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

Compound, preparation method and the usage with saltant type isocitric dehydrogenase inhibitory activity Download PDF

Info

Publication number
CN107556366A
CN107556366A CN201610506631.XA CN201610506631A CN107556366A CN 107556366 A CN107556366 A CN 107556366A CN 201610506631 A CN201610506631 A CN 201610506631A CN 107556366 A CN107556366 A CN 107556366A
Authority
CN
China
Prior art keywords
compound
unsubstituted
group
substituted
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610506631.XA
Other languages
Chinese (zh)
Inventor
江磊
耿美玉
郑乾刚
黄敏
万惠新
唐帅
付贤磊
兰小晶
曹建华
丁健
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Shanghai Haihe Pharmaceutical Co Ltd
Original Assignee
Shanghai Institute of Materia Medica of CAS
Shanghai Haihe Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS, Shanghai Haihe Pharmaceutical Co Ltd filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CN201610506631.XA priority Critical patent/CN107556366A/en
Priority to PCT/CN2017/090909 priority patent/WO2018001332A1/en
Publication of CN107556366A publication Critical patent/CN107556366A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides the compound with saltant type isocitric dehydrogenase inhibitory activity, preparation method and the usage, specifically, the invention provides the compound shown in a kind of Formulas I, or its pharmaceutically acceptable salt or its enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph or prodrug, wherein, the definition of each group is as noted in the discussion.Described compound to saltant type IDH with, with higher inhibitory activity, therefore can be used for treating the disease related to saltant type IDH.

Description

Compound with mutant isocitrate dehydrogenase inhibition activity, preparation method and application thereof
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a compound with mutant IDH inhibitory activity, a preparation method and application thereof.
Background
Isocitrate Dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (α -ketoglutarate) while producing carbon dioxide and NADPH/nadh, which plays an important role in the metabolic process of cells, these enzymes can be classified into two different subclasses depending on the electron acceptor, one utilizing NAD (+) and the other utilizing NADP (+). among 5 isocitrate dehydrogenases that have been reported, 3 are NAD (+) dependent isocitrate dehydrogenases that are mainly present in the mitochondrial matrix, and the other two are NADP (+) dependent, i.e., isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 isocitrate dehydrogenase 1 is mainly present in the cytoplasm, and isocitrate dehydrogenase 2 is mainly present in the mitochondria.
the mutation sites of isocitrate dehydrogenase 1 are generally located at R100, R132, H133 and A134 and the mutation sites of isocitrate dehydrogenase 2 are generally located at R140 and R172 non-mutated IDH1 catalyses the oxidative decarboxylation of isocitrate esters to α -ketoglutarate, thereby reducing NAD + (NADP +) to NADP (NADPH) in the following forward reaction:
isocitrate + NAD + (NADP +) → α -ketoglutarate + CO2+ NADH (NADPH).
mutant isocitrate dehydrogenases lose this normal function and have a novel capacity to catalyze the NAPH-dependent reduction of α -ketoglutarate to R (-) -2-hydroxyglutarate (2 HG). The 2HG concentration levels in normal cells are very low, while the production of high concentrations of 2HG will aid in the development and progression of cancer.
In view of the above, there is an urgent need in the art to develop mutated IDH inhibitors.
Disclosure of Invention
The invention aims to provide an inhibitor of mutant IDH, in particular IDH1 and IDH2 mutant inhibitors.
In a first aspect of the 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,
wherein,
W1、W2each independently selected from N or CRb；
W and W' are each independently selected from CRaRb；
RaSelected from H, C1-C6An alkyl group;
Rbselected from H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, phenyl, C1-C6 alkoxy;
n is 1,2,3,4 or 5; n' is 0 or 1;
R1is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted 4-8 membered carbocyclic group, substituted or unsubstituted C5-20 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein said heterocyclyl or heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, S or P;
R2is a substituted or unsubstituted C5-C20 aryl, a substituted or unsubstituted 5-to 10-membered heteroaryl, a substituted or unsubstituted 5-to 10-membered arylheterocyclo, wherein said heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of: n, O orS; said aryl-and heterocyclyl-group contains 1 to 3 heteroatoms selected from the group consisting of: n, O or S;
R3is halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, substituted or unsubstituted 5-to 10-membered aryl;
R4is- (CH)2)mR11；
Wherein m is an integer of 0 to 5; preferably an integer of 0 to 3;
R11is composed ofSubstituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocyclyl; wherein; x is selected from O, N or S; m is an integer of 0 to 5; rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; or Rc and Rd are joined to form a 4-8 membered saturated or unsaturated heterocyclyl or heteroaryl; wherein said heteroaryl group contains 1 to 4 heteroatoms selected from: n, O, S or P; said heterocyclyl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O, S or P;
any "substitution" described above means that one or more hydrogen atoms on the group is substituted with a substituent selected from the group consisting of: -D, halogen, -OH, -NO2、-NH2N (unsubstituted C1-C6 alkyl)2CN, -CN, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy-C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C3-C8 cycloalkyl-C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C1-C6 alkylcarbonyl, unsubstituted or halogenated C1-C6 alkoxycarbonyl, hydroxamic acid groups, unsubstituted or halogenated 5-to 8-membered aryl, unsubstituted or halogenated 5-to 8-membered heteroaryl, unsubstituted or halogenated 4-to 8-membered saturated heterocyclic or carbocyclic ring; wherein said heteroaryl group comprises1-4 heteroatoms selected from the group consisting of: n, O or S, the heterocycle comprising 1 to 4 heteroatoms selected from the group consisting of: n, O or S;
in another preferred embodiment, W is CRaRbAnd n is preferably an integer of 1 to 4.
