Benzo-fused five-membered heterocyclic derivative, preparation method therefor, use thereof, and pharmaceutical composition thereof

Abstract

Provided are a benzo-fused five-membered heterocyclic derivative represented by formula (I), a preparation method therefor, a use thereof, and a pharmaceutical composition thereof.

Description

Benzo-five-membered heterocyclic derivatives, preparation methods and applications thereof, and pharmaceutical compositions

[0001] The present invention claims the following priority:

[0002] CN202311225654.X, filing date: September 21, 2023;

[0003] CN202410003726.4, application date: January 2, 2024. Technical Field

[0004] The present application relates to the field of medical technology, and in particular to benzo-pentacyclic heterocyclic derivatives, preparation methods and applications thereof, and pharmaceutical compositions. Background Art

[0005] Diacylglycerol kinase (DGK) is a large family of enzymes consisting of 10 mammalian isoenzymes that catalyze the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Although multiple DGK isoforms are known to exist in T cells, only two (DGKα and DGKζ) are thought to play a key role in promoting DAG metabolism downstream of the TCR. Targeting DGKζ activity in T cells through germline deletion or chemical inhibitors results in enhanced and sustained signaling downstream of T cells. Therefore, DGK inhibition has the potential to enhance DAG downstream signaling, activate T cells, and thus exert anti-tumor effects.

[0006] Currently, there are a few DGK selective small molecule inhibitors in the clinical research stage, such as Astellas' ASP-1570, BMS's BMS-986408 and Bayer's BAY2965501. However, no DGK selective inhibitors have been approved so far. Therefore, there is an urgent need to develop novel, safe and effective DGK inhibitors that can treat multiple cancers, especially small molecule inhibitors that selectively target DGKζ, which may have better safety.

[0007] Summary of the Invention

[0008] The first aspect of the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] X is selected from S and O;

[0011] A is selected from C 6-10 Aryl and 5-10 membered heteroaryl;

[0012] Ring B1 is selected from a benzene ring and a 5-6 membered heteroaryl group;

[0013] Ring B2 is selected from benzene ring, 5-6 membered heteroaryl, C3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl and 3-10 membered heterocycloalkenyl;

[0014] Each R1 is independently selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl) 2, the C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 alkyl)2 is optionally substituted with 1, 2, 3 or 4 R;

[0015] Each R2 is independently selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl) 2, the C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 alkyl)2 is optionally substituted with 1, 2, 3 or 4 R;

[0016] R is selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl)2;

[0017] n is selected from 0, 1, 2, 3 and 4;

[0018] m is selected from 0, 1, 2, 3 and 4.

[0019] In some embodiments of the present application, wherein X is selected from S, and the other variables are as defined herein;

[0020] In some embodiments of the present application, wherein X is selected from O, and the other variables are as defined herein;

[0021] In some embodiments of the present application, wherein Ring A is selected from C 6-10 Aryl, other variables are as defined herein;

[0022] In some embodiments of the present application, wherein Ring A is selected from a benzene ring, and other variables are as defined herein;

[0023] In some embodiments of the present application, wherein Ring A is selected from naphthyl, the other variables are as defined herein

[0024] In some embodiments of the present application, wherein Ring A is selected from a 5-membered heteroaryl group, and the other variables are as defined herein;

[0025] In some embodiments of the present application, the above 5-membered heteroaryl group is selected from Other variables are as defined in this application;

[0026] In some embodiments of the present application, wherein Ring A is selected from 6-membered heteroaryl, and the other variables are as defined herein;

[0027] In some embodiments of the present application, the above 6-membered heteroaryl group is selected from Other variables are as defined in this application;

[0028] In some embodiments of the present application, wherein ring B1 is selected from a benzene ring, and other variables are as defined herein;

[0029] In some embodiments of the present application, wherein Ring B1 is selected from 5-membered heteroaryl, and the other variables are as defined herein;

[0030] In some embodiments of the present application, the above 5-membered heteroaryl group is selected from Other variables are as defined in this application;

[0031] In some embodiments of the present application, wherein Ring B1 is selected from 6-membered heteroaryl, and the other variables are as defined herein;

[0032] In some embodiments of the present application, the above 6-membered heteroaryl group is selected from Other variables are as defined in this application;

[0033] In some embodiments of the present application, wherein ring B2 is selected from a benzene ring, and other variables are as defined herein;

[0034] In some embodiments of the present application, wherein Ring B2 is selected from 5-membered heteroaryl, and the other variables are as defined herein;

[0035] In some embodiments of the present application, the above 5-membered heteroaryl group is selected from Other variables are as defined in this application;

[0036] In some embodiments of the present application, wherein Ring B2 is selected from 6-membered heteroaryl, and the other variables are as defined herein;

[0037] In some embodiments of the present application, the above 6-membered heteroaryl group is selected from Other variables are as defined in this application;

[0038] In some embodiments of the present application, wherein ring B2 is selected from C 5-10 Cycloalkyl, other variables are as defined herein;

[0039] In some embodiments of the present application, wherein ring B2 is selected from C 3-10 Cycloalkyl, other variables are as defined herein;

[0040] In some embodiments of the present application, the above-mentioned C 3-10 Cycloalkyl is selected from Other variables are as defined in this application;

[0041] In some embodiments of the present application, wherein ring B2 is selected from C 3-10 cycloalkenyl, and other variables are as defined herein;

[0042] In some embodiments of the present application, the above-mentioned C 3-10 Cycloalkenyl is selected from Other variables are as defined in this application;

[0043] In some embodiments of the present application, wherein Ring B2 is selected from 3-10 membered heterocycloalkyl, and other variables are as defined herein;

[0044] In some embodiments of the present application, the above 3-10 membered heterocycloalkyl group is selected from Other variables are as defined in this application;

[0045] In some embodiments of the present application, wherein ring B2 is selected from C 3-10 Cycloalkenyl, other variables are as defined in this application;

[0046] In some embodiments of the present application, the above C 3-10 Cycloalkenyl is selected from Other variables are as defined in this application;

[0047] In some embodiments of the present application, wherein the structural unit ring Selected from Other variables are as defined in this application;

[0048] In some embodiments of the present application, the structural unit Selected from Other variables are as defined in this application;

[0049] In some embodiments of the present application, wherein R is selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, NHCH3, NHCH2CH3 and NHCH2CH2CH3, and other variables are as defined herein;

[0050] In some embodiments of the present application, each R1 is independently selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, NHCH3, NHCH2CH3 and NHCH2CH2CH3, and the CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, NHCH3, NHCH2CH3 and NHCH2CH2CH3 are optionally substituted with 1, 2, 3 or 4 R, and other variables are as defined in the invention.

