CN107556366A - Compound, preparation method and the usage with saltant type isocitric dehydrogenase inhibitory activity - Google Patents

Abstract

The present invention provides a compound with mutant isocitrate dehydrogenase inhibitory activity, its preparation method and application, specifically, the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or Its enantiomers, diastereoisomers, tautomers, solvates, polymorphs or prodrugs, wherein the definition of each group is as described in the specification. The compound has high inhibitory activity on mutant IDH, and therefore can be used for treating diseases related to mutant IDH.

Description

Compound having mutant isocitrate dehydrogenase inhibitory activity, and preparation method thereof and use

technical field

The invention belongs to the field of chemical synthesis, and specifically relates to a compound with mutant IDH inhibitory activity, its preparation method and application.

Background technique

Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (α-ketoglutarate) with simultaneous production of carbon dioxide and NADPH/NADH. This process plays an important role in the metabolism of cells. Depending on the electron acceptor, these enzymes can be divided into two distinct subclasses, one utilizing NAD(+) and the other utilizing NADP(+). Among the five reported isocitrate dehydrogenases, three are NAD(+)-dependent isocitrate dehydrogenases, which mainly exist in the mitochondrial matrix; the other two are NADP(+)-dependent, namely isocitrate dehydrogenases. Citrate dehydrogenase 1 and isocitrate dehydrogenase 2. Isocitrate dehydrogenase 1 is mainly found in the cytoplasm, while isocitrate dehydrogenase 2 is mainly found in the mitochondria. Mutations of isocitrate dehydrogenase occur in many types of cancer, such as but not limited to the following, glioma, glioblastoma, paraneurocytoma, acute leukemia, prostate cancer, thyroid cancer, colon cancer , Chondrosarcoma, cholangiocarcinoma, peripheral T-cell leukemia, melanoma, etc.

The mutation sites of isocitrate dehydrogenase 1 are generally located at R100, R132, H133 and A134; the mutation sites of isocitrate dehydrogenase 2 are generally located at R140 and R172. Non-mutant IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, thereby reducing NAD+ (NADP+) to NADP (NADPH) in the following forward reaction:

Isocitrate+NAD+(NADP+)→α-ketoglutarate+CO2+NADH(NADPH).

Mutant isocitrate dehydrogenases lose this normal function and have a novel ability to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate ( 2HG). The concentration level of 2HG in normal cells is very low. The production of high concentrations of 2HG will help the formation and development of cancer. For example, high concentrations of 2-HG were detected in acute leukemia patients with IDH mutations. High concentrations of 2HG are well correlated with oncogenes. Therefore, inhibition of mutated IDH and its neoactivity is a potential therapeutic therapy for cancer.

In summary, there is an urgent need to develop mutant IDH inhibitors in this field.

Contents of the invention

The purpose of the present invention is to provide an inhibitor of mutant IDH, especially IDH1 and IDH2 mutant inhibitors.

The first aspect of the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or solvate thereof , polymorphs or prodrugs,

in,

W ₁ and W ₂ are each independently selected from N or CR _b ;

W and W' are independently selected from CR _a R _b ;

R _a is selected from H, C ₁ -C ₆ alkyl;

R _b is selected from H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, phenyl, C1-C6 alkoxy;

n is 1, 2, 3, 4 or 5; n' is 0 or 1;

R ₁ is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted 4-8 membered carbocyclic group, substituted or unsubstituted C5-20 aryl group, substituted or unsubstituted 5-10 membered heteroaryl group; wherein, the heterocyclic group or heteroaryl group contains 1-3 optional A heteroatom from the following group: N, O, S or P;

R ₂ is a substituted or unsubstituted C5-C20 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted 5-10 membered aryl and heterocyclic group, wherein the heteroaryl The group contains 1-3 heteroatoms selected from the group: N, O or S; the arylheterocyclyl group contains 1-3 heteroatoms selected from the group: N, O or S;

R ₃ is halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxyl, substituted or unsubstituted 5-10 membered aryl;

R ₄ is -(CH ₂ ) _m R ₁₁ ;

Wherein, m is an integer of 0-5; preferably an integer of 0-3;

_R11 is Substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocyclic group; wherein; X is selected from O, N or S; m is an integer of 0-5; Rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; Rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; or Rc and Rd are connected to form a 4-8 membered saturated or unsaturated heterocyclic or heteroaryl group; wherein, The heteroaryl group contains 1-4 heteroatoms selected from the following group: N, O, S or P; the heterocyclic group contains 1-4 heteroatoms selected from the group: N, O, S or P;

Any of the above "substitution" means that one or more hydrogen atoms on the group are replaced by substituents selected from the following group: -D, halogen, -OH, -NO ₂ , -NH ₂ , -N (unsubstituted C1-C6 alkyl) ₂ , -CN, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy-C1-C8 alkyl, unsubstituted or halogenated C3- C8 cycloalkyl, unsubstituted or halogenated C3-C8 cycloalkyl-C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C1-C6 alkylcarbonyl, Unsubstituted or halogenated C1-C6 alkoxycarbonyl, hydroxamic acid group, unsubstituted or halogenated 5-8 membered aryl, unsubstituted or halogenated 5-8 membered heteroaryl, unsubstituted or Halogenated 4-8 membered saturated heterocycle or carbocycle; wherein, the heteroaryl group contains 1-4 heteroatoms selected from the group consisting of N, O or S, and the heterocycle contains 1-4 a heteroatom selected from the group consisting of N, O or S;

In another preferred example, W is CR _a R _b , and n is preferably an integer of 1-4.

In another preferred example, W' is CR _a R _b , and n' is preferably 1.

_In another preference, R is selected from the following group: Wherein Rm is selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy.

In another preferred example, R ₄ is -(CH ₂ ) _m R ₁₁ ; m is preferably 0, 1 or 2.

In another preferred example, R ₁₁ is selected from the following group: Wherein, X is O or N; V1, V2 and V3 are selected from CRa or N respectively; m is an integer of 0-4; Ra is selected from H, C ₁ -C ₆ alkyl, halogen, cyano; Rc is selected from H , substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; Rd is selected from H, substituted or unsubstituted C1-C6 alkyl , substituted or unsubstituted C1-C6 alkylcarbonyl; wherein, the heteroaryl group contains 1-4 heteroatoms selected from the following: N, O or S; the heterocyclic group contains 1-4 A heteroatom selected from the group consisting of: N, O or S.

In another preferred embodiment, R ₄ is -(CH ₂ ) _m R ₁₁ ; m is preferably 0 or 1.

In another preferred example, R ₁₁ is preferably Wherein, m is an integer of 0-4; Rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; Rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; wherein, the heteroaryl group contains 1-4 heteroatoms selected from the following: N, O or S; said heterocyclic group contains 1-4 heteroatoms selected from the group consisting of N, O or S.

In another preferred embodiment, Rc is selected from the following group: Wherein, R' or R" are each independently selected from -CN, -OH, hydroxamic acid group, C1-C6 alkylcarbonyl, -NO ₂ , halogen, substituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.

In another preferred example, the compound has the structure shown in the following formula I-1:

Wherein, the definition of each group is as described above.

In another preferred example, the compound has the structure shown in the following formula I-2:

Wherein, the definition of each group is as described above.

In another preferred example, the compound is selected from compounds 1-133.

The second aspect of the present invention provides a method for preparing the compound of formula I as described in the first aspect of the present invention, said method comprising the following steps 1) or 2):

1) Compound 1a and compound Coupling is carried out under reaction conditions of an inert solvent, thereby forming a compound of formula I;

In the formula, the definition of each group is as described in the second aspect of the present invention;

2) Compound 1a and compound Coupling is carried out under the reaction conditions of inert solvent, and then with Reaction generates formula I compound;

In the formula, the definition of each group is as described in the second aspect of the present invention.

In another preferred embodiment, the reaction is carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.

The third aspect of the present invention provides a use of the compound of formula I as described in the first aspect of the present invention for:

(a) preparing medicines for treating diseases related to mutant IDH;

(b) preparing mutant IDH inhibitors;

(c) non-therapeutically inhibiting the IDH mutation in vitro;

(d) non-therapeutically inhibit tumor cell proliferation in vitro; and/or

(e) Treating diseases associated with mutant IDH.

In another preferred example, the mutant IDH-related diseases are selected from the group consisting of: cancer; preferably leukemia, glioma, cholangiocarcinoma, chondroarticular sarcoma, fibrosarcoma, intrahepatic cholangiocarcinoma, rectal cancer .

In another preferred embodiment, the mutant IDH is selected from the group consisting of IDH1, IDH2, or a combination thereof.

A fourth aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising:

(i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof ;with

(ii) A pharmaceutically acceptable carrier.

The fifth aspect of the present invention provides a method for inhibiting IDH mutation, said method comprising the step of: administering an inhibitory effective amount of the compound of formula I as described in the first aspect of the present invention or its pharmaceutically acceptable salt, or administer an inhibitory effective amount of the pharmaceutical composition as described in the third aspect of the present invention to the subject.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

detailed description

After long-term and in-depth research, the present inventors have prepared a class of compounds with the structure shown in formula I, and found that they have mutant IDH inhibitory activity. Moreover, the compound can inhibit a series of mutant IDHs at very low concentrations (as low as ≤100nmol/L), and the inhibitory activity is quite excellent, so it can be used to treat diseases related to mutant IDHs, such as tumors . Based on the above findings, the inventors have accomplished the present invention.

the term

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited in their entirety herein are hereby incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, unless the context clearly dictates otherwise, as used in the specification and claims, the singular includes the plural of the referents. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "comprises" as well as other forms, such as "comprises", "comprises" and "comprises" is not limiting.

Definitions of standard chemical terms can be found in references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectroscopy, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are set forth, terms employed herein in the relevant descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those that are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.

When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

The section headings used herein are for the purpose of organizing the article only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.

In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings shown below unless otherwise specified.

In this application, the term "halogen" means fluorine, chlorine, bromine or iodine.

"Hydroxy" means an -OH group.

"Hydroxyalkyl" means an alkyl group as defined below substituted with a hydroxyl group (-OH).

"Carbonyl" means a -C(=O)- group.

"Nitro" means -NO2.

"Cyano" means -CN.

"Amino" means -NH2.

"Substituted amino" means an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkyl Amylamino, aralkylamino, heteroaralkylamino.

"Carboxy" means -COOH.

In this application, the term "alkyl", as a group or part of another group (for example, in a group such as a halogen-substituted alkyl group), means a group consisting only of carbon and hydrogen atoms, free of unsaturation Bond, straight or branched hydrocarbon chain group having eg 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2- ,2-Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.

In this application, the term "alkenyl", as a group or part of another group, means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule by a single bond, such as but not limited to vinyl, propenyl, allyl, but- 1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.

In this application, the term "alkynyl", as a group or part of another group, means consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond, such as but not limited to ethynyl , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.

In this application, the term "cycloalkyl", as a group or part of another group, means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed only of carbon and hydrogen atoms, which may include fused Ring system, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and it is saturated or unsaturated and can be obtained via any suitable The carbon atoms are connected to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] Octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octa Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalenyl, etc.

In this application, the term "heterocyclyl", as a group or part of another group, means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic groups. Unless otherwise specified in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups comprising fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alkane-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, Imidazolidinyl, Quinazinyl, Thiazolidinyl, Isothiazolidinyl, Isoxazolidinyl, Indolinyl, Octahydroindolyl, Octahydroisoindolyl, Pyrrolidinyl, Pyrazolidinyl , Phthalimide, etc.

In the present application, the term "aryl", as a group or part of another group, means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a cycloalkyl or heterocyclyl as defined above, provided that the aryl is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like.

In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In this application, the term "heteroaryl", as a group or part of another group, means having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 carbon atoms selected from the group consisting of nitrogen A 5- to 16-membered conjugated ring system group of heteroatoms of oxygen and sulfur. Unless specifically stated otherwise in this specification, heteroaryl may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may be fused to a cycloalkyl or heterocyclyl as defined above, provided that hetero An aryl group is connected to the rest of the molecule by a single bond through an atom on the aromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridine Base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizyl, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.

In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.

In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or circumstance. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl.

As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.

"Stereoisomer" refers to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention will encompass each stereoisomer and mixtures thereof.

When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.

"Tautomer" refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography. ), see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; A.M. Stalcup, Chiral Separations, Annu.Rev.Anal.Chem.3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-amino salicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

"Polymorph" refers to the different solid crystalline phases of certain compounds of the present invention due to the existence of two or more different molecular arrangements in the solid state. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.

Often, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain adventitious water only or a mixture of water plus a portion of the adventitious solvent. The compounds of the present invention can be reacted in solvents or precipitated or crystallized from solvents. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The present invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Accordingly, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention. Prodrugs are generally transformed rapidly in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds typically provide solubility, tissue compatibility or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. For specific prodrug preparation methods, please refer to Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994, 4, 1985-1990; Greenwald, R.B., et al., J.Med.Chem.2000, 43, 475.

In this application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively nontoxic, i.e., the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.

In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.

The "tumor" and "diseases related to abnormal cell proliferation" in the present invention include but are not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.

As used herein, the terms "prophylactic", "prevention" and "prevention" include reducing the likelihood of a disease or condition occurring or worsening in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the occurrence of a disease or condition in a mammal, especially when such mammal is susceptible to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) inhibiting a disease or condition, i.e. arresting its development;

(iii) ameliorating a disease or condition, i.e., causing regression of the state of the disease or condition; or

(iv) Alleviating the symptoms caused by the disease or condition.

The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system. For example, a therapeutically "effective amount" is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.

As used herein, the terms "administering", "administering", "administering" and the like refer to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton , those discussed in Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

As used herein, the terms "pharmaceutical combination", "drug combination", "combination", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form. The term "variable combination" refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.

Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.

Compound of formula I

The present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, or polymorph or prodrugs,

In another preferred example, W, W', W ₁ , W ₂ , n, n', R ₁ , R ₂ , R ₃ , R ₄ , m, R ₁₁ , X, Rc, Rd are each independently Ground is the group corresponding to the following compounds.

The preparation of formula I compound

The compound of formula I provided by the present invention can be prepared by the following method 1) or 2):

1) Compound 1a and compound Coupling is carried out under reaction conditions of an inert solvent, thereby forming a compound of formula I;

In the formula, the definition of each group is as described above;

2) Compound 1a and compound Coupling is carried out under the reaction conditions of inert solvent, and then with Reaction generates formula I compound;

In the formula, the definition of each group is as described above.

In another preferred embodiment, the reaction is carried out in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, Tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or combinations thereof.

The main advantages of the present invention include:

1. A compound as shown in formula I is provided.

2. Provide a mutant IDH inhibitor with novel structure and its preparation and application, the inhibitor has higher inhibitory activity on mutant IDH.

3. A pharmaceutical composition for treating diseases related to mutant IDH is provided.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

Intermediate A1: Synthesis of N-(2,3-dihydro-1H-inden-1-yl)-3-fluoroaniline

Add 1-indanone (2g, 15mmol), m-fluoroaniline (2.2g, 19.7mmol), activated 4A molecular sieve (20g), and dry 1,2-dichloroethane to a dry 50ml single-necked bottle 40ml, refluxed for 36h under the protection of nitrogen, monitored by TLC, 60%-70% of the product was formed, some raw materials remained, filtered, the filtrate was collected and spin-dried to obtain 2.3g of the product. The crude product was used directly without purification.

Using the above method, react with substituted or unsubstituted (hetero) aromatic ring and cycloalkyl ketone, and substituted or unsubstituted aniline, heterocyclic aromatic amine, the solvent can be replaced by toluene or dioxane or other inert solvents, Obtain imine intermediates A2, A3, A4, A5, A6, A8, A9, A10, A16, A19, A20, A21, A22, A26, A28, A29, A31, A33, A34 and A35. Among them, A2, A3, A4, A5, A6, A8, A9, A10, A16, A28, A29, A31, A33, A34, A35 were directly used in the next reaction without purification; A19, A20, A21, A22, A26 were purified by column chromatography.

Described intermediate structure is as follows:

Intermediate A19: N-(2,3-Dihydro-1H-inden-1-yl)-3fluoro-4chloroaniline

¹ H-NMR (d6-DMSO, 400MHz): δ7.91-7.75 (dd, J 1 = 7.6Hz, J 2 = 13.6Hz 1H), 7.61-7.57 (m, 1H), 7.49-7.32 (m, 3H ), 6.74-6.65(dd, J 1 = 8.4Hz, J 2 = 24.8Hz 1H), 3.16-3.07(m, 2H), 2.71-2.64-(m, 2H).