In another preferred embodiment, W' is CRaRbAnd n' is preferably 1.
In another preferred embodiment, R2Selected from the group consisting of:wherein Rm is selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy.
In another preferred embodiment, R4Is- (CH)2)mR11(ii) a m is preferably 0, 1 or 2.
In another preferred embodiment, R11Selected from the group consisting of: wherein X is O or N; v1, V2 and V3 are respectively selected from CRa or N; m is an integer of 0 to 4; ra is selected from H, C1-C6Alkyl, halogen, cyano; rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; wherein said heteroaryl group contains 1 to 4 heteroatoms selected from: n, O or S; said heterocyclyl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O or S.
In another preferred embodiment, R4Is- (CH)2)mR11(ii) a m is preferably 0 or 1.
In another preferred embodiment, R11Preferably, it is Wherein m is an integer of 0 to 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 said heteroaryl group contains 1 to 4 heteroatoms selected from: n, O or S; said heterocyclyl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O or S.
In another preferred embodiment, Rc is selected from the group consisting of:wherein R 'or R' are each independently selected from the group consisting of-CN, -OH, hydroxamic acid group, C1-C6 alkylcarbonyl, -NO2Halogen, substituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.
In another preferred embodiment, the compound has the structure shown in the following formula I-1:
wherein each group is as defined above.
In another preferred embodiment, the compound has the structure shown in the following formula I-2:
wherein each group is as defined above.
In another preferred embodiment, the compound is selected from the group consisting of compounds 1-133.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I as described in the first aspect of the invention, said process comprising the following steps 1) or 2):
1) compound 1a and compoundCoupling under reaction conditions in an inert solvent to form a compound of formula I;
wherein each group is as defined in the second aspect of the invention;
2) compound 1a and compoundCoupling under the reaction conditions of an inert solvent and then reacting withReacting to generate a compound shown in the formula I;
wherein each group is as defined in the second aspect of the invention.
In another preferred embodiment, the reaction is carried out in a solvent, and the solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
In a third aspect of the invention, there is provided the use of a compound of formula I as described in the first aspect of the invention for:
(a) preparing a medicament for treating a disease associated with mutant IDH;
(b) preparing a mutant IDH inhibitor;
(c) non-therapeutically inhibiting IDH mutations in vitro;
(d) non-therapeutically inhibiting tumor cell proliferation in vitro; and/or
(e) Treating a disease associated with mutant IDH.
In another preferred embodiment, said mutant IDH-associated disease is selected from the group consisting of: cancer; preferably leukemia, brain glioma, cholangiocarcinoma, chondrosarcoma, fibrosarcoma, intrahepatic cholangiocarcinoma, and rectal cancer.
In another preferred embodiment, the mutant IDH is selected from the group consisting of: IDH1, IDH2, or a combination thereof.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising:
(i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof; and
(ii) a pharmaceutically acceptable carrier.
In a fifth aspect of the present invention, there is provided a method of inhibiting IDH mutation, the method comprising the steps of: administering to a subject an inhibitory effective amount of a compound of formula I as described in the first aspect of the invention or a pharmaceutically acceptable salt thereof, or administering to a subject an inhibitory effective amount of a pharmaceutical composition as described in the third aspect of the invention.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventors of the present invention have conducted extensive and intensive studies for a long time to prepare a compound having a structure represented by formula I, and found that it has a mutant IDH inhibitory activity. The compound has an inhibiting effect on a series of mutant IDH at an extremely low concentration (which can be as low as less than or equal to 100nmol/L), and has extremely excellent inhibiting activity, so that the compound can be used for treating diseases related to the mutant IDH, such as tumors. Based on the above findings, the inventors have completed the present invention.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter claimed. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the term "comprising" as well as other forms, such as "includes," "including," and "containing," are not limiting.
Definitions for the terms of the standardization can be found in the references including Carey and Sundberg "ADVANCED ORGANIC chemistry 4. Thed." vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH 2O-is equivalent to-OCH 2-.
The section headings used herein are for organizational purposes only and are not to be construed as limiting 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 treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
"hydroxy" means an-OH group.
"hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxyl group (-OH).
"carbonyl" refers to a-C (═ O) -group.
"nitro" means-NO 2.
"cyano" means-CN.
"amino" refers to-NH 2.
"substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino.
"carboxyl" means-COOH.