[0051] In some embodiments of the present application, each R2 is independently selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, NHCH3, NHCH2CH3 and NHCH2CH2CH3, and the CH3, CH2CH3, CH2CH2CH3, OCH3, OCH2CH3, OCH2CH2CH3, NHCH3, NHCH2CH3 and NHCH2CH2CH3 are optionally substituted with 1, 2, 3 or 4 R, and other variables are as defined in the invention.

[0052] In some embodiments of the present application, the compound is selected from the group consisting of

[0053] Other variables are as defined in the invention.

[0054] In some embodiments of the present application, the compound is selected from

[0055] Other variables are as defined in the invention.

[0056] Some technical solutions of this application are derived from the free combination of the above variables.

[0057] The present application provides the following compounds,

[0058] The second aspect of the present application provides the use of the compound defined in the above technical solution in the preparation of drugs for treating diseases related to DGKζ.

[0059] In some embodiments of the present application, the disease associated with DGKζ is selected from cancer.

[0060] The third aspect of the present application provides a pharmaceutical composition comprising the compound described in the first aspect of the present application or a pharmaceutically acceptable salt thereof,

[0061] and a pharmaceutically acceptable carrier.

[0062] Definition and Explanation

[0063] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0064] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0065] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared by reacting a compound with a specific substituent discovered in the present invention with a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, as well as salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either a base or acid addition salt.

[0066] The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, the compounds in the form of free acid or base are reacted with a stoichiometric amount of a suitable base or acid to prepare.

[0067] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are within the scope of the present invention.

[0068] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0069] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0070] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0071] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0072] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed key

[0073] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0074] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0075] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0076] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereoisomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0077] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and extended drug biological half-life. All isotopic variations of the compounds of this application, whether radioactive or not, are included within the scope of this application.

[0078] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0079] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The type and number of substituents can be any chemically feasible basis. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0080] When any variable (e.g., R1) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 instances of R1, the group may optionally be substituted with up to two instances of R1, with each instance of R1 being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0081] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0082] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0083] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the substituent is listed without specifying which atom it is connected to the substituted group, the substituent can be bonded through any atom of the substituent. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0084] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0085] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0086] When a non-positioning substituent is attached to a polycyclic ring system, In the structure shown above, the substituent is only connected to one ring, which means that the substituent is only connected to the ring. For example, in the structure shown above, the substituent is only connected to the ring. It is only connected to ring B1 but not to ring B2; when the connecting bond penetrates all rings in the ring system, it means that the substituent can be substituted to all rings on the ring system. For example, in the above structure, R2 can be substituted to both ring B1 and ring B2.

[0087] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "3-7 membered ring" refers to a "ring" having 3-7 atoms arranged around it.

[0088] Alicyclic refers to a saturated or partially unsaturated all-carbon ring system. Wherein "partially unsaturated" refers to a ring portion that includes at least one double bond or triple bond. "Partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein. Non-limiting examples include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl rings, cycloheptatrienyl rings, cyclopentanone rings, cyclopentane-1,3-dione rings, and the like.

[0089] Alicyclic groups are saturated or partially unsaturated alicyclic groups in which one, two or three ring carbon atoms are selected from nitrogen, oxygen or S(O) t (wherein t is an integer from 0 to 2) is substituted by a heteroatom, excluding -OO-, -OS- or -SS- ring moieties, and the remaining ring atoms are carbon. Non-limiting examples include an oxetane ring, an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidine-2-one ring, an oxetane-2-one ring, a pyrrolidine-2-one ring, a pyrrolidine-2,5-dione ring, a piperidin-2-one ring, a dihydrofuran-2(3H)-one ring, a dihydrofuran-2,5-dione ring, a tetrahydro-2H-pyran-2-one ring, a piperazin-2-one ring, and a morpholine-3-one ring. Non-limiting examples of partially unsaturated monocyclic heterocycles include 1,2-dihydroazetidine ring, 1,2-dihydrooxetadiene ring, 2,5-dihydro-1H-pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2,3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring. Cyclic, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine Ring, etc.

[0090] "Aryl" and "aromatic ring" are used interchangeably to refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, which may be fused to a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a heteroaryl ring. 6-10 The term "aryl" refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms. Non-limiting examples of aryl include phenyl, naphthyl, and the like.

[0091] "Heteroaryl" and "heteroaryl ring" are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the present application, heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. The heteroaryl ring may be optionally substituted. "5 to 10 membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms. "5- to 6-membered heteroaryl" refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. "8- to 10-membered heteroaryl" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, The term "heteroatom" refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.

[0092] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms, which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).

[0093]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0094] Unless otherwise specified, the term “C 6-10 Aryl" and "C 6-10 Aromatic ring" can be used interchangeably, the term "C 6-10 Aromatic ring" or "C 6-10 "Aryl" refers to a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. It can be monovalent, divalent or polyvalent, and C6-10 aryl includes C6-9, C9, C10 and C6 aryl. Examples of C6-10 aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl).