Intermediate A20: N-(2,3-dihydro-1H-inden-1-yl)aniline

LCMS: m/z 208.2 (M+H) ⁺ , RT=1.5min.

Intermediate A21: N-(2,3-dihydro-1H-inden-1-yl)-2,5-difluoroaniline

LCMS: m/z 244.1 (M+H) ⁺ , RT=1.7min.

Intermediate A22: N-(2,3-dihydro-1H-inden-1-yl)-3,5-difluoroaniline

¹ H-NMR (CDCl ₃ , 400MHz): δ7.88(d, J=7.6Hz, 1H), 7.51-7.37(m, 3H), 6.56-6.43(m, 3H), 3.09(t, J=6.4 Hz, 2H), 2.67 (t, J = 6.4Hz, 2H).

Intermediate A26: (N-(2,3-dihydro-1H-inden-1-yl)-2,5-difluoroaniline

¹ H-NMR (CDCl ₃ , 400MHz): δ7.93(d, J=8.0Hz, 1H), 7.51-7.36(m, 3H), 7.06-7.03(m, 1H), 6.76-6.69(m, 2H ), 3.10(t, J＝6.4Hz, 2H), 2.65(t, J＝6.4Hz, 2H)

Intermediate A11: N-(5-Chloro-2,3-dihydro-1H-inden-1-yl)-5-fluoro-3-pyridinamine

5-Chloro-1-indanone (333mg, 2mmol) and 3-amino-5-fluoropyridine (222mg, 2mmol) were put in a 10mL reaction vial and heated to 120°C under nitrogen protection to react. When it was detected by TLC/LCMS that the product no longer increased, dichloromethane was added to dissolve it, anhydrous sodium sulfate was added to dry, filtered, and spin-dried to obtain a crude Schiff base for use.

Using the above method, react with substituted or unsubstituted (hetero)aryl cycloalkyl ketones, and substituted or unsubstituted aniline, heterocyclic aromatic amine to obtain imine intermediates A7, A11, A13, A14, A15, A17, A18, A23, A24, A25, A27, A30.

Intermediate A12: N-(7-Chloro-2,3-dihydro-1H-inden-1-yl)-3-fluoroaniline

Add 7-chloroindanone (2.5g, 15mmol), m-fluoroaniline (2.2g, 19.7mmol), activated 4A molecular sieves (20g), dry 1,2-dichloro Add 40ml of ethane, add titanium tetrachloride (142mg, 0.05equiv) dropwise to catalyze, reflux under the protection of nitrogen, TLC monitors that the product no longer increases, filter, and spin the filtrate to obtain 2.5g of crude product, which is directly used in the next reaction.

In the above method, titanium tetrachloride can be replaced by other Lewis acids (boron trifluoride ether, aluminum trichloride, etc.), and the solvent can be replaced by toluene and dioxane.

The imine intermediate A32 was obtained by reacting 7-chloroindanone and 3,5-difluoroaniline using the above method.

Intermediate B1: Synthesis of 1,1-difluoro-3-cyclobutylisocyanate

Step 1: In a clean 250ml sealed tube, add B1-1 (25g, 175mmol) and ethyl formate 140ml, add triethylamine (53g, 525mmol) under stirring, stir overnight in an oil bath at 110°C, and cool After reaching room temperature, filter, the filter cake was washed 2-3 times with ethyl acetate, the filtrate was washed 2 times with saturated brine, and spin-dried to obtain compound 2 (22 g, yield: 93%).

¹ H-NMR (DMSO 400MHz): δ8.51(s, 1H), 8.00(s, 2H), 4.10(s, 1H), 2.90-2.88(m, 2H), 2.57-2.55(m, 2H).

Step 2: Add compound B1-2 (22g, 163mmol), triphenylphosphine (47g, 179mmol), carbon tetrachloride (25g, 163mmol), triethylamine (16.5g , 163mmol) and 500ml of dichloromethane, reflux overnight at 45°C, spin dry in a cold water bath, add 500ml ether for beating for 1 hour, filter, wash with ether, mix the filtrate with silica gel, spin dry in a cold water bath, The target compound (11.8 g, 62%) was purified by silica gel column (diethyl ether).

¹ H-NMR (DMSO 400MHz): δ 4.28-4.26 (m, 1H), 3.19-3.08 (m, 2H), 2.97-2.87 (m, 2H).

Using the above method, different amines were used to make different isocyan intermediates B2, B3, B5, B6, B7.

Intermediate B2: 1,1-difluoro-3-cyclohexyl isocyanide

¹ H-NMR (CDCl 400MHz): δ3.84(s,1H),1.93-2.17(m,8H)

Intermediate B3: 4-Isocyano-tetrahydropyran

¹ H NMR (CDCl ₃ -d ₁ , 400MHz): δ3.94-3.85(m,3H),3.61-3.56(m,2H),1.99-1.98(m,2H),1.86-1.83(m,2H) .

Intermediate B5: 4,4-Dimethylcyclohexylisocyanide

¹ H-NMR(CDCl ₃ ,400MHz):1.82-1.76(m,2H),1.53-1.51(m,1H),1.28-1.24(m,6H),0.92(s,6H).

Intermediate B6: The diethyl ether concentrated solution was not spin-dried, and the intermediate was not isolated, and was directly used in the next reaction.

Intermediate B7: The diethyl ether concentrate was not spin-dried, and the intermediate was not isolated, and was directly used in the next reaction.

Intermediate B4: Synthesis of phenylisocyanate

Add aniline (5.0g, 53.69mmol, 1.0eq), tetrabutylammonium bisulfate (1.82g, 5.37mmol, 0.1eq), dichloromethane (160mL), sodium hydroxide to a dry 500mL three-necked flask at room temperature Aqueous solution (50%, 80 mL). Chloroform (9.61g, 80.54mmol, 1.5eq) was slowly added dropwise at 0°C, and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was poured into water (500 mL), and extracted with dichloromethane (500 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product phenyl isocyanide (3.0 g, yellow oily liquid) was obtained through a silica gel column with a yield of 55%.

¹ H NMR (CDCl3-d1, 400MHz): δ7.39 (m, 5H).

Intermediate C1: Synthesis of (S)-1-(4-cyanopyridin-2-yl)pyrrolidine-2-carboxylic acid

Step 1: Compound L-proline methyl ester hydrochloride (4.98 grams, 30 mmol, CAS: 2133-40-6) and 2-bromo-4-cyanopyridine (2.28 grams, 20 mmol) were dissolved Yul), Xantphos (5.78 g, 10 mmol) and cesium carbonate (19.56 g, 60 mmol), in 1 dioxane (80 mL) were added Pd2(dba)3 (1.83 g, 2 millimolar reacted 12 hours under 00 degree Celsius of nitrogen protection. After the reaction was completed, 50 milliliters of ethyl acetate was added. The organic phase was washed with water (20 milliliters * 1) and saturated brine (20 milliliters * 1) successively. Collect the organic phase, without Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify through a column (petroleum ether: ethyl acetate = 20:1, 10:1) to obtain the product (S)-methyl 1-(4-cyanopyridine-2 -yl)pyrrolidine-2-carboxylic acid (1.34 g, yellow solid), yield: 29%. LCMS: m/z 232.1 (M+H) ⁺ ; RT = 1.387 min.

Step 2: Dissolve C1-1 (460 mg, 2 mmol) in tetrahydrofuran/water (15 ml/8 ml), add lithium hydroxide (84 mg, 2 mmol) at room temperature, and react 4 at room temperature Hour. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to 2, and 15 ml of ethyl acetate was added. The organic phase was washed successively with water (20 mL×1) and saturated brine (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain product C1: (S)-1-(4-cyanopyridin-2-yl)pyrrolidine-2-carboxylic acid (310 mg, yellow solid ), yield: 78.3%.

LCMS: m/z 218.1 (M+H) ⁺ ; RT = 1.076min.

Intermediate C2: Synthesis of 2-((4-cyanophenyl)amino)acetic acid

Step 1: sequentially add compound C2-1 (1g, 8.5mmol), sodium acetate (1.4g, 17mmol), ethyl bromoacetate (1.7g, 10mmol) and 30ml ethanol to a dry 50ml single-necked bottle, and reflux for 36 hours. Spin to dry the solvent, add 50ml of ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter and spin dry, and use (petroleum ether: ethyl acetate = 2:1) to purify through a silica gel column to obtain intermediate C2-2 ( 300 mg, yield: 17.4%) LCMS: m/z 205.2 (M+H) ⁺ , RT = 1.37 min.

Step 2: Add compound C2-2 (300mg, 1.47mmol), sodium hydroxide (118mg, 2.94mmol), 3ml of water and 12ml of methanol to a dry 50ml single-necked bottle successively, stir at room temperature for 3 hours, spin dry the solvent, and use dilute The pH was adjusted to about 5 with hydrochloric acid, and white solid C2 (120 mg, yield: 46.3%) was isolated by preparation.

LCMS: m/z = 175.2 (M-1) ^- , RT = 1.07 min.

Intermediate C4: 2-((2-fluoropyridin-3-yl)amino)acetic acid

Intermediate C4 was prepared using the same method as Intermediate C2.

¹ H NMR (CDCl ₃ -d1, 400MHz): δ7.64-7.65(m,1H),7.43-7.44(m,1H),7.30(m,2H),7.24(m,2H),7.14(m, 1H),6.89-6.92(m,2H),6.49-6.54(m,1H),5.34-5.45(m,2H),3.93(m,1H),3.49(s,2H),2.66-2.77(m, 2H),2.22-2.30(m,5H),1.79-1.86(m,3H).

LCMS: m/z 541.2 (M+H) ⁺ ; RT = 1.678min.

Intermediate C3: Synthesis of 2-(methyl(phenyl)amino)acetic acid

Step 1: Add compound C3-1 (3g, 16.7mmol, CAS23284-84-6), iodomethane (7.1g, 50mmol), 20ml of toluene to a dry sealed tube of 50ml successively, stir overnight at 80 degrees Celsius, cool, and add 30ml water, extracted with ethyl acetate (50ml*2), dried over anhydrous sodium sulfate, washed with saturated brine, and spin-dried, the crude product was passed through a silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain a yellow oily product 2- (Methyl(phenyl)amino)ethyl acetate (C3-2) 1.2g. Yield: 37%. LCMS: m/z 194.3 (M-1) R = 1.616.

Step 2: sequentially add compound C3-2 (1.2g, 6.2mmol) sodium hydroxide (0.62g, 15mmol) and 5ml water, 15ml methanol into a dry 25ml single-necked bottle, stir at room temperature for three hours, spin off the organic solvent, adjust The pH is approximately equal to 4, extracted with ethyl acetate (50ml*2), dried over anhydrous sodium sulfate, and spin-dried to obtain 420mg of yellow oil 2-(methyl(phenyl)amino)acetic acid (C3), yield: 41% .

LCMS: m/z 166.3(M-1) ^- , RT＝1.2min.

Intermediate C5: Synthesis of (S)-2-oxooxazolidine-4-carboxylic acid

Step 1: Add L-serine (10.0g, 95.2mmol, 1.0eq), sodium bicarbonate (20g, 238.0mmol, 2.5eq) and water (30mL) sequentially at room temperature into a dry 500mL single-necked bottle. Benzyl chloroformate (2.0 mL, 142.8 mmol, 1.5 eq) was added at 0°C and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was poured into water (200), and the impurities were extracted with ethyl acetate (300 mL). The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid, and extracted three times with ethyl acetate (300 mL). The organic phase was spin-dried, and the residue was washed with ethyl acetate for beating and filtered to obtain product C5-1: (S)-2-(((benzyloxy)carbonyl)amino)-3-hydroxypropionic acid (10g, white solid ), yield 45%. LCMS: m/z 238.2 (MH) ^- ; RT = 1.047min

Step 2: Add C5-1 (2.5g, 10.45mmol, 1.0eq), water (10mL) and sodium hydroxide (0.84g, 20.91mmol, 2.0eq) sequentially into a 100mL single-necked bottle at room temperature at 0°C. Stir at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water (20), and impurities were extracted with diethyl ether (300 mL). The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid, and extracted 5 times with ethyl acetate (300 mL). The product (S)-2-oxooxazolidine-4-carboxylic acid (600 mg, white solid) was obtained with a yield of 86%.

¹ H NMR(DMSO-d6,400MHz):δ13.30(br s,1H),8.15(s,1H),4.46-4.51(m,1H),4.28-4.36(m,2H).

Intermediate D1: Synthesis of 2-methyl-1H-imidazo[4,3-b]pyrazine

Add 2,3-diaminopiperazine (200mg, 1.82mmol) and acetic anhydride (445.4mg, 4.36mmol) sequentially into a dry 50ml single-necked bottle, react at 140°C for 2 hours, cool to room temperature, and spin dry the acetic anhydride , add 1ml of hot 10N NaOH solution, add 2ml of acetic acid, let stand overnight in the refrigerator, precipitate a solid, filter, wash with water, and dry to obtain 90mg of a brown solid product.

LCMS: m/z 135.2 (M+H) ⁺ ; RT = 0.53min.

Intermediate D2: Synthesis of 2-(2-methyl-1H-imidazol-5-yl)pyrimidine

Step 1: Add 30ml of anhydrous tetrahydrofuran to a dry 100ml three-necked flask, ventilate, protect with nitrogen, cool down to 0°C, slowly add 2mol/L LDA (10.5ml, 22.7mmol) and tributyltin hydride (5.64ml , 22.7mmol), stirred at 0°C for 15 minutes, then cooled to -78°C, added dropwise a solution of 2-chloropyrimidine (2g, 17.5mmol) in tetrahydrofuran (20ml), slowly rose to room temperature after adding, stirred overnight, added 30ml of water, extracted with ethyl acetate (50mlx3), dried over anhydrous sodium sulfate, spin-dried, the crude product was purified by silica gel column (PE:EA=10:1) to obtain yellow oily liquid product D2-1: 2.15g (yield: 35%).

Step 2: Add 5-bromo-2-methyl-1H-imidazole (CAS: 16265-11-5, 1g, 6.25mmol) and 20ml tetrahydrofuran into a dry 100ml single-necked bottle, cool down to 0°C, and batch Add NaH (0.375g, 9.4mmol), slowly warm to room temperature, stir for 1 hour, add SEM-Cl (1.25g, 7.5mmol), stir overnight at room temperature, quench with water, extract with ethyl acetate (50mlx3), saturated saline Washed, dried over anhydrous sodium sulfate, and spin-dried, the crude product was purified by silica gel column (PE:EA=1:1) to obtain light yellow oily product D2-2: 1.4g (yield: 78%). LCMS: m/z 293.1 [M+H] ⁺ , RT = 1.34 min.

Step 3: Add D2-2 (1g, 3.43mmol), D2-1 (1.18g, 4.12mmol) and tetrakistriphenylphosphinepalladium (300mg) in turn to a dry 50ml single-necked bottle, add 20ml of dry DMF, and replace gas three times, under nitrogen protection, stirred at 120°C for 4 hours, dried the solvent with an oil pump, added 20ml of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried, the crude product was passed through a silica gel column (PE:EA=1: 1) Obtain red solid D2-3: 0.97g (yield: 95%). LCMS: m/z 291.2 [M+H] ⁺ , RT = 0.980 min.

Step 4: Add D2-3 (500mg, 1.72mmol) to a dry 50ml single-necked bottle, add 20ml DCM, and 10ml trifluoroacetic acid, stir overnight at room temperature, spin to dry the solvent, wash with saturated aqueous sodium bicarbonate, and extract with ethyl acetate , spin-dried, the crude product was passed through a silica gel column (PE:EA=1:1) to obtain a red solid product D2: 160mg (58% yield).

LCMS: m/z 161.2 [M+H] ⁺ , RT = 0.445 min.

Intermediate D3: 2-(2-Methyl-1H-imidazol-5-yl)pyrazine

Starting with 2-chloropyrazine, using the method described above, 2-(2-methyl-1H-imidazol-5-yl)pyrazine was obtained.

Example 1: Compound 1 and Compound 2

Step 1: Add intermediate A1, L-pyroglutamic acid (260mg, 2mmol) into the microwave reaction tube, inject 2mL of anhydrous methanol to dissolve, stir at room temperature for 15 minutes, add intermediate B1 (240mg, 2mmol), seal the tube After that, it was reacted overnight in an oil bath at 40°C. After adding 10 mL of water, it was extracted three times with ethyl acetate (3*10 mL), the combined ethyl acetate phase was washed several times with saturated brine, dried with anhydrous sodium sulfate and then spin-dried to obtain a reaction crude product, which was analyzed by normal phase column chromatography (dichloro (2S)-N-(1-(3,3-difluorocyclobutylformyl)-2,3-dihydro-1H-indenyl)-N -3-fluorophenyl-5-oxo-pyrrolidine-2-carboxamide (intermediate 1-1, 140mg, yield=15%),

LCMS: m/z 943.4 (2M+H) ⁺ , RT=1.64min.