In the present application, the term "alkyl", as a group or as part of another group (e.g. as used in groups such as halogen-substituted alkyl), means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms and being attached to the rest of the molecule by single bonds. 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-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.
In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting of only carbon atoms 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 being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting solely of carbon 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 being connected to the rest of the molecule by single bonds, such as but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include fused, bridged or spiro ring systems, having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups 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-indanyl, 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-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 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, octahydro-2, 5-methylene-pentalenyl and the like.
In this application, the term "heterocyclyl" as a group or part of another group 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 specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl 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, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In this application, the term "aryl" as a group or as part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 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, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [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-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.
"stereoisomers" refers to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.
When the compounds of the present invention contain olefinic double bonds, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the present invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and 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 invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography.
conventional techniques for preparing/isolating individual isomers include Chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, Chiral high performance liquid chromatography, see, for example, GeraldGubitz 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; Fumis et al (Eds.), VOGEL' S CYCLOPROPELA ORICA ORGANIC CHEMISTRY 5. ED., Longman Scientific and chemical Ltd., EsX, 1991, Acc-816, Heler.1990. 23,128.
In the present application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring 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, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorph" refers to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form and the present invention is intended to include the various crystalline forms and mixtures thereof.
Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrate, hemihydrate, sesquihydrates, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases it is also possible to retain only adventitious water or a mixture of water plus a portion of adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" denotes a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound of the invention. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific prodrug preparation methods can be found in Saulnier, m.g., et al, bioorg.med.chem.lett.1994,4, 1985-1990; greenwald, r.b., et al, j.med.chem.2000,43,475.
In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
As used herein, a "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.
The "tumor" and "diseases related to abnormal cell proliferation" include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous cell lung cancer, 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, renal cancer, oral cancer, and the like.
The terms "preventing," "prevention," and "prevention" as used herein include reducing the likelihood of occurrence or worsening of a disease or disorder in a patient.
As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii) inhibiting the disease or disorder, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the state of the disease or condition; or
(iv) Alleviating the symptoms caused by the disease or disorder.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may 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 that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, the pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "drug combination", "administering other treatment", "administering other therapeutic agent" and the like as used herein refer to a drug treatment obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-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, concomitant administration, or sequential administration at variable intervals of at least one compound described herein and at least one synergistic formulation to a patient as separate entities. These also apply to cocktail therapy, for example the administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include-C (O) -R "(where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting Groups is described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in organic Synthesis, (1999),4th Ed., Wiley. The protecting group may also be a polymeric resin.
A compound of formula I
The invention provides a compound shown in formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, solvate, polymorph or prodrug thereof,
in another preferred embodiment, W, W' and W are1、W2、n、n’、R1、R2、R3、R4、m、R11X, Rc and Rd are each independently a group corresponding to the following compounds.
Preparation of Compounds of formula I
The compound of formula I provided by the invention can be prepared by the following method 1) or 2):
1) compound 1a and compoundCoupling under reaction conditions in an inert solvent to form a compound of formula I;
wherein each group is as defined above;
2) compound 1a and compoundCoupling under the reaction conditions of an inert solvent and then reacting withReacting to generate a compound shown in the formula I;
wherein each group is as defined above.
In another preferred embodiment, the reaction is carried out in a solvent, and the solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
The main advantages of the invention include:
1. provides a compound shown as a formula I.
2. Provides a mutant IDH inhibitor with novel structure, preparation and application thereof, wherein the inhibitor has higher inhibitory activity to the mutant IDH.
3. Pharmaceutical compositions for treating diseases associated with mutant IDH are provided.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Intermediate a 1: synthesis of N- (2, 3-dihydro-1H-inden-1-yl) -3-fluoroaniline
1-indanone (2g,15mmol), m-fluoroaniline (2.2g, 19.7mmol), activated 4A molecular sieve (20g) and 40ml of dried 1, 2-dichloroethane are sequentially added into a dry 50ml single-neck flask, reflux is carried out for 36h under the protection of nitrogen, TLC monitoring is carried out, 60% -70% of products are generated, raw materials are remained, filtering is carried out, filtrate is collected and dried by spinning, and 2.3g of products are obtained. The crude product was used without purification.
Using the above procedure, with substituted or unsubstituted (hetero) arylcyclocycloalkylketones, and substituted or unsubstituted anilines, heterocyclic aromatic amines, the solvent can be replaced with toluene or dioxane or other inert solvents to give imine intermediates a2, A3, A4, A5, A6, A8, a9, a10, a16, a19, a20, a21, a22, a26, a28, a29, a31, a33, a34 and a35, wherein a2, A3, A4, A5, A6, A8, a9, a10, a16, a28, a29, a31, a33, a34, a35 are used directly in the next reaction without purification; a19, A20, A21, A22 and A26 were purified by column chromatography.
The intermediate structure is as follows:
intermediate A19N- (2, 3-dihydro-1H-inden-1-yl) -3-fluoro-4-chloroaniline
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).
