeba sp.), Giardia lamblia (Girdia lambia), Cryptosporidium (Cryptosporidium sp.), Pneumocystis carinii (Pneumocystis carinii), Plasmodium vivax (Plasmodium vivax), Babesia cubensis (Babesia microti), Trypanosoma brucei (Trypanosoma brucei), Trypanosoma cruzi (Trypanosoma cruzi), Leishmania dorsalis (Leishmania donovani), Toxoplasma gondii (Toxoa ndii), and Neosardonia bractensis (Nippostrongoides).
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies and have unexpectedly found that such immunomodulators have high inhibitory activity particularly against enzymes such as PPI-HTRF. Therefore, the series of compounds are expected to be developed into medicaments for treating tumors. On this basis, the inventors have completed the present invention.
Definition of terms
As used herein, "alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups, C1-10Alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C1-8Alkyl, more preferably C1-6Alkyl, more preferably C1-3Alkyl, defined similarly; non-limiting examples of alkyl groups include: methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1-dimethylpropyl group, 1, 2-dimethylpropyl group, 2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1, 2-trimethylpropyl group, 1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2-dimethylbutyl group, 1, 3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2, 3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 2-methylpentyl group, 3-methylhexyl group, 4-methylhexyl group, 2-dimethylpropyl group, 2-pentyl group, 2-methylpropyl group, 2-methyl-pentyl group, 3-pentyl group, 2-methyl-pentyl group, 2-pentyl group, and 3-pentyl group, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, 2, 3-dimethylpentyl, 2-dimethylhexyl, 2, 3-dimethylhexyl, 2, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethylpentyl, 2-dimethylpentyl, 2-ethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 2-dimethylpentyl, 2-hexyl, 2-dimethylhexyl, 2-hexyl, and the like, N-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof.
As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, "C3-8Cycloalkyl "refers to a cyclic hydrocarbon group containing 3 to 8 carbon atoms, preferably C3-6Cycloalkyl, defined similarly; . Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclohexyl, and the like,Cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like, and cyclopropyl, cyclopentyl, cyclohexenyl are preferred.
As used herein, "C" is1-10Alkoxy means-O- (C)1-10Alkyl) wherein alkyl is as defined above. Preferably C1-8Alkoxy, more preferably C1-6Alkoxy, more preferably C1-3An alkoxy group. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
As used herein, "C" is3-8Cycloalkoxy means-O- (C)3-8Cycloalkyl), wherein cycloalkyl is as defined above. Preferably C3-6A cycloalkoxy group. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
As used herein, "C" is6-10Aryl "refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and refers to aryl groups containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
As used herein, "a bond" means that the two groups connected by it are linked by a covalent bond.
As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, "halo" refers to a group in which one or more (e.g., 1,2,3, 4, or 5) hydrogens are replaced with a halogen.
For example, "halo C1-8Alkyl "means an alkyl group substituted with one or more (e.g., 1,2,3, 4, or 5) halogens, wherein alkyl is as defined above. Is selected from halo C1-6Alkyl, more preferably halogenated C1-3An alkyl group. Halogen substituted C1-8Examples of alkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
Also for example, "halo C1-8Alkoxy "means an alkoxy group is substituted with oneOr multiple (e.g., 1,2,3, 4, or 5) halogen substitutions, wherein alkoxy is as defined above. Preferably a halogen atom1-6Alkoxy, more preferably halo C1-3An alkoxy group. Including, but not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
As used herein, "amino" refers to NH2"cyano" means CN, "cyanomethyl" means-CH2CN, "cyanoethyl" means-CH2CH2CN or-CH (CN) CH3By "nitro" is meant NO2"benzyl" means-CH2-phenyl, "oxo" means ═ O, "carboxy" means-c (O) OH, -COOH or-CO2H, "acetyl" means-C (O) CH3And "hydroxymethyl" means-CH2OH, "hydroxyethyl" means-CH2CH2OH or-CH (OH) CH3"hydroxy" means-OH, "thiol" means SH, and "cyclopropylene" has the structure:
Figure BDA0002531043340000121
"acetamido" refers to-NH-C (O) CH3"Pyrrolonyl" means
Figure BDA0002531043340000122
As used herein, "heteroaryl ring" is used interchangeably with "heteroaryl" and refers to a monocyclic heteroaryl group having 5 to 10 ring atoms, preferably 5 or 6 membered or a bicyclic heteroaryl group having 8 to 10 membered ring atoms; 6, 10 or 14 pi electrons are shared in the ring array; and a group having 1 to 5 hetero atoms in addition to carbon atoms. "heteroatom" means nitrogen, oxygen or sulfur.
As used herein, "5 or 6 membered monocyclic heteroaryl" refers to a monocyclic heteroaryl group containing 5 to 6 ring atoms having 1,2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, for example including (but not limited to): thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2, 3-triazole ring, 1,2, 4-triazole ring, 1,2, 5-triazole ring, 1,3, 4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, and the like.
As used herein, "8 to 10 membered bicyclic heteroaryl" refers to a bicyclic heteroaryl group containing 8 to 10 ring atoms having 1,2,3, 4, or 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, for example including (but not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, phthalazine. More preferred are benzo [ d ] isoxazole, 1H-indole, isoindole, 1H-benzo [ d ] imidazole, benzo [ d ] isothiazole, 1H-benzo [ d ] [1,2,3] triazole, benzo [ d ] oxazole, benzo [ d ] thiazole, indazole, benzofuran, benzo [ b ] thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido [3,2-d ] pyrimidine, pyrido [2,3-d ] pyrimidine, pyrido [3,4-d ] pyrimidine, pyrido [4,3-d ] pyrimidine, 1, 8-naphthyridine, 1, 7-naphthyridine, 1, 6-naphthyridine, 1, 5-naphthyridine.
As used herein, "3 to 7 membered saturated monocyclic heterocycle" means that 1,2 or 3 carbon atoms in the 3 to 7 membered monocyclic ring are substituted by a substituent selected from nitrogen, oxygen or S (O)t(wherein t is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon; preferably 4 to 6, more preferably 5 to 6. Examples of saturated monoheterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran, and the like.
As used herein, "substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are substituted independently of each other with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are substituted independently of each other with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
As used herein, any group herein may be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 or less groups independently selected from CN, halogen, C1-8Alkyl (preferably C)1-6Alkyl, more preferably C1-3Alkyl group), C1-8Alkoxy (preferably C)1-6Alkoxy, more preferably C1-3Alkoxy), halo C1-8Alkyl (preferably halogenated C)1-6Alkyl, more preferably halogenated C1-3Alkyl group), C3-8Cycloalkyl (preferably C)3-6Cycloalkyl), halo C1-8Alkoxy (preferably halo C)1-6Alkoxy, more preferably halo C1-3Alkoxy group), C1-8Alkyl substituted amino, halo C1-8An alkyl-substituted amino group, a 4-to 6-membered saturated monocyclic heterocycle, a 5-to 6-membered monocyclic heteroaryl ring, an 8-to 10-membered bicyclic heteroaryl ring, a spiro ring, a bridged ring, or a bridged heterocycle.
