Compounds with mutant isocitrate dehydrogenase inhibitory activity, preparation methods and uses thereof

Abstract

The present invention provides a compound having mutant isocitrate dehydrogenase inhibitory activity, a preparation method and use thereof. Specifically, the present invention provides a compound shown in formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, wherein the definition of each group is as described in the specification. The compound has a high inhibitory activity against mutant IDH, and thus can be used to treat diseases associated with mutant IDH.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and in particular relates to a compound having mutant IDH inhibitory activity, a preparation method and use thereof. Background Art

[0002] Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (α-ketoglutarate), producing carbon dioxide and NADPH / NADH. This process plays an important role in cellular metabolism. Depending on the electron acceptor, these enzymes can be divided into two different subclasses, one that utilizes NAD(+) and the other that utilizes NADP(+). Of the five reported isocitrate dehydrogenases, three are NAD(+)-dependent isocitrate dehydrogenases, which are mainly found in the mitochondrial matrix; the other two are NADP(+)-dependent, namely isocitrate 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 in isocitrate dehydrogenase occur in many types of cancer, such as but not limited to, glioma, glioblastoma, paraneurocytoma, acute leukemia, prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell leukemia, melanoma, etc.

[0003] 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-mutated IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, thereby reducing NAD+ (NADP+) to NADP (NADPH) in the following forward reaction:

[0004] Isocitrate + NAD+ (NADP+) → α-ketoglutarate + CO2 + NADH (NADPH).

[0005] Mutated isocitrate dehydrogenases lose this normal function and have a new 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 can help the formation and development of cancer. For example, high concentrations of 2-HG have been detected in acute leukemia patients with IDH mutations. High concentrations of 2HG are well associated with oncogenes. Therefore, inhibition of mutant IDH and its new activity is a potential therapeutic treatment for cancer.

[0006] In summary, there is an urgent need to develop mutant IDH inhibitors in this field. Summary of the invention

[0007] The purpose of the present invention is to provide an inhibitor of mutant IDH, in particular an inhibitor of mutant IDH1 and IDH2.

[0008] In a first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof,

[0009]

[0010] in,

[0011] W1 and W2 are each independently selected from N or CR b ;

[0012] W and W' are independently selected from CR a R b ;

[0013] R a Selected from H, C1-C6 alkyl;

[0014] R b Selected from H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, phenyl, C1-C6 alkoxy;

[0015] n is 1, 2, 3, 4 or 5; n' is 0 or 1;

[0016] R1 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl, substituted or unsubstituted 4-8 membered heterocyclyl, substituted or unsubstituted 4-8 membered carbocyclyl, substituted or unsubstituted C5-20 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein the heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, S or P;

[0017] R2 is a substituted or unsubstituted C5-C20 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, or a substituted or unsubstituted 5-10 membered aryl-heterocyclic group, wherein the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S; and the aryl-heterocyclic group contains 1-3 heteroatoms selected from the group consisting of N, O or S;

[0018] R3 is halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxyl, substituted or unsubstituted 5-10 membered aryl;

[0019] R4 is -(CH2) m R 11 ;

[0020] Wherein, m is an integer of 0-5; preferably an integer of 0-3;

[0021] R 11 for A substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted 5-10 membered aryl, or a 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, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted 5-10 membered aryl; Rd is selected from H, a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C1-C6 alkylcarbonyl; or Rc and Rd are linked to form a 4-8 membered saturated or unsaturated heterocyclic group or heteroaryl; wherein the heteroaryl contains 1-4 heteroatoms selected from the following: N, O, S or P; and the heterocyclic group contains 1-4 heteroatoms selected from the following group: N, O, S or P;

[0022] Any of the above "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following groups: -D, halogen, -OH, -NO2, -NH2, -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 heterocyclic ring or carbocyclic ring; wherein the heteroaryl contains 1-4 heteroatoms selected from the group consisting of N, O or S, and the heterocyclic ring contains 1-4 heteroatoms selected from the group consisting of N, O or S;

[0023] In another preferred embodiment, W is CR a R b , and n is preferably an integer of 1-4.

[0024] In another preferred embodiment, W' is CR a R b , and n' is preferably 1.

[0025] In another preferred embodiment, R2 is selected from the following group: Wherein Rm is selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy.

[0026] In another preferred embodiment, R4 is -(CH2) m R 11 ; m is preferably 0, 1 or 2.

[0027] In another preferred embodiment, R11 Select 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, C1-C6 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 contains 1-4 heteroatoms selected from the following: N, O or S; and the heterocyclic group contains 1-4 heteroatoms selected from the following group: N, O or S.

[0028] In another preferred embodiment, R4 is -(CH2) m R 11 ; m is preferably 0 or 1.

[0029] In another preferred embodiment, R 11 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 contains 1-4 heteroatoms selected from the following: N, O or S; and the heterocyclic group contains 1-4 heteroatoms selected from the following group: N, O or S.

[0030] In another preferred embodiment, Rc is selected from the following group: Wherein, R' or R" is independently selected from -CN, -OH, hydroxamate, C1-C6 alkylcarbonyl, -NO2, halogen, substituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.

[0031] In another preferred embodiment, the compound has a structure shown in the following formula I-1:

[0032]

[0033] Wherein, the definitions of each group are as described above.

[0034] In another preferred embodiment, the compound has a structure shown in the following formula I-2:

[0035] Wherein, the definitions of each group are as described above.

[0036] In another preferred embodiment, the compound is selected from compounds 1-133.

[0037] 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, the method comprising the following steps 1) or 2):

[0038] 1) Compound 1a and compound The coupling is carried out under reaction conditions in an inert solvent to form a compound of formula I;

[0039]

[0040] In the formula, the definitions of each group are as described in the second aspect of the present invention;

[0041] 2) Compound 1a and compound The coupling is carried out under reaction conditions in an inert solvent and then with Reaction to generate a compound of formula I;

[0042]

[0043] In the formula, the definitions of each group are as described in the second aspect of the present invention.

[0044] In another preferred embodiment, the reaction is carried out in a solvent, and the solvent is selected from the following group: 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 a combination thereof.

[0045] 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:

[0046] (a) preparing a drug for treating a disease associated with mutant IDH;

[0047] (b) preparing mutant IDH inhibitors;

[0048] (c) non-therapeutic inhibition of IDH mutations in vitro;

[0049] (d) inhibiting tumor cell proliferation in vitro non-therapeutic; and / or

[0050] (e) Treatment of diseases associated with mutant IDH.

[0051] In another preferred embodiment, the mutant IDH-related disease is selected from the following group: cancer; preferably leukemia, glioma, cholangiocarcinoma, chondromalacinoma, fibrosarcoma, intrahepatic bile duct carcinoma, and rectal cancer.

[0052] In another preferred embodiment, the mutant IDH is selected from the following group: IDH1, IDH2, or a combination thereof.

[0053] The fourth aspect of the present invention provides a pharmaceutical composition, comprising:

[0054] (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

[0055] (ii) a pharmaceutically acceptable carrier.

[0056] The fifth aspect of the present invention provides a method for inhibiting IDH mutation, which comprises the steps of administering to the inhibited object an inhibitory effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof as described in the first aspect of the present invention, or administering to the inhibited object an inhibitory effective amount of the pharmaceutical composition as described in the third aspect of the present invention.

[0057] 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 below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0058] After long-term and in-depth research, the inventors prepared a class of compounds having the structure shown in Formula I, and found that they have mutant IDH inhibitory activity. Moreover, the compounds have an inhibitory effect on a series of mutant IDHs at extremely low concentrations (as low as ≤100nmol / L), and the inhibitory activity is quite excellent, so they can be used to treat diseases related to mutant IDHs, such as tumors. Based on the above findings, the inventors have completed the present invention.

[0059] the term

[0060] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, and public materials cited in the entirety of this article are incorporated herein by reference in their entirety.

[0061] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular form used in this specification and claims includes the plural form of the referred thing. It should also be noted that unless otherwise stated, the "or" and "or" used mean "and / or". In addition, the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

[0062] Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THE ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the descriptions in the multiple summaries and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0063] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0064] The section headings used herein are only for the purpose of organizing the article and should not be interpreted 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, operating manuals and papers, are incorporated herein by reference in their entirety.

[0065] Certain chemical groups defined in this article are preceded by simplified symbols to represent 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 simplified symbols does not include carbons that may be present in the substituents of the group.

[0066] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0067] In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0068] "Hydroxy" refers to an -OH group.

[0069] "Hydroxyalkyl" means an alkyl group as defined below substituted with a hydroxy (-OH) group.

[0070] "Carbonyl" refers to a -C(=O)- group.

[0071] "Nitro" refers to -NO2.

[0072] "Cyano" refers to -CN.

[0073] "Amino" refers to -NH2.

[0074] "Substituted amino" refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylacylamino, aralkylamino, heteroaralkylamino.

[0075] "Carboxyl" refers to -COOH.

[0076] In the present application, as a group or as part of other groups (e.g., in groups such as halogen-substituted alkyl), the term "alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 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, decyl, and the like.

[0077] In the present application, the term "alkenyl", as a group or part of other groups, means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as but not limited to ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0078] In the present application, the term "alkynyl", as a group or part of other groups, means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and 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.

[0079] In the present application, as a group or part of other groups, the term "cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which is saturated or unsaturated and can be connected to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, the carbon atoms in the cycloalkyl group may be optionally oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl, 5,6,7,8,9,10-hexahydro-benzo Cyclooctenyl, 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, octahydro-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-pentalenyl, etc.

[0080] In the present application, as a group or part of other groups, the term "heterocyclyl" means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specified in this specification, the heterocyclyl can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spiro ring system; the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. The heterocyclyl can be connected to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl containing a fused ring, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of connection with the rest of the molecule is a non-aromatic ring atom. For the purpose of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and 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]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0081] In the present application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl is connected to the rest of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, and the like.

[0082] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0083] In the present application, as a group or part of other groups, the term "heteroaryl" means a 5- to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specified in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused with a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purpose 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 a stable 5- to 10-membered aromatic group containing 1 to 4 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, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [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, etc.

[0084] In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.

[0085] In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

[0086] As used herein, the terms "part", "moiety", "chemical moiety", "group", "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0087] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0088] When the compounds of the present invention contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0089] "Tautomer" refers to an isomer formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0090] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0091] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) 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 OF PRACTICAL ORGANIC CHEMISTRY 5. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0092] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0093] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, decanoates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamate, pyroglutamate, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginate, ascorbate, salicylates, 4-aminosalicylates, naphthalene disulfonates, and the like. These salts may be prepared by methods known in the art.