Step 2: Add intermediate 1-1 (140mg, 0.3mmol), cesium carbonate (145mg, 0.45mmol), Pd ₂ (dba) ₃ (14mg, 0.015mmol), Xant-phos (9mg, 0.015mmol) and 2-chloro-4-cyanopyridine (50mg, 0.36mmol), inject 5mL of anhydrous 1,4-dioxane, seal the tube and place it at 70°C for 3h. After filtration, the filtrate was spin-dried and separated by column chromatography (petroleum ether/ethyl acetate=4/1) to obtain the crude products of Compound 1 and Compound 2, which were further purified by HPLC to obtain the target compound 1 and 2.

Compound 1: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)formyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.77(s,1H), 8.23-8.18(m,1H), 7.53-7.29(m,5H), 7.29-7.07(m,2H), 6.98-6.78( m,1H),5.55–5.45(m,1H),4.67-4.60(m,1H),4.13-4.03(m,1H),2.96–2.68(m,4H),2.65–2.50(m,2H), 2.39–2.18(m,4H),2.10–1.90(m,2H).

LCMS: m/z 574.1 (M+H) ⁺ , RT=1.84min.

Compound 2: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)formyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(d, J=0.9Hz, 1H), 8.56-8.51(m, 1H), 7.33-7.11(m, 7H), 7.08-6.94(m, 2H) ,5.83–5.71(m,1H),4.72–4.62(m,1H),4.18-4.08(m,1H),2.98-2.84(m,5H),2.65–2.07(m,6H),2.03–1.90( m,1H).

LCMS: m/z 574.1 (M+H) ⁺ , RT=1.84min.

Embodiment 2: compound 3 and compound 4

Using the same method as in Example 1, the product obtained by using imine intermediate A2, isocyan intermediate B1 and L-pyroglutamic acid was reacted with 2-chloro-4-cyanopyridine, and purified to obtain Compound 3 and Compound 4.

Compound 3: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbonyl)-2,3-di Hydrogen-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.75(s, 1H), 8.55-8.25(m, 3H), 7.81-7.42(m, 1H), 7.31-6.95(m, 5H), 5.82(dd, J＝34.3,6.2Hz,1H),4.64–4.47(m,1H),4.25-4.10(m,1H),3.14–2.77(m,6H),2.60–1.91(m,6H).

LCMS: m/z 575.2 (M+H) ⁺ , RT=1.74min.

Compound 4: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbonyl)-2,3-di Hydrogen-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.76 (d, J=7.9Hz, 1H), 8.65–8.16 (m, 3H), 7.77–7.32 (m, 3H), 7.32–7.07 (m, 3H) ,5.60-5.54(m,1H),4.59-4.52(m,1H),4.16-4.05(m,1H),2.97–2.71(m,4H),2.68–2.47(m,2H),2.45–2.14( m,4H),2.12–1.83(m,2H).

LCMS: m/z 575.2 (M+H) ⁺ , RT=1.74min.

Embodiment 3: compound 7 and compound 8

Using the same method as in Example 1, the product obtained by using imine intermediate A2, isocyan intermediate B2 and L-pyroglutamic acid was reacted with 2-chloro-4-cyanopyridine, and purified to obtain Compound 7 and Compound 8.

Compound 7: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((4,4-difluorocyclohexane)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.79-8.53(m,2H),8.42-8.09(m,2H),7.52-7.06(m,6H),5.46-5.12(m,1H),4.62- 4.36(m,1H),3.90-3.75(m,1H),3.17–2.44(m,5H),2.40–2.15(m,3H),2.16–1.75(m,8H).

LCMS: m/z 603.3 (M+H) ⁺ , RT=1.79min.

Compound 8: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((4,4-difluorocyclohexane)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.75(s,1H), 8.59–8.18(m,2H), 7.81–7.69(m,1H), 7.45-7.15(m,5H), 7.06-6.93( m,1H),5.53-5.42(m,1H),4.67–4.46(m,1H),3.94–3.74(m,1H),3.11–2.83(m,2H),2.65–2.35(m,2H), 2.30–2.13(m,2H),2.10-1.78(m,10H).

LCMS: m/z 603.3 (M+H) ⁺ , RT=1.79min.

Embodiment 4: Compound 9 and Compound 10

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A4, cyclohexyl isocyanate and L-pyroglutamic acid, reacted with 2-chloro-4-cyanopyridine, and purified to obtain Compound 9 and Compound 10.

Compound 9: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(cyclohexylformyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.75(s,1H), 8.59–8.50(m,1H), 7.36–7.30(m,1H), 7.25–7.07(m,4H), 7.07–7.01(m ,1H),7.01–6.89(m,2H),6.89–6.82(m,1H),5.41–5.30(m,1H),4.72(dd,J＝9.2,3.1Hz,1H),3.85–3.63(m ,1H),3.08–2.74(m,5H),2.58–2.44(m,1H),2.40–2.09(m,3H),2.03–1.77(m,6H),1.43–1.34(m,1H),1.17 –0.98(m,2H),0.98–0.78(m,2H).

LCMS: m/z 580.3[M+H] ⁺ , RT=2.0min.

Compound 10: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(cyclohexylformyl)-1,2,3,4-tetrahydronaphthalene-1 -yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.78(s,1H),8.48–8.39(m,1H),7.72–7.61(m,1H),7.49–7.39(m,1H),7.37–7.30(m ,1H),7.14–7.08(m,2H),7.08–6.99(m,2H),6.95–6.89(m,1H),6.88–6.79(m,1H),5.04–4.96(m,1H),4.63 –4.54(m,1H),3.71–3.60(m,1H),3.04–2.91(m,1H),2.84–2.50(m,4H),2.44–2.34(m,1H),2.32–2.20(m, 1H),2.23–1.95(m,2H),1.56–1.42(m,4H),1.23–1.11(m,2H),1.09–0.79(m,5H).

LCMS: m/z 580.3[M+H] ⁺ , RT=2.01min.

Embodiment 5: Compound 12 and Compound 13

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A1, isocyan intermediate B2 and L-pyroglutamic acid, reacted with 2-chloro-4-cyanopyridine, and purified to obtain Compound 12 and Compound 13.

Compound 12: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((4,4-difluorocyclohexane)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.74(s, 1H), 8.52(dd, J=13.0, 5.1Hz, 1H), 7.24–6.92(m, 9H), 5.44(dd, J=7.6, 4.1Hz,1H),4.70–4.61(m,1H),3.99-3.77(m,1H),3.01–2.78(m,3H),2.73–2.32(m,3H),2.25-2.13(m,1H) ,2.09–1.66(m,7H),1.45-1.22(m,2H).

LCMS: m/z 602.2 (M+H) ⁺ , RT=1.88min.

Compound 13: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((4,4-difluorocyclohexane)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.79–8.73(m,1H),8.21-8.16(m,1H),7.50–7.28(m,4H),7.25-7.06(m,4H),6.98– 6.82(m,1H),5.26-5.20(m,1H),4.68–4.56(m,1H),3.86-3.76(m,1H),2.95–2.68(m,2H),2.64–2.46(m,2H ),2.34–2.19(m,2H),2.07–1.67(m,8H),1.38-1.24(m,2H).

LCMS: m/z 602.2 (M+H) ⁺ , RT=1.88min.

Example 6: Compound 14 and Compound 15

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A1, cyclohexyl isocyanate and L-pyroglutamic acid, and then reacting with 2-chloro-4-cyanopyridine to obtain compound 14 and compound 15.

Compound 14: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(cyclohexylcarbamoyl)-2,3-dihydro-1H-indene-1 -yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(s, 1H), 8.51(dd, J=11.9, 5.0Hz, 1H), 7.37–7.06(m, 6H), 7.04–6.88(m, 3H) ,5.42(d,J＝7.8Hz,1H),4.68-4.64(m,1H),3.76-3.64(m,1H),3.05–2.80(m,3H),2.78–2.11(m,4H),2.07 –1.58(m,5H),1.43–0.81(m,6H).

LCMS: m/z 566.2 (M+H) ⁺ , RT=1.95min.

Compound 15: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(cyclohexylcarbamoyl)-2,3-dihydro-1H-indene-1 -yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.76(s, 1H), 8.18(dd, J＝8.1, 5.0Hz, 1H), 7.51–7.41(m, 3H), 7.35–6.86(m, 6H) ,5.24–5.15(m,1H),4.66–4.61(m,1H),3.74–3.59(m,1H),2.98–2.68(m,2H),2.63–2.41(m,2H),2.39–2.17( m,2H),2.09–1.69(m,5H),1.54(s,2H),1.30-1.26(m,1H),1.15-0.66(m,4H).

LCMS: m/z 566.2 (M+H) ⁺ , RT=1.95min.

Example 7: Compound 19 and Compound 20

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A31, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 19 and compound 20.

Compound 19: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methyl Base-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(s, 1H), 8.55(dd, J=11.9, 5.0Hz, 1H), 7.30-7.23(m, 1H), 7.25-6.94(m, 7H) ,5.74(d,J=6.1Hz,1H),4.69-4.65(m,J=9.1,3.4Hz,1H),4.13-4.09(m,1H),2.93–2.77(m,5H),2.58–2.28 (m,5H),2.24(d,J=3.5Hz,3H),2.17-2.11(m,1H),2.00–1.92(m,1H).

LCMS: m/z 588.2 (M+H) ⁺ , RT=1.91min.

Compound 20: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methyl Base-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.76(s,1H), 8.24–8.17(m,1H), 7.50–7.43(m,1H), 7.42–7.27(m,2H), 7.24–7.19( m,1H),7.18–7.10(m,2H),7.03(dd,J=7.6,4.8Hz,1H),6.93((d,J=9.1Hz,0.5H),6.81(d,J=9.1Hz ,0.5H),5.53(t,J＝5.6Hz,1H),4.68–4.56(m,1H),4.12-4.08(m,1H),2.93-2.82(m,3H),2.71–2.29(m, 7H), 2.26(2,3H), 2.11–1.90(m,2H).

LCMS: m/z 588.2 (M+H) ⁺ , RT=1.91min.

Example 8: Compound 21

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A22, isocyan intermediate B2 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyrimidine to obtain the compound twenty one.

Compound 21: (2S)-1-(4-cyanopyrimidin-2-yl)-N-(1-((4,4-difluorocyclohexyl)carbamoyl)-2,3-dihydro-1H -Inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ9.0-8.9(m,1H),7.6(d,1H),7.3–7.4(m,3H),7.2(d,1H),6.8-7.0(m, 2H),6.7(dd,1H),5.5-5.3(m,1H),4.6(m,2H),3.7-3.9(m,2H),2.8-3.2(m,4H),2.4–2.7(m, 2H),2.3(m,2H),1.7–2.1(m,4H),1.3–1.5(m,2H).

LCMS: m/z 621.0 (M+H) ⁺ , RT=1.61min.

Example 9: Compound 22

Using the same method as in Example 1, the product obtained by reacting imine intermediate A16, isocyan intermediate B1 and acid intermediate C5 was reacted with 2-chloro-4-cyanopyrimidine to obtain compound 22.

Compound 22: (2S)-3-(4-cyanopyrimidin-2-yl)-N-(1–(3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H -Inden-1-yl)-N-(3,5-difluorophenyl)-2-oxooxazolidine-4-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ9.0-8.9(m,1H),7.3-7.6(m,3H),6.9-7.2(m,3H),6.7-6.9(m,2H),5.5- 5.7(m,1H),4.8(m,1H),4.4(m,1H),4.1-4.3(m,2H),2.7-3.2(m,4H),2.2–2.6(m,4H).

LCMS: m/z 595.1 (M+H) ⁺ , RT=1.45min.

Example 10: Compound 23

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A6, isocyan intermediate B2 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound twenty three.

Compound 23: (2S)-1-(4-cyanopyridin-2-yl)-N-(7-((4,4-difluorocyclohexane)carbamoyl)bicyclo[4.2.0]octane -1(6),2,4-trien-7-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.76(d, J=6.0Hz, 1H), 8.69–8.44(m, 3H), 8.28-8.02(m, 2H), 7.40-7.28(m, 1H) ,7.26-7.15(m,3H),5.75-5.50(m,1H),4.90-4.73(m,1H),3.79(s,1H),3.09–2.36(m,4H),2.31–1.19(m, 10H).

LCMS: m/z 561.1 (M+H) ⁺ , RT=1.72min.

Example 11: Compound 27

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A1, isocyan intermediate B3 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 27.

Compound 27: (2S)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxo-N-(1-((tetrahydro-2H-pyran -4-yl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-2-carboxamide.

¹ H NMR (MeOD-d ₄ , 400MHz): δ8.74-8.76(m,1H),8.16-8.54(m,1H),7.41-7.48(m,2H),7.32-7.33(m,2H), 6.84-7.21(m,5H),5.24-5.47(m,1H),4.62-4.68(m,1H),3.82-3.95(m,4H),3.39-3.45(m,2H),2.50-2.95(m ,5H),2.22-2.1(m,2H),1.99-2.04(m,3H).

LCMS: m/z 568.3 (M+H) ⁺ , RT=1.526min.

Example 12: Compound 28 and Compound 29

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A7, isocyan intermediate B2 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 28 and compound 29.

Compound 28: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((4,4-difluorocyclohexyl)carbamoyl)-6-fluoro- 2,3-Dihydro-1H-inden-1yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.75(s, 1H), 8.56-8.25(m, 4H), 7.82-7.47(m, 2H), 7.24-6.76(m, 2H), 5.49(dd, J＝44.3,7.8Hz,1H),4.59-4.51(m,1H),3.87(s,1H),3.10–2.74(m,4H),2.66–2.38(m,3H),2.26–2.17(m, 3H),2.11–1.94(m,6H).

LCMS: m/z 621.2 (M+H) ⁺ , RT=1.79min.

Compound 29: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((4,4-difluorocyclohexyl)carbamoyl)-6-fluoro- 2,3-Dihydro-1H-inden-1yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.80–8.55(m,2H),8.37–7.70(m,2H),7.34–7.01(m,5H),5.20(t,J＝8.5Hz,1H) ,4.59-4.51(m,1H),3.81(s,1H),2.96–2.14(m,4H),2.11–1.55(m,4H),1.48–1.10(m,8H).

LCMS: m/z 621.2 (M+H) ⁺ , RT=1.79min.

Example 13: Compound 30

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A8, isocyan intermediate B2 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 30.

Compound 30: (2S)-1-(4-cyanopyridin-2-yl)-N-(1-(4,4-difluorocyclohexyl)carbamoyl)-2,3-dihydro-1H- Inden-1-yl)-5-oxo-N-(3-methoxyphenyl)pyrrolidine-2-carboxamide

¹ H-NMR(CDCl ₃ ,400MHz):8.72(s,1H),8.12(s,1H),7.51-7.35(m,3H),7.26-7.11(m,4H),6.95-6.93(m,1H ),6.61-6.52(m,1H),5.47-5.43(m,1H),4.70-4.66(m,1H),3.86(s,3H),3.64(s,1H),2.92-2.46(m,4H ),2.34-1.67(m,9H),1.41-1.32(m,3H).

LCMS: m/z 614 (M+H) ⁺ , RT=1.558min.

Example 14: Compound 31

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A9, isocyan intermediate B2 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 31.

Compound 31: (2S)-1-(4-cyanopyridin-2-yl)-N-(1-(4,4-difluorocyclohexyl)carbamoyl)-2,3-dihydro-1H- Inden-1-yl)-5-oxo-N-(3-methylphenyl)pyrrolidine-2-carboxamide

¹ H-NMR(CDCl3 400MHz):8.74-8.75(m,1H),8.14-8.71(m,1H),7.31-7.49(m,3H),7.02-7.21(m,5H),6.87(s,1H ),5.32-5.55(m,1H),4.63-4.71(m,1H),3.82-3.84(m,1H),2.83-2.89(m,3H),2.34-2.54(m,4H),2.20-2.33( m, 5H), 1.63-1.67 (m, 4H), 1.29-1.34 (m, 2H).

LCMS: m/z 598.2 (M+H) ⁺ , RT=1.76min.

Example 14: Compound 32 and Compound 33

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A2, tert-butyl isocyanate and L-pyroglutamic acid, and then reacting with 2-chloro-4-cyanopyridine to obtain compound 32 and Compound 33.