[0095] Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" are used interchangeably. The term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-10 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-10 membered heteroaryl includes 10-membered, 9-membered, 9-10-membered, 5-8-membered, 5-7-membered, 5-6-membered, 5-membered and 6-membered heteroaryl groups, etc. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0096] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably, and the term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl), and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0097] Unless otherwise specified, the term “C 3-10 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-7 Cycloalkyl groups include C 3-6 、C 4-6 、C 4-5 、C 5-7 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0098] Unless otherwise specified, the term “C 3-10 "Monocycloalkyl" means a saturated monocyclic hydrocarbon group consisting of 3 to 10 carbon atoms, wherein the C 3-10 Monocyclic alkyl groups include C 3-6 、C 4-6 、C 4-5 、C 5-7 or C 5-6 Monocyclic alkyl, etc.; it may be monovalent, divalent or polyvalent.3-10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0099] Unless otherwise specified, the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-10 membered heterocycloalkyl includes 3-4 membered, 4-5 membered, 5-7 membered, 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8-9 membered, 8-10 membered heterocycloalkyl, etc. Examples of 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, etc.

[0100] Unless otherwise specified, the term "3-10 membered monoheterocycloalkyl" by itself or in combination with other terms means a single saturated cyclic group consisting of 3 to 10 ring atoms, which is a monocyclic ring system, and the other definitions are the same as 3-10 membered heterocycloalkyl.

[0101] Unless otherwise specified, the term “C 3-10 "Cycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic hydrocarbon group consisting of 3 to 10 ring atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic ring systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. The C 3-10 Cycloalkenyl groups include C 3-6 、C 4-6 、C 4-5 、C 5-7 or C 5-6 Cycloalkenyl, etc.; which may be monovalent, divalent or polyvalent. 3-10 Examples of cycloalkyl groups include, but are not limited to

[0102] Unless otherwise specified, the term "3-10 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 3 to 10 ring atoms containing at least one carbon-carbon double bond, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "3-10 membered heterocycloalkenyl", heteroatoms can occupy the connection position of the heterocycloalkenyl group to the rest of the molecule. The 3-10 membered heterocycloalkenyl group includes 3-membered, 4-membered, 5-membered and 6-membered heterocycloalkenyl groups, etc. Examples of 3-10 membered heterocycloalkenyl groups include, but are not limited to

[0103] Unless otherwise specified, the terms "5-membered heteroaryl ring" and "5-membered heteroaryl" are used interchangeably herein. The term "5-membered heteroaryl" refers to a monocyclic group consisting of 5 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or carbon atom. Examples of the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2 (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.).

[0104] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0105] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

[0106] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0107] Unless otherwise defined, the "substituents independently selected from..." mentioned herein means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be of the same or different types, and the substituents selected are of independent types.

[0108] Generally, the compounds of the present application or their pharmaceutically acceptable salts, or their stereoisomers can be administered in a suitable dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, oral, and other parenteral administrations (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present application contained in these preparations can be solid powders or particles; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc. The above dosage forms can be prepared from the active compound and one or more carriers or excipients via common pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, and polyethylene glycol, etc. The active compound can form a solution or suspension with the above carriers.

[0109] The compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.

[0110] "Therapeutically effective amount" refers to the amount of the compound of the present invention that will induce a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0111] The therapeutically effective amount of the compound of the present application or its pharmaceutically acceptable salt, or its stereoisomer contained in the pharmaceutical composition or the pharmaceutical composition of the present application is preferably 0.1 mg-5 g / kg (body weight).

[0112] "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.

[0113] "Treatment" refers to alleviating, slowing the progression of, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.

[0114] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0115] The structures of the compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0116] The solvents used in this application are commercially available. This application uses the following abbreviations: FA stands for formic acid; NH2CN stands for cyanamide; K2CO3 stands for potassium carbonate; DMF stands for N,N-dimethylformamide; prep-HPLC stands for preparative high performance liquid chromatography; HCl stands for hydrochloric acid; PE stands for petroleum ether; EA stands for ethyl acetate; Lawessons reagent stands for Lawesson's reagent; DPPP stands for bis(diphenylphosphino)propane; DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene; CO2 stands for carbon dioxide; iPrOH stands for isopropyl alcohol; EtOH stands for ethanol; MeOH stands for methanol; psi is a unit of pressure, representing pounds-force per square inch.

[0117] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. Beneficial effects

[0118] The compounds of the present application have DGKζ inhibitory activity, specifically 0.1-500 nM DGKζ inhibitory activity, preferably 0.1-200 nM, more preferably 0.1-100 nM, further preferably 0.1-50 nM, and even more preferably 0.1-10 nM. The compounds of the present application can effectively activate T cells, thereby achieving the effect of inhibiting tumors. DETAILED DESCRIPTION

[0119] The present invention is described in detail below through examples, but is not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0120] Example 1: Compounds 1_P1 and 1_P2

[0121] Step 1:

[0122] At room temperature, compound 1-a (2.00 g, 11.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.63 g, 13.7 mmol), and triethylamine (1.39 g, 13.7 mmol, 1.91 mL) were dissolved in dichloromethane (15.0 mL). A solution of compound 1-b (1.34 g, 13.7 mmol) in DMF (5.00 mL) was then added. The mixture was allowed to react at 25°C for 12 hours. The reaction solution was poured into water (100 mL) and extracted three times with dichloromethane (80.0 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. Purification by silica gel column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 5:1) afforded compound 1-c.

[0123] LCMS: m / z=219.1 (M+H) + ;

[0124] 1 HNMR: (400MHz, CDCl3) δ7.98(s,1H),7.54(dd,J=8.4,1.6Hz,1H),7.25(dd,J=8.4,0.8Hz,1H),7.03(d ,J=3.2Hz,1H),6.42-6.53(m,1H),3.75(d,J=0.8Hz,3H),3.51(d,J=0.8Hz,3H),3.32(d,J=0.8Hz,3H).

[0125] Step 2:

[0126] At room temperature, compound 1-c (1.50 g, 6.87 mmol) was dissolved in tetrahydrofuran (15.0 mL). The nitrogen atmosphere was replaced three times, and the temperature was lowered to 0°C. Methylmagnesium chloride (3 M, 4.58 mL) was then slowly added dropwise to the reaction mixture. After the addition was complete, the temperature was raised to 25°C and the reaction was allowed to react for 1 hour. The reaction mixture was poured into water (200 mL) and extracted three times with ethyl acetate (80.0 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (100.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1-e.