The various substituent groups described herein above may themselves be substituted with groups described herein.
When the 3-to 7-membered (or 5-to 6-membered) saturated mono-heterocyclic rings described herein are substituted, the positions of the substituents may be at their possible chemical positions, and representative substitution of exemplary mono-heterocyclic rings are as follows:
Figure BDA0002531043340000131
Figure BDA0002531043340000132
wherein "Sub" represents the various types of substituents described herein;
Figure BDA0002531043340000133
representing a connection to another atom.
The 4-to 6-or 5-to 6-membered saturated monoheterocyclic ring of the present invention, or when the 4-to 6-or 5-to 6-membered saturated monoheterocyclic ring of the present invention is a substituent, it may itself be unsubstituted or substituted with 1,2 or 3 substituents selected from the group consisting of: halogen, hydroxy, C1-3Alkyl, O ═ NRa0Rb0Hydroxymethyl, hydroxyethyl, carboxy, -C (O) OC1-3Alkyl, acetyl, halo C1-3Alkyl radical, C1-3Alkoxy radical, C3-6Cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran, thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring; wherein R isa0、Rb0Each independently is hydrogen or C1-3An alkyl group.
The "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects.
"pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts, and the like. Including but not limited to salts with organic bases such as ammonium, triethylamine, lysine, arginine, and the like.
Reference to a "solvate" in the present invention refers to a complex formed between a compound of the present invention and a solvent. They either react in a solvent or precipitate out of a solvent or crystallize out. For example, a complex with water is referred to as a "hydrate". Solvates of the compounds of formula (I) are within the scope of the invention.
The compounds of the formula (I) according to the invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound comprises enantiomers. The present invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When the compounds of formula (I) contain more than one chiral center, diastereoisomers may be present. The present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.
The present invention includes prodrugs of the above compounds. Prodrugs include known amino protecting groups and carboxy protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to give the parent compound. Specific prodrug preparation methods are referenced (Saulnier, M.G.; Frannesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.chem Lett.1994, 4, 1985-.
In general, a compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, may be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like. The above-mentioned dosage forms can be prepared from the active compounds and one or more carriers or adjuvants by customary pharmaceutical methods. The above-mentioned carriers need to be compatible with the active compound or other adjuvants. For solid formulations, non-toxic carriers that are commonly used include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, polyethylene glycol and the like. The active compound may be in solution or suspension with the carrier(s) mentioned above.
The compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice specifications. The "therapeutically effective amount" of a compound to be administered will depend on, among other factors, the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
As used herein, "therapeutically effective amount" refers to an amount of a compound of the invention that will elicit the biological or medical response of an individual, e.g., decrease or inhibit enzyme or protein activity or ameliorate symptoms, alleviate a condition, slow or delay disease progression or prevent disease, etc.
The therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1mg to 5g/kg (body weight).
As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary formulation or any type of adjuvant that is compatible with the patient, preferably a mammal, more preferably a human, and that is suitable for delivering an active agent to a target site without terminating the activity of the agent.
As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, and humans.
As used herein, "treating" or "treatment" refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or disorder (e.g., cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent one or more symptoms of the disease or disorder.
Preparation method
Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations.
Compared with the prior art, the invention has the main advantages that:
provides a series of immunomodulators with high inhibitory activity to PD-1/PD-L1, which can be used as drugs for treating tumors.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Unless otherwise indicated, percentages and parts are by weight. Unless otherwise defined, terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention.
As used herein, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, DCM is dichloromethane, Pd (dppf) Cl2Is 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, Pd2(dba)3Is tris (dibenzylideneacetone) dipalladium, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, and Xant-Phos is 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene. As used herein, room temperature means about 20-25 ℃.
Example 1: (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (oxetan-3-ylmethoxy) phenyl) piperidine-2-carboxylic acid (Z-1)
Figure BDA0002531043340000151
Step 1: 3- (bromomethyl) oxetane (225mg, 1.5mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (236mg, 1.0mmol), potassium carbonate (276mg, 2.0mmol) were dissolved in 20mL of acetonitrile and the reaction was stirred at 80 ℃ for 2 hours. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 70% ethyl acetate in petroleum ether to give 4-bromo-5-chloro-2- (oxetan-3-ylmethoxy) benzaldehyde (200mg, light brown liquid), yield: 68.1 percent. MS M/z (ESI) 305.1[ M +1 ].
Step 2: add to a 20mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (40mg, 0.20mmol), 4-bromo-5-chloro-2- (oxetan-3-ylmethoxy) benzaldehyde (62mg, 0.30mmol), palladium acetate (2.0mg, 0.01mmol), tris (o-methylbenzene) phosphonium (3.0mg, 0.01mmol), 0.3mL triethylamine and 3mL dimethylacetamide. Argon gas is blown for 1 minute, a microwave cover is covered, and microwave reaction is carried out for 45 minutes at 160 ℃. Vacuum concentrating, purifying with 0% -60% ethyl acetate in petroleum ether by silica gel column chromatography to obtain (E) -2- (2-chloro-4-formyl-5- (oxetan-3-ylmethoxy) styryl-4-phenylnicotinamide (43mg, yellow solid), yield: 41.6%. MS M/z (ESI):431.1[ M +1 ].
And step 3: (E) -2- (2-chloro-4-formyl-5- (oxetan-3-ylmethoxy) styryl-4-phenylnicotinamide (43mg, 0.1mmol) and (S) -piperidine-2-carboxylic acid (26mg, 0.2mol) were dissolved in 10mL of methanol, sodium cyanoborohydride (10mg, 0.15mmol) was added, the reaction was stirred under reflux for 1 hour, concentrated under reduced pressure, and subjected to preparative HPLC chromatography to give (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (oxetan-3-ylmethoxy) phenyl) piperidine-2-carboxylic acid Z-1(7.37mg, white solid), yield: 15.2 percent. MS M/z (ESI) 544.1[ M +1]]。1H NMR(400MHz,DMSO-d6)δ8.88(d,2H),8.28(d,2H),7.66-7.46(m,7H),4.70(d,2H),4.49(d,2H),4.28(d,2H),3.67(dd,2H),3.15(d,2H),2.80(d,1H),2.25(d,2H),1.74(d,2H),1.49(d,2H),1.38(d,1H).
Example 2: (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (3-morpholinopropoxy) benzyl) piperidine-2-carboxylic acid (Z-2)
Figure BDA0002531043340000161
Step 1: 4-bromo-5-chloro-2-hydroxybenzaldehyde (100mg, 0.42mmol), 4- (3-bromopropyl) morpholine (177mg, 0.85mmol), potassium carbonate (100mg, 0.42mmol), sodium iodide (10mg) were dissolved in 10mL acetonitrile, refluxed overnight, filtered, and the crude product was purified by concentration under reduced pressure (methanol/dichloromethane: 0-100%) to give 4-bromo-5-chloro-2- (3-morpholinopropoxy) benzaldehyde (140mg, 0.39mmol), yield: 92 percent. MS M/z (ESI) 361.9[ M +1 ].