[0094] "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 salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. The salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines 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, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the profession.

[0095] "Polymorphs" refers to different solid crystalline phases produced by the presence of two or more different molecular arrangements in the solid state of certain compounds of the present invention. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include various crystalline forms and mixtures thereof.

[0096] Typically, crystallization will produce a solvate of the compounds of the present invention. The term "solvate" used in the present invention refers to an aggregate comprising one or more molecules of the compounds 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. Therefore, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, only adventitious water or a mixture of water plus a portion of an adventitious solvent may also be retained. The compounds of the present invention may react in a solvent or precipitate or crystallize out from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

[0097] The present invention also includes prodrugs of the above-mentioned compounds. In the present application, the term "prodrug" means a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvent decomposition. Therefore, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. When administered to an individual in need, the prodrug may not be active, but is converted into an active compound of the present invention in vivo. Prodrugs are usually rapidly converted in vivo to produce the parent compound of the present invention, for example, by hydrolysis in the blood. Prodrug compounds generally provide advantages of solubility, tissue compatibility or sustained release in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific prodrug preparation methods can refer to Saulnier, MG, et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, RB, et al., J. Med. Chem. 2000, 43, 475.

[0098] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0099] 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 non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

[0100] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0101] The "tumor" and "diseases related to abnormal cell proliferation" mentioned 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, squamous cell carcinoma of the lung, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.

[0102] As used herein, the terms "prophylactic," "prevention," and "prevention" include reducing the likelihood of a disease or condition occurring or becoming worse in a patient.

[0103] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0104] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0105] (ii) inhibiting a disease or condition, i.e. arresting its development;

[0106] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0107] (iv) alleviating the symptoms caused by the disease or condition.

[0108] As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant symptom alleviation effect. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.

[0109] As used herein, the terms "administering", "administering", "dosing", etc. refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0110] As used herein, the terms "drug combination", "drug combination", "combination therapy", "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, including fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities, in combination or sequentially at variable intervals. These also apply to cocktail therapies, for example the administration of three or more active ingredients.

[0111] It will also be appreciated by those skilled in the art that in the methods described below, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, sulfhydryl and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

[0112] 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, TW and PGM Wuts, Protective Groups in OrganiSynthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymer resin.

[0113] Compounds of formula I

[0114] The present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof,

[0115]

[0116] In another preferred embodiment, W, W', W1, W2, n, n', R1, R2, R3, R4, m, R 11 , X, Rc, and Rd are each independently a group corresponding to the following compounds.

[0117]

[0118]

[0119]

[0120]

[0121]

[0122] Preparation of compounds of formula I

[0123] The compound of formula I provided by the present invention can be prepared by the following method 1) or 2):

[0124] 1) Compound 1a and compound The coupling is carried out under reaction conditions in an inert solvent to form a compound of formula I;

[0125]

[0126] In the formula, the definitions of the groups are as described above;

[0127] 2) Compound 1a and compound The coupling is carried out under reaction conditions in an inert solvent and then with Reaction to generate a compound of formula I;

[0128]

[0129] In the formula, the definitions of the groups are as described above.

[0130] In another preferred embodiment, the reaction is carried out in a solvent, and the solvent is selected from the following group: 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 a combination thereof.

[0131] The main advantages of the present invention include:

[0132] 1. Provided is a compound as shown in formula I.

[0133] 2. Provided are a novel mutant IDH inhibitor and its preparation and use, wherein the inhibitor has high inhibitory activity against mutant IDH.

[0134] 3. Provided is a class of pharmaceutical compositions for treating diseases associated with mutant IDH.

[0135] The present invention will be further described below in conjunction with specific examples. 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. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0136] Intermediate A1: Synthesis of N-(2,3-dihydro-1H-inden-1-yl)-3-fluoroaniline

[0137]

[0138] In a dry 50ml single-mouth bottle, add 1-indanone (2g, 15mmol), m-fluoroaniline (2.2g, 19.7mmol), activated 4A molecular sieve (20g), and dry 1,2-dichloroethane 40ml in sequence, reflux under nitrogen protection for 36h, TLC monitoring, the product is 60%-70%, and there is residual raw material, filter, collect the filtrate and spin dry to obtain 2.3g of product. The crude product is used directly without purification.

[0139] Using the above method, substituted or unsubstituted (hetero)aromatic cycloalkyl ketones are reacted with substituted or unsubstituted aniline or heterocyclic aromatic amines. The solvent can be replaced by toluene or dioxane or other inert solvents to 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 are directly used in the next reaction without purification; A19, A20, A21, A22, A26 are purified by column chromatography.

[0140] The intermediate structure is as follows:

[0141]

[0142] Intermediate A19: N-(2,3-dihydro-1H-inden-1-yl)-3-fluoro-4-chloroaniline

[0143]

[0144] 1H-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).

[0145] Intermediate A20: N-(2,3-dihydro-1H-inden-1-yl)aniline

[0146]

[0147] LCMS: m / z 208.2 (M+H) + ,RT=1.5min.

[0148] Intermediate A21: N-(2,3-dihydro-1H-inden-1-yl)-2,5-difluoroaniline

[0149]

[0150] LCMS: m / z 244.1 (M+H) + ,RT=1.7min.

[0151] Intermediate A22: N-(2,3-dihydro-1H-inden-1-yl)-3,5-difluoroaniline

[0152]

[0153] 1 H-NMR (CDCl3, 400MHz): δ7.88 (d, J=7.6Hz, 1H), 7.51-7.37 (m, 3H), 6.56-6.43 (m, 3H), 3.09 (t, J=6.4Hz, 2H), 2.67 (t, J=6.4Hz, 2H).

[0154] Intermediate A26: (N-(2,3-dihydro-1H-inden-1-yl)-2,5-difluoroaniline

[0155]

[0156] 1H-NMR (CDCl3, 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)

[0157] Intermediate A11: N-(5-chloro-2,3-dihydro-1H-inden-1-yl)-5-fluoro-3-pyridinamine

[0158]

[0159] 5-Chloro-1-indanone (333 mg, 2 mmol) and 3-amino-5-fluoropyridine (222 mg, 2 mmol) were placed in a 10 mL reaction bottle test tube, sealed and heated to 120°C under nitrogen protection. When TLC / LCMS detected that the product was no longer increasing, dichloromethane was added to dissolve, anhydrous sodium sulfate was added to dry, filtered, and the crude Schiff base was dried to obtain a standby use.

[0160] Using the above method, substituted or unsubstituted (hetero)aryl cycloalkyl ketone compounds are reacted with substituted or unsubstituted aniline or heterocyclic aromatic amine to obtain imine intermediates A7, A11, A13, A14, A15, A17, A18, A23, A24, A25, A27, A30.

[0161]

[0162] Intermediate A12: N-(7-chloro-2,3-dihydro-1H-inden-1-yl)-3-fluoroaniline

[0163]

[0164] In a dry 50 ml single-mouth bottle, add 7-chloroindanone (2.5 g, 15 mmol), m-fluoroaniline (2.2 g, 19.7 mmol), activated 4A molecular sieves (20 g), and 40 ml of dry 1,2-dichloroethane in sequence, drop titanium tetrachloride (142 mg, 0.05 equiv) into the catalytic reaction, reflux under nitrogen protection, monitor by TLC until the product no longer increases, filter, and spin-dry the filtrate to obtain 2.5 g of crude product, which is directly used in the next reaction.

[0165] In the above method, titanium tetrachloride can be replaced by other Lewis acids (boron trifluoride etherate, aluminum trichloride, etc.), and the solvent can be replaced by toluene or dioxane.

[0166] Using the above method, 7-chloroindanone and 3,5-difluoroaniline were reacted to give the imine intermediate A32.

[0167]

[0168] Intermediate B1: Synthesis of 1,1-difluoro-3-cyclobutylisocyanate

[0169]

[0170] Step 1: In a clean 250ml sealed tube, add B1-1 (25g, 175mmol) and 140ml of ethyl formate, add triethylamine (53g, 525mmol) under stirring, stir overnight in an oil bath at 110°C, cool to room temperature, filter, wash the filter cake with ethyl acetate 2-3 times, wash the filtrate with saturated brine twice, and spin dry to obtain compound 2 (22g, yield: 93%).

[0171] 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).

[0172] Step 2: In a dry 1L single-mouth bottle, add compound B1-2 (22 g, 163 mmol), triphenylphosphine (47 g, 179 mmol), carbon tetrachloride (25 g, 163 mmol), triethylamine (16.5 g, 163 mmol) and 500 ml of dichloromethane in sequence, reflux at 45 ° C overnight, spin dry in a cold water bath, add 500 ml of ether and beat for 1 hour, filter, wash with ether, mix the filtrate with silica gel, spin dry in a cold water bath, and purify by silica gel column (ether) to obtain the target compound (11.8 g, 62%).

[0173] 1 H-NMR (DMSO 400MHz): δ4.28-4.26(m,1H), 3.19-3.08(m,2H), 2.97-2.87(m,2H).

[0174] Using the above method, different isocyanate intermediates B2, B3, B5, B6, and B7 are prepared using different amines.

[0175] Intermediate B2: 1,1-difluoro-3-cyclohexyl isocyanate

[0176]

[0177] 1 H-NMR (CDCl 400MHz): δ3.84(s,1H),1.93-2.17(m,8H)

[0178] Intermediate B3: 4-isocyanate-tetrahydropyran

[0179]

[0180] 1 H NMR (CDCl3-d1, 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).

[0181] Intermediate B5: 4,4-Dimethylcyclohexyl isocyanide

[0182]

[0183] 1 H-NMR (CDCl3, 400MHz): 1.82-1.76 (m, 2H), 1.53-1.51 (m, 1H), 1.28-1.24 (m, 6H), 0.92 (s, 6H).

[0184] Intermediate B6: The ether concentrate was not dried and the intermediate was not isolated, but was directly used in the next reaction.

[0185]

[0186] Intermediate B7: The ether concentrate was not spin-dried to dryness and the intermediate was not isolated, but was directly used in the next reaction.