[0127] 1HNMR: (400MHz, CDCl3) δ8.31(d,J=1.2Hz,1H),7.92(dd,J=8.8,1.6Hz,1H),7.35(d,J=8.4Hz,1H), 7.13(d,J=3.2Hz,1H),6.62(dd,J=3.2,0.8Hz,1H),3.84(s,3H),2.61-2.73(m,3H).

[0128] Step 3:

[0129] Compound 1-e (1.00 g, 5.77 mmol) was dissolved in tetrahydrofuran (10.0 mL) at room temperature, followed by the addition of pyridine tribromide (1.95 g, 6.10 mmol). The reaction was allowed to proceed at 25°C for 1 hour. The reaction solution was concentrated, diluted with a 3 / 1 PE / EA mixture (20.0 mL), and filtered. The filter cake was repeatedly rinsed with a 3 / 1 PE / EA mixture, and the filtrate was concentrated to obtain the crude product, which was then isolated and purified using a reverse-phase column (formic acid conditions: column: 330 g Flash Column Agela C8, 20-35 μm, 100 Å; mobile phase: MeCN / H2O; gradient: 10%-40% B, 90 min) to obtain compound 1-2.

[0130] LCMS: m / z=331.8 (M+H) + ;

[0131] 1 HNMR: (400MHz, CDCl3) δ8.23 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 8.8, 1.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 4.58 (s, 2H), 3.84 (s, 3H).

[0132] Step 4:

[0133] Compound 1-1 (129 mg, 845 μmol) was dissolved in acetonitrile (2.00 mL) at room temperature, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (193 mg, 1.27 mmol, 191 μL) and aminonitrile (35.5 mg, 845 μmol). After stirring at 25°C for 2 hours, compound 1-2 (280 mg, 845 μmol) was added to the reaction mixture. The mixture was reacted at 25°C for 1 hour. The reaction mixture was diluted with water (5.00 mL) and filtered. The filter cake was rinsed with ethyl acetate and dried under reduced pressure to yield compound 1-3.

[0134] LCMS: m / z=446.9 (M+H) + ;

[0135] 1 HNMR: (400MHz DMSO-d6) δ7.75(s,1H),7.62(s,1H),7.55-7.60(m,1H),7.47-7.53(m,1H),7.26-7.39(m,2H),7.01-7.08(m,2H),3.81(s,3H).

[0136] Step 5:

[0137] Compound 1-3 (350 mg, 785 μmol) was dissolved in tetrahydrofuran (5.00 mL) at room temperature, and wet palladium on carbon (300 mg, 281 μmol, 10%) was added to the reaction mixture. The hydrogen atmosphere was replaced three times, and the reaction was continued at 25°C under 15 psi for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound 1-4.

[0138] LCMS: m / z=367.0 (M+H) + .

[0139] Step 6:

[0140] Compound 1-4 (285 mg, 777 μmol), compound 1-5 (177 mg, 1.17 mmol), and K2CO3 (537 mg, 3.89 mmol) were dissolved in DMF (1.00 mL) at room temperature and stirred at 90°C for 1 hour. Water (200 mL) was added to the mixture, and the mixture was extracted three times with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product, which was then purified by reverse phase chromatography (formic acid conditions: column: 330 g Flash Column Welch Ultimate XB_C18 20-40 μm; 120A; mobile phase: MeCN / H2O; gradient: 10%-80% B over 60 min) to afford compound 1-6.

[0141] LCMS: m / z=438.0[M+H] + .

[0142] Step 7:

[0143] Compounds 1-6 were separated by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -i -PrOH (0.1% NH 3 ·H 2 O)]; B%: 50%, isocratic elution) to give compounds 1_P1 and 1_P2.

[0144] Compound 1_P1: SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A: CO 2 , phase B: IPA (0.05% DEA); elution gradient: 40% B in A; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar), RT = 1.31 min, 99.4% purity (220 nm);

[0145] LCMS: m / z = 438.0 [M+H] + .

[0146] Compound 1_P2: SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm; mobile phase: phase A: CO 2 , phase B: IPA (0.05% DEA); elution gradient: 40% B in A; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar), RT=2.138 min, 99.0% purity (220 nm);

[0147] LCMS: m / z = 438.1 [M+H] + .

[0148] Example 2: Compounds 2_P1 and 2_P2

[0149] Step 1:

[0150] At room temperature, compound 1_P1 (48.2 mg, 110 μmol) was dissolved in dichloromethane (1.00 mL), followed by the addition of Lawessons reagent (44.5 mg, 110 μmol) and stirring at 25°C for 1 hour. Water (200 mL) was added, and the mixture was extracted three times with ethyl acetate (50.0 mL x 3). The organic phases were combined, washed three times with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (formic acid conditions) to yield compound 2_P1 (14.59 mg, 31.2 μmol).

[0151] LCMS: m / z=454.1[M+H] + .

[0152] 1H NMR: (400MHz, DMSO-d6) δ11.25(br s,1H),9.12(br d,J=2.4Hz,1H),7.55-7.62(m,3H),7.45(s,1H),7.24-7.35(m,5H),7.09(br d,J=8.4Hz,1H),6.38(d,J=2.8Hz,1H),4.80-5.35(m,1H),3.75(s,3H),1.15(d,J=7.2Hz,3H).

[0153] Step 2:

[0154] At room temperature, compound 1_P2 (48.2 mg, 110.24 μmol) was dissolved in dichloromethane (1.00 mL), followed by the addition of Lawessons reagent (44.5 mg, 110 μmol) and stirring at 25°C for 1 hour. Water (200 mL) was added, and the mixture was extracted three times with ethyl acetate (50.0 mL x 3). The organic phases were combined, washed three times with saturated sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by prep-HPLC (formic acid conditions) to yield compound 2_P2.

[0155] LCMS: m / z=454.0[M+H] + .

[0156] 1 HNMR: (400MHz, DMSO-d6) δ11.25(br d,J=1.6Hz,1H),9.12(br d,J=3.2Hz,1H),7.55-7.62(m,3H),7.45(s,1H),7.22-7.33(m,5H),7.09(br d,J=8.0Hz,1H),6.38(d,J=3.2Hz,1H),4.88-5.24(m,1H),3.75(s,3H),1.15(d,J=7.2Hz,3H).