Compound 32: (S)-N-((S)-1-(tert-butylformyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl )-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.74 (d, J=7.3Hz, 1H), 8.59 (s, 1H), 8.54–8.48 (m, 1H), 8.29–8.24 (m, 1H), 7.98– 7.89(m,1H),7.30–7.27(m,1H),7.25–7.16(m,2H),7.16–7.07(m,1H),7.06–6.93(m,1H),5.59–5.44(m,1H ),4.62–4.53(m,1H),3.17–2.94(m,1H),2.94–2.79(m,3H),2.62–2.47(m,1H),2.43–2.31(m,1H),2.32–2.18 (m,1H),2.04–1.88(m,1H),1.31(s,5H),1.23(s,4H).

LCMS: m/z 541.1[M+H] ⁺ , RT=1.81min.

Compound 33: (S)-N-((R)-1-(tert-butylformyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl )-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.74(d, J=6.5Hz, 1H), 8.55–8.51(m, 1H), 8.31–8.26(m, 1H), 8.23–8.17(m, 1H), 7.92–7.85(m,1H),7.50–7.39(m,1H),7.34–7.28(m,1H),7.25–7.17(m,2H),7.13–7.06(m,1H),5.30–5.21(m ,1H),4.57–4.48(m,1H),2.95–2.70(m,2H),2.63–2.46(m,2H),2.38–2.19(m,2H),2.08–1.87(m,2H),1.21 (s,4H),1.21(s,5H).

LCMS: m/z 541.1[M+H] ⁺ , RT=1.8min.

Example 15: Compound 34

Using the same method as in Example 1, the product obtained by reacting imine intermediate A2, isocyan intermediate B2 and L-pyroglutamic acid was reacted with 2-chloropyrimidine to obtain compound 34.

Compound 34: (2S)-N-(1-(4,4-difluorocyclohexyl)formyl)-2,3-dihydro-1H-inden-1yl)-N-(5-fluoropyridine-3 -yl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.74–8.60(m,1H),8.59–8.51(m,2H),8.43–8.25(m,1H),7.86–7.75(m,1H),7.55–7.43 (m,1H),7.38–7.28(m,1H),7.25–6.92(m,3H),5.61–5.31(m,1H),4.54–4.43(m,1H),3.93–3.77(m,1H) ,3.00–2.77(m,2H),2.67–2.49(m,2H),2.47–2.15(m,2H),2.11–1.67(m,8H),1.45–1.23(m,2H).

LCMS: m/z 579.2[M+H] ⁺ , RT=1.61min.

Example 16: Compound 35

Using the same method as in Example 1, the product obtained by reacting imine intermediate A2, isocyan intermediate B2 and L-pyroglutamic acid was reacted with 3-chlorobenzonitrile to obtain compound 35.

Compound 35: (2S)-1-(3-cyanophenyl)-N-(1-(N-(4,4-difluorocyclohexyl)formyl)-2,3-dihydro-1H-indene -1 base)-N-(5-fluoro-3-pyridyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.63–8.36(m,1H),8.18–7.93(m,1H),7.80–7.56(m,2H),7.53–7.38(m,2H),7.37–7.27 (m,2H),7.23–7.16(m,1H),7.15–7.03(m,1H),7.02–6.94(m,1H),5.51–5.24(m,1H),4.35–4.18(m,1H) ,4.00–3.63(m,1H),3.04–2.62(m,2H),2.60–2.41(m,1H),2.41–2.15(m,2H),2.13–1.92(m,4H),1.94–1.69( m,4H),1.46–1.20(m,3H).

LCMS: m/z 602.2[M+H] ⁺ , RT=1.74min.

Example 17: Compound 36 and Compound 37

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A10, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 36 and compound 37.

Compound 36: (S)-N-((S)-1-((4,4-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1-yl)-1- (4-cyanopyridin-2-yl)-N-(3-chlorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR (CDCl ₃ , 400MHz): 8.74(s, 1H), 8.54(dd, J=4.8Hz, J=24Hz, 1H), 7.44(d, J=14Hz, 1H), 7.25-7.14(m ,6H),7.06(d,J=2.8Hz,1H),5.77(t,J=5.2Hz,1H),4.66(d,J=6.8Hz,1H),4.15-4.10(m,1H),2.95 -2.86(m,5H),2.58-2.48(m,2H),2.44-2.27(m,3H),2.18-2.12(m,1H),2.10-1.93(m,1H).

LCMS: m/z 590.1 (M+H) ⁺ , RT=1.59min.

Compound 37: (S)-N-((R)-1-((4,4-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1-yl)-1- (4-cyanopyridin-2-yl)-N-(3-chlorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR (CDCl ₃ , 400MHz): 8.77(s, 1H), 8.21(dd, J=4.8Hz, J=23.2Hz, 1H), 7.52-7.04(m, 9H), 5.51(s, 1H) ,4.62(d,J＝6.8Hz,1H),4.15-4.10(m,1H),2.89-2.74(m,4H),2.61-2.51(m,2H),2.39-2.14(m,4H),2.07 -1.96(m,2H).

LCMS: m/z 590.1 (M+H) ⁺ , RT=1.606min.

Example 18: Compound 39

Using the same method as in Example 1, the product obtained by reacting imine intermediate A2, isocyan intermediate B2 and L-pyroglutamic acid was reacted with 2-fluoropyridine to obtain compound 39.

Compound 39: (2S)-N-(1-((4,4-difluorocyclohexyl)formyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-fluoropyridine -2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.63–8.49(m,1H),8.39–8.18(m,2H),8.05–7.98(m,1H),7.83–7.69(m,1H),7.46–7.37 (m,1H),7.36–7.28(m,1H),7.24–7.07(m,1H),7.04–6.90(m,1H),6.83–6.75(m,1H),5.62–5.21(m,1H) ,4.60–4.47(m,1H),3.98–3.68(m,1H),3.15–2.75(m,2H),2.62–2.49(m,2H),2.47–2.29(m,1H),2.26–2.12( m,1H),2.10–1.68(m,8H),1.39–1.22(m,2H).

LCMS: m/z 596.2[M+H] ⁺ .

Example 19: Compound 40

Using the same method as in Example 1, the product obtained by reacting imine intermediate A11, isocyan intermediate B1 and L-pyroglutamic acid was reacted with 2-chloropyridine to obtain compound 40.

Compound 40: (2S)-N-(5-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1 -(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.76(s,1H),8.64–8.43(m,2H),8.41–8.20(m,2H),7.81–7.52(m,1H),7.42–7.30(m ,1H),7.05-7.22(m,2H),5.95–5.42(m,1H),4.69–4.39(m,1H),4.05-4.22(m,1H),3.00–2.74(m,4H),2.66 –1.75(m,8H).

LCMS: m/z 609.2[M+H] ⁺ , RT=1.81min.

Example 20: Compound 41 and Compound 42

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A2, isocyan intermediate B1 and L-pyroglutamic acid, and then reacting with 2-bromo-4-chloropyridine to obtain compound 41 and compound 42.

Compound 41: (S)-1-(4-chloropyridin-2-yl)-N-((S)-1((3,3-difluorocyclobutyl)formyl)-2,3-dihydro -1H-inden-1-yl)-1-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (500MHz, CDCl ₃ )δ8.60–8.54(m,1H),8.52(s,1H),8.43–8.34(m,1H),8.24(d,J＝5.2Hz,1H),7.79– 7.73(m,1H),7.25–7.21(m,2H),7.20–7.14(m,1H),7.11–7.07(m,1H),7.02–6.95(m,1H),5.96–5.85(m,1H ),4.67–4.52(m,1H),4.23-4.21(m,1H),3.18–2.83(m,5H),2.67–2.41(m,3H),2.37–2.27(m,1H),2.25–2.14 (m,1H),2.10–1.88(m,1H),1.72–1.57(m,1H).

LCMS: m/z 584.1[M+H] ⁺ , RT=1.81min.

Compound 42: (S)-1-(4-chloropyridin-2-yl)-N-((R)-1((3,3-difluorocyclobutyl)formyl)-2,3-dihydro -1H-inden-1-yl)-1-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (500MHz, CDCl ₃ ) δ8.65–8.56 (m, 1H), 8.54 (s, 1H), 8.53–8.33 (m, 1H), 7.98 (d, J=5.2Hz, 1H), 7.76– 7.70(m,1H),7.50–7.40(m,1H),7.39–7.33(m,1H),7.34–7.30(m,1H),7.18–7.11(m,1H),7.09–7.02(m,1H ),5.69–5.47(m,1H),4.65–4.49(m,1H),4.19–4.05(m,1H),3.02–2.75(m,4H),2.66–2.49(m,2H),2.45–2.14 (m,4H),2.10–1.94(m,2H).

LCMS: m/z 584.1[M+H] ⁺ , RT=1.81min.

Example 21: Compound 43 and Compound 44

Using the same method as in Example 1, the product obtained by reacting imine intermediate A12, isocyan intermediate B1 and L-pyroglutamic acid was reacted with 2-chloropyridine to obtain compound 43 and compound 44.

Compound 43: (S)-N-((S)-7-chloro-1-((3,3-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1yl) -1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.76(s,1H), 8.51–8.41(m,1H), 7.55–7.46(m,1H), 7.34–7.27(m,1H), 7.24–7.20(m ,1H),7.16–7.11(m,1H),7.08–7.02(m,1H),7.00–6.92(m,1H),6.90–6.84(m,1H),6.83–6.70(m,1H),6.02 –5.90(m,1H),4.69(dd,J＝6.3,3.0Hz,1H),4.36–4.20(m,1H),3.41–3.25(m,1H),3.23–3.10(m,1H),3.10 –2.99(m,1H),2.99–2.84(m,3H),2.72–2.49(m,3H),2.48–2.17(m,3H),2.10–1.87(m,1H).

LCMS: m/z 608.2[M+H] ⁺ , RT＝1.84min.

Compound 44: (S)-N-((R)-7-chloro-1-((3,3-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1yl) -1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.72(s,1H),8.57–8.49(m,1H),7.57–7.38(m,1H),7.31–7.26(m,1H),7.25–7.19(m ,1H),7.15–7.05(m,3H),7.05–6.98(m,1H),6.96–6.82(m,1H),6.81–6.72(m,1H),4.73–4.62(m,1H),4.04 –3.93(m,1H),3.27–3.14(m,1H),3.09–2.94(m,2H),2.91–2.79(m,3H),2.77–2.65(m,1H),2.62–2.48(m, 1H),2.40–2.18(m,2H),2.16–2.01(m,1H),1.90–1.74(m,1H).

LCMS: m/z 608.2[M+H] ⁺ , RT＝1.84min.

Example 22: Compound 46 and Compound 47

Using the same method as in Example 1, the product obtained by reacting imine intermediate A13, isocyan intermediate B1 and L-pyroglutamic acid was reacted with 2-chloropyridine to obtain compound 46 and compound 47.

Compound 46: (S)-N-((S)-6-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(s, 1H), 8.53(dd, J＝9.1, 5.2Hz, 1H), 7.38–7.01(m, 8H), 5.82(d, J＝6.3Hz ,1H),4.69-4.63(m,1H),4.15-4.11(m,1H),3.01–2.79(m,5H),2.62–2.25(m,5H),2.20–1.90(m,2H).

LCMS: m/z 608.2 (M+H) ⁺ , RT=1.90min.

Compound 47: (S)-N-((R)-6-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.77(s, 1H), 8.33(dd, J=5.0, 2.5Hz, 1H), 7.53–7.23(m, 5H), 7.23–7.11(m, 2H) ,6.92(dd,J=49.4,8.7Hz,1H),5.41(d,J=4.0Hz,1H),4.69–4.59(m,1H),4.13–3.99(m,1H),2.80-2.70(m ,4H),2.63–2.49(m,2H),2.44–2.16(m,4H),2.07-1.90(m,2H).

LCMS: m/z 608.2 (M+H) ⁺ , RT=1.88min.

Example 23: Compound 48 and Compound 49

Using the same method as in Example 1, using the imine intermediate A14, the isocyan intermediate B1 and L-pyroglutamic acid to react, the purified product was reacted with 2-chloropyridine to obtain compound 48 and compound 49.

Compound 48: (S)-N-((S)-5-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(s, 1H), 8.53(dd, J=14.9, 5.0Hz, 1H), 7.38–6.97(m, 8H), 5.85–5.73(m, 1H) ,4.72–4.59(m,1H),4.14–4.10(m,1H),3.03–2.79(m,5H),2.63–1.86(m,7H).

LCMS: m/z 608.2 (M+H) ⁺ , RT=1.90min.

Compound 49: (S)-N-((R)-5-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.76(s, 1H), 8.23(dd, J=11.7, 5.1Hz, 1H), 7.52–7.29(m, 4H), 7.25–7.21(m, 1H) ,7.19–7.05(m,2H),6.91(dd,J＝40.0,8.6Hz,1H),5.46(s,1H),4.63(dd,J＝6.6,2.8Hz,1H),4.09(s,1H ),2.96–2.71(m,4H),2.65–2.18(m,6H),2.08–1.92(m,2H).

LCMS: m/z 608.2 (M+H) ⁺ , RT=1.90min.

Example 24: Compound 50 and Compound 51

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A2, isocyan intermediate B1 and L-pyroglutamic acid, and then reacting with 2-chloropyrazine to obtain compound 50 and compound 51 .

Compound 50: (S)-N-((S)-1-((3,3-difluorocyclobutyl)formyl)2,3-dihydro-1H-inden-1-yl)-N-( 5-fluoropyridin-3-yl)-5-oxo-1-(pyrazin-2-yl)pyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ9.73(s,1H),8.64–8.57(m,1H),8.34–8.25(m,2H),8.08(s,1H),7.85–7.76(m,1H ),7.50–7.42(m,1H),7.30–7.26(m,1H),7.20–7.11(m,1H),7.02–6.95(m,1H),6.00–5.70(m,1H),4.55–4.44 (m,1H),4.26–4.04(m,1H),3.03–2.75(m,4H),2.64–2.51(m,2H),2.39–2.18(m,3H),2.16–1.90(m,3H) .

LCMS: m/z 551.1[M+H] ⁺ , RT=1.62min.

Compound 51: (S)-N-((R)-1-((3,3-difluorocyclobutyl)formyl)2,3-dihydro-1H-inden-1-yl)-N-( 5-fluoropyridin-3-yl)-5-oxo-1-(pyrazin-2-yl)pyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ9.73(s,1H),8.64–8.57(m,1H),8.45–8.33(m,2H),8.08(s,1H),7.85–7.76(m,1H ),7.50–7.42(m,1H),7.41–7.33(m,1H),7.20–7.11(m,1H),7.09–7.02(m,1H),5.65–5.56(m,1H),4.55–4.44 (m,1H),4.26–4.04(m,1H),3.07–2.79(m,4H),2.65–2.51(m,3H),2.22–2.18(m,2H),2.16–1.90(m,3H) .

LCMS: m/z 551.1[M+H] ⁺ , RT=1.62min.

Example 25: Compound 52 and Compound 53

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A1, isocyan intermediate B1 and L-pyroglutamic acid, and then reacting with 2-chloro-4-trifluoromethylpyridine, Compound 52 and Compound 53 were obtained

Compound 52: (S)-N-((S)-1-(N-(3,3-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1yl)-N -(3-fluorophenyl)-5-oxo-1-(4-trifluoromethylpyridin-2-yl)-pyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.71(s, 1H), 8.57-8.52(m, 1H), 7.31-7.27(m, 1H), 7.25-7.09(m, 6H), 7.05-6.92(m ,2H),5.85–5.77(m,1H),4.74–4.63(m,1H),4.21–3.95(m,1H),2.99–2.79(m,5H),2.68–2.48(m,2H),2.46 –2.27(m,3H),2.20–2.09(m,1H),2.02–1.91(m,1H).

LCMS: m/z 617.2[M+H] ⁺ , RT=1.93min.

Compound 53: (S)-N-((R)-1-(N-(3,3-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1yl)-N -(3-fluorophenyl)-5-oxo-1-(4-trifluoromethylpyridin-2-yl)-pyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.74(s,1H),8.34–8.10(m,1H),7.51–7.40(m,2H),7.40–7.26(m,3H),7.25–7.20(m ,1H),7.17–7.09(m,2H),7.04–6.86(m,1H),5.63–5.42(m,1H),4.73–4.62(m,1H),4.17–3.90(m,1H),2.96 –2.82(m,3H),2.81–2.68(m,1H),2.65–2.45(m,2H),2.38–2.17(m,4H),2.11–1.89(m,2H).

LCMS: m/z 617.2[M+H] ⁺ , RT=1.95min.

Example 26: Compound 54 and Compound 55

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A1, isocyan intermediate B1 and L-pyroglutamic acid, and then reacting with 2-chloro-4-methoxypyridine to obtain Compound 54 and Compound 55.