Step 2: dissolving 4-bromo-5-chloro-2- (3-morpholinopropoxy) benzaldehyde (140mg, 0.39mmol), 4-phenyl-2-vinyl nicotinonitrile (80mg,0.39 mmol), trimethylphenylphosphine (24mg, 0.08 mmol), palladium acetate (9mg,0.04mmol), triethylamine (0.2mL) in 4mL of N, N-dimethylacetamide, heating at 160 ℃ under the protection of argon gas, filtering, washing with a saline solution, extracting with ethyl acetate, concentrating the organic phase under reduced pressure, purifying the residue with silica gel column chromatography (dichloromethane/methanol: 0-100%) to obtain (E) -2- (2-chloro-4-formyl-5- (3-morpholinopropoxy) styryl) -4-nicotinonitrile (215mg, brown oily liquid), yield: 100 percent. MS M/z (ESI) 488.1[ M +1 ].
And step 3: (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (3-morpholinopropoxy) benzyl) piperidine-2-carboxylic acid Z-2(67mg, white solid) was prepared by dissolving (E) -2- (2-chloro-4-formyl-5- (3-morpholinopropoxy) styryl) -4-benzonitrile (215mg, 0.44mmol), (S) -piperidine-2-carboxylic acid (85mg, 0.66mmol) in 20mL of methanol, refluxing for 2 hours, and concentrating under reduced pressure: 25 percent. MS M/z (ESI) 601.2[ M +1]]。1H NMR(400MHz,DMSO-d6)δ8.91(d,J＝4.9Hz,1H),8.31(d,J＝15.5Hz,1H),7.75-7.50(m,8H),7.42(s,1H),4.14(s,2H),3.74(d,J＝15.4Hz,1H),3.67-3.55(m,5H),3.22(s,1H),2.89(s,1H),2.46-2.20(m,7H),1.96-1.70(m,4H),1.56-1.35(m,4H).
Example 3: (2S) -1- (5-chloro-4- ((E) -2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (1- (5-cyanopyridin-3-yl) ethoxy) phenyl) piperidine-2-carboxylic acid (Z-3)
Figure BDA0002531043340000171
Step 1: 5-bromonicotinaldehyde (980mg, 5.0mmol), dissolved in 45mL THF, added 1M methylmagnesium bromide solution (10mL, 10mmol) and stirred at room temperature for 1 hour, added 50mL saturated aqueous ammonium chloride solution to the reaction solution, extracted with dichloromethane (100 mL. times.2), combined organic phases, washed with brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 1- (5-bromopyridin-3-yl) ethanol (1.1g, colorless liquid) in yield: 98.1 percent. MS M/z (ESI) 202.1[ M +1 ].
Step 2: 1- (5-bromopyridin-3-yl) ethanol (1.1g, 5.4mmol), zinc cyanide (1.3g, 10.8mmol), Pd (dba)3(370mg, 0.5mmol), Xant-Phos (290mg, 0.5mmol), potassium acetate (1.1g, 10.8mmol) were dissolved in 30mL dioxane, protected with nitrogen, and the reaction was stirred at 100 ℃ overnight. Concentrated under reduced pressure and purified by silica gel column chromatography with 0% -60% ethyl acetate in petroleum ether to give 5- (1-hydroxyethyl) nicotinonitrile (710mg, yellow solid) in yield: 87.6 percent. MS M/z (ESI) 149.1[ M +1 ].
And step 3: dissolving 5- (1-hydroxyethyl) nicotinonitrile (355mg, 2.4mmol) in 45mL of DCM, adding phosphorus tribromide (0.35mL, 3.6mmol), stirring at room temperature for reaction for 1 hour, adding 50mL of saturated aqueous sodium bicarbonate solution to the reaction solution to adjust PH to 8, extracting with dichloromethane (60mL × 2), combining organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 5- (1-bromoethyl) nicotinonitrile (445mg, light brown liquid), yield: 98.1 percent. MS M/z (ESI) 211.1[ M +1 ].
And 4, step 4: 5- (1-bromoethyl) nicotinonitrile (245mg, 2.0mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (236mg, 2.0mmol) and potassium carbonate (552mg, 4.0mmol) were dissolved in 30mL of acetonitrile and the reaction was stirred at 80 ℃ for 2 hours. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 60% ethyl acetate in petroleum ether to give 5- (1- (5-bromo-4-chloro-2-formylphenoxy) ethyl) benzonitrile (210mg, light brown liquid), yield: 41.1 percent. MS M/z (ESI) 365.1[ M +1 ].
And 5: add to a 20mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (35mg, 0.17mmol), 5- (1- (5-bromo-4-chloro-2-formylphenoxy) ethyl) nicotinonitrile (95mg, 0.25mmol), palladium acetate (3.0mg, 0.03mmol), tris (o-methylbenzene) phosphonium (4.0mg, 0.03mmol), 0.4mL triethylamine and 4mL dimethylacetamide. Argon gas is blown for 1 minute, a microwave cover is covered, and microwave reaction is carried out for 45 minutes at 160 ℃. Concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 70% ethyl acetate in petroleum ether to give (E) -2- (2-chloro-5- (1- (5-cyanopyridin-3-yl) ethoxy) -4-formylstyryl) -4-phenylnicotinonitrile (30mg, yellow solid) in yield: 27.6 percent. MS M/z (ESI) 491.1[ M +1 ].
Step 6: (E) -2- (2-chloro-5- (1- (5-cyanopyridin-3-yl) ethoxy) -4-formylstyryl) -4-phenylnicotinonitrile (30mg, 0.07mmol) and (S) -piperidine-2-carboxylic acid (18mg, 0.14mol) were dissolved in 15mL of methanol, sodium cyanoborohydride (6mg, 0.10mmol) was added, and the reaction was stirred at reflux for 2 hours. Concentrating under reduced pressure, and performing preparative HPLC chromatography to obtain (2S) -1- (5-chloro-4- ((E) -2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (1- (5-cyano)Pyridin-3-yl) ethoxy) phenyl) piperidine-2-carboxylic acid Z-3(3.53mg, white solid), yield: 12.2 percent. MS M/z (ESI) 604.1[ M +1]]。1H NMR(400MHz,DMSO-d6)δ8.98(d,1H),8.90(m,2H),8.38(dd,2H),8.17(d,1H),7.66-7.33(m,7H),5.93(s,1H),4.45(dd,1H),3.82(s,1H),3.71(s,1H),3.49(d,2H),2.86(d,1H),2.23(d,1H),1.78(s,2H),1.62(d,3H),1.48(s,2H),1.32(s,1H).
Example 4: (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- ((5- (trifluoromethyl) pyridin-3-yl) methoxy) phenyl) piperidine-2-carboxylic acid (Z-4)
Figure BDA0002531043340000181
Step 1: 5- (trifluoromethyl) nicotinic acid (2g, 10.5mmol), dissolved in 10mL THF, 1M borane-tetrahydrofuran solution (30mL, 30mmol) was added and the reaction was stirred at room temperature for 5 hours, 50mL saturated aqueous ammonium chloride solution was added to the reaction solution, extraction was performed with dichloromethane (60 mL. times.3), the organic phases were combined, washed with brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (5- (trifluoromethyl) pyridin-3-yl) methanol (1.5g, colorless liquid) in yield: 78.1 percent. MS M/z (ESI) 178.1[ M +1 ].