[0187]

[0188] Intermediate B4: Synthesis of phenyl isocyanate

[0189]

[0190] In a dry 500mL three-necked flask, add aniline (5.0g, 53.69mmol, 1.0eq), tetrabutylammonium hydrogen sulfate (1.82g, 5.37mmol, 0.1eq), dichloromethane (160mL), and sodium hydroxide aqueous solution (50%, 80mL) in sequence at room temperature. Slowly add chloroform (9.61g, 80.54mmol, 1.5eq) at 0°C and stir at room temperature for 18 hours. After the reaction is completed, pour the reaction solution into water (500mL) and extract with dichloromethane (500mL). Dry the organic phase with sodium sulfate and concentrate under reduced pressure. Pass through a silica gel column to obtain the product phenylisocyanate (3.0g, yellow oily liquid) with a yield of 55%.

[0191] 1 H NMR (CDCl3-d1, 400MHz): δ7.39 (m, 5H).

[0192] Intermediate C1: Synthesis of (S)-1-(4-cyanopyridin-2-yl)pyrrolidine-2-carboxylic acid

[0193]

[0194] Step 1: Dissolve the compound L-proline methyl ester hydrochloride (4.98 g, 30 mmol, CAS: 2133-40-6) and 2-bromo-4-cyanopyridine (2.28 g, 20 mmol) in 1,2-dioxane (80 ml), add Pd2(dba)3 (1.83 g, 2 mmol) at room temperature and react at 00 degrees Celsius under nitrogen protection for 12 hours. . After the reaction was completed, 50 ml of ethyl acetate was added. The organic phase was washed with water (20 ml × 1) and saturated brine (20 ml × 1) in sequence. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column (petroleum ether: ethyl acetate = 20:1, 10:1) gave the product (S)-methyl 1-(4-cyanopyridin-2-yl)pyrrolidine-2-carboxylic acid (1.34 g, yellow solid), yield: 29%. LCMS: m / z 232.1 (M+H) + ;RT=1.387min.

[0195] 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 at room temperature for 4 hours. After the reaction is completed, add dilute hydrochloric acid to adjust the pH to 2, and add 15 ml of ethyl acetate. The organic phase is washed with water (20 ml × 1) and saturated brine (20 ml × 1) in turn. Collect the organic phase, dry it over anhydrous sodium sulfate, filter it, and concentrate the filtrate under reduced pressure to obtain the product C1: (S)-1-(4-cyanopyridin-2-yl)pyrrolidine-2-carboxylic acid (310 mg, yellow solid), yield: 78.3%.

[0196] LCMS: m / z 218.1 (M+H) + ; RT = 1.076min.

[0197] Intermediate C2: Synthesis of 2-((4-cyanophenyl)amino)acetic acid

[0198]

[0199] Step 1: Compound C2-1 (1 g, 8.5 mmol), sodium acetate (1.4 g, 17 mmol), ethyl bromoacetate (1.7 g, 10 mmol) and 30 ml of ethanol were added to a dry 50 ml single-mouth bottle in sequence, refluxed for 36 hours, the solvent was dried, 50 ml of ethyl acetate was added, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and purified by silica gel column with (petroleum ether: ethyl acetate = 2:1) to obtain intermediate C2-2 (300 mg, yield: 17.4%) LCMS: m / z 205.2 (M+H) + ,RT=1.37min.

[0200] Step 2: Add compound C2-2 (300 mg, 1.47 mmol), sodium hydroxide (118 mg, 2.94 mmol), 3 ml of water and 12 ml of methanol in a dry 50 ml single-necked bottle, stir at room temperature for 3 hours, spin dry the solvent, adjust the pH to about 5 with dilute hydrochloric acid, and obtain white solid C2 (120 mg, yield: 46.3%) by preparation and separation.

[0201] LCMS: m / z=175.2 (M-1) - ,RT=1.07min.

[0202] Intermediate C4: 2-((2-fluoropyridin-3-yl)amino)acetic acid

[0203] Intermediate C4 was prepared using the same method as intermediate C2.

[0204]

[0205] 1 H NMR (CDCl3-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).

[0206] LCMS: m / z 541.2 (M+H) + ; RT = 1.678min.

[0207] Intermediate C3: Synthesis of 2-(methyl(phenyl)amino)acetic acid

[0208]

[0209] Step 1: Add compound C3-1 (3 g, 16.7 mmol, CAS 23284-84-6), iodomethane (7.1 g, 50 mmol), and 20 ml toluene to a dry 50 ml sealed tube, stir overnight at 80 degrees Celsius, cool, add 30 ml water, extract with ethyl acetate (50 ml*2), dry over anhydrous sodium sulfate, wash with saturated brine, spin dry, and pass the crude product through a silica gel column with (petroleum ether: ethyl acetate = 20:1) to obtain 1.2 g of yellow oily product 2-(methyl(phenyl)amino)ethyl acetate (C3-2). Yield: 37%. LCMS: m / z 194.3 (M-1) R = 1.616.

[0210] Step 2: Add compound C3-2 (1.2 g, 6.2 mmol), sodium hydroxide (0.62 g, 15 mmol), 5 ml of water and 15 ml of methanol in a dry 25 ml single-mouth bottle, stir at room temperature for three hours, spin off the organic solvent, adjust the pH to about 4, extract with ethyl acetate (50 ml * 2), dry over anhydrous sodium sulfate, and spin dry to obtain 420 mg of yellow oily 2-(methyl(phenyl)amino)acetic acid (C3), yield: 41%.

[0211] LCMS: m / z 166.3 (M-1) - ,RT=1.2min.

[0212] Intermediate C5: Synthesis of (S)-2-oxooxazolidine-4-carboxylic acid

[0213]

[0214] Step 1: Add L-serine (10.0 g, 95.2 mmol, 1.0 eq), sodium bicarbonate (20 g, 238.0 mmol, 2.5 eq) and water (30 mL) in a dry 500 mL single-mouth bottle at room temperature. Add benzyl chloroformate (2.0 mL, 142.8 mmol, 1.5 eq) at 0 ° C and stir at room temperature for 18 hours. After the reaction is completed, pour the reaction solution into water (200) and extract the impurities with ethyl acetate (300 mL). The aqueous phase is acidified to a pH of 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (300 mL) 3 times. The organic phase is spin-dried, and the residue is washed and pulped with ethyl acetate and filtered to obtain the product C5-1: (S)-2-(((benzyloxy)carbonyl)amino)-3-hydroxypropionic acid (10 g, white solid), with a yield of 45%. LCMS: m / z 238.2 (MH) - ; RT = 1.047 min

[0215] Step 2: At 0°C, C5-1 (2.5 g, 10.45 mmol, 1.0 eq), water (10 mL) and sodium hydroxide (0.84 g, 20.91 mmol, 2.0 eq) were added to a 100 mL single-mouth bottle at room temperature. Stir at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water (20) and the impurities were extracted with ether (300 mL). The aqueous phase was acidified with concentrated hydrochloric acid to a pH of 1, and then extracted with ethyl acetate (300 mL) 5 times. The product (S)-2-oxoxazolidine-4-carboxylic acid (600 mg, white solid) was obtained with a yield of 86%.

[0216] 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).

[0217] Intermediate D1: Synthesis of 2-methyl-1H-imidazo[4,3-b]pyrazine

[0218]

[0219] In a dry 50ml single-necked bottle, add 2,3-diaminopiperazine (200mg, 1.82mmol) and acetic anhydride (445.4mg, 4.36mmol) in sequence, react at 140°C for 2 hours, cool to room temperature, spin-dry acetic anhydride, add 1ml of hot 10N NaOH solution, add 2ml of acetic acid, put in the refrigerator and stand overnight, precipitate solid, filter, wash with water, and dry to obtain 90mg of brown solid product.

[0220] LCMS: m / z 135.2 (M+H) + ; RT = 0.53min.

[0221] Intermediate D2: Synthesis of 2-(2-methyl-1H-imidazol-5-yl)pyrimidine

[0222]

[0223] Step 1: Add 30 ml of anhydrous tetrahydrofuran to a dry 100 ml three-necked flask, ventilate, protect with nitrogen, cool to 0°C, slowly add 2 mol / L LDA (10.5 ml, 22.7 mmol) and tributyltin hydride (5.64 ml, 22.7 mmol), stir at 0°C for 15 minutes, then cool to -78°C, dropwise add a tetrahydrofuran solution (20 ml) of 2-chloropyrimidine (2 g, 17.5 mmol), slowly warm to room temperature after addition, stir overnight, add 30 ml of water, extract with ethyl acetate (50 ml x 3), dry over anhydrous sodium sulfate, spin dry, and purify the crude product by silica gel column (PE: EA = 10: 1) to obtain a yellow oily liquid product D2-1: 2.15 g (yield: 35%).

[0224] Step 2: In a dry 100ml single-mouth bottle, add 5-bromo-2-methyl-1H-imidazole (CAS: 16265-11-5, 1g, 6.25mmol) and 20ml of tetrahydrofuran, cool to 0°C, add NaH (0.375g, 9.4mmol) in batches, slowly warm to room temperature, stir for 1 hour, add SEM-Cl (1.25g, 7.5mmol), stir at room temperature overnight, quench with water, extract with ethyl acetate (50mlx3), wash with saturated brine, dry with anhydrous sodium sulfate, spin dry, and purify the crude product by silica gel column (PE:EA=1:1) to obtain a light yellow oily product D2-2: 1.4g (yield: 78%). LCMS: m / z 293.1[M+H] + ,RT=1.34min.

[0225] Step 3: Add D2-2 (1 g, 3.43 mmol), D2-1 (1.18 g, 4.12 mmol) and tetrakistriphenylphosphine palladium (300 mg) in a dry 50 ml single-mouth bottle, add 20 ml of dry DMF, ventilate three times, protect with nitrogen, stir at 120 ° C for 4 hours, use an oil pump to dry the solvent, add 20 ml of water, extract with ethyl acetate, dry with anhydrous sodium sulfate, spin dry, and pass the crude product through a silica gel column (PE: EA = 1: 1) to obtain a red solid D2-3: 0.97 g (yield: 95%). LCMS: m / z 291.2 [M+H] + ,RT=0.980min.

[0226] Step 4: Add D2-3 (500 mg, 1.72 mmol) to a dry 50 ml single-mouth bottle, add 20 ml DCM, and 10 ml trifluoroacetic acid, stir at room temperature overnight, spin dry the solvent, wash with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, spin dry, and pass the crude product through a silica gel column (PE: EA = 1: 1) to obtain a red solid product D2: 160 mg (yield 58%).

[0227] LCMS: m / z 161.2 [M+H] + ,RT=0.445min.