Intermediate A20N- (2, 3-dihydro-1H-inden-1-yl) aniline
LCMS:m/z 208.2(M+H)+,RT＝1.5min.
Intermediate A21N- (2, 3-dihydro-1H-inden-1-yl) -2, 5-difluoroaniline
LCMS:m/z 244.1(M+H)+,RT＝1.7min.
Intermediate A22N- (2, 3-dihydro-1H-inden-1-yl) -3, 5-difluoroaniline
1H-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)。
Intermediate A26 (N- (2, 3-dihydro-1H-inden-1-yl) -2, 5-difluoroaniline
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)
Intermediate a 11: n- (5-chloro-2, 3-dihydro-1H-inden-1-yl) -5-fluoro-3-pyridylamine
5-chloro-1-indanone (333mg,2mmol) and 3-amino-5-fluoropyridine (222mg,2mmol) are put in a10 mL reaction bottle and tube and heated to 120 ℃ for reaction under the protection of sealed tube nitrogen. And (3) detecting by TLC/LCMS (thin layer chromatography/liquid crystal display system) until the product is not increased any more, adding dichloromethane for dissolving, adding anhydrous sodium sulfate for drying, filtering, and spin-drying to obtain a Schiff base crude product for later use.
Using the above procedure, imine intermediates A7, A11, A13, A14, A15, A17, A18, A23, A24, A25, A27, A30 were obtained by reacting a substituted or unsubstituted (hetero) arylcycloalkylketone compound with a substituted or unsubstituted aniline, a heterocyclic aromatic amine.
Intermediate a 12: n- (7-chloro-2, 3-dihydro-1H-inden-1-yl) -3-fluoroaniline
In a dry 50ml single-neck flask were added in sequence 7-chloroindanone (2.5g, 15mmol), m-fluoroaniline (2.2g, 19.7mmol), activated 4A molecular sieve (20g), dry 1, 2-dichloroethane (40 ml), titanium tetrachloride (142mg,0.05equiv) was added dropwise for catalysis, the mixture was refluxed under nitrogen protection, TLC was monitored until no more product was added, filtered, and the filtrate was spin-dried to obtain 2.5g of crude product which was used directly in the next reaction.
In the method, titanium tetrachloride can be replaced by other Lewis acid (boron trifluoride diethyl etherate, aluminum trichloride and the like), and the solvent can be replaced by toluene and dioxane.
Using the procedure described above, reaction with 7-chloroindanone and 3, 5-difluoroaniline gives imine intermediate A32.
Synthesis of intermediate B1:1, 1-difluoro-3-cyclobutyl isocyan
The method comprises the following steps: b1-1(25g,175mmol) and 140ml ethyl formate were added to a clean 250ml sealed tube, triethylamine (53g, 525mmol) was added with stirring, the mixture was stirred overnight at 110 ℃ in an oil bath, cooled to room temperature, filtered, the filter cake was washed 2-3 times with ethyl acetate, the filtrate was washed 2 times with saturated brine and dried by spinning to obtain Compound 2(22g, yield: 93%).
1H-NMR(DMSO 400MHz):δ8.51(s,1H),8.00(s,2H),4.10(s,1H),2.90-2.88(m,2H),2.57-2.55(m,2H)。
Step two: in a dry 1L single-neck bottle, compound B1-2(22g,163mmol), triphenylphosphine (47g,179mmol), carbon tetrachloride (25g,163mmol), triethylamine (16.5g,163mmol) and 500ml dichloromethane were added in this order, refluxed overnight at 45 ℃, spun dry under a cold water bath, slurried with 500ml diethyl ether for 1 hour, filtered, washed with diethyl ether, the filtrate was stirred with silica gel, spun dry under a cold water bath, and purified by a silica gel column (diethyl ether) to give the title compound (11.8g, 62%).
1H-NMR(DMSO 400MHz):δ4.28-4.26(m,1H),3.19-3.08(m,2H),2.97-2.87(m,2H)。
Using the above procedure, different isocyano intermediates B2, B3, B5, B6, B7 were made with different amines.
Intermediate B2 1, 1-difluoro-3-cyclohexylisocyano
1H-NMR(CDCl 400MHz):δ3.84(s,1H),1.93-2.17(m,8H)
Intermediate B3: 4-Isocyanato-tetrahydropyrans
1H 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).
Intermediate B5: 4, 4-dimethylcyclohexylisocyanide
1H-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).
Intermediate B6: the concentrated solution of ether is not spin-dried, and the intermediate is not separated, and is directly used for the next reaction.
Intermediate B7: the concentrated solution of ether is not spin-dried, and the intermediate is not separated, and is directly used for the next reaction.
Intermediate B4 Synthesis of phenylisocyano
Aniline (5.0g,53.69mmol,1.0eq), tetrabutylammonium hydrogen sulfate (1.82g,5.37mmol,0.1eq), dichloromethane (160mL), and aqueous sodium hydroxide (50%, 80mL) were added sequentially at room temperature in a dry 500mL three-necked flask. Chloroform (9.61g, 80.54mmol, 1.5eq) was slowly added dropwise at 0 ℃ and stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was poured into water (500mL) and extracted with dichloromethane (500 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The product phenylisocyanide (3.0g, a yellow oily liquid) was obtained in 55% yield by passage through a silica gel column.