Step 2: (5- (trifluoromethyl) pyridin-3-yl) methanol (750mg, 4.2mmol) was dissolved in 45mL of DCM, phosphorus tribromide (0.61mL, 6.3mmol) was added and the reaction was stirred at room temperature for 1 hour, 50mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust PH 8, extraction was performed with dichloromethane (60mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3- (bromomethyl) -5- (trifluoromethyl) pyridine (780mg, light brown liquid) in yield: 88.1 percent. MS M/z (ESI) 240.1[ M +1 ].
And step 3: 3- (bromomethyl) -5- (trifluoromethyl) pyridine (780mg, 3.2mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (378mg, 3.2mmol), and potassium carbonate (883mg, 6.4mmol) were dissolved in 30mL of acetonitrile, and the reaction was stirred at 80 ℃ for 2 hours. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 60% ethyl acetate in petroleum ether to give 4-bromo-5-chloro-2- ((5- (trifluoromethyl) pyridin-3-yl) methoxy) benzaldehyde (210mg, light brown solid), yield: 41.1 percent. MS M/z (ESI) 394.1[ M +1 ].
And 4, step 4: add to a 20mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (35mg, 0.17mmol), 4-bromo-5-chloro-2- ((5- (trifluoromethyl) pyridin-3-yl) methoxy) benzaldehyde (95mg, 0.25mmol), palladium acetate (3.0mg, 0.03mmol), tris (o-methylbenzene) phosphonium (4.0mg, 0.03mmol), 0.4mL triethylamine and 4mL dimethylacetamide. Argon gas is blown for 1 minute, a microwave cover is covered, and microwave reaction is carried out for 45 minutes at 160 ℃. Concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 60% ethyl acetate in petroleum ether to give (E) -2- (2-chloro-4-formyl-5- ((5- (trifluoromethyl) pyridin-3-yl) methoxy) styryl) -4-phenylnicotinonitrile (40mg, yellow solid) in yield: 37.6 percent. MS M/z (ESI) 520.1[ M +1 ].
And 5: (E) -2- (2-chloro-4-formyl-5- ((5- (trifluoromethyl) pyridin-3-yl) methoxy) styryl) -4-phenylnicotinonitrile (40mg, 0.07mmol) and (S) -piperidine-2-carboxylic acid (18mg, 0.14mol) were dissolved in 15mL of methanol, sodium cyanoborohydride (6mg, 0.10mmol) was added, and the reaction was stirred at reflux for 2 hours. Concentrated under reduced pressure and chromatographed by preparative HPLC to give (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- ((5- (trifluoromethyl) pyridin-3-yl) methoxy) phenyl) piperidine-2-carboxylic acid Z-4(5.48mg, white solid), yield: 12.8 percent. MS M/z (ESI) 633.1[ M +1]]。1H NMR(400MHz,DMSO-d6)δ8.98(dd,3H),8.33(dd,2H),7.71-7.56(m,9H),5.45(s,2H),3.75(d,1H),3.63(d,1H),3.24(d,1H),2.89(d,1H),2.26(d,1H),1.77(s,2H),1.48(s,4H).
Example 5: (E) -N- (2- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- ((5-cyanopyridin-3-yl) methoxy) benzylamino) ethyl) acetamide (Z-5)
Figure BDA0002531043340000191
Step 1: (5-Bromopyridin-3-yl) methanol (1.87g, 10mmol), zinc cyanide (2.1g, 20mmol), Pd (dba)3(770mg, 1mmol), Xant-Phos (587mg, 1mmol), potassium acetate (2g, 20mmol) were dissolved in 50mL dioxane, protected with nitrogen, and the reaction was stirred at 100 ℃ overnight. Concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 78% ethyl acetate in petroleum ether to give 5- (hydroxymethyl) nicotinonitrile (1g, yellow solid) in yield: 57.6 percent. MS M/z (ESI) 135.1[ M +1 ].
Step 2: 5- (hydroxymethyl) nicotinonitrile (405mg, 3mmol) was dissolved in 35mL of DCM, phosphorus tribromide (0.44mL, 4.5mmol) was added and the reaction was stirred at room temperature for 1 hour, 50mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust PH 8, extraction was performed with dichloromethane (60mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5- (bromomethyl) nicotinonitrile (680mg, light brown liquid) in yield: 100 percent. MS M/z (ESI) 197.1[ M +1 ].
And step 3: the product, 5- (bromomethyl) nicotinonitrile (680mg, 3.5mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (543mg, 2.3mmol) and potassium carbonate (635mg, 4.6mmol) were dissolved in 30mL of acetonitrile and the reaction was stirred at 80 ℃ for 2 hours. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 60% ethyl acetate in petroleum ether to give 5- ((5-bromo-4-chloro-2-formylphenoxy) methyl) benzonitrile (210mg, light brown liquid), yield: 41.1 percent. MS M/z (ESI) 351.1[ M +1 ].
And 4, step 4: add to a 20mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (35mg, 0.17mmol), 5- ((5-bromo-4-chloro-2-formylphenoxy) methyl) nicotinonitrile (95mg, 0.25mmol), palladium acetate (3.0mg, 0.03mmol), tris (o-methylbenzene) phosphonium (4.0mg, 0.03mmol), 0.4mL triethylamine and 4mL dimethylacetamide. Argon gas is blown for 1 minute, a microwave cover is covered, and microwave reaction is carried out for 45 minutes at 160 ℃. Concentrated under reduced pressure and purified by silica gel column chromatography with 0% to 70% ethyl acetate in petroleum ether to give (E) -2- (2-chloro-5- ((5-cyanopyridin-3-yl) methoxy) -4-formylstyryl) -4-phenylnicotinonitrile (36mg, yellow solid) in yield: 27.6 percent. MS M/z (ESI) 477.1[ M +1 ].
And 5: (E) -2- (2-chloro-5- ((5-cyanopyridin-3-yl) methoxy) -4-formylstyryl) -4-phenylnicotinonitrile (36mg, 0.07mmol) and N- (2-aminoethyl) acetamide (18mg, 0.14mol) were dissolved in 15mL of methanol, sodium cyanoborohydride (6mg, 0.10mmol) was added, and the reaction was stirred under reflux for 2 hours. Concentrating under reduced pressure, and performing preparative HPLC chromatography to obtain (E) -N- (2- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- ((5-cyanogen)Pyrid-3-yl) methoxy) benzylamino) ethyl) acetamide Z-5(6.53mg, white solid), yield: 13.2 percent. MS M/z (ESI):563.1[ M +1]]。1H NMR(400MHz,DMSO-d6)δ8.98(dd,3H),8.35(dd,4H),7.79(s,1H),7.68-7.53(m,8H),5.36(s,2H),3.71(s,2H),3.08(d,2H),2.54(d,2H),1.75(s,3H).