[0228] Intermediate D3: 2-(2-methyl-1H-imidazol-5-yl)pyrazine

[0229] Using the method described above, starting with 2-chloropyrazine, 2-(2-methyl-1H-imidazol-5-yl)pyrazine was obtained.

[0230] Example 1: Compound 1 and Compound 2

[0231]

[0232] Step 1: Add intermediate A1, L-pyroglutamic acid (260 mg, 2 mmol) to a microwave reaction tube, inject 2 mL of anhydrous methanol to dissolve, stir at room temperature for 15 minutes, add intermediate B1 (240 mg, 2 mmol), seal the tube and react in a 40°C oil bath overnight. Add 10 mL of water and extract three times with ethyl acetate (3*10 mL), combine the ethyl acetate phases and wash several times with saturated brine, dry with anhydrous sodium sulfate and spin dry to obtain a crude reaction product, separate using normal phase column chromatography (dichloromethane / methanol=95 / 5) to obtain a light brown solid, namely (2S)-N-(1-(3,3-difluorocyclobutylcarbonyl)-2,3-dihydro-1H-indenyl)-N-3-fluorophenyl-5-oxo-pyrrolidine-2-carboxamide (intermediate 1-1, 140 mg, yield=15%),

[0233] LCMS: m / z 943.4 (2M+H) + ,RT=1.64min.

[0234] Step 2: Add the intermediate 1-1 (140 mg, 0.3 mmol) obtained in step 1, cesium carbonate (145 mg, 0.45 mmol), Pd2(dba)3 (14 mg, 0.015 mmol), Xant-phos (9 mg, 0.015 mmol) and 2-chloro-4-cyanopyridine (50 mg, 0.36 mmol) to a microwave reaction tube, inject 5 mL of anhydrous 1,4-dioxane, seal the tube and place it at 70°C for 3 hours. Filter, spin dry the filtrate and separate it using a chromatography column (petroleum ether / ethyl acetate = 4 / 1) to obtain the crude products of compound 1 and compound 2, and then use high performance liquid preparative liquid chromatography to further purify them to obtain the target compounds 1 and 2.

[0235] 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

[0236]

[0237] 1 H NMR (400MHz, CDCl3): 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).

[0238] LCMS: m / z 574.1 (M+H) + ,RT=1.84min.

[0239] 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

[0240]

[0241] 1 H NMR (400MHz, CDCl3): 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).

[0242] LCMS: m / z 574.1 (M+H) + ,RT=1.84min.

[0243] Example 2: Compound 3 and Compound 4

[0244] The same method as in Example 1 was used to react the product obtained by using the imine intermediate A2, the isocyanate intermediate B1 and L-pyroglutamic acid, and then reacted with 2-chloro-4-cyanopyridine and purified to obtain compound 3 and compound 4.

[0245] Compound 3: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbonyl)-2,3-dihydro-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

[0246]

[0247] 1 H NMR (400MHz, CDCl3): 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).

[0248] LCMS: m / z 575.2 (M+H) + ,RT=1.74min.

[0249] Compound 4: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbonyl)-2,3-dihydro-1H-inden-1-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

[0250]

[0251] 1 H NMR (400MHz, CDCl3): 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,1 H),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).

[0252] LCMS: m / z 575.2 (M+H) + ,RT=1.74min.

[0253] Example 3: Compound 7 and Compound 8

[0254] The same method as in Example 1 was used to react the product obtained by using the imine intermediate A2, the isocyanate intermediate B2 and L-pyroglutamic acid, and then reacted with 2-chloro-4-cyanopyridine and purified to obtain Compound 7 and Compound 8.

[0255] 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

[0256]

[0257] 1 H NMR (400MHz, CDCl3): 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).

[0258] LCMS: m / z 603.3 (M+H) + ,RT=1.79min.

[0259] 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

[0260]

[0261] 1 H NMR (400MHz, CDCl3): 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).

[0262] LCMS: m / z 603.3 (M+H) + ,RT=1.79min.

[0263] Example 4: Compound 9 and Compound 10

[0264] The same method as in Example 1 was used to react the imine intermediate A4 with cyclohexyl isocyanide and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine and purified to obtain Compounds 9 and 10.

[0265] Compound 9: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(cyclohexylcarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0266]

[0267] 1 H NMR(400MHz, CDCl3)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).

[0268] LCMS: m / z 580.3 [M+H] + ,RT=2.0min.

[0269] Compound 10: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(cyclohexylcarbonyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0270]

[0271] 1H NMR(400MHz, CDCl3)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).

[0272] LCMS: m / z 580.3 [M+H] + ,RT=2.01min.

[0273] Example 5: Compound 12 and Compound 13

[0274] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine and purified to obtain Compound 12 and Compound 13.

[0275] 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

[0276]

[0277] 1 H NMR (400MHz, CDCl3): 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),4.70–4.6 1(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).

[0278] LCMS: m / z 602.2 (M+H) + ,RT=1.88min.

[0279] 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

[0280]

[0281] 1 H NMR (400MHz, CDCl3): 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).

[0282] LCMS: m / z 602.2 (M+H) + ,RT=1.88min.

[0283] Example 6: Compound 14 and Compound 15

[0284] The same method as in Example 1 was used to react the imine intermediate A1, cyclohexyl isocyanide and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 14 and Compound 15.

[0285] Compound 14: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(cyclohexylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0286]

[0287] 1H NMR (400MHz, CDCl3): 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).

[0288] LCMS: m / z 566.2 (M+H) + ,RT=1.95min.

[0289] Compound 15: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(cyclohexylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0290]

[0291] 1 H NMR (400MHz, CDCl3): 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).

[0292] LCMS: m / z 566.2 (M+H) + ,RT=1.95min.

[0293] Example 7: Compound 19 and Compound 20

[0294] The same method as in Example 1 was used to react the imine intermediate A31, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 19 and Compound 20.

[0295] Compound 19: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0296]

[0297] 1 H NMR (400MHz, CDCl3): 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).

[0298] LCMS: m / z 588.2 (M+H) + ,RT=1.91min.

[0299] Compound 20: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methyl-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0300]

[0301] 1 H NMR (400MHz, CDCl3): 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),4.1 2-4.08(m,1H),2.93-2.82(m,3H),2.71–2.29(m,7H),2.26(2,3H),2.11–1.90(m,2H).

[0302] LCMS: m / z 588.2 (M+H) + ,RT=1.91min.

[0303] Example 8: Compound 21

[0304] The same method as in Example 1 was used to react the imine intermediate A22, the isocyanate intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyrimidine to obtain compound 21.

[0305] 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

[0306]

[0307] 1 H NMR (400MHz, CDCl3): 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).

[0308] LCMS: m / z 621.0 (M+H) + ,RT=1.61min.

[0309] Example 9: Compound 22

[0310] The same method as in Example 1 was used to react the imine intermediate A16, the isocyanide intermediate B1 and the acid intermediate C5 to obtain a product, which was then reacted with 2-chloro-4-cyanopyrimidine to obtain compound 22.

[0311] 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

[0312]

[0313] 1H NMR (400MHz, CDCl3): 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).

[0314] LCMS: m / z 595.1 (M+H) + ,RT=1.45min.

[0315] Example 10: Compound 23

[0316] The same method as in Example 1 was used to react the imine intermediate A6, the isocyanide intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 23.

[0317] Compound 23: (2S)-1-(4-cyanopyridin-2-yl)-N-(7-((4,4-difluorocyclohexane)carbamoyl)bicyclo[4.2.0]oct-1(6),2,4-trien-7-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

[0318]

[0319] 1 H NMR (400MHz, CDCl3): 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),7.2 6-7.15(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).

[0320] LCMS: m / z 561.1 (M+H) + ,RT=1.72min.

[0321] Example 11: Compound 27

[0322] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B3 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain compound 27.

[0323] 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.

[0324]

[0325] 1 H NMR (MeOD-d4, 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).

[0326] LCMS: m / z 568.3 (M+H) + ,RT=1.526min.

[0327] Example 12: Compound 28 and Compound 29

[0328] The same method as in Example 1 was used to react the imine intermediate A7, the isocyanide intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 28 and Compound 29.

[0329] Compound 28: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((4,4-difluorocyclohexyl)carbamoyl)-6-fluoro-2,3-dihydro-1H-indene-1yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

[0330]

[0331] 1H NMR (400MHz, CDCl3): 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=44.3,7.8H z,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).

[0332] LCMS: m / z 621.2 (M+H) + ,RT=1.79min.

[0333] Compound 29: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((4,4-difluorocyclohexyl)carbamoyl)-6-fluoro-2,3-dihydro-1H-indene-1yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

[0334]

[0335] 1 H NMR (400MHz, CDCl3): δ8.80–8.55(m,2H),8.37–7.70(m,2H),7.34–7.01(m,5H),5.20(t,J=8.5H z,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).

[0336] LCMS: m / z 621.2 (M+H) + ,RT=1.79min.

[0337] Example 13: Compound 30

[0338] The same method as in Example 1 was used to react the imine intermediate A8, the isocyanide intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain compound 30.

[0339] 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

[0340]

[0341] 1 H-NMR(CDCl3,400MHz):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).

[0342] LCMS: m / z 614 (M+H) + ,RT=1.558min.

[0343] Example 14: Compound 31

[0344] The same method as in Example 1 was used to react the imine intermediate A9, the isocyanide intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain compound 31.

[0345] 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

[0346]

[0347] 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).

[0348] LCMS: m / z 598.2 (M+H) + ,RT=1.76min.

[0349] Example 14: Compound 32 and Compound 33

[0350] The same method as in Example 1 was used to react the imine intermediate A2, tert-butyl isocyanide and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 32 and Compound 33.

[0351] 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

[0352]

[0353] 1 H NMR(400MHz, CDCl3)δ8.74(d,J=7.3Hz,1H),8.59(s,1H),8.54–8.48(m,1H),8.29–8.24(m,1 H),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),2.62–2.4 7(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).

[0354] LCMS: m / z 541.1 [M+H] + ,RT=1.81min.

[0355] 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

[0356]

[0357] 1H NMR(400MHz, CDCl3)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),7.25–7.1 7(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).

[0358] LCMS: m / z 541.1 [M+H] + ,RT=1.8min.

[0359] Example 15: Compound 34

[0360] The same method as in Example 1 was used to react the imine intermediate A2, the isocyanate intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloropyrimidine to obtain compound 34.