1H NMR(CDCl3-d1,400MHz)：δ7.39(m,5H).
Intermediate C1: synthesis of (S) -1- (4-cyanopyridin-2-yl) pyrrolidine-2-carboxylic acid
The method comprises the following steps: the compounds L-proline methyl ester hydrochloride (4.98 g, 30 mmol, CAS:2133-40-6) and 2-bromo-4-cyanopyridine (2.28 g,20 mmol) were dissolved in mol), Xantphos (5.78 g,1mmol)0mmol) and cesium carbonate (19.56 g, 60 mmol) were added to 1 dioxane (80 ml) at room temperature under nitrogen atmosphere Pd2(dba)3(1.83 g,2mmol 00 ℃ for 12 hours. After the reaction was completed, 50ml of ethyl acetate was added. The organic phase was washed successively with water (20 ml. times.1), saturated brine (20 ml. times.1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column (petroleum ether: ethyl acetate ═ 20:1, 10: 1) afforded the product (S) -methyl 1- (4-cyanopyridin-2-yl) pyrrolidine-2-carboxylic acid (1.34 g, yellow solid), yield: 29 percent. LCMS M/z232.1(M + H)+；RT＝1.387min。
Step two: c1-1(460 mg,2mmol) was dissolved in tetrahydrofuran/water (15 ml/8 ml), and lithium hydroxide (84 mg,2mmol) was added at room temperature to react at room temperature for 4 hours. After the reaction was completed, diluted hydrochloric acid was added to adjust the pH to 2, and 15ml of ethyl acetate was added. The organic phase was washed successively with water (20 ml. times.1), saturated brine (20 ml. times.1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give product C1: (S) -1- (4-cyanopyridin-2-yl) pyrrolidine-2-carboxylic acid (310 mg, yellow solid), yield: 78.3 percent.
LCMS:m/z 218.1(M+H)+；RT＝1.076min.
Intermediate C2: synthesis of 2- ((4-cyanophenyl) amino) acetic acid
The method comprises the following steps: in a dry 50ml single neck flask were added compound C2-1(1g, 8.5mmol), sodium acetate (1.4g, 17mmol), ethyl bromoacetate (1.7g, 10mmol) and 30ml ethanol in order, refluxed for 36 hours, the solvent was spin-dried, 50ml ethyl acetate was added, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried by filtration, and purified by silica gel column (petroleum ether: ethyl acetate ═ 2:1) to give intermediate C2-2(300mg, yield: 17.4%) LCMS: M/z 205.2(M + H)+,RT＝1.37min。
Step two: compound C2-2(300mg, 1.47mmol), sodium hydroxide (118mg, 2.94mmol), water 3ml and 12ml methanol were added sequentially in a dry 50ml single neck flask, stirred at room temperature for 3 hours, the solvent was dried by spinning, the pH was adjusted to about 5 with dilute hydrochloric acid, and C2(120mg, yield: 46.3%) was isolated as a white solid.
LCMS:m/z＝175.2(M-1)-,RT＝1.07min。
Intermediate C4 2- ((2-Fluoropyridin-3-yl) amino) acetic acid
Intermediate C4 was prepared using the same method as intermediate C2.
1H 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).
LCMS:m/z 541.2(M+H)+；RT＝1.678min.
Intermediate C3: synthesis of 2- (methyl (phenyl) amino) acetic acid
The method comprises the following steps: compound C3-1(3g, 16.7mmol, CAS23284-84-6), iodomethane (7.1g, 50mmol), 20ml toluene, were added sequentially in a dry 50ml sealed tube, stirred at 80 ℃ overnight, cooled, 30ml water was added, extracted with ethyl acetate (50ml × 2), dried over anhydrous sodium sulfate, washed with saturated brine, spun dry, the crude product was passed through a silica gel column (petroleum ether: ethyl acetate ═ 20:1) to give the product ethyl 2- (methyl (phenyl) amino) acetate (C3-2) as a yellow oil, 1.2g yield: 37 percent. LCMS M/z 194.3(M-1) R ═ 1.616.
Step two: in a dry 25ml single neck flask were added in sequence compound C3-2(1.2g, 6.2mmol) sodium hydroxide (0.62g, 15mmol) and 5ml water, 15ml methanol, stirred at room temperature for three hours, the organic solvent was spun off, the PH adjusted to about 4, extracted with ethyl acetate (50ml x 2), dried over anhydrous sodium sulfate and spun dry to give 420mg of 2- (methyl (phenyl) amino) acetic acid (C3) as a yellow oil in yield: 41 percent.
LCMS:m/z 166.3(M-1)-,RT＝1.2min.