Compound 54: (S)-N-((S)-1-((3,3,-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1-yl)-N -(3-fluorophenyl)-1-(4-methoxypyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.25–8.09(m,1H),7.97(s,1H),7.39–7.27(m,1H),7.24–7.08(m,4H),7.07–6.92(m ,3H),6.69–6.62(m,1H),6.10–5.90(m,1H),4.74–4.64(m,1H),4.21–4.06(m,1H),3.88(s,3H),2.91–2.80 (m,5H),2.62–2.40(m,3H),2.37–2.22(m,2H),2.13–1.97(m,1H),1.96–1.81(m,1H).

LCMS: m/z 579.2[M+H] ⁺ , RT＝1.84min.

Compound 55: (S)-N-((R)-1-((3,3,-difluorocyclobutyl)formyl)-2,3-dihydro-1H-inden-1-yl)-N -(3-fluorophenyl)-1-(4-methoxypyridin-2-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.06 (d, J=2.1Hz, 1H), 7.97–7.87 (m, 1H), 7.46–7.26 (m, 4H), 7.24–7.19 (m, 1H), 7.14–6.96(m,3H),6.67–6.53(m,1H),5.73–5.54(m,1H),4.70–4.60(m,1H),4.15–4.00(m,1H),3.87(s,3H ),2.95–2.75(m,4H),2.68–2.58(m,1H),2.56–2.45(m,1H),2.45–2.35(m,1H),2.35–2.23(m,2H),2.20–2.10 (m,1H),2.07–1.89(m,2H).

LCMS: m/z 579.2[M+H] ⁺ , RT＝1.84min.

Example 27: Compound 56 and Compound 57

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A15, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 56 and compound 57.

Compound 56: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3,-difluorocyclobutyl)formyl)-4-chloro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(s, 1H), 8.62-8.47(m, 1H), 7.35-7.27(m, 2H), 7.25-7.17(m, 2H), 7.17-7.08( m,2H),7.08-6.96(m,2H),5.88-5.69(m,1H),4.74-4.58(m,1H),4.21-4.01(m,1H),3.07-2.77(m,5H), 2.65-2.42(m,3H),2.41-2.22(m,2H),2.20-2.04(m,1H),2.00-1.89(m,1H).

LCMS: m/z 609.2[M+H] ⁺ ; RT=1.89min.

Compound 57: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3,-difluorocyclobutyl)formyl)-4-chloro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.7(d, J=1.1Hz, 1H), 8.38-8.08(m, 1H), 7.53-7.29(m, 4H), 7.25-7.20(m, 1H) ,7.18-7.12(m,1H),7.11-7.04(m,1H),6.96-6.82(m,1H),5.49(d,J=6.1Hz,1H),4.62(dd,J=9.3,3.0Hz ,1H),4.18-3.97(m,1H),2.98-2.81(m,3H),2.72-2.59(m,1H),2.61-2.48(m,1H),2.47-2.15(m,4H),2.13 -1.92(m,2H).

LCMS: m/z 609.2[M+H] ⁺ ; RT=1.89min

Example 28: Compound 58 and Compound 59

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A16, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 58 and compound 59.

Compound 58: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3,-difluorocyclobutyl)formyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(3-chloro-5-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl3 400MHz):δ8.74(m,1H),8.54-8.50(m,1H),7.30(m,1H),7.24-7.13(m,4H),7.10-7.01(m,3H ),5.76(m,1H),4.67-4.65(m,1H),4.30-4.12(m,1H),2.95-2.87(m,2H),2.57-2.55(m,2H),2.44-2.37(m ,2H),2.18-2.13(m,1H),2.04-2.00(m,1H),1.59-1.27(m,2H),0.98-0.85(m,2H).

LCMS: m/z 608.2[M+H] ⁺ , RT=1.748min.

Compound 59: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3,-difluorocyclobutyl)formyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(3-chloro-5-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl3 400MHz):δ8.77(s,1H),8.23-8.18(m,1H),7.48-7.39(m,1H),7.38-7.29(m,3H),7.23-7.10(m ,3H),5.49(m,1H),4.65-4.63(m,1H),4.08(s,1H),2.92-2.77(m,2H),2.65-2.54(m,2H),2.31-2.27(m ,2H),2.08-1.97(m,2H),1.27-1.25(m,2H),0.98-0.85(m,2H).

LCMS: m/z 608.2[M+H] ⁺ , RT=1.75min.

Example 28: Compound 60 and Compound 61

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A1, isocyan intermediate B4 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 60 and compound 61.

Compound 60: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(phenylcarbamoyl)-2,3-dihydro-1H-indene-1 -yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR(MeOD-d ₄ ,400MHz):δ8.73(s,1H),8.58-8.54(m,1H),7.41-7.29(m,9H),7.08-7.01(m,6H),4.73- 4.71(m,1H),2.98-2.88(m,3H),2.61-2.55(m,3H),2.17-1.98(m,2H).

LCMS: m/z 560.2 (M+H) ⁺ ; RT = 1.72min.

Compound 61: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(phenylcarbamoyl)-2,3-dihydro-1H-indene-1 -yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (MeOD-d ₄ , 400MHz): δ8.76s, 1H), 8.22-8.21(m, 1H), 7.58-7.33(m, 6H), 7.24-7.01(m, 9H), 4.68-4.67( m,1H),2.91-2.24(m,2H),2.57-2.01(m,6H).

LCMS: m/z 560.2 (M+H) ⁺ ; RT = 1.72min.

Example 29: Compound 62 and Compound 63

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A1, isocyan intermediate B1 and acid intermediate C5, and then reacting with 2-chloro-4-cyanopyridine to obtain compound 62 and Compound 63.

Compound 62: (S)-3-(4-cyanopyridin-2-yl)-N-((S)-1-(3,3-difluorocyclobutyl)carbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)2-oxooxazolidine-4-carboxamide

¹ H NMR(MeOD-d ₄ ,400MHz):δ8.52-8.4(m,2H),7.32-7.01(m,9H),5.77(m,1H),4.83-4.82(m,1H),4.41- 4.13(m,3H),2.96-2.29(m,8H).

LCMS: m/z 576.2 (M+H) ⁺ ; RT = 1.66min.

Compound 63: (S)-3-(4-cyanopyridin-2-yl)-N-((R)-1-(3,3-difluorocyclobutyl)carbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide

¹ H NMR(MeOD-d ₄ ,400MHz):δ8.56(s,1H),8.21-8.17(m,1H),7.49-6.83(m,9H),5.52(m,1H),4.83-4.79( m,1H),4.49-4.1(m,3H),2.96-1.98(m,8H).

LCMS: m/z 576.2 (M+H) ⁺ ; RT = 1.66min.

Example 30: Compound 64 and Compound 65

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A17, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 64 and compound 65.

Compound 64: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-6-fluoro -2,3-Dihydro-1H-inden-1-yl-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(s, 1H), 8.53(dd, J=9.8, 5.1Hz, 1H), 7.35-6.93(m, 8H), 5.81(d, J=6.0Hz ,1H),4.66(dd,J=8.6,2.8Hz,1H),4.12(d,J=7.1Hz,1H),2.95-2.83(m,5H),259-2.25(m,5H),2.18- 1.85(m,2H).

LCMS: m/z 592.2 (M+H) ⁺ ; RT = 1.83min.

Compound 65: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-6-fluoro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.71(s, 1H), 8.25(dd, J=7.4, 5.2Hz, 1H), 7.47-7.27(m, 2H), 7.24-7.21(m, 1H) ,7.19-7.07(m,3H),7.04-6.97(m,1H),6.89(dd,J＝43.0,8.6Hz,1H),5.57(d,J＝5.7Hz,1H),4.67-4.60(m ,1H),4.17-3.94(m,1H),2.95-2.62(m,4H),2.59-2.13(m,5H),2.05-1.83(m,3H).

LCMS: m/z 592.2 (M+H) ⁺ ; RT = 1.84min.

Example 31: Compound 66

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A18, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 66.

Compound 66: (2S)-1-(4-cyanopyridin-2-yl)-N-(1-((3,3-difluorocyclobutyl)carbamoyl)-4-(trifluoromethyl )-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.82-8.67(m,1H),8.57-8.15(m,1H),7.76-7.57(m,1H),7.53-6.79(m,7H),5.94- 5.38(m,1H),4.63(dd,J=9.3,3.1Hz,1H),4.10(s,1H),3.22-2.70(m,4H),2.62-1.81(m,8H).

LCMS: m/z 642.2 (M+H) ⁺ ; RT = 1.92min.

Example 32: Compound 67 and Compound 68

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A19, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 67 and compound 68.

Compound 67: (S)-N-(4-chloro-3-fluorophenyl)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3- Difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.74(s, 1H), 8.53-8.48(dd, J 1=4.8Hz, J 2=15.2Hz1H), 7.37-7.30(m, 1H), 7.23-7.18(m,6H),7.07(s,1H),5.75(s,1H),4.66-4.64(d,J＝6.8Hz,1H),4.11(s,1H),2.95-2.84(m, 5H),2.62-2.52(m,2H),2.43-2.27(m,3H),2.16-2.11(m,1H),2.02-1.94(m,1H).

LCMS: m/z 608.2 (M+H) ⁺ , RT=1.75min.

Compound 68: (S)-N-(4-chloro-3-fluorophenyl)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3- Difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.77(s,1H), 8.20-8.16(dd, J 1=4.0Hz, J 2=12.8Hz1H), 7.53-7.47(m,1H), 7.42-7.35(m,3H),7.23-7.22(m,2H),7.12(s,1H),6.95(t,1H),5.49(s,1H),4.64-4.62(m,1H),4.08( s,1H),2.88-2.77(m,4H),2.60-2.57(m,2H),2.38-2.24(m,4H),2.03-1.98(m,2H).

LCMS: m/z 608.2 (M+H) ⁺ ; RT = 1.76min.

Example 33: Compound 69 and Compound 70

Using the same method as in Example 1, the product obtained after the reaction of imine intermediate A20, isocyan intermediate B1 and L-pyroglutamic acid is used, and then reacted with 2-chloro-4-cyanopyridine to obtain the compound 69 and compound 70.

Compound 69: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-5-oxo-N-phenylpyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.72(s, 1H), 8.56-8.54(d, J=4.8Hz, 1H), 7.41(s, 1H), 7.30-7.28(m, 6H ),7.19(s,2H),7.04(s,1H),5.81-5.80(d,J=5.6Hz,1H),4.68-4.66(d,J=6.0Hz,1H),4.11(s,1H) ,2.91-2.83(m,5H),2.55-2.26(m,1H),2.16-2.10(m,1H),1.98-1.88(m,1H).

LCMS: m/z 556.2 (M+H) ⁺ ; RT = 1.64min.

Compound 70: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-5-oxo-N-phenylpyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.76(s, 1H), 8.20-8.21(d, J=4.0Hz, 1H), 7.58-7.60(d, J=6.8Hz, 1H), 7.47-7.48(d, J=7.2Hz, 2H), 7.40(t, 1H), 7.31-7.33(d, J=6.4Hz, 2H), 7.20-7.23(m, 2H), 7.11(s, 2H) ,5.53-5.54(d,J=4.8Hz,1H),4.62-4.64(d,J=8.4Hz,1H),4.09(m,1H),2.82-2.88(m,3H),2.71-2.78(m ,1H),2.54-2.55(m,2H),2.27-2.37(m,4H),1.95-2.04(m,2H).

LCMS: m/z 556.2 (M+H) ⁺ ; RT = 1.66min.

Example 34: Compound 71 and Compound 72

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A21, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 71 and compound 72.

Compound 71: (S)-N-(3,4-difluorophenyl)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-di Fluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrole-2-carboxamide

¹ H NMR(MeOD-d ₄ ,400MHz):δ8.74(s,1H),8.54-8.48(m,1H),7.40-6.97(m,8H),5.79-5.78(m,1H),4.67- 4.65(d, J=8.8Hz, 1H), 4.1(m, 1H), 2.9-2.8(m, 5H), 2.7-2.2(m, 6H), 1.9(m, 1H).

LCMS: m/z 592.2 (M+H) ⁺ ; RT = 1.69min.

Compound 72: (S)-N-(3,4-difluorophenyl)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-di Fluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrole-2-carboxamide

¹ H NMR (MeOD-d ₄ , 400MHz): δ8.77(s, 1H), 8.21-8.17(m, 1H), 7.42-6.96(m, 8H), 5.52(m, 1H), 4.64-4.62( m,1H),4.08(m,1H),2.9-2.8(m,4H),2.6-2.5(m,2H),2.5-2.2(m,4H),2.1-1.9(m,2H).

LCMS: m/z 592.2 (M+H) ⁺ ; RT = 1.691 min.

Example 35: Compound 73 and Compound 74

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A22, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 73 and compound 74.

Compound 73 (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3-di Hydrogen-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR (CDCl ₃ , 400MHz): δ8.74(s, 1H), 8.52(d, J=4.8Hz, 1H), 7.26-7.20(m, 5H), 7.07-7.05(m, 2H), 6.91-6.89(m,1H),6.76-6.72(m,1H),5.77(m,1H),4.67-4.69(m,1H),4.14-4.09(m,1H),2.98-2.85(m,5H ),2.61-2.54(m,2H),2.45-2.40(m,3H),2.38-2.30(m,1H).

LCMS: m/z 5921[M+H] ⁺ ; RT=1.8min.

Compound 74: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR (CDCl ₃ , 400MHz): δ8.77(s, 1H), 8.20(d, J=4.8Hz, 1H), 7.42-7.21(m, 5H), 7.13-7.10(m, 1H), 6.93 -6.92(m,1H),6.74-6.72(m,1H),5.49(s,1H),4.67-4.64(m,1H),4.08(s,1H),2.77-2.85(m,4H),2.65 -2.54(m,2H),2.38-2.26(m,3H),2.11-1.98(m,2H).

LCMS: m/z 5921[M+H] ⁺ ; RT=1.7min.

Example 36: Compound 75 and Compound 76

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A23, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 75 and compound 76.

Compound 75: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3,-difluorocyclobutyl)formyl)-5-fluoro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.73 (d, J = 1.0Hz, 1H), 8.52 (dd, J = 13.5, 5.1Hz, 1H), 7.35-7.27 (m, 1H), 7.25-7.08 ( m,4H),7.06-6.97(m,1H),6.92-6.85(m,1H),6.76-6.69(m,1H),5.89-5.77(m,1H),4.70-4.60(m,1H), 4.20-4.04(m,1H),3.01-2.77(m,5H),2.69-2.41(m,3H),2.40-2.24(m,2H),2.18-2.08(m,1H),2.03-1.89(m ,1H).

LCMS: m/z 592.1 [M+H] ⁺ ; RT = 1.85min.

Compound 76: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3,-difluorocyclobutyl)formyl)-5-fluoro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.76(s, 1H), 8.31-8.20(m, 1H), 7.53-7.31(m, 3H), 7.25-7.08(m, 2H), 7.02-6.75(m ,3H),5.74-5.44(m,1H),4.79-4.46(m,1H),4.22-3.94(m,1H),3.00-2.67(m,4H),2.66-2.47(m,2H),2.40 -2.18(m,4H),2.10-1.94(m,2H).

LCMS: m/z 592.1 [M+H] ⁺ ; RT = 1.86min.

Example 37: Compound 77 and Compound 78

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A24, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 77 and compound 78.

Compound 77: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl-4-fluoro- 2,3-Dihydro-1H-inden-1-yl-)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.73(s, 1H), 8.54(dd, J=15.8, 4.4Hz, 1H), 7.35-6.84(m, 8H), 5.85-5.74(m, 1H) ,4.70-4.61(m,1H),4.11(s,1H),3.06-2.80(m,5H),2.65-1.89(m,7H).

LCMS: m/z 592.2[M+H] ⁺ ; RT=1.86min.

Compound 78: (S)-1-(4-cyanopyridin-2-yl)-N–((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-fluoro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.76(s, 1H), 8.19(dd, J=17.6, 5.1Hz, 1H), 7.48(dd, J=14.4, 8.1Hz, 1H), 7.43-7.01 (m,6H),6.90(dd,J=39.4,8.5Hz,1H),5.52(d,J=6.0Hz,1H),4.62(dd,J=9.3,2.8Hz,1H),4.10(s, 1H),2.95-2.50(m,6H),2.47-2.18(m,4H),2.13-1.90(m,2H).

LCMS: m/z 592.1 [M+H] ⁺ ; RT = 1.87min.

Example 37: Compound 79 and Compound 80

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A25, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 79 and compound 80.