Example 6: (S, E) -1- (5-chloro-2- (5-cyanopyridin-3-yl) methoxy) -4- (2- (3-methyl-4-phenylpyridin-2-yl) vinyl) benzyl) piperidine-2-carboxylic acid (Z-6)
Figure BDA0002531043340000201
Step 1: 5-Hydroxymethylnicotinonitrile (300mg, 2.24mmol) was dissolved in 20mL of 1, 4-dioxane and a solution of hydrogen chloride in 1, 4-dioxane (4M, 20mL) was added. After the mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure to give 3-cyano-5-hydroxymethylpyridine hydrochloride (380mg, yellow solid) which was used directly in the next reaction.
Step 2: to 3-cyano-5-hydroxymethylpyridine hydrochloride (380mg) was added 20mL of thionyl chloride, heated to 90 ℃ and reacted under reflux for 3 hours, followed by concentration under reduced pressure to give 3-cyano-5-chloromethylpyridine hydrochloride (421mg, yellow oily substance) which was used as it was in the next reaction.
And step 3: 3-cyano-5-chloromethylpyridine hydrochloride (421mg) was dissolved in 10mL of N, N-dimethylformamide, and 4-bromo-5-chloro-2-hydroxybenzaldehyde (524mg, 2.24mmol) and potassium carbonate (927mg, 6.72mmol) were added in this order. The mixture was stirred overnight at room temperature, filtered and concentrated under reduced pressure to give 5- ((5-bromo-4-chloro-2-formylphenoxy) methyl) nicotinonitrile (500mg, yellow solid) which was used directly in the next reaction. MS M/z (ESI) 351.2[ M +1 ].
And 4, step 4: dissolving 5- ((5-bromo-4-chloro-2-formylphenoxy) methyl) nicotinonitrile (100mg) in 2mL of N, N-dimethylacetamide, adding 3-methyl-4-phenyl-2-vinylpyridine (37mg, 0.19mmol), palladium acetate (4mg, 0.02mmol), tris (o-methylbenzene) phosphorus (11mg, 0.04mmol) and triethylamine (1mL) in this order, heating the mixture to 140 ℃ in a microwave oven, stirring for 45min, cooling to room temperature, concentrating under reduced pressure, separating and purifying by column chromatography to obtain (E) -5- ((4-chloro-2-formyl-5- (2- (3-methyl-4-phenylpyridin-2-yl) vinyl) phenoxy) methyl) nicotinonitrile (77mg, yellow solid), yield: 88 percent. MS M/z (ESI) 466.2[ M +1 ].
And 5: a mixture of (E) -5- ((4-chloro-2-formyl-5- (2- (3-methyl-4-phenylpyridin-2-yl) vinyl) phenoxy) methyl) nicotinonitrile (77mg, 0.17mmol), (S) -piperidine-2-carboxylic acid (32mg, 0.25mmol), sodium cyanoborohydride (31mg, 0.50mmol) and methanol (30mL) was heated to 85 ℃ for two days, filtered, concentrated under reduced pressure, and separated and purified by preparative liquid phase to give (S, E) -1- (5-chloro-2- (5-cyanopyridin-3-yl) methoxy) -4- (2- (3-methyl-4-phenylpyridin-2-yl) vinyl) benzyl) piperidine-2-carboxylic acid Z-6(23.2 mg), white solid), yield: 24 percent. MS M/z (ESI) 579.2[ M +1]]。1H NMR(400MHz,DMSO-d6)δ8.99(d,J＝6.8Hz,2H),8.51–8.39(m,2H),8.05(d,J＝15.5Hz,1H),7.59–7.28(m,8H),7.13(d,J＝4.7Hz,1H),5.37(s,2H),3.77-3.58(m,1H),3.17-3.16(m,2H),2.87-2.84(m,1H),2.34(s,3H),2.29–2.25(m,1H),1.75(s,2H),1.46-1.38(m,4H).
Example 7: (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- ((5-cyanopyridin-3-yl) methoxy) benzyl) piperidine-2-carboxylic acid (Z-7)
Figure BDA0002531043340000211
Step 1: dissolving 5- ((5-bromo-4-chloro-2-formylphenoxy) methyl) nicotinonitrile (170mg, 0.49mmol) in 2mLN, N-dimethylacetamide, adding 3-cyano-4-phenyl-2-vinylpyridine (100mg, 0.49mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (40mg, 0.05mmol), and triethylamine (1mL) in this order, heating the mixture to 150 ℃ in a microwave oven, stirring and reacting for 60min, cooling to room temperature, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain (E) -2- (2-chloro-5- ((5-cyanopyridin-3-yl) methoxy) -4-formylstyryl) -4-phenylnicotinonitrile (100mg, yellow solid), yield: and 43 percent. MS M/z (ESI) 477.2[ M +1 ].
Step 2: (E) -5- ((4-chloro-2-formyl-5- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) phenoxy) methyl) nicotinonitrile (100mg,0.21mmol), (S) -piperidine-2-carboxylic acid (136mg, 1.05mmol), sodium cyanoborohydride (66mg, 1.05mmol) and methanol (10mL) were heated to 80 ℃ for 16 hours, filtered, concentrated under reduced pressure, and purified by preparative liquid phase separation to give (S, E) -1- (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- ((5-cyanopyridin-3-yl) methoxy) benzyl) piperidine-2-carboxylic acid Z-7(14.2mg, white solid) yield: 11 percent. MS M/z (ESI) 590.2[ M +1]]。1H NMR(400MHz,DMSO-d6)δ9.01(s,2H),8.92(d,J＝5.1Hz,1H),8.46(d,J＝1.9Hz,1H),8.31(d,J＝15.4Hz,1H),7.87–7.43(m,9H),5.40(s,2H),3.78(d,J＝15.0Hz,1H),3.64(d,J＝14.8Hz,1H),3.21(d,J＝5.3Hz,2H),2.92–2.84(m,1H),2.31–2.23(m,1H),1.78(s,2H),1.50(s,3H).
Example 8: (S, E) -1- (2- (2- (5-carbamoylpyridin-3-yl) ethyl) -4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Z-8)
Figure BDA0002531043340000221
Step 1:
2- (trifluoromethyl) -5-vinylaniline (700mg, 3.74mmol) was dissolved in 4mL of N, N-dimethylacetamide, and 5-bromonicotinic acid methyl ester (965mg, 4.49mmol), palladium acetate (42mg, 0.19mmol), tris (o-methylphenyl) phosphorus (114mg, 0.37mmol) and 2mL of triethylamine were sequentially added, nitrogen was replaced three times, heating was carried out to 150 ℃, reaction was stirred in a microwave reactor for 50 minutes and then cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 60:40) to obtain (E) -5- (3-amino-4- (trifluoromethyl) styryl) nicotinic acid methyl ester (660mg, yellow solid) in yield: and 55 percent. MS M/z (ESI) 323.2[ M +1 ].
Step 2: methyl (E) -5- (3-amino-4- (trifluoromethyl) styryl) nicotinate (660mg, 2.05mmol) was dissolved in 20mL of ethyl acetate, and 10% palladium on charcoal (70mg) was added to replace hydrogen three times. The mixture was stirred at room temperature for 1 hour, filtered and concentrated under reduced pressure to give methyl 5- (3-amino-4- (trifluoromethyl) phenethyl) nicotinate (600mg, yellow oil) which was used directly in the next reaction. MS M/z (ESI) 325.1[ M +1 ].