Intermediate C5: synthesis of (S) -2-oxooxazolidine-4-carboxylic acid
The method comprises the following steps: in a dry 500mL single neck flask L-serine (10.0g,95.2mmol,1.0eq), sodium bicarbonate (20g,238.0mmol,2.5eq) and water (30mL) were added sequentially at room temperature. Benzyl chloroformate (2.0mL, 142.8mmol,1.5eq) was added at 0 ℃ and stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was poured into water (200), and impurities were extracted with ethyl acetate (300 mL). The aqueous phase was acidified to pH 1 with concentrated HCl and extracted 3 times with ethyl acetate (300 mL). And (3) spin-drying the organic phase, washing the residue with ethyl acetate, pulping, and filtering to obtain a product C5-1: (S) -2- (((benzyloxy) carbonyl) amino) -3-hydroxypropionic acid (10g, white solid) yield 45%. LCMS M/z 238.2(M-H)-；RT＝1.047min
Step two: c5-1(2.5g,10.45mmol,1.0eq), water (10mL) and sodium hydroxide (0.84g,20.91mmol,2.0eq) were added sequentially at room temperature in a 100mL single neck flask at 0 ℃. Stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water (20), and the impurities were extracted with diethyl ether (300 mL). The aqueous phase was acidified to pH 1 with concentrated HCl and extracted 5 times with ethyl acetate (300 mL). The product (S) -2-oxooxazolidine-4-carboxylic acid (600mg, white solid) was obtained in 86% yield.
1H 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).
Synthesis of intermediate D1, 2-methyl-1H-imidazo [4,3-b ] pyrazine
2, 3-diaminopiperazine (200mg, 1.82mmol) and acetic anhydride (445.4mg, 4.36mmol) were added sequentially to a dry 50ml single-neck flask, reacted at 140 ℃ for 2 hours, cooled to room temperature, the acetic anhydride was spin-dried, 1ml of a hot 10N NaOH solution was added, 2ml of acetic acid was added, placed in an ice box and left overnight, a solid precipitated, filtered, washed with water and dried to give 90mg of a brown solid product.
LCMS:m/z 135.2(M+H)+；RT＝0.53min.
Intermediate D2: synthesis of 2- (2-methyl-1H-imidazol-5-yl) pyrimidine
The method comprises the following steps: adding 30ml of anhydrous tetrahydrofuran into a dry 100ml three-neck flask, ventilating, protecting with nitrogen, cooling to 0 ℃, slowly adding 2mol/L of LDA (10.5ml, 22.7mmol) and tributyltin hydride (5.64ml, 22.7mmol), stirring at 0 ℃ for 15 minutes, then cooling to-78 ℃, dropwise adding 2-chloropyrimidine (2g, 17.5mmol) in tetrahydrofuran (20ml), slowly raising to room temperature after the addition, stirring overnight, adding 30ml of water, extracting with ethyl acetate (50ml x3), drying with anhydrous sodium sulfate, spin drying, and purifying the crude product by a silica gel column (PE: EA ═ 10: 1) to obtain a yellow oily liquid product D2-1: 2.15g (yield: 35%).
Step two: in a dry 100ml single neck flask, 5-bromo-2-methyl-1H-imidazole (CAS:16265-11-5,1g,6.25mmol) and tetrahydrofuran 20ml are added, the temperature is reduced to 0 ℃, NaH (0.375g, 9.4mmol) is added in portions, the temperature is slowly raised to room temperature, stirring is carried out for 1 hour, SEM-Cl (1.25g, 7.5mmol) is added, stirring is carried out overnight at room temperature, quenching is carried out with water, ethyl acetateThe ester was extracted (50mlx3), washed with saturated brine, dried over anhydrous sodium sulfate, dried, and the crude product was purified by silica gel column (PE: EA ═ 1:1) to give D2-2:1.4g (yield: 78%) as a pale yellow oily product. LCMS M/z 293.1[ M + H ]]+,RT＝1.34min。
Step three: d2-2(1g,3.43mmol), D2-1(1.18g,4.12mmol) and tetrakistriphenylphosphine palladium (300mg) were added sequentially to a dry 50ml single-neck flask, 20ml of dry DMF was added, purging was carried out three times, nitrogen was added, stirring was carried out at 120 ℃ for 4 hours, the solvent was dried by oil pump, 20ml of water was added, extraction was carried out with ethyl acetate, drying was carried out over anhydrous sodium sulfate, spin-drying was carried out, and the crude product was passed through a silica gel column (PE: EA ═ 1:1) to obtain D2-3:0.97g (yield: 95%) as a red solid. LCMS M/z 291.2[ M + H ]]+,RT＝0.980min。
Step four: in a dry 50ml single neck flask D2-3(500mg, 1.72mmol) was added 20ml DCM and 10ml trifluoroacetic acid and stirred at rt overnight, the solvent was dried off, washed with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried off and the crude product passed through a silica gel column (PE: EA ═ 1:1) to give D2:160mg (58% yield) as a red solid product.
LCMS:m/z 161.2[M+H]+,RT＝0.445min。
Intermediate D3: 2- (2-methyl-1H-imidazol-5-yl) pyrazines
Using the above procedure, 2- (2-methyl-1H-imidazol-5-yl) pyrazine was obtained starting from 2-chloropyrazine.