[0361] Compound 34: (2S)-N-(1-(4,4-difluorocyclohexyl)formyl)-2,3-dihydro-1H-inden-1yl)-N-(5-fluoropyridin-3-yl)-5-oxo-1-(pyrimidin-2-yl)pyrrolidine-2-carboxamide

[0362]

[0363] 1 H NMR (400MHz, CDCl3) 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).

[0364] LCMS: m / z 579.2 [M+H] +,RT=1.61min.

[0365] Example 16: Compound 35

[0366] The same method as in Example 1 was used to react the imine intermediate A2, the isocyanate intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 3-chlorobenzonitrile to obtain compound 35.

[0367] Compound 35: (2S)-1-(3-cyanophenyl)-N-(1-(N-(4,4-difluorocyclohexyl)formyl)-2,3-dihydro-1H-inden-1yl)-N-(5-fluoro-3-pyridyl)-5-oxopyrrolidine-2-carboxamide

[0368]

[0369] 1 H NMR (400MHz, CDCl3) 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).

[0370] LCMS: m / z 602.2 [M+H] + ,RT=1.74min.

[0371] Example 17: Compound 36 and Compound 37

[0372] The same method as in Example 1 was used to react the imine intermediate A10, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 36 and Compound 37.

[0373] 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

[0374]

[0375] 1 H-NMR (CDCl3, 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).

[0376] LCMS: m / z 590.1 (M+H) + ,RT=1.59min.

[0377] 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

[0378]

[0379] 1 H-NMR (CDCl3, 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).

[0380] LCMS: m / z 590.1 (M+H) + ,RT=1.606min.

[0381] Example 18: Compound 39

[0382] The same method as in Example 1 was used to react the imine intermediate A2, the isocyanate intermediate B2 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-fluoropyridine to obtain compound 39.

[0383] Compound 39: (2S)-N-(1-((4,4-difluorocyclohexyl)formyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-fluoropyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide

[0384]

[0385] 1 H NMR (400MHz, CDCl3) 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),2.6 2–2.49(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).

[0386] LCMS: m / z 596.2 [M+H] + .

[0387] Example 19: Compound 40

[0388] The same method as in Example 1 was used to react the imine intermediate A11, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloropyridine to obtain compound 40.

[0389] 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

[0390]

[0391] 1H NMR(400MHz, CDCl3)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).

[0392] LCMS: m / z 609.2 [M+H] + ,RT=1.81min.

[0393] Example 20: Compound 41 and Compound 42

[0394] The same method as in Example 1 was used to react the imine intermediate A2, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-bromo-4-chloropyridine to obtain Compound 41 and Compound 42.

[0395] 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

[0396]

[0397] 1 H NMR (500MHz, CDCl3) 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),7.02–6.9 5(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).

[0398] LCMS: m / z 584.1[M+H] + ,RT=1.81min.

[0399] 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

[0400]

[0401] 1 H NMR (500MHz, CDCl3) 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),4.19–4.0 5(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).

[0402] LCMS: m / z 584.1[M+H] + ,RT=1.81min.

[0403] Example 21: Compound 43 and Compound 44

[0404] The same method as in Example 1 was used to react the imine intermediate A12, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloropyridine to obtain Compound 43 and Compound 44.

[0405] 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

[0406]

[0407] 1H NMR(400MHz, CDCl3)δ8.76(s,1H),8.51–8.41(m,1H),7.55–7.46(m,1H),7.34–7.27(m,1H),7.24–7.2 0(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,1 H),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).

[0408] LCMS: m / z 608.2 [M+H] + ,RT=1.84min.

[0409] 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

[0410]

[0411] 1 H NMR(400MHz, CDCl3)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).

[0412] LCMS: m / z 608.2 [M+H] + ,RT=1.84min.

[0413] Example 22: Compound 46 and Compound 47

[0414] The same method as in Example 1 was used to react the imine intermediate A13, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloropyridine to obtain Compound 46 and Compound 47.

[0415] Compound 46: (S)-N-((S)-6-Chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0416]

[0417] 1 H NMR (400MHz, CDCl3): 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).

[0418] LCMS: m / z 608.2 (M+H) + ,RT=1.90min.

[0419] Compound 47: (S)-N-((R)-6-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0420]

[0421] 1H NMR (400MHz, CDCl3): 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).

[0422] LCMS: m / z 608.2 (M+H) + ,RT=1.88min.

[0423] Example 23: Compound 48 and Compound 49

[0424] The same method as in Example 1 was used to react the imine intermediate A14, the isocyanate intermediate B1 and L-pyroglutamic acid, and the purified product was then reacted with 2-chloropyridine to obtain Compound 48 and Compound 49.

[0425] Compound 48: (S)-N-((S)-5-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0426]

[0427] 1 H NMR (400MHz, CDCl3): 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).

[0428] LCMS: m / z 608.2 (M+H) + ,RT=1.90min.

[0429] Compound 49: (S)-N-((R)-5-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0430]

[0431] 1 H NMR (400MHz, CDCl3): 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).

[0432] LCMS: m / z 608.2 (M+H) + ,RT=1.90min.

[0433] Example 24: Compound 50 and Compound 51

[0434] The same method as in Example 1 was used to react the imine intermediate A2, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloropyrazine to obtain Compound 50 and Compound 51.

[0435] 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

[0436]

[0437] 1 H NMR(400MHz, CDCl3)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).

[0438] LCMS: m / z 551.1 [M+H] + ,RT=1.62min.

[0439] 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

[0440]

[0441] 1 H NMR(400MHz, CDCl3)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).

[0442] LCMS: m / z 551.1 [M+H] + ,RT=1.62min.

[0443] Example 25: Compound 52 and Compound 53

[0444] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain the product, which was then reacted with 2-chloro-4-trifluoromethylpyridine to obtain Compound 52 and Compound 53.

[0445] 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

[0446]

[0447] 1H NMR(400MHz, CDCl3)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).

[0448] LCMS: m / z 617.2 [M+H] + ,RT=1.93min.

[0449] 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

[0450]

[0451] 1 H NMR(400MHz, CDCl3)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).

[0452] LCMS: m / z 617.2 [M+H] + ,RT=1.95min.

[0453] Example 26: Compound 54 and Compound 55

[0454] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-methoxypyridine to obtain Compound 54 and Compound 55.

[0455] 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

[0456]

[0457] 1 H NMR (400MHz, CDCl3) 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).

[0458] LCMS: m / z 579.2 [M+H] + ,RT=1.84min.

[0459] 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

[0460]

[0461] 1 H NMR (400MHz, CDCl3) δ8.06 (d, J = 2.1Hz, 1H), 7.97–7.87 (m, 1H), 7.46–7.26 (m, 4H), 7.2 4–7.19(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),2.56–2.4 5(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).

[0462] LCMS: m / z 579.2 [M+H] + ,RT=1.84min.

[0463] Example 27: Compound 56 and Compound 57

[0464] The same method as in Example 1 was used to react the imine intermediate A15, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 56 and Compound 57.

[0465] 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

[0466]

[0467] 1 H NMR (400MHz, CDCl3): 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).

[0468] LCMS: m / z 609.2 [M+H] + ; RT = 1.89 min.

[0469] 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

[0470]

[0471] 1H NMR (400MHz, CDCl3): 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),5.4 9(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).

[0472] LCMS: m / z 609.2 [M+H] + ; RT = 1.89 min

[0473] Example 28: Compound 58 and Compound 59

[0474] The same method as in Example 1 was used to react the imine intermediate A16, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 58 and Compound 59.

[0475] 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

[0476]

[0477] 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).

[0478] LCMS: m / z 608.2 [M+H] +,RT=1.748min.

[0479] 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

[0480]

[0481] 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).

[0482] LCMS: m / z 608.2 [M+H] + ,RT=1.75min.

[0483] Example 28: Compound 60 and Compound 61

[0484] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B4 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 60 and Compound 61.

[0485] Compound 60: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(phenylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0486]

[0487] 1 H NMR(MeOD-d4,400MHz): δ8.73(s,1H),8.58-8.54(m,1H),7.41-7.29(m,9H),7.08-7.0 1(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).

[0488] LCMS: m / z 560.2 (M+H) + ; RT = 1.72min.

[0489] Compound 61: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-(phenylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0490]

[0491] 1 H NMR(MeOD-d4,400MHz): 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).

[0492] LCMS: m / z 560.2 (M+H) + ; RT = 1.72min.

[0493] Example 29: Compound 62 and Compound 63

[0494] The same method as in Example 1 was used to react the product obtained by reacting the imine intermediate A1, the isocyanide intermediate B1 and the acid intermediate C5, and then reacting with 2-chloro-4-cyanopyridine to obtain Compound 62 and Compound 63.

[0495] 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

[0496]

[0497] 1 H NMR (MeOD-d4, 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).

[0498] LCMS: m / z 576.2 (M+H) + ; RT = 1.66min.

[0499] 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

[0500]

[0501] 1 H NMR(MeOD-d4,400MHz): 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).

[0502] LCMS: m / z 576.2 (M+H) + ; RT = 1.66min.

[0503] Example 30: Compound 64 and Compound 65

[0504] The same method as in Example 1 was used to react the imine intermediate A17, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 64 and Compound 65.

[0505] 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

[0506]

[0507] 1 H NMR (400MHz, CDCl3): 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).

[0508] LCMS: m / z 592.2 (M+H) + ; RT = 1.83min.

[0509] 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

[0510]

[0511] 1 H NMR (400MHz, CDCl3): 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),6.8 9(dd,J=43.0,8.6Hz,1H),5.57(d,J=5.7Hz,1H),4.67-4.60(m,1H),4.1 7-3.94(m,1H),2.95-2.62(m,4H),2.59-2.13(m,5H),2.05-1.83(m,3H).

[0512] LCMS: m / z 592.2 (M+H) + ; RT = 1.84min.

[0513] Example 31: Compound 66

[0514] The same method as in Example 1 was used to react the imine intermediate A18, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain compound 66.

[0515] 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

[0516]

[0517] 1 H NMR (400MHz, CDCl3): 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).

[0518] LCMS: m / z 642.2 (M+H) + ; RT = 1.92min.

[0519] Example 32: Compound 67 and Compound 68

[0520] The same method as in Example 1 was used to react the imine intermediate A19, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 67 and Compound 68.

[0521] 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

[0522]

[0523] 1 H-NMR (DMSO-d6, 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).

[0524] LCMS: m / z 608.2 (M+H) + ,RT=1.75min.