[0157] Example 3: Compounds 3_P1 and 3_P2

[0158] Step 1:

[0159] Compound 3-a (5.00 g, 23.6 mmol), ethyl vinyl ether (5.12 g, 71.0 mmol, 6.80 mL), palladium acetate (212 mg, 947 μmol), DPPP (781 mg, 1.90 mmol), and triethylamine (5.99 g, 59.2 mmol, 8.24 mL) were dissolved in dimethyl sulfoxide (40 mL). The atmosphere was replaced with nitrogen three times, and the reaction mixture was reacted at 115°C for 12 hours. 4N HCl (30 mL) was added to the reaction system, and the mixture was stirred at 25°C for 0.5 hours. Water (300 mL) was then added and the mixture was extracted with dichloromethane (80 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 4 / 1) to obtain compound 3-b.

[0160] LCMS: MS (ESI) m / z = 175.1 [M+H] + ;

[0161] 1 HNMR: (400MHz, CDCl3) δ 8.40 (d, J = 0.4Hz, 1H), 8.11 (s, 1H), 8.08-8.04 (m, 1H), 7.42 (d, J = 8.8Hz, 1H), 4.11 (s, 3H), 2.68 (s, 3H).

[0162] Step 2:

[0163] Compound 3-b (2.06 g, 11.8 mmol) was dissolved in tetrahydrofuran (25 mL). Pyridinium tribromide (3.78 g, 11.8 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 2 hours. Saturated sodium bicarbonate (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase separation (FA system) to obtain compound 3-1.

[0164] LCMS: MS (ESI) m / z=253.0 and 255.0[M+H] + .

[0165] 1 HNMR: (400MHz, CDCl3) δ 8.48-8.44 (m, 1H), 8.14 (d, J = 0.8Hz, 1H), 8.09-8.03 (m, 1H), 7.46 (d, J = 8.8Hz, 1H), 4.52 (s, 2H), 4.12 (s, 3H).

[0166] Step 3:

[0167] Compound 1-2 (400 mg, 2.61 mmol) was dissolved in acetonitrile (10 mL), and NH2CN (120 mg, 2.87 mmol) and DBU (397 mg, 2.61 mmol, 393 uL) were added. After reacting at 25°C for 1 hour, compound 2-1 (660 mg, 2.61 mmol) and DBU (198 mg, 1.31 mmol, 196 uL) were added. The reaction mixture was reacted at 25°C for 3 hours. Water (25 mL) was added to the reaction system, and a solid precipitated. The solid was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 3-2.

[0168] LCMS: MS (ESI) m / z = 368.1 [M+H] + ;

[0169] 1 HNMR: (400MHz, DMSO-d6) δ 8.14 (d, J = 18.0 Hz, 4H), 7.76-7.64 (m, 2H), 7.58 (s, 2H), 7.18 (t, J = 8.8 Hz, 2H), 4.07 (s, 3H).

[0170] Step 4:

[0171] Compound 3-2 (1.10 g, 2.99 mmol) was dissolved in DMF (15 mL). Compound 1-5 (682 mg, 4.49 mmol) and K2CO3 (2.07 g, 14.9 mmol) were added to the above reaction solution. The reaction mixture was stirred at 90°C for 0.5 hours. The reaction solution was poured into water (60 mL). Solids precipitated and were filtered. The filter cake was washed with water (10 mL) and concentrated under reduced pressure to obtain a crude product. The crude product was added to ethyl acetate (20 mL) and slurried for purification (stirring at 25°C for 0.5 hours) to obtain compound 3-3.

[0172] LCMS: MS (ESI) m / z = 439.1 [M+H] + ;

[0173] 1 HNMR: (400MHz, DMSO-d6)δ8.10(s,3H),7.91(s,1H),7.66-7.60(m,3H),7.58-7.52(m,2H),7 .30(t,J=8.8Hz,2H),7.23(s,1H),5.06(d,J=7.2Hz,1H),4.02(s,3H),1.16(d,J=7.2Hz,3H).

[0174] Step 5:

[0175] Compound 3-3 (700 mg, 1.60 mmol) was dissolved in dichloromethane (20 mL). Lawessons reagent (322 mg, 798 μmol) was added to the above reaction solution, and the reaction mixture was stirred at 25°C for 0.5 hours. Water (40 mL) was added to the system, and the mixture was extracted with dichloromethane (20 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (FA conditions) to obtain compound 3-4.

[0176] LCMS: m / z=455.1[M+H] + ;

[0177] 1 HNMR: (400MHz, DMSO-d6) δ11.22(br s,1H),9.25(br d,J=3.2Hz,1H),8.01(s,1H),7.62-7.56(m,4H),7.52(br d,J=8.8Hz,1H),7.34-7.24(m,4H),5.35-4.97(m,1H),4.00(s,3H),1.15(d,J=7.2Hz,3H).

[0178] Step 6:

[0179] Compound 3-4 was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -EtOH / ACN]; B%: 50%, isocratic elution) to obtain compounds 3_P1 and 3_P2.

[0180] Compound 3_P1: Product: RT = 0.923 mins, SFC (column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm, mobile phase: phase A CO2, phase B EtOH (0.05% DEA); elution gradient: 50% EtOH (0.05% DEA), flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar);

[0181] LCMS: m / z = 455.1 [M+H] + ;

[0182] 1HNMR: (400MHz, DMSO-d6) δ11.22(br s,1H),9.25(br d,J=3.2Hz,1H),8.01(s,1H),7.64-7.56(m,4H),7.52(br d,J=8.8Hz,1H),7.36-7.24(m,4H),5.33-4.95(m,1H),4.00(s,3H),1.15(d,J=7.2Hz,3H).