Example 1: compound 1 and compound 2
The method comprises the following steps: intermediate A1, L-pyroglutamic acid (260mg,2mmol) was added to a microwave reaction tube, and after dissolving in 2mL of anhydrous methanol, it was stirred at room temperature for 15 minutes, intermediate B1(240mg,2mmol) was added, and after closing the tube, it was reacted overnight in an oil bath at 40 ℃. Adding 10mL of water, extracting with ethyl acetate three times (3X 10mL), combining the ethyl acetate phases, washing with saturated brine for several times, drying with anhydrous sodium sulfate, spin-drying to obtain a crude reaction product, separating by normal-phase column chromatography (dichloromethane/methanol 95/5) to obtain a light brown solid, namely (2S) -N- (1- (3, 3-difluorocyclobutylformyl) -2, 3-dihydro-1H-indenyl) -N-3-fluorophenyl-5-oxo-pyrrolidine-2-carboxamide (intermediate 1-1,140mg, yield 15%),
LCMS:m/z 943.4(2M+H)+,RT＝1.64min.
step two: adding the intermediate 1-1(140mg, 0.3mmol) obtained in the step one, cesium carbonate (145mg,0.45mmol) and Pd into a microwave reaction tube2(dba)3(14mg,0.015mmol), Xant-phos (9mg,0.015mmol) and 2-chloro-4-cyanopyridine (50mg,0.36mmol) were injected into 5mL of anhydrous 1, 4-dioxane, the tube was sealed and the reaction was allowed to proceed at 70 ℃ for 3 h. Filtering, spin-drying the filtrate, separating with a chromatographic column (petroleum ether/ethyl acetate 4/1) to obtain crude compounds of compound 1 and compound 2, and further purifying with high performance liquid preparative liquid chromatography to obtain the target compounds 1 and 2.
Compound 1: (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3, 3-difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 574.1(M+H)+,RT＝1.84min.
Compound 2: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 574.1(M+H)+,RT＝1.84min.
Example 2: compound 3 and Compound 4
The same procedure as in example 1 was repeated except for using imine intermediate A2, isocyanide intermediate B1 and L-pyroglutamic acid as a reaction product, and reacting with 2-chloro-4-cyanopyridine, followed by purification to give Compound 3 and Compound 4.
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
1H 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).
LCMS:m/z 575.2(M+H)+,RT＝1.74min.
Compound 4: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbonyl) -2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
1H 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,1H),4.59-4.52(m,1H),4.16-4.05(m,1H),2.97–2.71(m,4H),2.68–2.47(m,2H),2.45–2.14(m,4H),2.12–1.83(m,2H).
LCMS:m/z 575.2(M+H)+,RT＝1.74min.
Example 3: compound 7 and Compound 8
The same procedure as in example 1 was repeated except for using imine intermediate A2, isocyanide intermediate B2 and L-pyroglutamic acid as a reaction product, and reacting with 2-chloro-4-cyanopyridine, followed by purification to obtain Compound 7 and Compound 8.
Compound 7: (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((4, 4-difluorocyclohexane) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 603.3(M+H)+,RT＝1.79min.
Compound 8: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((4, 4-difluorocyclohexane) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 603.3(M+H)+,RT＝1.79min.
Example 4: compound 9 and compound 10
The same procedure as in example 1 was repeated except for reacting imine intermediate A4, cyclohexylisocyanide and L-pyroglutamic acid to give a product, and reacting the product with 2-chloro-4-cyanopyridine, followed by purification to give compound 9 and compound 10.
Compound 9: (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- (cyclohexylformyl) -1, 2,3, 4-tetrahydronaphthalen-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 580.3[M+H]+,RT＝2.0min.
Compound 10: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- (cyclohexylformyl) -1, 2,3, 4-tetrahydronaphthalen-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 580.3[M+H]+,RT＝2.01min.
Example 5: compound 12 and compound 13
The same procedure as in example 1 was followed, using imine intermediate A1, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine and purified to give compound 12 and compound 13.
Compound 12: (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((4, 4-difluorocyclohexane) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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),4.70–4.61(m,1H),3.99-3.77(m,1H),3.01–2.78(m,3H),2.73–2.32(m,3H),2.25-2.13(m,1H),2.09–1.66(m,7H),1.45-1.22(m,2H).
LCMS:m/z 602.2(M+H)+,RT＝1.88min.
Compound 13: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((4, 4-difluorocyclohexane) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 602.2(M+H)+,RT＝1.88min.
Example 6: compound 14 and compound 15
The same procedure as in example 1 was adopted, and the product obtained by reacting imine intermediate A1, cyclohexylisocyanide and L-pyroglutamic acid was further reacted with 2-chloro-4-cyanopyridine to obtain compound 14 and compound 15.
Compound 14: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- (cyclohexylcarbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 566.2(M+H)+,RT＝1.95min.
Compound 15: (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- (cyclohexylcarbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 566.2(M+H)+,RT＝1.95min.