[0525] 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

[0526]

[0527] 1H-NMR (DMSO-d6, 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).

[0528] LCMS: m / z 608.2 (M+H) + ; RT = 1.76min.

[0529] Example 33: Compound 69 and Compound 70

[0530] The same method as in Example 1 was used to react the imine intermediate A20, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 69 and Compound 70.

[0531] 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

[0532]

[0533] 1 H-NMR (DMSO-d6, 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), 5.81-5.8 0(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).

[0534] LCMS: m / z 556.2 (M+H) + ; RT = 1.64min.

[0535] 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

[0536]

[0537] 1 H-NMR (DMSO-d6, 400MHz): δ8.76 (s, 1H), 8.20-8.21 (d, J = 4.0Hz, 1H), 7.58-7.60 (d, J = 6.8H z,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),2.8 2-2.88(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).

[0538] LCMS: m / z 556.2 (M+H) + ; RT = 1.66min.

[0539] Example 34: Compound 71 and Compound 72

[0540] The same method as in Example 1 was used to react the imine intermediate A21, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 71 and Compound 72.

[0541] Compound 71: (S)-N-(3,4-difluorophenyl)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrole-2-carboxamide

[0542]

[0543] 1H NMR(MeOD-d4,400MHz): 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).

[0544] LCMS: m / z 592.2 (M+H) + ; RT = 1.69 min.

[0545] Compound 72: (S)-N-(3,4-difluorophenyl)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrole-2-carboxamide

[0546]

[0547] 1 H NMR (MeOD-d4, 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).

[0548] LCMS: m / z 592.2 (M+H) + ; RT = 1.691min.

[0549] Example 35: Compound 73 and Compound 74

[0550] The same method as in Example 1 was used to react the imine intermediate A22, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 73 and Compound 74.

[0551] Compound 73 (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0552]

[0553] 1H-NMR (CDCl3, 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).

[0554] LCMS: m / z 5921[M+H] + ; RT = 1.8 min.

[0555] 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

[0556]

[0557] 1 H-NMR (CDCl3, 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).

[0558] LCMS: m / z 5921[M+H] + ; RT = 1.7 min.

[0559] Example 36: Compound 75 and Compound 76

[0560] The same method as in Example 1 was used to react the imine intermediate A23, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 75 and Compound 76.

[0561] 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

[0562]

[0563] 1 H NMR(400MHz, CDCl3)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).

[0564] LCMS: m / z 592.1[M+H] + ; RT = 1.85min.

[0565] 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

[0566]

[0567] 1 H NMR(400MHz, CDCl3)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).

[0568] LCMS: m / z 592.1[M+H] + ; RT = 1.86min.

[0569] Example 37: Compound 77 and Compound 78

[0570] The same method as in Example 1 was used to react the imine intermediate A24, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 77 and Compound 78.

[0571] 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

[0572]

[0573] 1 H NMR (400MHz, CDCl3): 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).

[0574] LCMS: m / z 592.2 [M+H] + ; RT = 1.86min.

[0575] 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

[0576]

[0577] 1 H NMR (400MHz, CDCl3): 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).

[0578] LCMS: m / z 592.1[M+H] + ; RT = 1.87min.

[0579] Example 37: Compound 79 and Compound 80

[0580] The same method as in Example 1 was used to react the imine intermediate A25, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 79 and Compound 80.

[0581] Compound 79: (S)-N-((S)-4-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

[0582]

[0583] 1 H NMR (400MHz, CDCl3): 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,1 H),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).

[0584] LCMS: m / z 609.1[M+H] + ; RT = 1.80min.

[0585] Compound 80: (S)-N-((R)-4-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

[0586]

[0587] 1H NMR (400MHz, CDCl3): 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).

[0588] LCMS: m / z 609.1[M+H] + ; RT = 1.81 min.

[0589] Example 39: Compound 81 and Compound 82

[0590] The same method as in Example 1 was used to react the imine intermediate A26, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain the product, which was then reacted with 2-chloro-4-cyanopyridine to obtain 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-oxypyrrolidine-2-carboxamide

[0591]

[0592] 1 H-NMR (CDCl3, 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).

[0593] LCMS: m / z 592.1[M+H] + ; RT = 1.8 min.

[0594] 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

[0595]

[0596] 1 H-NMR (CDCl3, 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).

[0597] LCMS: m / z 592.1[M+H] + ; RT = 1.82min.

[0598] Example 40: Compound 83

[0599] The same method as in Example 1 was used to react the imine intermediate A27, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 83.

[0600] 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

[0601]

[0602] 1H NMR (400MHz, CDCl3): 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).

[0603] LCMS: m / z 592.1[M+H] + ; RT = 1.83min.

[0604] Example 40: Compound 84 and Compound 85

[0605] The same method as in Example 1 was used to react the imine intermediate A28, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 84 and Compound 85.

[0606] 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

[0607]

[0608] 1 H-NMR (DMSO-d6, 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).

[0609] LCMS: m / z 592.2 [M+H] + ; RT = 1.67min.

[0610] 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

[0611]

[0612] 1 H-NMR (DMSO-d6, 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).

[0613] LCMS: m / z 592.2 [M+H] + ; RT = 1.67min.

[0614] Example 41: Compound 88 and Compound 89

[0615] The same method as in Example 1 was used to react the imine intermediate A29, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 88 and Compound 89.

[0616] Compound 88: (S)-1-(4-cyanopyridin-2-yl)-N-((S)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methoxy-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrole-2-carboxamide

[0617]

[0618] 1H-NMR (DMSO-d6, 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).

[0619] LCMS: m / z 604.2 [M+H] + ; RT = 1.64min.

[0620] Compound 89: (S)-1-(4-cyanopyridin-2-yl)-N-((R)-1-((3,3-difluorocyclobutyl)carbamoyl)-4-methoxy-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrole-2-carboxamide

[0621]

[0622] 1 H-NMR (DMSO-d6, 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).

[0623] LCMS: m / z 604.2 [M+H] + ; RT = 1.65min.

[0624] Example 42: Compound 90

[0625] The same method as in Example 1 was used to react the imine intermediate A22, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyrimidine to obtain compound 90.

[0626] Compound 90: (S)-1-(4-nitrilopyrimidin-2-yl)-N-((S)-1-(3,3-difluorocyclobutylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0627]

[0628] 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).

[0629] LCMS: m / z 593.3 [M+H] + ; RT = 1.3min.

[0630] Example 43: Compound 91

[0631] The same method as in Example 1 was used to react the imine intermediate A22, the isocyanide intermediate B1 and the acid intermediate C5 to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 91.

[0632] 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

[0633]

[0634] 1 H NMR(MeOD-d4,400MHz): 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).

[0635] LCMS: m / z 594.2 [M+H] +; RT = 1.7 min.

[0636] Example 44: Compound 92 and Compound 93

[0637] The same method as in Example 1 was used to react the imine intermediate A30, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 92 and Compound 93.

[0638] Compound 92: (S)-N-((S)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0639]

[0640] 1 H NMR (400MHz, CDCl3): 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=8.7Hz,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).

[0641] LCMS: m / z 626.1[M+H] + ; RT = 1.91 min.

[0642] Compound 93: (S)-N-((R)-4-chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0643]

[0644] 1H NMR (400MHz, CDCl3): 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).

[0645] LCMS: m / z 626.2 [M+H] + ; RT = 1.93min.

[0646] Example 44: Compound 96 and Compound 97

[0647] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B6 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 96 and Compound 97.

[0648] Compound 96: (S)-1-(4-nitrilopyridin-2-yl)-N-((S)-1-(cyclopropylmethylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0649]

[0650] 1 H NMR (400MHz, CDCl3): 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).

[0651] LCMS: m / z 538.6 (M+H) + ; RT = 1.79 min.

[0652] Compound 97: (S)-1-(4-nitrilopyridin-2-yl)-N-((R)-1-(cyclopropylmethylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-N-(3-fluorophenyl)-5-oxopyrrolidine-2-carboxamide

[0653]

[0654] 1 H NMR (400MHz, CDCl3): 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).

[0655] LCMS: m / z 538.6 [M+H] + ; RT = 1.81 min.

[0656] Example 46: Compound 98 and Compound 99

[0657] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B5 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 98 and Compound 99.

[0658] Compound 98: (S)-1-(4-nitrilopyridin-2-yl)-N-(3-fluorophenyl)-N-((S)-1-(4,4-dimethylcyclohexylcarbonyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrolidine-2-carboxamide

[0659]

[0660] 1H-NMR (CDCl3, 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).

[0661] LCMS: m / z 594.2 [M+H] + ; RT = 1.83min.

[0662] Compound 99: (S)-1-(4-nitrile pyridin-2-yl)-N-(3-fluorophenyl)-N-((R)-1-(4,4-dimethylcyclohexylcarbonyl)-2,3-dihydro-1H-inden-1-yl)-5-oxopyrrolidine-2-carboxamide

[0663]

[0664] 1 H-NMR (CDCl3, 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).

[0665] LCMS: m / z 594.2 [M+H] + ; RT = 1.86min.

[0666] Example 47: Compound 100

[0667] The same method as in Example 1 was used to react the imine intermediate A12, the isocyanide intermediate B1 and the acid intermediate C5 to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain compound 100.

[0668] 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

[0669]

[0670] 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).

[0671] LCMS: m / z=611.1[M+H] + ; RT = 1.84min.

[0672] Example 48: Compound 101

[0673] The same method as in Example 1 was used to react the imine intermediate A1, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyrimidine to obtain compound 101 (a pair of diastereomeric mixtures were not separated).

[0674] 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

[0675]

[0676] 1H-NMR (CDCl3, 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).

[0677] LCMS: m / z 575.6 [M+H] + ; RT = 1.44min.

[0678] Example 49: Compound 102 and Compound 103

[0679] The same method as in Example 1 was used to react the imine intermediate A12, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain the product, which was then reacted with 2-chloro-4-cyanopyrimidine to obtain Compound 102 and Compound 103.

[0680] 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

[0681]

[0682] 1 H NMR (400MHz, CDCl3): δ8.94 (d, J = 4.3Hz, 1H), 7.62-7.46 (m, 1H), 7.35-7.2 8(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).

[0683] LCMS: m / z=610.2[M+H] + ; RT = 1.81 min.

[0684] 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

[0685]

[0686] 1 H NMR (400MHz, CDCl3): 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).

[0687] LCMS: m / z=610.2[M+H] + ; RT = 1.81 min.