[0183] Compound 3_P2: Product: RT = 1.405 mins, SFC (column: Chiralpak IG-3 50×4.6 mm ID, 3 μm, mobile phase: phase A CO 2 , phase B EtOH (0.05% DEA); elution gradient: 50% EtOH (0.05% DEA), flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar);

[0184] LCMS: m / z = 455.1 [M+H] + ;

[0185] 1 HNMR: (400MHz, DMSO-d6) δ11.22(br s,1H),9.25(br d,J=3.2Hz,1H),8.01(s,1H),7.63-7.57(m,4H),7.52(br d,J=8.8Hz,1H),7.35-7.24(m,4H),5.36-4.99(m,1H),4.00(s,3H),1.16(d,J=7.2Hz,3H).

[0186] Example 4: Compounds 4_P1 and 4_P2

[0187] Step 1:

[0188] Compound 4-1 (180 mg, 1.06 mmol) was dissolved in acetonitrile (5 mL). To this solution were added aminonitrile (49.0 mg, 1.17 mmol) and DBU (161 mg, 1.06 mmol). After reacting at 25°C for 1 hour, compound 3-1 (268 mg, 1.06 mmol) and DBU (80.7 mg, 530 μmol) were added. The reaction mixture was reacted at 25°C for 2 hours. Water (10 mL) was added to the reaction system, and a solid precipitated. The solid was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 4-2.

[0189] LCMS: MS (ESI) m / z = 384.1 [M+H] + .

[0190] 1 H NMR: (400MHz, DMSO-d6) δ8.13-7.97(m,2H),7.71-7.56(m,2H),7.19(br s,4H),4.04(s,3H).

[0191] Step 2:

[0192] Compound 4-2 (470 mg, 1.22 mmol) was dissolved in DMF (8 mL), and compound 1-5 (279 mg, 1.84 mmol) and K2CO3 (846 mg, 6.12 mmol) were added. The reaction mixture was stirred at 90°C for 0.5 h. Water (80 mL) was added to the system, and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was then added to ethyl acetate (8 mL) and slurried for purification (stirring at 25°C for 0.5 h) to obtain compound 4-3.

[0193] LCMS: MS (ESI) m / z = 455.1 [M+H] + .

[0194] 1 H NMR: (400MHz, DMSO-d6) δ8.11(d,J=0.8Hz,1H),7.92(s,1H),7.66-7.52(m,7H),7.25(s,1H),5.10-5.02(m,1H),4.03(s,3H),1.18-1.15(m,3H).

[0195] Step 3:

[0196] Compound 4-3 (265 mg, 582 μmol) was dissolved in dichloromethane (6 mL), and Lawesson's reagent (117 mg, 291 μmol) was added. The reaction mixture was stirred at 25°C for 0.5 hours. Water (30 mL) was added to the system, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water(FA)-ACN]; gradient: 35%-65% B over 15 min) to obtain compound 4-4.

[0197] LCMS: m / z=471.1[M+H] + .

[0198] 1 H NMR: (400MHz, DMSO-d6) δ11.22(s,1H),9.27(d,J=2.8Hz,1H),8.02(s,1H),7.62(s,2H),7. 58-7.49(m,5H),7.36-7.28(m,2H),5.26-4.96(m,1H),4.01(s,3H),1.16(d,J=7.2Hz,3H).

[0199] Step 4:

[0200] Compound 4-4 (145 mg) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO2-i-PrOH / ACN]; B%: 45%, isocratic elution) to give compounds 4_P1 and 4_P2.

[0201] Compound 4_P1: Product: RT = 0.624 mins, SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, mobile phase: phase A CO2, phase B IPA + ACN (0.05% DEA); elution gradient: 50% IPA + ACN (0.05% DEA), flow rate: 3 ml / min; detector: PDA; column temperature: 35 degrees Celsius; back pressure: 100 Bar).

[0202] LCMS: m / z=471.1[M+H] + .

[0203] 1 H NMR: (400MHz, DMSO-d6) δ11.22(s,1H),9.27(d,J=1.2Hz,1H),8.02(s,1H),7.61(d,J=4.0Hz,2H),7.58-7 .54(m,2H),7.54-7.49(m,3H),7.36-7.29(m,2H),5.28-5.00(m,1H),4.01(s,3H),1.16(d,J=7.2Hz,3H).

[0204] Compound 4_P2: Product: RT = 0.844 mins, SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, mobile phase: phase A CO2, phase B IPA + ACN (0.05% DEA); elution gradient: 50% IPA + ACN (0.05% DEA), flow rate: 3 ml / min; detector: PDA; column temperature: 35 degrees Celsius; back pressure: 100 Bar).

[0205] LCMS: m / z=471.1[M+H] + .

[0206] 1 H NMR: (400MHz, DMSO-d6) δ11.21(s,1H),9.26(d,J=3.2Hz,1H),8.02(s,1H),7.61(d,J=4.0Hz,2H),7.58-7 .54(m,2H),7.54-7.49(m,3H),7.35-7.28(m,2H),5.23-5.02(m,1H),4.01(s,3H),1.16(d,J=7.2Hz,3H).

[0207] Example 5: Compounds 5_P1 and 5_P2

[0208] Step 1:

[0209] Compound 5-1 (500 mg, 2.66 mmol) was dissolved in acetonitrile (10 mL) at room temperature, and NH2CN (123 mg, 2.93 mmol, 123 μL) and DBU (405 mg, 2.66 mmol) were added. After reacting at 25°C for 1 hour, compound 3-1 (674 mg, 2.66 mmol) and DBU (202 mg, 1.33 mmol) were added and reacted at 25°C for 12 hours. A yellow solid precipitated in the reaction system. The reaction solution was filtered, and the filter cake was washed three times with acetonitrile (2 mL*3) and dried at 45°C to obtain compound 5-2.

[0210] LCMS: MS (ESI) m / z = 402.0 [M+H] + .

[0211] Step 2:

[0212] Compound 5-2 (400 mg, 995 μmol) and compound 1-5 (226 mg, 1.49 mmol) were dissolved in DMF (10 mL) at room temperature, followed by the addition of K2CO3 (687 mg, 4.98 mmol) and stirring at 90°C for 1 hour. Water (80 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (20 mL*3). The combined organic phases were washed three times with water (10 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was slurried in ethyl acetate / petroleum ether (v / v = 1 / 1, 10 mL) at room temperature for half an hour, then filtered. The filter cake was washed three times with ethyl acetate / petroleum ether (v / v = 1 / 1, 1 mL*3) and dried at 45°C to obtain compound 5-3.