Compound 79: (S)-N-((S)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.75(s, 1H), 8.48(dd, J=30.3, 3.8Hz, 2H), 8.38-8.22(m, 1H), 7.62(dd, J=96.1, 8.5Hz,1H),7.31-7.24(m,1H),7.21-7.13(m,1H),7.10-6.90(m,2H),5.84(m,1H),4.63-4.49(m,1H),4.22 -4.15(m,1H),3.11-2.82(m,5H),2.63-2.45(m,2H),2.26-2.20(m,2H),2.08-1.96(m,2H).

LCMS: m/z 609.1 [M+H] ⁺ ; RT=1.80min.

Compound 80: (S)-N-((R)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.76 (d, J = 8.5Hz, 1H), 8.64-8.27 (m, 2H), 8.20 (dd, J = 10.3, 5.0Hz, 1H), 7.79-7.34 (m,2H),7.34-7.20(m,2H),7.10(t,J=7.9Hz,1H),5.53(m,1H),4.53(t,J=9.4Hz,1H),4.13-4.09( m,1H),2.96-2.77(m,4H),2.56-2.62(m,2H),2.45-2.19(m,4H),1.94-2.13(m,2H).

LCMS: m/z 609.1 [M+H] ⁺ ; RT = 1.81 min.

Example 39: Compound 81 and Compound 82

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A26, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 81 and compound 82. Compound 81: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(2,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl ₃ ,400MHz):δ8.72(s,1H),8.48-8.40(m,1H),7.39-7.10(m,5H),6.99-6.94(m,3H),6.68-6.67 (m,1H),5.90(s,1H),4.68-4.64(m,1H),4.20-4.19(m,1H),3.05-2.88(m,5H),2.62-2.56(m,1H),2.45 -2.39(m,3H),2.38-2.31(m,1H).

LCMS: m/z 592.1 [M+H] ⁺ ; RT=1.8min.

Compound 82: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(2,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl ₃ ,400MHz):δ8.75(s,1H),8.32-8.24(m,1H),7.33-6.96(m,9H),5.73(s,1H),4.67-4.63(m ,1H),4.11(s,1H),2.89-2.80(m,4H),2.58-2.53(m,2H),2.34-2.29(m,3H).

LCMS: m/z 592.1 [M+H] ⁺ ; RT = 1.82min.

Example 40: Compound 83

Using the same method as in Example 1, the product obtained after the reaction of imine intermediate A27, isocyan intermediate B1 and L-pyroglutamic acid is used, and then reacted with 2-chloro-4-cyanopyridine to obtain the compound 83.

Compound 83: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3,-difluorocyclobutyl)formyl)-7-fluoro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.75(s, 1H), 8.44(dd, J=10.1, 5.1Hz, 1H), 7.39-7.32(m, 1H), 7.25-7.08(m, 2H) ,7.03-6.93(m,2H),6.92-6.78(m,1H),6.62-6.47(m,1H),6.13-5.98(m,1H),5.45-5.25(m,1H),4.70-4.61( m,1H),4.34-4.22(m,1H),3.14-3.08(m,2H),2.96-2.88(m,3H),2.64-2.51(m,1H),2.39-2.28(m,3H), 2.24-2.19(m,1H),2.12-2.00(m,2H).

LCMS: m/z 592.1 [M+H] ⁺ ; RT = 1.83min.

Example 40: Compound 84 and Compound 85

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A28, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 84 and compound 85.

Compound 84: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(2,3-difluorophenyl)-5-oxopyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.74(d, J=5.2Hz, 1H), 8.47-8.43dd, J 1=4.8Hz, J 2=8.8Hz 1H), 7.38(s, 1H),7.27-6.90(m,7H),6.59-5.89(m,1H),4.69-4.60(m,1H),4.20(s,1H),3.18-2.87(m,6H),2.77-2.15( m,6H).

LCMS: m/z 592.2[M+H] ⁺ ; RT=1.67min.

Compound 85: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(2,3-difluorophenyl)-5-oxopyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.75(s, 1H), 8.35-8.22(dd, J 1=4.8Hz, J 2=9.6Hz1H), 7.32-7.29(m, 2H), 7.21(s,3H),7.13-7.03(m,3H),6.01-5.73(m,1H),4.66-4.64(d,J＝8.8Hz,1H),4.11(s,1H),2.93-2.82( m,4H),2.67-2.54(m,2H),2.34-2.02(m,6H).

LCMS: m/z 592.2[M+H] ⁺ ; RT=1.67min.

Example 41: Compound 88 and Compound 89

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A29, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 88 and compound 89.

Compound 88: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methyl Oxy-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.72(s, 1H), 8.56-8.51(dd, J1=4.4Hz, J2=13.6Hz, 1H), 7.29(s, 1H), 7.22- 7.12(m,3H),7.05-6.99(dd,J1=8.0Hz,J2=16.4Hz,2H),6.85(t,1H),6.71(t,1H),5.75-5.74(d,J=4.8Hz ,1H),4.67-4.65(d,J＝8.8Hz,1H),4.11(s,1H),3.82(s,3H),2.90-2.77(m,5H),2.57-2.28(m,5H), 2.15-2.10(m,1H),2.01-1.95(m,1H).

LCMS: m/z 604.2[M+H] ⁺ ; RT=1.64min.

Compound 89: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methyl Oxy-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrole-2-carboxamide

¹ H-NMR (DMSO-d ₆ , 400MHz): δ8.76(s, 1H), 8.22-8.18(dd, J1=4.4Hz, J2=12.0Hz, 1H), 7.47-7.29(m, 2H), 7.21(t,1H),7.15-7.02(m,3H),6.96-6.83(d,J＝8.4Hz,2H),5.57(s,1H),4.63-4.61(m,1H),4.09(s, 1H),3.85(s,3H),2.88-2.82(m,3H),2.66-2.51(m,3H),2.40-2.26(m,4H),2.04-1.97(m,2H).

LCMS: m/z 604.2[M+H] ⁺ ; RT=1.65min.

Example 42: Compound 90

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A22, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyrimidine to obtain the compound 90.

Compound 90: (S)-1-(4-cyanopyrimidin-2-yl)-N-((S)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl3,400MHz):δ8.90(s,1H),7.29-6.85(m,7H),6.65-6.63(m,1H),5.73(s,1H),4.52-4.49(m, 1H),4.09(s,1H),2.9-2.6(m,5H),2.51-1.98(m,7H).

LCMS: m/z 593.3[M+H] ⁺ ; RT=1.3min.

Example 43: Compound 91

Using the same method as in Example 1, the product obtained by reacting imine intermediate A22, isocyan intermediate B1 and acid intermediate C5 was reacted with 2-chloro-4-cyanopyridine to obtain compound 91.

Compound 91: (S)-3-(4-cyanopyridin-2-yl)-N-((S)-1-(3,3-difluorocyclobutyl)carbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-2-oxooxazolidine-4-carboxamide

¹ H NMR (MeOD-d ₄ , 400MHz): δ8.5(s, 1H), 8.49-8.47(m, 1H), 6.74-7.22(m, 8H), 5.75(m, 1H), 4.85-4.82( m,1H),4.44-4.41(m,1H),4.27-4.15(m,2H),3.00-2.29(m,8H).

LCMS: m/z 594.2[M+H] ⁺ ; RT=1.7min.

Example 44: Compound 92 and Compound 93

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A30, isocyan intermediate B1 and L-pyroglutamic acid, and then reacting with 2-chloro-4-cyanopyridine to obtain the compound 92 and compound 93.

Compound 92: (S)-N-((S)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.74(s, 1H), 8.53(d, J=5.0Hz, 1H), 7.28(dd, J=5.1, 1.2Hz, 1H), 7.24(d, J =7.9Hz, 1H), 7.14(d, J=7.6Hz, 1H), 7.04(t, J=7.8Hz, 2H), 6.93(d, J=9.1Hz, 1H), 6.78(t, J=8.7 Hz,1H),5.77(d,J=6.3Hz,1H),4.67(dd,J=9.1,3.5Hz,1H),4.14-4.11(m,1H),3.06-2.82(m,5H),2.61 -2.53(m,2H),2.51-2.02(m,5H).

LCMS: m/z 626.1 [M+H] ⁺ ; RT = 1.91 min.

Compound 93: (S)-N-((R)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.77(s, 1H), 8.20(d, J=5.1Hz, 1H), 7.36(t, J=7.4Hz, 2H), 7.23(dt, J=9.3 ,4.7Hz,2H),7.09(t,J=7.9Hz,1H),6.97-6.89(m,1H),6.73(d,J=8.3Hz,1H),5.45(d,J=6.1Hz,1H ),4.64(dd,J＝9.3,3.0Hz,1H),4.10-4.09(m,1H),2.97-2.68(m,5H),2.61-2.55(m,1H),2.46-2.19(m,4H ),2.11-1.96(m,2H).

LCMS: m/z 626.2[M+H] ⁺ ; RT=1.93min.

Example 44: Compound 96 and Compound 97

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A1, isocyan intermediate B6 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 96 and compound 97.

Compound 96: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(cyclopropylmethylcarbamoyl)-2,3-dihydro-1H -Inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.8(s, 1H), 8.40(d, J=5.1Hz, 1H), 7.3-7.1(m, 6H), 7.1(m, 1H), 7.0-6.9 (m,2H),5.6(d,J=6.1Hz,1H),4.6(dd,J=9.3,3.0Hz,1H),3.2-2.8(m,4H),2.7-2.3(m,4H), 2.2(m,1H),1.9(m,1H),1.5(m,1H),0.8(m,1H),0.4(m,2H),0.1(m,2H).

LCMS: m/z 538.6 (M+H) ⁺ ; RT = 1.79min.

Compound 97: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(cyclopropylmethylcarbamoyl)-2,3-dihydro-1H -Inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.7(s, 1H), 8.10(d, J=5.1Hz, 1H), 7.4(m, 3H), 7.4-7.0(m, 5H), 7.0-6.7 (m,1H),5.4(d,J=6.1Hz,1H),4.6(dd,J=9.3,3.0Hz,1H),3.2(m,1H)2.9-2.6(m,4H),2.5(m ,2H),2.2(m,1H),1.9(m,1H),1.7(m,1H),0.7(m,1H),0.3(m,2H),0.0(m,2H).

LCMS: m/z 538.6[M+H] ⁺ ; RT=1.81min.

Example 46: Compound 98 and Compound 99

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A1, isocyan intermediate B5 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 98 and compound 99.

Compound 98: (S)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-N-((S)-1-(4,4-dimethylcyclohexane Formyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl ₃ ,400MHz):δ8.73(s,1H),8.53-8.49(m,1H),7.30-6.91(m,8H),5.43(s,1H),4.65(s,1H ),3.64(s,1H),3.50-3.47(m,1H),3.00-2.90(m,3H),2.56-2.48(m,3H),2.47-2.44(m,1H),2.01-1.98(m ,1H),1.97-1.95(m,1H),1.75-1.59(m,6H),1.24(s,3H),1.22(s,3H).

LCMS: m/z 594.2[M+H] ⁺ ; RT=1.83min.

Compound 99: (S)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-N-((R)-1-(4,4-dimethylcyclohexane Formyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl ₃ ,400MHz):δ8.76(s,1H),8.20-8.17(m,1H),7.47-6.88(m,8H),5.22(s,1H),4.65-4.63(m ,1H),3.64-3.62(m,1H),2.91-2.73(m,2H),2.60-2.55(m,2H),2.34-2.24(m,2H),2.03-1.95(m,2H),1.73 -1.70(m,1H),1.20-1.11(m,7H),0.85(s,3H),0.77(s,3H).

LCMS: m/z 594.2[M+H] ⁺ ; RT=1.86min.

Example 47: Compound 100

Using the same method as in Example 1, the product obtained by reacting imine intermediate A12, isocyan intermediate B1 and acid intermediate C5 was reacted with 2-chloro-4-cyanopyridine to obtain compound 100.

Compound 100: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3,-difluorocyclobutyl)formyl)-7-chloro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide

¹ H NMR (400MHz, DMSO): δ8.73(dd, J=23.0, 4.9Hz, 1H), 8.28(s, 1H), 8.16(d, J=6.6Hz, 1H), 7.65-7.56(m, 1H),7.55-7.48(m,1H),7.40-7.24(m,2H),7.21-7.02(m,2H),6.89-6.80(m,1H),6.73-6.53(m,1H),4.65- 4.53(m,2H),4.40-4.22(m,1H),4.21-4.08(m,1H),3.30-3.20(m,1H),3.17-3.05(m,1H),3.02-2.92(m,1H ),2.91-2.77(m,2H),2.74-2.50(m,3H).

LCMS: m/z=611.1[M+H] ⁺ ; RT=1.84min.

Example 48: Compound 101

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A1, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyrimidine to obtain the compound 101 (a pair of diastereomeric mixtures not resolved).

Compound 101: (2S)-N-(1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-(4- Cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl ₃ ,400MHz):δ8.90(s,1H),7.6(d,1H),7.2-7.4(m,7H),7.0(m,1H),5.5-5.7(m,1H ),4.6(m,1H),4.2(m,1H),3.2-2.7(m,4H),2.6-2.5(m,2H),2.4-2.3(m,4H),2.1-2.0(m,2H ).

LCMS: m/z 575.6[M+H] ⁺ ; RT=1.44min.

Example 49: Compound 102 and Compound 103

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A12, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyrimidine to obtain the compound 102 and compound 103.

Compound 102: (S)-1-(4-cyanopyrimidin-2-yl)-N-((S)-1-((3,3,-difluorocyclobutyl)formyl)-7-chloro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.94(d, J=4.3Hz, 1H), 7.62-7.46(m, 1H), 7.35-7.28(m, 1H), 7.25-7.17(m, 1H) ,7.13-7.02(m,2H),6.99-6.90(m,1H),6.90-6.77(m,2H),6.03-5.84(m,1H),4.53(d,J＝8.3Hz,1H),4.40 -4.18(m,1H),3.52-3.24(m,2H),3.15-2.78(m,4H),2.71-2.23(m,5H),2.13-1.91(m,1H).

LCMS: m/z=610.2[M+H] ⁺ ; RT=1.81min.

Compound 103: (S)-1-(4-cyanopyrimidin-2-yl)-N-((R)-1-((3,3,-difluorocyclobutyl)formyl)-7-chloro -2,3-Dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ): δ8.94(d, J=4.2Hz, 1H), 7.72-7.57(m, 1H), 7.56-7.46(m, 1H), 7.39-7.28(m, 1H) ,7.19-6.98(m,4H),6.78-6.69(m,1H),4.66-4.55(m,1H),4.01-3.86(m,1H),3.40-3.29(m,1H),3.09-2.96( m,2H),2.93-2.79(m,3H),2.77-2.51(m,2H),2.41-2.05(m,4H),1.88-1.75(m,1H).

LCMS: m/z=610.2[M+H] ⁺ ; RT=1.81min.

Example 50: Compound 104

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A30, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyrimidine to obtain the compound 104.

Compound 104: (S)-N–(S)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl )-1-(4-aminopyrimidin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamidecyclobutyl

¹ H NMR (400MHz, CDCl ₃ ) δ8.96 (dd, J=16.2, 4.7Hz, 1H), 7.49–7.31(m, 2H), 7.25–7.15(m, 2H), 7.13–6.99(m, 1H ),6.92(dd,J=34.9,8.9Hz,1H),6.78(t,J=8.7Hz,1H),5.88-5.47(m,1H),4.62–4.50(m,1H),4.12(s, 1H),3.16–3.00(m,1H),2.97–2.54(m,5H),2.50-2.0(m 5H),2.10–1.97(m,1H).

LCMS: m/z 627.0[M+H] ⁺ ; RT=1.80min.

Example 51: Compound 105 and Compound 106

Using the same method as in Example 1, the product obtained after the reaction of imine intermediate A2, isocyan intermediate B1 and acid intermediate C5 is used, and then reacted with 2-chloro-4-cyanopyridine to obtain compound 105 and Compound 106.

Compound 105: (S)-3-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-2-oxooxazolidine-4-carboxamide

¹ H-NMR(CDCl3400MHz):δ8.51-8.38(m,4H),7.88(m,1H),7.27-7.17(m,2H),7.05-6.96(m,3H),5.99-5.89(m, 1H),4.73-4.72(m,1H),4.47(s,1H),4.26-4.12(m,2H),2.99-2.88(m,2H),2.62-2.61(m,3H),2.03(m, 1H),1.23-1.27(m,1H),0.85-0.87(m,1H).

LCMS: m/z 577.3[M+H] ⁺ ; RT=1.70min.