[0688] Example 50: Compound 104

[0689] The same method as in Example 1 was used to react the imine intermediate A30, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyrimidine to obtain compound 104.

[0690] 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-carboxamide cyclobutyl

[0691]

[0692] 1H NMR(400MHz, CDCl3)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=34.9,8.9H z,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).

[0693] LCMS: m / z 627.0 [M+H] + ; RT = 1.80min.

[0694] Example 51: Compound 105 and Compound 106

[0695] The same method as in Example 1 was used to react the imine intermediate A2, the isocyanide intermediate B1 and the acid intermediate C5 to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 105 and Compound 106.

[0696] 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

[0697]

[0698] 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).

[0699] LCMS: m / z 577.3 [M+H] + ; RT = 1.70min.

[0700] 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

[0701]

[0702] 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).

[0703] LCMS: m / z 577.3 [M+H] + ; RT = 1.69 min.

[0704] Example 52: Compound 107 and Compound 108

[0705] The same method as in Example 1 was used to react the imine intermediate A22, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-nitropyridine to obtain Compound 107 and Compound 108.

[0706] 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

[0707]

[0708] 1H-NMR (CDCl3, 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).

[0709] LCMS: m / z 612.2 [M+H] + ; RT = 1.60min.

[0710] 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

[0711]

[0712] 1 H-NMR (CDCl3, 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).

[0713] LCMS: m / z 612.2 [M+H] + ; RT = 1.61 min.

[0714] Example 53: Compound 109 and Compound 110

[0715] The same method as in Example 1 was used to react the imine intermediate A33, the isocyanate intermediate B1 and the acid L-pyroglutamic acid to obtain the product, which was then reacted with 2-chloro-4-cyanopyrimidine to obtain Compound 109 and Compound 110.

[0716] 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

[0717]

[0718] 1 H-NMR (CDCl3, 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).

[0719] LCMS: m / z=607.6 [M+H] + ; RT = 1.52min.

[0720] 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

[0721]

[0722] 1 H-NMR (CDCl3, 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).

[0723] LCMS: m / z=607.6 [M+H] + ; RT = 1.51 min.

[0724] Example 54: Compound 111 and Compound 112

[0725] The same method as in Example 1 was used to react the imine intermediate A35, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 111 and Compound 112.

[0726] Compound 111: (S)-7-((S)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide)-N-(3,3-difluorocyclobutyl)-6,7-dihydro-5H-cyclopentanopyridine-7-carboxamide

[0727]

[0728] 1 H-NMR(CDCl3,400 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).

[0729] LCMS: m / z=593.0[M+H]+; RT=1.59 min.

[0730] Compound 112: (R)-7-((S)-1-(4-cyanopyridin-2-yl)-N-(3,5-difluorophenyl)-5-oxopyrrolidine-2-carboxamide)-N-(3,3-difluorocyclobutyl)-6,7-dihydro-5H-cyclopentanopyridine-7-carboxamide

[0731]

[0732] 1 H-NMR(CDCl3,400 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).

[0733] LCMS: m / z=593.0[M+H]+; RT=1.58 min.

[0734] Example 55: Compound 113 and Compound 114

[0735] The same method as in Example 1 was used to react the imine intermediate A32, the isocyanide intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain Compound 113 and Compound 114.

[0736] 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

[0737]

[0738] 1 H NMR (400 MHz, CDCl3) 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).

[0739] LCMS: m / z=626.2[M+H]+; RT=1.85 min.

[0740] 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

[0741]

[0742] 1H NMR (400 MHz, CDCl3) 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),4.8 0–4.60(m,1H),4.11–3.93(m,1H),3.2-2.58(m,6H),2.40–1.90(m,6H).

[0743] LCMS: m / z=626.2[M+H]+; RT=1.85 min.

[0744] Example 56: Compound 115

[0745] The same method as in Example 1 was used to react the imine intermediate A22, the isocyanate intermediate B7 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloro-4-cyanopyridine to obtain compound 115 (a pair of diastereomeric mixtures were not separated).

[0746] 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

[0747]

[0748] 1 H NMR (400MHz, CDCl3) 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.

[0749] Example 57: Compound 116

[0750] The same method as in Example 1 was used to react the imine intermediate A12, the isocyanate intermediate B1 and L-pyroglutamic acid to obtain a product, which was then reacted with 2-chloropyrimidine to obtain compound 116.

[0751] 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

[0752]

[0753] 1 H NMR (400MHz, CDCl3) 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).

[0754] LCMS: m / z=584.0 [M+H] + ; RT = 1.67 min

[0755] Example 58: Compound 117 and Compound 118

[0756] The same method as in Example 1 was used to react the imine intermediate A22, the isocyanide intermediate B1 and D-pyroglutamic acid to obtain a product, which was then reacted with 4-cyano-2-chloropyridine to obtain Compound 117 and Compound 118.

[0757] 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

[0758]

[0759] 1H NMR (400MHz, CDCl3) 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=6.2 Hz,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).

[0760] LCMS: m / z 592.1 (M+H) + ,RT=1.80min.

[0761] 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

[0762] 1 H NMR (400MHz, CDCl3) 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).

[0763] LCMS: m / z 592.1 (M+H) + ,RT=1.80min.

[0764] Example 59: Compound 119 and Compound 120

[0765] The same method as in Example 1 was used to react the product obtained by reacting the imine intermediate A12, the isocyanide intermediate B1 and the acid intermediate C5 with 4-cyano-2-chloropyrimidine to obtain Compound 119 and Compound 120.

[0766] Compound 119: (S)-N-((S)-7-Chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-3-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide

[0767]

[0768] 1 H NMR (400MHz, CDCl3) 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).

[0769] LCMS: m / z=611.1[M+H] + ; RT = 1.74 min

[0770] Compound 120: (S)-N-((R)-7-Chloro-1-((3,3-difluorocyclobutyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)-3-(4-cyanopyrimidin-2-yl)-N-(3-fluorophenyl)-2-oxooxazolidine-4-carboxamide

[0771]

[0772] 1 H NMR(400MHz, CDCl3)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).

[0773] LCMS: m / z=611.1[M+H] + ; RT = 1.74 min

[0774] Example 60: Compound 5

[0775]

[0776] Step 1: Weigh chloroacetic acid (190 mg, 2 mmol) in a microwave reaction tube, dissolve the Schiff base in 1 mL of anhydrous methanol and inject it into the microwave tube. Stir for 30 minutes and then add cyclohexyl isonitrile (220 mg, 2 mmol). Seal the microwave tube and react overnight at 30°C. Add 10 mL of water to quench the reaction and extract with ethyl acetate (3*15 mL). The combined ethyl acetate is washed with brine several times and dried over anhydrous sodium sulfate, filtered, and the filtrate is dried by column chromatography (eluent dichloromethane: 50:1) to obtain intermediate 5-1 (200 mg, white solid) with a yield of 23.3%.

[0777] 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,2 H),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).

[0778] LCMS: m / z 451.3 [M+Na] + ; RT = 2.0 min.

[0779] Step 2: Add 2-methylimidazole (19 mg, 0.23 mmol), triethylamine (46 mg, 0.46 mmol) and 5 mL of dichloromethane to the intermediate 5-1 (100 mg, 0.23 mmol) in a 100 mL reaction bottle, and heat under reflux under nitrogen protection overnight. The reaction solution was filtered with diatomaceous earth, and the filtrate was dried by column chromatography (eluent dichloromethane: 20:1) to obtain compound 5 (80 mg, white solid), 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.

[0780] 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,1 H),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).

[0781] LCMS: m / z 475.3 (M+H) + ; RT = 1.64min.

[0782] Example 61: Compound 6

[0783] The same method as in Example 54 was used to react the imine intermediate A3, cyclohexyl isocyanate and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with 2-methylimidazole to obtain Compound 6.

[0784] Compound 6: N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamide)-2,3-dihydro-1H-indene-2-carboxamide

[0785]

[0786] 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).

[0787] LCMS: m / z 475.2 (M+H) + ; RT = 1.65min.

[0788] Example 62: Compound 11

[0789] The same method as in Example 54 was used to react the imine intermediate A5 with cyclohexyl isocyanate and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with 2-methylimidazole to obtain Compound 11.

[0790] Compound 11: N-cyclohexyl-7-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamide)bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxamide

[0791]

[0792] 1HNMR (400MHz, CDCl3): 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).

[0793] LCMS: m / z 461.2 [M+H] + ; RT = 1.58min.

[0794] Example 63: Compound 16

[0795] The same method as in Example 54 was used to react the imine intermediate A1, the isocyanate intermediate B2 and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with piperidine to obtain Compound 16.

[0796] Compound 16: N-(4,4-difluorocyclohexyl)-1-(N-3-fluorophenyl)-2-(piperidin-1-yl)acetylamino)-2,3-dihydro-1H-indene-1-carboxamide

[0797]

[0798] 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).

[0799] LCMS: m / z 514.2 [M+H] + ; RT = 1.057min.

[0800] Example 64: Compound 25

[0801] The same method as in Example 54 was used to react the imine intermediate A1, the isocyanate intermediate B2 and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with dimethylbenzimidazole to obtain Compound 25.

[0802] Compound 25: N-(4,4-difluorocyclohexyl)-1-(N-3-fluorophenyl)-2-(2-methyl-1H-benzimidazol-1-yl)acetylamino)-2,3-dihydro-1H-indene-1-carboxamide

[0803]

[0804] 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).

[0805] LCMS: m / z 561.2 [M+H] + ; RT = 1.124min.

[0806] Example 65: Compound 28

[0807] The same method as in Example 54 was used to react the imine intermediate A2, the isocyanate intermediate B1 and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with 2-methylimidazole to obtain Compound 28.

[0808] Compound 28: N-(4,4-difluorocyclobutyl)-1-(N-(5-pyridin-3-yl)-2-(2-methylimidazol-1-yl)acetylamino)-2,3-dihydro-1H-inden-1-yl-carboxamide

[0809]

[0810] 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).

[0811] LCMS: m / z 484.3 [M+H]+ ; RT = 0.937min.

[0812] Example 66: Compound 45

[0813] The same method as in Example 54 was used to react the imine intermediate A1, the isocyanate intermediate B1 and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with the intermediate D1 to obtain compound 45.

[0814] Compound 45: N-(4,4-difluorocyclohexyl)-1-(N-3-fluorophenyl)-2-(2-methyl-1H-imidazo[4,5-b]pyrazin-1-yl)acetamido)-2,3-dihydro-1H-indene-1-carboxamide

[0815]

[0816] 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).