[0213] LCMS: MS (ESI) m / z = 473.1 [M+H]+ .

[0214] 1 H NMR: (400MHz, DMSO-d6) δ8.17(s,1H),7.99(s,1H),7.80-7.76(m,2H),7.70(s,2H),7.63-7.60(m,1H),7 .55(dd,J=1.6,8.8Hz,1H),7.37-7.32(m,1H),5.07(q,J=7.2Hz,1H),4.08(s,3H),1.24(d,J=7.2Hz,3H).

[0215] Step 3:

[0216] Compound 5-3 (300 mg, 634 μmol) was dissolved in dichloromethane (5 mL) at room temperature, followed by the addition of Lawesson's reagent (128 mg, 317 μmol) and stirring at room temperature for 0.5 hours. Water (60 mL) was added to the reaction system, and the mixture was extracted five times with dichloromethane (20 mL x 5). The combined organic phases were washed three times with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified using prep-HPLC (preparative column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (FA)-ACN]; gradient: 38% - 68% B over 15 mins) to yield compound 5-4.

[0217] LCMS: MS (ESI) m / z = 489.1 [M+H] + .

[0218] Step 4:

[0219] Compound 5-4 (176 mg) was separated by SFC (preparative column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO 2 -EtOH]; B%: 40%, isocratic elution) to obtain compounds 5_P1 and 5_P2.

[0220] Compound 5_P1: Product: RT = 2.372 mins. SFC (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm, mobile phase: CO2 in phase A, EtOH (0.05% DEA) in phase B; elution gradient: 5% to 40% EtOH (0.05% DEA), flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0221] LCMS: m / z = 489.0 [M+H] + ;

[0222] 1 H NMR: (400MHz, DMSO-d6) δ11.37-11.07(m,1H),9.32(br d,J=3.2Hz,1H),8.04(s,1H),7.74-7.69(m,2H),7.65(br s,2H),7.55(d,J=8.8Hz,1H),7.48(dd,J=1.2,8.8Hz,1H),7.40-7.32(m,2H),5.29-4.88(m,1H),4.02(s,3H),1.19(d,J=7.6Hz,3H).

[0223] Compound 5_P2: Product: RT = 2.619 mins. SFC (column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm, mobile phase: CO2 in phase A, EtOH (0.05% DEA) in phase B; elution gradient: 5% to 40% EtOH (0.05% DEA), flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar).

[0224] LCMS: m / z = 489.1 [M+H] + ;

[0225] 1 H NMR: (400MHz, DMSO-d6) δ11.22(br s,1H),9.32(br s,1H),8.04(s,1H),7.74-7.69(m,2H),7.65(br s,2H),7.55(d,J=8.8Hz,1H),7.48(br d,J=8.4Hz,1H),7.40-7.32(m,2H),5.23-4.87(m,1H),4.02(s,3H),1.19(br d,J=7.6Hz,3H).

[0226] Example 6: Compounds 6_P1 and 6_P2

[0227] Step 1:

[0228] Compound 6-1 (200 mg, 1.17 mmol) was dissolved in acetonitrile (6 mL), and aminonitrile (54.0 mg, 1.29 mmol) and DBU (177 mg, 1.17 mmol) were added. After reacting at 25°C for 1 hour, compound 3-1 (295 mg, 1.17 mmol) and DBU (88.9 mg, 584 μmol) were added. The reaction mixture was reacted at 25°C for 1 hour. Water (10 mL) was added to the reaction system, and a solid precipitated. The solid was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 6-2.

[0229] LCMS: MS (ESI) m / z = 386.1 [M+H] + .

[0230] 1 H NMR: (400MHz, DMSO-d6) δ8.10(s,1H),8.01(s,1H),7.69(d,J=8.8Hz,1H),7.59( d,J=8.8Hz,1H),7.51-7.33(m,1H),7.21-7.09(m,1H),6.91(s,1H),4.04(s,3H).

[0231] Step 2:

[0232] Compound 6-2 (543 mg, 1.41 mmol) was dissolved in DMF (10 mL). Compound 1-5 (321 mg, 2.11 mmol) and potassium carbonate (973 mg, 7.04 mmol) were added to the above reaction solution, and the reaction mixture was stirred at 90°C for 0.5 hours. Water (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (30 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was added to ethyl acetate (8 mL) and slurried for purification (stirring at 25°C for 0.5 hours) to obtain compound 6-3.

[0233] LCMS: MS (ESI) m / z = 457.1 [M+H] + .

[0234] 1 H NMR: (400MHz, DMSO-d6) δ8.12 (d, J = 0.8Hz, 1H), 7.93 (s, 1H), 7.81-7.73 (m, 1H), 7.67-7.53 (m,4H),7.52-7.46(m,1H),7.27(s,1H),5.09-4.99(m,1H),4.03(s,3H),1.21-1.17(m,3H).

[0235] Step 3:

[0236] Compound 6-3 (275 mg, 602 μmol) was dissolved in dichloromethane (8 mL). Lawesson's reagent (121 mg, 301 μmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 0.5 hours. Water (30 mL) was added to the system, and the mixture was extracted with dichloromethane (20 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water(FA)-ACN]; gradient: 32%-62% B over 15 min) to obtain compound 6-4.

[0237] LCMS: m / z=473.1[M+H] + .

[0238] 1 H NMR: (400MHz, DMSO-d6) δ11.22(s,1H),9.28(d,J=3.2Hz,1H),8.03(s,1H),7.76-7.69(m,1H),7.63(s,2H),7. 58-7.50(m,2H),7.49-7.41(m,1H),7.37-7.31(m,2H),5.24-4.93(m,1H),4.01(s,3H),1.18(d,J=7.2Hz,3H).