And step 3: methyl 5- (3-amino-4- (trifluoromethyl) phenethyl) nicotinate (600mg, 1.85mmol) was dissolved in 10mL of N, N-dimethylformamide, N-bromosuccinimide (330mg, 1.85mmol) was added, nitrogen gas was substituted three times, the reaction was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 40:60) to give methyl 5- (5-amino-2-bromo-4- (trifluoromethyl) phenethyl) nicotinate (560mg, yellow oily substance), yield: 75 percent. MS M/z (ESI) 403.2[ M +1],405.2[ M +3 ].
And 4, step 4: methyl 5- (5-amino-2-bromo-4- (trifluoromethyl) phenethyl) nicotinate (560mg, 1.39mmol) was dissolved in 2mL of N-methylpyrrolidone, cuprous cyanide (248mg, 2.79mmol) was added, nitrogen was substituted three times, the reaction was heated to 220 ℃ and stirred in a microwave reactor for 40 minutes and then cooled to room temperature. The reaction solution was poured into 20mL of ethyl acetate, washed with 17% aqueous ammonia (20mL), brine (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 50:50) to give methyl 5- (5-amino-2-cyano-4- (trifluoromethyl) phenethyl) nicotinate (224mg, yellow solid) in yield: 46 percent. MS M/z (ESI) 350.1[ M +1 ].
And 5: methyl 5- (5-amino-2-cyano-4- (trifluoromethyl) phenethyl) nicotinate (224mg, 0.64mmol) was dissolved in 20mL acetonitrile, copper bromide (212mg, 0.96mmol) was added, the mixture was cooled to 0 ℃ in an ice-water bath, isoamyl nitrite (113mg, 0.96mmol) was slowly added dropwise, after the addition was completed, the temperature was raised to room temperature, and the reaction was continued with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into 20mL of ethyl acetate, washed with 17% aqueous ammonia (20mL), brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound methyl 5- (5-bromo-2-cyano-4- (trifluoromethyl) phenethyl) nicotinate (256mg, yellow solid) which was used directly in the next reaction. MS M/z (ESI) 413.1[ M +1], 415.1[ M +3 ].
Step 6: methyl 5- (5-bromo-2-cyano-4- (trifluoromethyl) phenethyl) nicotinate (256mg) was dissolved in a mixed solvent of 10mL of methanol, 10mL of tetrahydrofuran and 2mL of water, and lithium hydroxide monohydrate (130mg, 3.1mmol) was added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure to remove methanol and tetrahydrofuran, and the residue was adjusted to pH 2 with 3N hydrochloric acid and concentrated under reduced pressure to dryness to give 5- (5-bromo-2-cyano-4- (trifluoromethyl) phenethyl) nicotinic acid (246mg, yellow solid) which was used directly in the next reaction. MS M/z (ESI) 399.1[ M +1], 401.1[ M +3 ].
And 7: 5- (5-bromo-2-cyano-4- (trifluoromethyl) phenethyl) nicotinic acid (50mg, 0.13mmol) was dissolved in 10mL of N, N-dimethylformamide and 2mL of triethylamine, and ammonium chloride (10mg, 0.19mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (73mg, 0.19mmol) were added in that order. The mixture was stirred at room temperature for 20 hours, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 90:10) to give 5- (5-bromo-2-cyano-4- (trifluoromethyl) phenethyl) nicotinamide (41mg, yellow solid), yield: 82 percent. MS M/z (ESI) 398.2[ M +1],400.2[ M +3 ].
And 8: 5- (5-bromo-2-cyano-4- (trifluoromethyl) phenethyl) nicotinamide (76mg, 0.19mmol) was dissolved in 20mL of dichloromethane, the dry ice acetone bath cooled to-78 deg.C, diisobutylaluminum hydride (1.1M, 0.2mL, 0.21mmol) was slowly added dropwise, and the reaction was allowed to stir at this temperature for 1 hour. Methanol (5mL) and 36% hydrochloric acid (5mL) were added sequentially. The reaction solution was warmed to room temperature, stirred for 0.5 hour, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:50) to give 5- (5-bromo-2-formyl-4- (trifluoromethyl) phenethyl) nicotinamide (60mg, yellow solid) in yield: 79 percent. MS M/z (ESI) 401.1[ M +1 ].
And step 9: dissolving 5- (5-bromo-2-formyl-4- (trifluoromethyl) phenethyl) nicotinamide (60mg, 0.15mmol) in 2mL of N, N-dimethylacetamide, adding 4-phenyl-2-vinyl nicotinonitrile (31mg, 0.15mmol), palladium acetate (3mg, 0.015mmol), tris (o-methylphenyl) phosphorus (9mg,0.03 mmol) and 1mL of triethylamine in this order, replacing with nitrogen three times, heating to 150 ℃, stirring in a microwave reactor for 50 minutes, cooling to room temperature, filtering the reaction solution through celite, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (dichloromethane: methanol: triethylamine: 80: 15: 5) to obtain (E) -5- (5- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2-formyl-4- (trifluoromethyl) Phenethyl) nicotinamide (55mg, yellow oil), yield: 70 percent. MS M/z (ESI) 527.2[ M +1 ].
Step 10: dissolving (E) -5- (5- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2-formyl-4- (trifluoromethyl) phenethyl) nicotinamide (55mg, 0.11mmol) in 15mL of methanol, adding (S) -piperidine-2-carboxylic acid (40mg, 0.31mmol), sodium cyanoborohydride (20mg, 0.31mmol) sequentially, displacing with nitrogen three times, heating to 80 ℃, stirring for reaction for 16 hours, cooling to room temperature, concentrating the reaction solution under reduced pressure, and purifying the residue with preparative chromatography to obtain (S, E) -1- (2- (2- (5-carbamoylpyridin-3-yl) ethyl) -4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -5- (trifluoromethyl) Benzyl) piperidine-2-carboxylic acid Z-8(1.5mg, white solid), yield: 2.2 percent. MS M/z (ESI) 640.3[ M +1 ].
Example 9: (S, E) -1- (4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-3- (yl) ethyl) benzyl) piperidine-2-carboxylic acid (Z-9)
Figure BDA0002531043340000241
Step 1: 5-bromo-2- (trifluoromethyl) aniline (10.1g, 42.08mmol) was dissolved in 100mL of 1, 4-dioxane, potassium vinyltrifluoroborate (6.77g, 50.5mmol), potassium carbonate (11.61g, 84.16mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (3.44g, 4.21mmol) and 10mL of water were sequentially added, nitrogen was substituted three times, heating was carried out to 100 ℃, stirring was carried out for 20 hours, then cooling was carried out to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate: 80:20) to give 2- (trifluoromethyl) -5-vinylaniline (5.2g, yellow solid) in yield: 66 percent. MS M/z (ESI) 188.1[ M +1 ].