Compound 106: (S)-3-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutane)carbamoyl)-2,3 -Dihydro-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-2-oxooxazolidine-4-carboxamide

¹ H-NMR (CDCl3400MHz): δ8.59-8.53 (m, 2H), 8.29-8.17 (m, 1H), 7.48-7.46 (m, 1H), 7.40-7.36 (m, 2H), 7.30-7.28 ( m,2H),7.27-7.25(m,1H),7.23-7.15(m,1H),5.62(m,1H),4.47(m,1H),4.31-4.27(m,1H),4.14-4.12( m,1H),4.11(m,1H),2.91-2.90(m,2H),2.53-2.51(m,1H),2.39-2.29(m,2H),2.04(m,1H),1.76m,1H ),1.27-1.24(m,1H).

LCMS: m/z 577.3[M+H] ⁺ ; RT=1.69min.

Example 52: Compound 107 and Compound 108

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A22, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-nitropyridine to obtain the compound 107 and compound 108.

Compound 107: (S)-1-(4-nitropyridin-2-yl)-N-((S)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR (CDCl ₃ , 400MHz): δ9.18(s, 1H), 8.60(d, J=6.4Hz, 1H), 7.76(d, J=3.2Hz, 1H), 7.26-7.21(m, 3H),7.07-7.05(m,2H),6.95-6.92(m,1H),6.77-6.75(m,1H),5.73(s,1H),4.74-4.71(m,1H),4.12(s, 1H),2.98-2.85(m,5H),2.44-2.40(m,3H),2.12-2.04(m,1H),2.02-1.98(m,1H).

LCMS: m/z 612.2[M+H] ⁺ ; RT=1.60min.

Compound 108: (S)-1-(4-nitropyridin-2-yl)-N-((R)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3- Dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR (CDCl ₃ , 400MHz): δ9.21(s, 1H), 8.29(d, J=5.6Hz, 1H), 7.74(d, J=3.6Hz, 1H), 7.41-7.21(m, 4H),7.13-7.10(m,1H),7.09-6.94(m,1H),6.76-6.74(m,1H),5.47(s,1H),4.71-4.68(m,1H),4.08(s, 1H),2.93-2.86(m,4H),2.60-2.79(m,2H),2.38-2.10(m,4H),2.06-2.01(m,2H).

LCMS: m/z 612.2 [M+H] ⁺ ; RT = 1.61 min.

Example 53: Compound 109 and Compound 110

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A33, isocyan intermediate B1 and acid L-pyroglutamic acid, reacted with 2-chloro-4-cyanopyrimidine to obtain Compound 109 and Compound 110.

Compound 109: (S)-1-(4-cyanopyrimidin-2-yl)-N-((S)-1-(3,3-difluorocyclobutylcarbamoyl)-7-methyl -2,3-Dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR(CDCl ₃ ,400MHz):δ8.9(s,1H),7.3(m,2H),7.2-7.1(m,2H),6.7(m,2H),6.4(m,1H), 5.7(d,1H),4.4(d,1H),4.3(m,1H),3.4-3.3(m,2H),3.2-2.8(m,4H),2.8-2.3(m,5H),2.10( m,1H),1.9(s,3H).

LCMS: m/z=607.6[M+H] ⁺ ; RT=1.52min.

Compound 110: (S)-1-(4-cyanopyrimidin-2-yl)-N-((R)-1-(3,3-difluorocyclobutylcarbamoyl)-7-methyl -2,3-Dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H-NMR (CDCl ₃ , 400MHz): δ9.0(s,1H),7.7(d,1H),7.5(d,1H),7.4(m,1H),7.3(m,2H),6.7( m,1H),6.3(d,1H),5.9(d,1H),4.7(m,1H),4.3(m,1H),3.1-2.8(m,6H),2.6-2.5(m,2H) ,2.4-2.3(m,2H),2.10(m,1H),1.9(s,3H).

LCMS: m/z=607.6[M+H] ⁺ ; RT=1.51min.

Example 54: Compound 111 and Compound 112

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A35, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 111 and compound 112.

Compound 111: (S)-7-((S)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2- Formamide)-N-(3,3-difluorocyclobutyl)-6,7-dihydro-5H-cyclopentapyridine-7-carboxamide

¹ H-NMR (CDCl ₃ , 400 MHz): δ8.7(s,1H),8.45(d,1H),8.3(d,1H),7.5(d,1H),7.22(d,1H),7.2 -6.9(m,3H),6.8(m,1H),4.7(m,1H),4.05(m,1H),3.4(m,1H),3.1-2.8(m,6H),2.6-2.5(m ,2H),2.4-2.3(m,2H),2.10(m,1H).

LCMS: m/z=593.0[M+H]+; RT=1.59 min.

Compound 112: (R)-7-((S)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2- Formamide)-N-(3,3-difluorocyclobutyl)-6,7-dihydro-5H-cyclopentapyridine-7-carboxamide

¹ H-NMR (CDCl ₃ , 400 MHz): δ8.7(s,1H),8.45(d,1H),8.3(d,1H),7.5(d,1H),7.22(d,1H),7.2 (m,2H),7.0(m,1H),6.8(m,1H),4.7(m,1H),3.9(m,1H),3.35(m,1H),2.9(m,2H),2.85- 2.7(m,3H),2.6-2.4(m,2H),2.25(m,1H),2.10(m,3H).

LCMS: m/z=593.0[M+H]+; RT=1.58 min.

Example 55: Compound 113 and Compound 114

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A32, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloro-4-cyanopyridine to obtain the compound 113 and compound 114.

Compound 113: (S)-N-((S)-7-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- (4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ8.77(s, 1H), 8.45(d, J=5.1 Hz, 1H), 7.39(d, J=9.1Hz, 1H), 7.24(s, 2H), 7.16(t, J=7.7 Hz, 1H), 6.91(d, J=7.7 Hz, 1H), 6.72(t, J=8.6Hz, 1H), 6.46(d, J=8.2 Hz, 1H), 5.80( d, J＝6.9 Hz, 1H), 4.66(dd, J＝9.3, 2.7 Hz, 1H), 4.34(s, 1H), 3.39(dd, J＝12.8, 5.8 Hz, 1H), 3.20–2.92(m ,5H),2.63–2.31(m,5H),2.13–1.97(m,1H).

LCMS: m/z=626.2[M+H]+; RT=1.85 min.

Compound 114: (S)-N-((R)-7-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- (4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400 MHz, CDCl ₃ ) δ8.73(s, 1H), 8.53(d, J=5.1 Hz, 1H), 7.40–7.27(m, 2H), 7.16(d, J=6.3 Hz, 1H ),7.06(s,1H),6.85(s,1H),6.68-6.57(m,2H),5.34(s,1H),4.80–4.60(m,1H),4.11–3.93(m,1H), 3.2-2.58(m,6H),2.40–1.90(m,6H).

LCMS: m/z=626.2[M+H]+; RT=1.85 min.

Example 56: Compound 115

Using the same method as in Example 1, the product obtained after the reaction of imine intermediate A22, isocyan intermediate B7 and L-pyroglutamic acid is used, and then reacted with 2-chloro-4-cyanopyridine to obtain the compound 115 (pair of diastereomeric mixtures not resolved).

Compound 115: (2S)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxo-N-1-((3,3,3 -Trifluoropropyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.80(s, 1H), 8.2(d, J=5.1Hz, 1H), 7.70(m, 1H), 7.52(m, 1H), 7.40-7.32(m, 2H),7.26-7.20(m,1H),7.10(m,1H),6.94(m,1H),6.85(m,1H),5.6(m,1H),4.65–4.60(m,1H),4.11 –3.93(m,1H),2.90-2.70(m,3H),2.60-2.55(m,3H),2.40–2.2(m,5H),2.10–1.98(m,1H).LCMS:m/z＝ 598.0[M+H] ⁺ ; RT=1.74min.

Example 57: Compound 116

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A12, isocyan intermediate B1 and L-pyroglutamic acid, and then react with 2-chloropyrimidine to obtain compound 116

Compound 116: (S)-N-((S)-7-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- (Pyrimidin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.70(s,1H),7.5(t,1H),7.40(m,1H),7.25(m,1H),7.10-6.8(m,5H),6.7( m,1H),6.05(d 1H),4.65–4.60(m,1H),4.35–4.3(m,1H),3.4-3.3(m,1H),3.2-3.1(m,1H),2.9-2.8 (m,1H),2.70-2.3(m,8H),2.0(m,1H).

LCMS: m/z=584.0[M+H] ⁺ ; RT=1.67min

Example 58: Compound 117 and Compound 118

Using the same method as in Example 1, use the product obtained after the reaction of imine intermediate A22, isocyan intermediate B1 and D-pyroglutamic acid, and then react with 4-cyano-2-chloropyridine to obtain the compound 117 and compound 118.

Compound 117: (R)-1-(4-aminopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutane)carbamoyl)-2,3- 1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.75(s, 1H), 8.52(d, J=5.0Hz, 1H), 7.30–7.18(m, 4H), 7.09-7.04(m, 2H), 6.91( d,J=8.6Hz,1H),6.78-6.72(m,1H),5.75(d,J=6.2Hz,1H),4.68(dd,J=9.2,3.4Hz,1H),4.18-4.09(m ,1H),3.00–2.82(m,5H),2.62–2.52(m,2H),2.45–2.25(m,3H),2.22-2.14(m,1H),2.09–1.97(m,1H).

LCMS: m/z 592.1 (M+H) ⁺ , RT=1.80min.

Compound 118: (R)-1-(4-aminopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutane)carbamoyl)-2,3- 1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

¹ H NMR (400MHz, CDCl ₃ ) δ8.74(s, 1H), 8.52(d, J=5.1Hz, 1H), 7.31–7.17(m, 4H), 7.07(s, 2H), 6.91(d, J＝8.9Hz, 1H), 6.74(t, J＝8.7Hz, 1H), 5.75(d, J＝6.1Hz, 1H), 4.68(dd, J＝9.1, 3.3Hz, 1H), 4.13(s, 1H),3.01–2.84(m,6H),2.63–2.52(m,2H),2.43–2.26(m,3H),2.06–1.98(m,1H).

LCMS: m/z 592.1 (M+H) ⁺ , RT=1.80min.

Example 59: Compound 119 and Compound 120

Using the same method as in Example 1, using the product obtained after the reaction of imine intermediate A12, isocyanic intermediate B1 and acid intermediate C5, and then reacting with 4-cyano-2-chloropyrimidine to obtain compound 119 and Compound 120.

Compound 119: (S)-N-((S)-7-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-3-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.90(s,1H),7.6(m,1H),7.40(m,2H),7.25-7.10(m,4H),6.9-6.8(m,1H), 6.6(m,1H),4.82(m,1H),4.60(m,1H),4.40(m,1H),3.95(m,1H),3.40(m,1H),3.0(m,2H),2.9 -2.7(m,3H),2.25(m,1H),1.75(m,1H).

LCMS: m/z=611.1[M+H] ⁺ ; RT=1.74min

Compound 120: (S)-N-((R)-7-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-indene-1- Base)-3-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide

¹ H NMR (400MHz, CDCl ₃ )δ8.90(s,1H),7.6(m,1H),7.40(m,1H),7.25-7.10(m,4H),6.8(m,1H),6.6( m,1H),5.75(m,1H),4.75-4.60(m,2H),4.40-4.20(m,2H),3.65(m,1H),3.40(m,1H),3.1(m,1H) ,3.0(m,2H),2.60-2.35(m,3H).

LCMS: m/z=611.1[M+H] ⁺ ; RT=1.74min

Example 60: Compound 5

Step 1: Weigh chloroacetic acid (190mg, 2mmol) in a microwave reaction tube, dissolve the Schiff base in 1mL of anhydrous methanol and inject it into the microwave tube, stir for 30 minutes, add cyclohexylisonitrile (220mg, 2mmol), seal the microwave tube React overnight at 30°C. The reaction was quenched by adding 10 mL of water and extracted with ethyl acetate (3*15 mL). The combined ethyl acetate was washed several times with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried before column chromatography (eluent dichloro Methane: 50:1) isolated intermediate 5-1 (200mg, white solid), yield 23.3%.

¹ H NMR(DMSO-d6,400MHz):δ7.39-7.33(m,1H),7.27-7.22(m,2H),7.12-7.03(m,6H),3.90-3.82(m,2H),3.81 -3.49(m,3H),3.07-3.00(m,2H),1.72-1.68(m,4H),1.59-1.54(m,1H),1.31-1.07(m,5H).

LCMS: m/z 451.3 [M+Na] ⁺ ; RT = 2.0 min.

Step 2: Intermediate 5-1 (100mg, 0.23mmol) and 100mL reaction flask were added with 2-methylimidazole (19mg, 0.23mmoL), triethylamine (46mg, 0.46mmol) and 5mL of dichloromethane The reaction was heated to reflux overnight under the protection of nitrogen. The reaction solution was filtered with diatomaceous earth, and the filtrate was spin-dried to obtain compound 5 (80 mg, white solid) by column chromatography (eluent dichloromethane: 20:1) with a yield of 73%. Compound 5: N-cyclohexyl-1-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamide)-2,3-dihydro-1H- Indene-1-carboxamide.

¹ H NMR (600MHz,MeOD):δ7.40-7.35(m,1H),7.30-7.03(m,5H),7.01-6.93(m,1H),6.88(s,2H),6.77(d,J ＝1.3Hz,1H),5.50-5.49(m,1H),4.51-4.35(m,2H),3.75-3.61(m,1H),2.86-2.57(m,2H),2.22(s,3H), 1.87-1.58(m,6H),1.40-1.28(m,4H),1.27-1.05(m,2H).

LCMS: m/z 475.3 (M+H) ⁺ ; RT = 1.64min.

Example 61: Compound 6

Using the same method as in Example 54, using the imine intermediate A3, the product obtained by reacting cyclohexylisocyanate and chloroacetic acid, and then performing a substitution reaction with 2-methylimidazole to obtain compound 6.

Compound 6: N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamide)-2,3-dihydro-1H- Indene-2-carboxamide

¹ HNMR(400MHz,DMSO):δ7.44-7.37(m,1H),7.30-7.24(m,1H),7.23-7.07(m,6H),7.06-7.00(m,2H),6.84(d, J＝1.1Hz, 1H), 6.63(d, J＝1.1Hz, 1H), 4.29(q, J＝17.3Hz, 3H), 3.62-3.47(m, 3H), 3.10-3.01(m, 2H), 2.05(s,3H),1.69-1.44(m,5H),1.30-1.11(m,5H).

LCMS: m/z 475.2 (M+H) ⁺ ; RT = 1.65min.

Example 62: Compound 11

Using the same method as in Example 54, using the imine intermediate A5, the product obtained by reacting cyclohexylisocyanate and chloroacetic acid, and then performing a substitution reaction with 2-methylimidazole to obtain compound 11.

Compound 11: N-cyclohexyl-7-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamide)bicyclo[4.2.0]octyl-1 (6),2,4-triene-7-carboxamide

¹ HNMR (400MHz, CDCl ₃ ): δ7.30-7.16(m, 7H), 6.99(t, J=7.3Hz, 1H), 6.89(d, J=1.1Hz, 1H), 6.66(d, J= 1.1Hz,1H),6.47(d,J＝7.4Hz,1H),4.50(s,2H),4.12-3.98(m,1H),3.61-3.50(m,1H),3.34(s,1H), 2.12(s,3H),1.75-1.42(m,5H),1.40-0.96(m,5H).

LCMS: m/z 461.2 [M+H] ⁺ ; RT = 1.58min.

Example 63: Compound 16

Using the same method as in Example 54, the product obtained by reacting imine intermediate A1, isocyan intermediate B2 and chloroacetic acid was used for substitution reaction with piperidine to obtain compound 16.

Compound 16: N-(4,4-difluorocyclohexyl)-1-(N-3-fluorophenyl)-2-(piperidin-1-yl)acetamido)-2,3-dihydro- 1H-indene-1-carboxamide

¹ H-NMR(MeOD 400MHz):δ7.47-7.36(m,1H),7.24-6.93(m,6H),6.81(d,1H),3.88(s,1H),3.76-3.61(m,2H) ,3.52-3.45(m,2H),3.01-2.79(m,6H),2.02-.199(m,2H),1.88-1.50(m,9H),1.47-1.43(m,4H).

LCMS: m/z 514.2[M+H] ⁺ ; RT=1.057min.

Example 64: Compound 25

Using the same method as in Example 54, using the product obtained by reacting imine intermediate A1, isocyan intermediate B2 and chloroacetic acid, and then performing a substitution reaction with dimethylbenzimidazole to obtain compound 25.

Compound 25: N-(4,4-difluorocyclohexyl)-1-(N-3-fluorophenyl)2-(2-methyl-1H-benzimidazol-1-yl)acetamido)- 2,3-Dihydro-1H-indene-1-carboxamide

¹ H-NMR(MeOD 400MHz):δ7.90-7.88(m,1H),7.49-7.42(m,5H),7.35-7.32(m,3H),7.23-7.17(m,2H),6.98-6.93 (m,1H),5.40-5.39(m,1H),4.60-4.54(m,2H),3.82(s,1H),2.82-2.73(m,3H),2.71-2.67(m,2H),2.33 -2.29(m,2H),1.96-1.72(m,6H),1.39-1.29(m,2H).