[0817] LCMS: m / z 535.2 [M+H] + ; RT = 1.44min.

[0818] Example 67: Compound 86

[0819] The same method as in Example 54 was used to react the imine intermediate A1, the isocyanate intermediate B2 and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with the intermediate D2 to obtain compound 86.

[0820] 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

[0821]

[0822] 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).

[0823] LCMS: m / z 589.2 [M+H] + ; RT = 1.056min.

[0824] Example 68: Compound 87

[0825] The same method as in Example 54 was used to react the imine intermediate A2, the isocyanate intermediate B2 and chloroacetic acid to obtain a product, which was then subjected to a substitution reaction with 2-methylimidazole to obtain Compound 87.

[0826] Compound 87: N-(4,4-difluorocyclohexyl)-1-(N-(5-fluoropyridin-3-yl)-2-(2-methylimidazol-1-yl)acetylamino)-2,3-dihydro-1H-inden-1-ylcarboxamide

[0827]

[0828] 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).

[0829] LCMS: m / z 512.3 [M+H] + ; RT = 0.944 min.

[0830] Example 69: Compound 18

[0831] N-(4,4-difluorocyclohexyl)-1-(N-(3-fluorophenyl)-2-(methyl(phenyl)amino)acetylamino)-2,3-dihydro-1-indene-1-carboxamide

[0832]

[0833] Into a dry 25 ml single-necked bottle, compound C3 (165 mg, 1 mmol), A1 (225 mg, 1 mmol), and 2 ml of anhydrous methanol were added in sequence. After stirring at room temperature for 4 hours, B2 (145 mg, 1 mmol) was added and stirring was continued overnight. By separation, 19 mg of gray solid product N-(4,4-difluorocyclohexyl)-1-(N-(3-fluorophenyl)-2-(methyl(phenyl)amino)acetylamino)-2,3-dihydro-1-indene-1-carboxamide was obtained. The yield was 3.6%.

[0834] 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).

[0835] LCMS: m / z 536.2 [M+H] + ; RT = 1.84min.

[0836] Example 70: Compound 17

[0837] The same method as in Example 62 was used to react the imine intermediate A1, the isocyanate intermediate B2 and the acid intermediate C3 to obtain compound 17.

[0838] Compound 17: 1-(2-((4-cyanophenyl)amino)-N-(3-fluorophenyl)acetylamino)-N-(4,4-difluorocyclohexyl)-2,3-dihydro-1-indene-1-carboxamide

[0839]

[0840] 1H-NMR(CDCl3 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).

[0841] LCMS: m / z 569.2[M+2] + ; RT = 1.71 min.

[0842] Example 71: Compound 24

[0843] The same method as in Example 62 was used to react the imine intermediate A1, the isocyanate intermediate B2 and 4-pyridineacetic acid to obtain compound 24.

[0844] Compound 24: N-(4,4-difluorocyclohexyl)-1-(N-(3-fluorophenyl)-2-(pyridin-4-yl)acetylamino)-2,3-dihydro-1H-indene-1-carboxamide

[0845]

[0846] 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).

[0847] LCMS: m / z 508.2 [M+H] + ; RT = 1.116min.

[0848] Example 72: Compound 26

[0849] The same method as in Example 62 was used to react the imine intermediate A1, the isocyanate intermediate B2 and the acid intermediate C4 to obtain compound 26.

[0850] Compound 26: N-(4,4-difluorocyclohexyl)-1-(N-(3-fluorophenyl)-2-((2-fluoropyridin-3-yl)amino)acetylamino)-2,3-dihydro-1H-indene-1-carboxamide

[0851]

[0852] 1 H NMR(CDCl3-d1,400MHz): 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).

[0853] LCMS: m / z 541.2 [M+H] + ; RT = 1.678min.

[0854] The reference compound AGI-5198, CAS: 1355326-35-0, was purchased from Selleck.

[0855]

[0856] Test Example 1 Effect of the Compounds of the Invention on IDH1 Enzyme Activity at the Molecular Level

[0857] Reagents, consumables and instruments:

[0858] The enzymes used in the experiment were purchased from Cayman Company.

[0859] The substrate α-KG, NADPH and Diaphorase were purchased from Sigma; Resazurin was purchased from J&K; and the other reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0860] The reaction microplate (6008260) was purchased from PerkinElmer.

[0861] The multifunctional microplate reader used for plate reading in the experiment is a product of PerkinElmer, model: EnVison.

[0862] The experimental water was distilled water produced by Sinopharm Group.

[0863] Compound preparation: The compound was centrifuged at 12000g for 5 min, DMSO was added to prepare a 10 mM stock solution, vortexed evenly, and then ultrasonicated for 10 min before use, and stored at -40°C. When testing, it was first diluted with DMSO to a 10 μM solution, and then gradiently diluted 3× to different test concentrations.

[0864] Experimental method: The enzymatic activity of IDH1 in converting α-KG to 2HG is measured by the consumption of NADPH. After the enzymatic reaction is completed, diaphorase and reazurin are added in excess, and the fluorescent signal generated can reflect the amount of remaining NADPH. In a 384-well plate, 5μL of enzyme system (150mM NaCl, 20mM Tris pH=7.5, 10mMMgCl2, 0.05% (w / v) bovine serum albumin, 0.012μL enzyme), 2.5μL compound, 2.5μL of substrate α-KG and NADPH mixture (substrate α-KG final concentration 1mM, NADPH final concentration 4μM) are added, and incubated at room temperature in the dark for 60min. Detection reaction: 5μL 1×detection buffer diluted with 0.01unit diaphroase and 5μM resazurin are added to each well, and incubated at room temperature in the dark for 10min. Reading plate: Use PerkinElmer at Ex 544Em 590. Test board. IC 50 The values ​​were calculated using GraphPad Prism software.

[0865] result

[0866] Table 1 shows the IC values ​​of some compounds of the present invention. 50 value.

[0867] The letter A stands for IC 50 Less than 100nm;

[0868] The letter B stands for IC 50 100nm to 1000nm;

[0869] The letter C stands for IC 50 1uM to 10uM;

[0870] The letter D stands for IC 50 More than 10uM.

[0871] Table 1 IC of some compounds of the present invention 50 value

[0872]

[0873]

[0874] The results show that the compounds of the present invention can effectively inhibit the activity of IDH1 at extremely low concentrations (≤10 uM, preferably ≤100 nm).

[0875] Test Example 2: Determination of the proliferation inhibition of the compounds of the present invention on the malignant glioma cell line U87

[0876] In this experiment, the following method was used to determine the proliferation inhibitory activity of the compounds of the present invention on the malignant glioma cell line U87.

[0877] Determination method: First, U87 cells (cell bank of the Chinese Academy of Sciences Typical Culture Collection Committee) were inoculated on a 96-well culture plate at an appropriate cell concentration of 2000 cells / well, with 90 μL of culture medium per well. After being cultured overnight at 37°C in a carbon dioxide incubator, different concentrations of the test compound were added for 96 hours, and a solvent control group (negative control) was set up. After 96 hours, the CCK8 (Cell Counting Kit-8) method was used to test the compound's activity in inhibiting cell proliferation. IC 50 The value can be calculated by the inhibition value of the test compound on the cells at a series of different concentrations.

[0878] It was determined that the test compounds 1-133 all had inhibitory effects on the malignant glioma cell line U87.

[0879] Test Example 3: Determination of the proliferation inhibitory activity of the compounds of the present invention on tumor cell lines other than the malignant glioma cell line U87

[0880] Using the same method as in 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.

[0881] Cell line name Tumor cell type HT1080 Human fibrosarcoma cells MCF-7 Human breast cancer cells T47D Human breast cancer cell lines ZR-75 Human breast cancer cell lines MAD-MB-468 Human breast cancer cell lines

[0882] It was determined that the test compound 1-133 had an inhibitory effect on different tumor cell lines HT1080, MCF-7, T47D, ZR-75, and MAD-MB-468.

[0883] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings 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 claims attached to this application.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, in, W1 and W2 are each independently selected from CR b ; W and W' are each independently selected from CH2; R b Selected from H, C1-C6 alkyl, halogen, C1-C6 alkoxy; n is 1, 2 or 3; n' is 0; R1 is a substituted or unsubstituted C1-C6 alkyl group, or a substituted or unsubstituted 4-8 membered carbocyclic group; R2 is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 6-membered heteroaryl group, wherein the heteroaryl group contains 1 heteroatom selected from the group consisting of: N; R3 is none or halogen; R4 is -(CH2) m R 11 ; Wherein, m is 0 or 1; R 11 Select from the following group: Wherein, X is O; V1, V2 and V3 are selected from CRa or N respectively; Ra is selected from H; Rc' is methyl; Rc is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered aryl; Rd is selected from H, substituted or unsubstituted C1-C6 alkyl; wherein the heteroaryl contains 1-4 heteroatoms selected from the following: N, O or S; Any of the above "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: -D, halogen, -NO2, -NH2, -N(unsubstituted C1 alkyl)2, -CN, unsubstituted or halogenated C1 alkyl, unsubstituted C1 alkoxy.

2. The compound of formula (I) according to claim 1, characterized in that R2 is selected from the following group: Where R m Selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy.

3. The compound of formula I according to claim 1, characterized in that Rc is selected from the group consisting of: Wherein, R' or R" is independently selected from -CN, -OH, hydroxamate, C1-C6 alkylcarbonyl, -NO2, halogen, substituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.

4. A compound selected from the following structures:

5. A method for preparing a compound as claimed in any one of claims 1 to 4, characterized in that: The method comprises the following steps 1) or 2): 1) Compound 1a and compound The coupling is carried out under reaction conditions in an inert solvent to form a compound of formula I; In the formula, the definition of each group is as described in any one of claims 1-4; 2) Compound 1a and compound The coupling is carried out under reaction conditions in an inert solvent and then with The reaction generates a compound of formula IA; In the formula, the definitions of each group are as described in any one of claims 1 to 4.

6. The use of the compound according to any one of claims 1 to 4, characterized in that: For preparing drugs for treating diseases associated with high expression of mutant IDH; Wherein, the mutant IDH is IDH R132 mutation; the disease associated with high expression of mutant IDH is selected from the following group: leukemia, brain glioma, cholangiocarcinoma, chondromalacinoma, fibrosarcoma, intrahepatic bile duct carcinoma, and rectal cancer.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (i) an effective amount of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

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