Step 2: 2- (trifluoromethyl) -5-vinylaniline (300mg, 1.6mmol) was dissolved in 6mL of N, N-dimethylacetamide, 3-bromo-5- (trifluoromethyl) pyridine (399mg, 1.76mmol), palladium acetate (36mg, 0.16mmol), tris (o-methylphenyl) phosphorus (49mg, 0.16mmol) and triethylamine (485mg,4.8mmol) were sequentially added, nitrogen gas was replaced, the reaction mixture was heated to 160 ℃ in a microwave reactor and stirred for 45 minutes and then cooled to room temperature, the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 80:20) to give (E) -2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridin-3-yl) vinyl) aniline (520mg, yellow solid), yield: 58.6 percent. MS M/z (ESI) 333.1[ M +1 ].
And step 3: (E) -2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridin-3-yl) vinyl) aniline (520mg,1.57mmol) was dissolved in 10ml of methanol, 50mg of 10% palladium on charcoal was added, the mixture was replaced with hydrogen three times, the mixture was stirred at room temperature for two hours, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) aniline (420mg, yellow oil). MS M/z (ESI) 335.1[ M +1 ].
And 4, step 4: dissolving 2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) aniline (420mg) in 10mL of N, N-dimethylformamide, adding N-bromosuccinimide (224mg, 1.26mmol), stirring at room temperature for 2 hours, pouring the reaction mixture into water, extracting with ethyl acetate (2X 30mL), combining the organic phases, washing with water (3X 50mL), washing with saturated brine (50mL), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue with silica gel column chromatography (petroleum ether: ethyl acetate 80:20) to obtain 4-bromo-2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) aniline (420mg, white solid), yield: 81.1 percent. MS M/z (ESI) 413.0[ M +1 ].
And 5: 4-bromo-2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) aniline (420mg, 1.02mmol) was dissolved in 10mL of N-methylpyrrolidinone, cuprous cyanide (918mg, 10.2mmol) was added, the reaction was stirred in a microwave reactor heated to 220 ℃ for 30 minutes and then cooled to room temperature. The reaction was poured into water, extracted with ethyl acetate (3 × 30ml), the organic phases combined and washed with water (3 × 60ml), washed with saturated brine (60ml), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography (petroleum ether: ethyl acetate 80:20) to give 4-amino-5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) benzonitrile (245mg, pink solid) in yield: 67.1 percent. MS M/z (ESI) 360.1[ M +1 ].
Step 6: 4-amino-5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) benzonitrile (245mg, 0.68mmol) was dissolved in 10mL acetonitrile, cooled to 0 ℃ in an ice-water bath, isoamyl nitrite (120mg, 1.02mmol) was slowly added dropwise, after addition, the reaction was continued for 30 minutes, cupric bromide (227mg, 1.02mmol) was added, the temperature was raised to room temperature, and the reaction was continued with stirring for 16 hours. The reaction solution was poured into saturated brine, extracted with ethyl acetate (2 × 20mL) and washed, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 60:40) to give 4-bromo-5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) benzonitrile (215mg, brown oil), yield: 74.4 percent. MS M/z (ESI) 423.0[ M +1 ].
And 7: dissolving 4-bromo-5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) benzonitrile (115mg, 0.27mmol) in 5mL of dichloromethane, cooling to-78 ℃ with a dry ice acetone bath, slowly adding diisobutylaluminum hydride (1M, 0.49mL, 0.49mmol) dropwise, after the addition, heating the reaction mixture to room temperature, continuing to stir for 0.5 hour, quenching with 1N dilute sulfuric acid, extracting with dichloromethane (2X 20mL), combining the organic phases, washing with saturated brine (20mL), drying the organic phases over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the residue with silica gel column chromatography (petroleum ether: ethyl acetate 60:40) to obtain 4-bromo-5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) benzaldehyde (80mg, yellow oil), yield: 69.6 percent. MS M/z (ESI) 426.0[ M +1 ].
And 8: dissolving 4-bromo-5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) benzaldehyde (100mg, 0.24mmol) in 4mL of N, N-dimethylacetamide, adding 4-phenyl-2-vinyl nicotinonitrile (48mg, 0.24mmol), palladium acetate (6mg, 0.024mmol), tris (o-methylphenyl) phosphorus (8mg, 0.024mmol) and triethylamine (71mg, 0.705mmol) in this order, displacing with nitrogen three times, heating to 160 ℃ in a microwave reactor, stirring for 45 minutes, cooling to room temperature, filtering the reaction solution through celite, concentrating the filtrate under reduced pressure, and purifying the residue with silica gel column chromatography (petroleum ether: ethyl acetate ═ 60:40) to obtain (E) -2- (4-formyl-2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridine Pyridin-3-yl) ethyl) styryl) -4-phenyl nicotinonitrile (65mg, yellow solid), yield: 50 percent. MS M/z (ESI) 552.2[ M +1 ].
And step 9: (E) -2- (4-formyl-2- (trifluoromethyl) -5- (2- (5- (trifluoromethyl) pyridin-3-yl) ethyl) styryl) -4-phenylnicotinonitrile (65mg, 0.118mmol) was dissolved in 2mL of N, N-dimethylacetamide, and (S) -piperidine-2-carboxylic acid (30mg, 0.236mmol) was added thereto, followed by stirring at room temperature for half an hour, sodium cyanoborohydride (22mg, 0.354mmol) was added thereto, the reaction was further stirred for 16 hours, the reaction mixture was filtered to remove solids, and the filtrate was purified by preparative chromatography to give (S, E) -1- (4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -5- (trifluoromethyl) -2- (2- (5- (trifluoromethyl) pyridin-2-yl) vinyl acetate -3-yl) ethyl) benzyl) piperidine-2-carboxylic acid Z-9(10mg, white solid), yield: 12.8 percent. MS M/z (ESI) 665.3[ M +1]]。1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.90(d,J＝5.0Hz,1H),8.78(d,J＝7.0Hz,2H),8.28(d,J＝15.3Hz,1H),8.08(s,1H),7.88(s,1H),7.73(s,1H),7.66(dd,J＝7.5,2.2Hz,2H),7.63–7.46(m,5H),3.94(s,1H),3.46(s,1H),3.18(d,J＝7.5Hz,2H),3.04(d,J＝7.1Hz,3H),2.71(s,1H),2.12(s,1H),1.84–1.65(m,2H),1.58–1.28(m,4H).
Example 10: (E) - (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (pyridin-3-ylmethoxy) benzyl) -L-serine (Z-10)
Figure BDA0002531043340000261
Step 1: 4-bromo-5-chloro-2-hydroxybenzaldehyde (189mg,0.81mmol) and 3- (bromomethyl) pyridine hydrobromide (204mg, 0.81mmol) were dissolved in 5mL of N, N-dimethylformamide, and potassium carbonate (334mg, 2.42mmol) was added. The reaction was carried out at 70 ℃ for 20 hours under nitrogen protection. To the reaction solution was added 20mL of water, extracted with ethyl acetate (10mL × 3), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1: 1) to give 4-bromo-5-chloro-2- (pyridin-3-ylmethoxy) benzaldehyde (200mg, yellow solid) in a yield of 76%. MS M/z (ESI) 325.9[ M +1], 327.9[ M +3 ].