[0239] Step 4:

[0240] Compound 6-4 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase: [CO 2 -MeOH]; B%: 35%, isocratic elution) to obtain compounds 6_P1 and 6_P2.

[0241] Compound 6_P1: Product: RT = 2.249 mins, SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, mobile phase: phase A CO 2 , phase B MeOH (0.05% DEA); elution gradient: MeOH (0.05% DEA), flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar);

[0242] LCMS: m / z = 473.1 [M+H] + ;

[0243] 1H NMR: (400MHz, DMSO-d6) δ11.21 (s, 1H), 9.28 (d, J = 3.2Hz, 1H), 8.03 (s, 1H), 7.76-7.70 (m, 1H), 7.63 (s, 2H), 7. 58-7.49(m,2H),7.49-7.43(m,1H),7.37-7.31(m,2H),5.26-4.95(m,1H),4.01(s,3H),1.18(d,J=7.2Hz,3H).

[0244] Compound 6_P2: Product: RT = 2.529 mins, SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3 μm, mobile phase: phase A CO 2 , phase B MeOH (0.05% DEA); elution gradient: MeOH (0.05% DEA), flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar);

[0245] LCMS: m / z = 473.1 [M+H] + ;

[0246] 1 HNMR: (400MHz, DMSO-d6) δ11.22(br s,1H),9.25(br d,J=3.2Hz,1H),8.01(s,1H),7.63-7.57(m,4H),7.52(br d,J=8.8Hz,1H),7.35-7.24(m,4H),5.36-4.99(m,1H),4.00(s,3H),1.16(d,J=7.2Hz,3H).

[0247] 1 H NMR: (400MHz, DMSO-d6) δ11.22(s,1H),9.28(s,1H),8.02(s,1H),7.77-7.69(m,1H),7.64(s,2H),7.5 8-7.49(m,2H),7.46(s,1H),7.38-7.30(m,2H),5.30-4.92(m,1H),4.01(s,3H),1.18(d,J=7.2Hz,3H).

[0248] Test Example 1: In vitro activity test

[0249] 2.1. Reagents, consumables, and instruments are shown in Table 1

[0250] Table 1 Reagents, consumables and instruments used in the test

[0251] 2.2. DGKζ and DGKα Enzyme Assays

[0252] Take the compound of the present application example, dissolve it in DMSO to make a 10mM stock solution; transfer 60μL of the compound to a 384-well assay plate and centrifuge at 1000rpm for 1 minute. Serially dilute 10 gradients in DMSO at a ratio of 1:3. Use the ECHO acoustic liquid handling system to transfer 0.1μL of the diluted compound solution to a 384-well assay plate (make sure the DMSO concentration is 1%), with each well containing 2 replicates. Transfer 5μL of enzyme to a 384-well assay plate and centrifuge at 1000rpm for 1 minute. Incubate at 25°C for 10min; transfer 5μL of substrate and ATP to a 384-well assay plate and centrifuge at 1000rpm for 1 minute. Incubate at 25°C for 240 minutes; transfer 5μL of tyrosine kinase reagent buffer to a 384-well assay plate and centrifuge at 1000rpm for 1 minute. Incubate at 25°C for 40 minutes. Transfer 10 μL of Detection Solution buffer to a 384-well assay plate, centrifuge at 1000 rpm for 1 minute, incubate at 25°C for 40 minutes, and read the luminescence signal using a microplate reader.

[0253] 2.3. ELISA detection of the effects of compounds on IL-2 secretion by T cells

[0254] Cryopreserved human PBMCs (SAILYIBIO, WPBZ1012T01) were revived in 1640 medium (Invitrogen, A10491-01) containing 10% inactivated FBS (GIBCO, 10099-141) and 1% P / S. T cells were isolated from the PBMCs using a T cell isolation kit (STEMCELL, 17951) and incubated overnight. A 96-well plate was coated with a CD3 antibody (eBioscience, 16-0037-85). T cells were harvested overnight, a cell suspension was prepared in culture medium, and plated onto CD3-coated 96-well plates (Coring, 3599). Diluted test substances were added to each well and incubated in a 37°C, 5% CO2 incubator for 24 hours. The supernatant was collected by centrifugation and stored at -80°C. IL-2 was detected using an ELISA (Tetrasporine, CHE0003) according to the manufacturer's instructions.

[0255] 2.4. The results of in vitro activity test are shown in Table 2

[0256] Table 2 DGKζ inhibitory activity and IL-2 agonist activity of the test compounds

[0257] - stands for untested

[0258] 2.5. Experimental Conclusions

[0259] The compound of the present application has excellent DGKζ inhibitory activity and effectively activates T cell activity.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X is selected from S and O; A is selected from C 6-10 Aryl and 5-10 membered heteroaryl; Ring B1 is selected from a benzene ring and a 5-6 membered heteroaryl group; Ring B2 is selected from a benzene ring, a 5-6 membered heteroaryl ring, a C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkenyl and 3-10 membered heterocycloalkenyl; Each R1 is independently selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl)2, the C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl)2 is optionally substituted with 1, 2, 3 or 4 R; Each R2 is independently selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl)2, the C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl)2 is optionally substituted with 1, 2, 3 or 4 R; R is selected from H, D, F, Cl, Br, OH, CN, NH2, NO2, C 1-3 Alkyl, OC 1-3 Alkyl, NHC 1-3 Alkyl and N(C 1-3 Alkyl)2; n is selected from 0, 1, 2, 3 and 4; m is selected from 0, 1, 2, 3 and 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from a benzene ring.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B1 is selected from a benzene ring.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B2 is selected from a 5-membered heterocycloalkyl group. 5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B2 is selected from a 6-membered heterocycloalkyl group.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit ring Selected from 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit ring Selected from 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from H.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, F, Cl and CH3.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, F, Cl and CH3.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from, in, A, B1, B2, R1, R2, X, n and m are as defined in claims 1-10.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from in, B1, B2, R1, R2, n and m are as defined in claims 1-10.

13. The following compound or a pharmaceutically acceptable salt thereof, 14. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with DGKζ.

15. The use according to claim 14, wherein the disease associated with DGKζ is cancer.

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