LCMS: m/z 561.2[M+H] ⁺ ; RT=1.124min.

Example 65: Compound 28

Using the same method as in Example 54, the product obtained by reacting imine intermediate A2, isocyan intermediate B1 and chloroacetic acid was used for substitution reaction with 2-methylimidazole to obtain compound 28.

Compound 28: N-(4,4-difluorocyclobutyl)-1-(N-(5-pyridin-3-yl)-2–(2-methylimidazol-1-yl)acetamido)-2 ,3-Dihydro-1H-inden-1-yl-carboxamide

¹ H-NMR(MeOD 400MHz):δ8.70-8.42(m,1H),8.38-8.04(m,1H),7.42-739(m,3H),7.26-7.16(m,2H),6.95-6.87 (m,2H),4.90-4.75(m,2H),4.25(m,1H),3.07-3.05(m,2H),2.93-2.86(m,4H),2.74-2.59(m,1H),2.57 (s,3H),2.56-2.50(m,1H).

LCMS: m/z 484.3[M+H] ⁺ ; RT=0.937min.

Example 66: Compound 45

Using the same method as in Example 54, using the product obtained after the reaction of imine intermediate A1, isocyan intermediate B1 and chloroacetic acid, and then performing a substitution reaction with intermediate D1 to obtain compound 45.

Compound 45: N-(4,4-difluorocyclohexyl)-1-(N-3-fluorophenyl)2-(2-methyl-1H-imidazo[4,5-b]pyrazine- 1-yl)acetylamino)-2,3-dihydro-1H-indene-1-carboxamide

¹ H-NMR(MeOD 400MHz):δ8.45(s,1H),8.34(s,1H),7.45-7.43(m,1H),7.26-7.15(m,2H),7.09-6.96(m,5H ),4.92(m,1H),4.81(m,1H),4.10-4.08(m,1H),2.98(m,2H),2.86-2.79(m,4H),2.74(s,3H),2.69- 2.46(m,2H).

LCMS: m/z 535.2[M+H] ⁺ ; RT=1.44min.

Example 67: Compound 86

Using the same method as in Example 54, the product obtained after the reaction of imine intermediate A1, isocyan intermediate B2 and chloroacetic acid was used, and then subjected to substitution reaction with intermediate D2 to obtain compound 86.

Compound 86: N-(3,3-difluorocyclobutyl)-1-(N-(3-fluorophenyl)-2-(2-methyl-4-(pyrimidin-2-yl)-1H- imidazol-1-yl)acetamido)-2,3-dihydro-1H-inden-1-ylcarboxamide

H-NMR(CDCl3 400MHz):δ8.74(m,1H),7.65(m,1H),7.57-7.45(m,2H),7.38-7.33(m,3H),7.28(m,1H),7.23 -7.19(m,2H),6.89-6.82(m,1H),5.50(m,1H),4.51-4.44(m,2H),3.88-3.87(m,1H),2.81-2.77(m,2H) ,2.69(s,3H),2.33-2.32(m,1H),1.98-1.73(m,6H),1.44-1.37(m,2H).

LCMS: m/z 589.2[M+H] ⁺ ; RT=1.056min.

Example 68: Compound 87

Using the same method as in Example 54, the product obtained by reacting imine intermediate A2, isocyan intermediate B2 and chloroacetic acid was used for substitution reaction with 2-methylimidazole to obtain compound 87.

Compound 87: N-(4,4-difluorocyclohexyl)-1-(N-(5-fluoropyridin-3-yl)-2-(2-methylimidazol-1-yl)acetamido)-2 ,3-Dihydro-1H-inden-1-ylcarboxamide

¹ H-NMR(CDCl3 400MHz):δ8.56-8.48(m,1H),8.37-8.34(m,1H),7.65-7.63(m,1H),7.40-7.28(m,2H),7.21-7.08 (m,3H),7.03-7.00(m,1H),5.80-5.63(m,1H),4.48-4.40(m,2H),3.88-3.84(m,1H),2.92-2.72(m,2H) ,2.56(s,3H),2.38(s,1H),2.01-1.74(m,7H),1.50-1.41(m,2H).

LCMS: m/z 512.3[M+H] ⁺ ; RT=0.944min.

Example 69: Compound 18

N-(4,4-difluorocyclohexyl)-1-(N-(3-fluorophenyl)-2-(methyl(phenyl)amino)acetamido)-2,3-dihydro-1- Indene-1-carboxamide

Add compound C3 (165mg, 1mmol), A1 (225mg, 1mmol), and 2ml of anhydrous methanol to a dry 25ml single-necked bottle successively, stir at room temperature for 4 hours, add B2 (145mg, 1mmol) and continue stirring overnight, and prepare by separation The gray solid product N-(4,4-difluorocyclohexyl)-1-(N-(3-fluorophenyl)-2-(methyl(phenyl)amino)acetamido)-2,3-di Hydrogen-1-indene-1-carboxamide 19 mg, yield: 3.6%.

¹ H-NMR(CDCl3 400MHz):δ7.23-7.19(m,1H),7.15-7.05(m,5H),7.03-6.86(m,4H),6.78-6.68(m,3H),3.89-3.78 (m,2H),3.06(s,3H),2.94-2.79(m,2H),2.58-2.56(m,1H),2.02-1.59(m,7H),1.48-1.44(m,3H).

LCMS: m/z 536.2[M+H] ⁺ ; RT=1.84min.

Example 70: Compound 17

Using the same method as in Example 62, compound 17 was obtained after reaction using imine intermediate A1, isocyan intermediate B2 and acid intermediate C3.

Compound 17: 1-(2-((4-cyanophenyl)amino)-N-(3-fluorophenyl)acetamido)-N-(4,4-difluorocyclohexyl)-2,3- Dihydro-1-indene-1-carboxamide

¹ H-NMR(CDCl ₃ 400MHz):δ7.49-7.45(m,2H),7.25(s,1H),7.12-7.07(m,4H),6.99-6.93(m,3H),6.75(s, 2H),6.56(d,1H),3.41-3.78(m,3H),2.91-3.27(m,4H),2.09-1.82(m,4H),1.69-1.52(m,4H).

LCMS: m/z 569.2[M+2] ⁺ ; RT=1.71min.

Example 71: Compound 24

Using the same method as in Example 62, compound 24 was obtained after reaction using imine intermediate A1, isocyan intermediate B2 and 4-pyridineacetic acid.

Compound 24: N-(4,4-difluorocyclohexyl)-1-(N-(3-fluorophenyl)-2-(pyridin-4-yl)acetamido)-2,3-dihydro-1H -indene-1-carboxamide

¹ H-NMR(CDCl3 400MHz):δ8.74(s,2H),7.64-7.58(m,3H),7.36-7.29(m,3H),7.23-7.13(m,3H),6.72-6.68(m ,1H),5.46-5.44(m,1H),3.91-3.90(m,1H),3.59-3.55(m,2H),2.76(m,1H),2.61(m,1H),2.28(s,2H ),2.00-1.78(m,6H),1.45-1.37(m,2H).

LCMS: m/z 508.2[M+H] ⁺ ; RT=1.116min.

Example 72: Compound 26

Using the same method as in Example 62, compound 26 was obtained after using imine intermediate A1, isocyanine intermediate B2 and acid intermediate C4 to react.

Compound 26: N-(4,4-difluorocyclohexyl)-1–(N-(3-fluorophenyl)-2-((2-fluoropyridin-3-yl)amino)acetamido)-2, 3-Dihydro-1H-indene-1-carboxamide

¹ H NMR(CDCl ₃ -d ₁ ,400MHz):δ7.65-7.64(m,1H),7.44-7.43(m,1H),7.30(m,2H),7.24(m,2H),7.14(m ,1H),692-6.89(m,2H),6.54-6.49(m,1H),5.45-5.34(m,2H),3.93(m,1H),3.49(s,2H),2.77-2.66(m ,2H),2.30-2.22(m,5H),1.86-1.79(m,3H).

LCMS: m/z 541.2 [M+H] ⁺ ; RT=1.678min.

The control compound AGI-5198, CAS: 1355326-35-0, was purchased from Selleck Company.

Test example 1 The influence of compound of the present invention on IDH1 enzyme activity at molecular level

Reagents, consumables and instruments:

The enzymes used in the experiment were purchased from cayman company.

The substrates α-KG, NADPH and Diaphorase were purchased from Sigma; Resazurin was purchased from Behringwei; the rest of the reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd.

Reaction microplate (6008260) was purchased from PerkinElmer.

The multifunctional microplate reader used for plate reading is a product of PerkinElmer, model: EnVision.

The experimental water was distilled water produced by Sinopharm Group.

Compound preparation: The compound was centrifuged at 12000 g for 5 min, added DMSO to prepare a 10 mM stock solution, vortexed evenly, ultrasonicated for 10 min, and stored at -40°C. When testing, first dilute to 10 μM solution with DMSO, and then serially dilute 3× times to different test solubility.

Test method: The enzymatic function of IDH1 converting α-KG to 2HG was measured by the depletion of NADPH. After the end of the enzymatic reaction, excess catalytic diaphorase and reazurin are added, and the fluorescent signal generated can reflect the amount of remaining NADPH. In a 384-well plate, add 5 μL enzyme system (150 mM NaCl, 20 mM Tris pH=7.5, 10 mM MgCl ₂ , 0.05% (w/v) bovine serum albumin, 0.012 μL enzyme), 2.5 μL compound, 2.5 μL substrate α-KG The mixed solution with NADPH (substrate α-KG final concentration 1 mM, NADPH final concentration 4 μM) was incubated at room temperature in the dark for 60 min. Detection reaction: Add 5 μL of 0.01 unit diaphroase and 5 μM resazurin diluted in 1× detection buffer to each well, and incubate at room temperature for 10 minutes in the dark. Plate reading: with PerkinElmer at Ex 544Em 590. Test plate. _IC50 values were calculated using GraphPad Prism software.

result

Table 1 shows the IC ₅₀ values of some compounds of the present invention.

Letter A stands for IC ₅₀ less than 100nm;

Letter B stands for IC ₅₀ of 100nm to 1000nm;

Letter C stands for IC ₅₀ of 1uM to 10uM;

The letter D represents _IC50 above 10uM.

Table 1 _IC50 values of some compounds of the present invention

The results show that the compound of the present invention can effectively inhibit the activity of IDH1 at an extremely low concentration (≤10uM, preferably ≤100nm).

Test example 2: Determination of the proliferation inhibition of the compound of the present invention on malignant glioma cell line U87

In this experiment, the following method was used to measure the proliferation inhibitory activity of the compound of the present invention on malignant glioma cell line U87.

Determination method: first inoculate U87 cells (Cell Bank of Typical Culture Collection Committee, Chinese Academy of Sciences) on a 96-well culture plate at an appropriate cell concentration of 2000 cells/well, with 90 μL of medium per well, and culture overnight at 37°C in a carbon dioxide incubator , adding different concentrations of test compounds to act for 96 hours, and setting a solvent control group (negative control). After 96 hours, the CCK8 (Cell Counting Kit-8) method can be used to test the activity of the compound on inhibiting cell proliferation. The IC ₅₀ value can be calculated by the inhibitory value of the test compound on cells at a series of different concentrations.

It was determined that the test compound 1-133 had an inhibitory effect on the malignant glioma cell line U87.

Test example 3: Determination of the proliferation inhibitory activity of the compound of the present invention on tumor cell lines other than malignant glioma cell line U87

Using the same method as Test Example 2, the present invention also determined the proliferation inhibitory activity of some compounds on other tumor cell lines other than Test Example 2, such as HT1080, MCF-7, T47D, ZR-75, MAD-MB-468, etc. .

Cell line name tumor cell type HT1080 human fibrosarcoma cells MCF-7 human breast cancer cells T47D human breast cancer cell line ZR-75 human breast cancer cell line MAD-MB-468 human breast cancer cell line

It has been determined that the test compound 1-133 has inhibitory effects on different tumor cell lines HT1080, MCF-7, T47D, ZR-75, and MAD-MB-468.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof,

wherein,

W₁、W₂each independently selected from N or CR_b；

W and W' are givenIs independently selected from CR_aR_b；

R_aSelected from H, C₁-C₆An alkyl group;

R_bselected from H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, phenyl, C1-C6 alkoxy;

n is 1,2,3,4 or 5; n' is 0 or 1;

R₁is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted 4-8 membered carbocyclic group, substituted or unsubstituted C5-20 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein said heterocyclyl or heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, S or P;

R₂is a substituted or unsubstituted C5-C20 aryl, a substituted or unsubstituted 5-to 10-membered heteroaryl, a substituted or unsubstituted 5-to 10-membered arylheterocyclo, wherein said heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of: n, O or S; said aryl-and heterocyclyl-group contains 1 to 3 heteroatoms selected from the group consisting of: n, O or S;

R₃is halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, substituted or unsubstituted 5-to 10-membered aryl;

R₄is- (CH)₂)_mR₁₁；

Wherein m is an integer of 0 to 5; preferably an integer of 0 to 3;

R₁₁is composed ofSubstituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocyclyl; wherein; x is selected from O, N or S; m is an integer of 0 to 5; rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; or Rc and Rd are joined to form a 4-8 membered saturated or unsaturated heterocyclyl or heteroaryl; wherein, theThe heteroaryl group of (a) comprises 1 to 4 heteroatoms selected from: n, O, S or P; said heterocyclyl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O, S or P;

any "substitution" described above means that one or more hydrogen atoms on the group is substituted with a substituent selected from the group consisting of: -D, halogen, -OH, -NO₂、-NH₂N (unsubstituted C1-C6 alkyl)₂CN, -CN, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy-C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C3-C8 cycloalkyl-C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C1-C6 alkylcarbonyl, unsubstituted or halogenated C1-C6 alkoxycarbonyl, hydroxamic acid groups, unsubstituted or halogenated 5-to 8-membered aryl, unsubstituted or halogenated 5-to 8-membered heteroaryl, unsubstituted or halogenated 4-to 8-membered saturated heterocyclic or carbocyclic ring; wherein said heteroaryl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O or S, the heterocycle comprising 1 to 4 heteroatoms selected from the group consisting of: n, O or S.

2. A compound of formula I according to claim 1, wherein R is₂Selected from the group consisting of: wherein Rm is selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy.

In another preferred embodiment, R₄Is- (CH)₂)_mR₁₁(ii) a m is preferably 0, 1 or 2.

3. A compound of formula I according to claim 1, wherein R is₁₁Selected from the group consisting of: wherein X is O or N; v1, V2 and V3 are respectively selected from CRa or N; m is an integer of 0 to 4; ra is selected from H, C₁-C₆Alkyl, halogen, cyano; rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; wherein said heteroaryl group contains 1 to 4 heteroatoms selected from: n, O or S; said heterocyclyl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O or S.

4. The compound of formula I according to claim 1, wherein Rc is selected from the group consisting of: wherein R 'or R' are each independently selected from the group consisting of-CN, -OH, hydroxamic acid group, C1-C6 alkylcarbonyl, -NO₂Halogen, substituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.

5. The compound of formula I according to claim 1, selected from the following structures:

6. a process for the preparation of a compound of formula I according to any one of claims 1 to 5, comprising the following steps 1) or 2):

1) compound 1a and compoundCoupling under reaction conditions in an inert solvent to form a compound of formula I;

wherein each group is as defined in any one of claims 1 to 5;

2) compound 1a and compoundCoupling under the reaction conditions of an inert solvent and then reacting withReacting to generate a compound shown in the formula I;

wherein each group is as defined in any one of claims 1 to 5.

7. Use of a compound of formula I according to claim 1 for:

(a) preparing a medicament for treating a disease associated with mutant IDH;

(b) preparing a mutant IDH inhibitor;

(c) non-therapeutically inhibiting IDH mutations in vitro;

(d) non-therapeutically inhibiting tumor cell proliferation in vitro; and/or

(e) Treating a disease associated with mutant IDH.

8. The use of claim 7, wherein the mutant IDH is selected from the group consisting of: IDH1, IDH2, or a combination thereof.

9. A pharmaceutical composition, comprising:

(i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof; and

(ii) a pharmaceutically acceptable carrier.

10. A method of inhibiting IDH mutation comprising the steps of: administering to a subject an inhibitory effective amount of a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, or administering to a subject an inhibitory effective amount of a pharmaceutical composition as described in claim 7.