Step 2: 4-phenyl-2-vinyl nicotinonitrile (76mg,0.37mmol) and 4-bromo-5-chloro-2- (pyridin-3 ylmethoxy) benzaldehyde (120mg,0.37mmol) were dissolved in 3mL of N, N-dimethylacetamide and 1mL of triethylamine, and palladium acetate (9mg,0.037mmol) and tris (o-methylphenyl) phosphine (23mg, 0.074mmol) were added and reacted with microwave at 165 ℃ for 35 minutes under nitrogen. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with a developing solvent system (ethyl acetate: petroleum ether ═ 1: 1) to give (E) -2- (2-chloro-4-formyl-5- (pyridin-3-ylmethoxy) styryl) -4-benzonitrile (60mg, yellow solid), yield: 36.1 percent. MS M/z (ESI) 452.1[ M +1 ].
And step 3: (E) -2- (2-chloro-4-formyl-5- (pyridin-3-ylmethoxy) styryl) -4-benzonitrile (60mg,0.13mmol) and L-serine (28mg,0.26mmol) were dissolved in 15mL of methanol, and sodium cyanoborohydride (17mg,0.26mmol) was added. The reaction solution was stirred at room temperature for 20 hours. Concentrated under reduced pressure and purified by preparative chromatography to give (E) - (5-chloro-4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (pyridin-3-ylmethoxy) benzyl) -L-serine Z-10(20mg, white solid) in yield: 27.8 percent. MS M/z (ESI) 541.2[ M +1]]。1H NMR(400MHz,DMSO-d6)δ8.93(d,1H),8.75(s,1H),8.55(d,1H),8.31(d,1H),8.00(d,1H),7.70-7.61(m,9H),7.45(m,1H),5.36(s,2H),3.98-3.85(m,2H),3.66-3.60(m,2H),3.20(m,1H)。
Example 11: (S, E) -1- (4- (2- (3-cyano-4-phenylpyridin-2-yl) vinyl) -2- (2- (pyridin-3-yl) ethyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Z-11)
Figure BDA0002531043340000262
The procedure is as in example 9, except that 3-bromo-5- (trifluoromethyl) pyridine from step 2 is replaced by 3-bromopyridine. MSm/z (ESI) 597.2[ M +1 ].
Test example 1PD-1/PD-L1 binding assay
Experimental materials:
DMSO from Sigma, product No.: d5879; 384 well small volume plates (white) from Greiner, product No.: 784075, respectively; anti-PD 1 blocking antibody (IC50:10nM) from Cisbio, product number: 64CUS000C-1 a; anti-PDL 1 blocking antibody (IC50:0.3nM) was from Cisbio, product number: 64CUS000C-1 b; HTRF PD1/PD-L1 binding test kit is from Cisbio, product number: 63ADK000 CPDPEB.
Reagent preparation
1. Preparing a compound to be detected with a concentration of 2X in a 1X reaction buffer solution containing 4% DMSO;
2. the Tag1-PD-L1 protein and the Tag2-PD1 protein are respectively prepared in a 1X reaction buffer solution at the concentrations of 50nM and 10nM, and the final reaction concentrations of the experiment are Tag 1-PD-L110 nM and Tag 1-PD-L12 nM;
3. anti-Tag1-Eu3+ antibody is configured in 1X concentration detection buffer solution according to the proportion of 1: 100;
4. anti-Tag2-XL665 antibody is configured in a 1X concentration detection buffer solution according to the proportion of 1: 25;
experimental procedure
1. Adding 5 μ L of 2X test compound;
2. respectively adding 2.5 mu L of Tag1-PD-L1 protein and Tag2-PD1 protein, wherein the total reaction system is 10 mu L, and reacting for 15 minutes at 25 ℃;
3. respectively adding 5 mu L of anti-Tag1-Eu3+ antibody and anti-Tag2-XL665 antibody, and reacting for 16 hours at 25 ℃;
4. reading two readings with the wavelengths of 665nm and 620nm by using a fluorescent microplate reader HTRF reading plate program, judging the activity of the compound by using the ratio of the two wavelengths, and calculating the IC50 of the compound to be detected by using XLFIT5.0 (IDBS). The test results are shown in table 1.
TABLE 1 PPI-HTRF test results
Compound (I)Numbering PPI-HTRF(IC50/nM) Compound numbering PPI-HTRF(IC50/nM)
Z-1 11 Z-2 3
Z-4 3 Z-5 5
Z-6 1 Z-7 1
Z-8 3 Z-9 37
Z-10 3 Z-11 20
As can be seen from Table 1, the exemplary compounds of the present invention have superior inhibitory activity against PPI-HTRF.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (12)

1. A compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003223720490000011
in the formula (I), the compound is shown in the specification,
Z1is CR1；Z2Is CR2；Z3Is CR3；Z4Is N;
RAis phenyl;
R1is cyano or C1-3An alkyl group;
R2、R3is hydrogen;
R5、R 6 、R7each independently is hydrogen, halogen or halogeno C1-3An alkyl group;
Rc、Rdeach independently is hydrogen;
Figure FDA0003223720490000012
selected from:
Figure FDA0003223720490000013
l is a bond or O;
n is 1,2 or 3;
Re、Rfare the same or different and are each independently hydrogen or C1-3An alkyl group;
RBis a 4 to 6 membered saturated mono-heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur; a 5 or 6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the 4-to 6-membered saturated monoheteroRing, 5 or 6 membered monocyclic heteroaryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group S: halogen, cyano, C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkyl, -CONRa3Rb3(ii) a Wherein R isa3、Rb3Each independently is hydrogen or C1-3An alkyl group.
2. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein RBIs azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, or pyridine, said azetidine, oxetane, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, tetrahydropyran, pyridine being unsubstituted or substituted with 1,2, or 3 substituents independently selected from the group consisting of: cyano, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CONH2、-CONHCH3、-CON(CH3)2。
3. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1Is cyano or methyl; r2、R3Is hydrogen.
4. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R6Is halogen or halogeno C1-3An alkyl group; r5、R7Is hydrogen.
5. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R6Is fluorine, chlorine, chloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, trichloroethyl, monobromoethyl, monofluorineMethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl; r5、R7Is hydrogen.
6. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
Figure FDA0003223720490000021
selected from:
Figure FDA0003223720490000022
7. the compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond or O; n is 1,2 or 3.
8. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Re、RfThe same or different, each independently hydrogen, methyl or ethyl.
9. The compound of claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003223720490000023
Figure FDA0003223720490000031
10. a pharmaceutical composition comprising a compound of any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
11. Use of a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the treatment of cancer or an infectious disease.
12. Use of a compound according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the treatment of a disease mediated by the PD-1 signalling pathway.
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CN107573332A (en) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application
WO2018119263A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds derivatives as pd-l1 internalization inducers
CN108368090A (en) * 2015-10-15 2018-08-03 百时美施贵宝公司 Compounds as Immunomodulators

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108368090A (en) * 2015-10-15 2018-08-03 百时美施贵宝公司 Compounds as Immunomodulators
CN107573332A (en) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application
WO2018119263A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds derivatives as pd-l1 internalization inducers

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