Example 7: compound 19 and compound 20
The same procedure as in example 1 was followed using imine intermediate A31, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 19 and compound 20.
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
1H 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).
LCMS:m/z 588.2(M+H)+,RT＝1.91min.
Compound 20: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -4-methyl-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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),4.12-4.08(m,1H),2.93-2.82(m,3H),2.71–2.29(m,7H),2.26(2,3H),2.11–1.90(m,2H).
LCMS:m/z 588.2(M+H)+,RT＝1.91min.
Example 8: compound 21
The same procedure as in example 1 was followed using imine intermediate A22, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyrimidine to give compound 21.
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
1H 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).
LCMS:m/z 621.0(M+H)+,RT＝1.61min.
Example 9: compound 22
The product obtained by the reaction of imine intermediate a16, isocyanide intermediate B1 and acid intermediate C5 was reacted with 2-chloro-4-cyanopyrimidine in the same manner as in example 1 to obtain compound 22.
Compound 22: (2S) -3- (4-cyanopyrimidin-2-yl) -N- (1- (3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -2-oxooxazolidine-4-carboxamide
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).
LCMS:m/z 595.1(M+H)+,RT＝1.45min.
Example 10: compound 23
The same procedure as in example 1 was followed using imine intermediate A6, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 23.
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
1H 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),7.26-7.15(m,3H),5.75-5.50(m,1H),4.90-4.73(m,1H),3.79(s,1H),3.09–2.36(m,4H),2.31–1.19(m,10H).
LCMS:m/z 561.1(M+H)+,RT＝1.72min.
Example 11: compound 27
The same procedure as in example 1 was followed, using imine intermediate A1, isocyanide intermediate B3 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyridine to give compound 27.
Compound 27: (2S) -1- (4-cyanopyridin-2-yl) -N- (3-fluorophenyl) -5-oxo-N- (1- ((tetrahydro-2H-pyran-4-yl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) pyrrolidine-2-carboxamide.
1H 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).
LCMS:m/z 568.3(M+H)+,RT＝1.526min.
Example 12: compound 28 and compound 29
The same procedure as in example 1 was followed using imine intermediate A7, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 28 and compound 29.
Compound 28: (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((4, 4-difluorocyclohexyl) carbamoyl) -6-fluoro-2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
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＝44.3,7.8Hz,1H),4.59-4.51(m,1H),3.87(s,1H),3.10–2.74(m,4H),2.66–2.38(m,3H),2.26–2.17(m,3H),2.11–1.94(m,6H).
LCMS:m/z 621.2(M+H)+,RT＝1.79min.
Compound 29: (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((4, 4-difluorocyclohexyl) carbamoyl) -6-fluoro-2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
1H 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＝8.5Hz,1H),4.59-4.51(m,1H),3.81(s,1H),2.96–2.14(m,4H),2.11–1.55(m,4H),1.48–1.10(m,8H).
LCMS:m/z 621.2(M+H)+,RT＝1.79min.
Example 13: compound 30
The same procedure as in example 1 was followed, using imine intermediate A8, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 30.
Compound 30: (2S) -1- (4-cyanopyridin-2-yl) -N- (1- (4, 4-difluorocyclohexyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxo-N- (3-methoxyphenyl) pyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 614(M+H)+,RT＝1.558min.
Example 14: compound 31
The same procedure as in example 1 was followed, using imine intermediate A9, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 31.
Compound 31: (2S) -1- (4-cyanopyridin-2-yl) -N- (1- (4, 4-difluorocyclohexyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxo-N- (3-tolyl) pyrrolidine-2-carboxamide
1H-NMR(CDCl3 400MHz):8.74-8.75(m,1H),8.14-8.71(m,1H),7.31-7.49(m,3H),7.02-7.21(m,5H),6.87(s,1H),5.32-5.55(m,1H),4.63-4.71(m,1H),3.82-3.84(m,1H)2.83-2.89(m,3H)，2.34-2.54(m，4H)，2.20-2.33(m，5H),1.63-1.67(m，4H),1.29-1.34(m,2H)。
LCMS:m/z 598.2(M+H)+,RT＝1.76min.
Example 14: compound 32 and compound 33
The same procedure as in example 1 was adopted, and the product obtained by reacting imine intermediate A2, t-butylisocyanide and L-pyroglutamic acid, and 2-chloro-4-cyanopyridine were further reacted to obtain compound 32 and compound 33.
Compound 32: (S) -N- ((S) -1- (tert-butylformyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
1H 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,1H),7.98–7.89(m,1H),7.30–7.27(m,1H),7.25–7.16(m,2H),7.16–7.07(m,1H),7.06–6.93(m,1H),5.59–5.44(m,1H),4.62–4.53(m,1H),3.17–2.94(m,1H),2.94–2.79(m,3H),2.62–2.47(m,1H),2.43–2.31(m,1H),2.32–2.18(m,1H),2.04–1.88(m,1H),1.31(s,5H),1.23(s,4H).
LCMS:m/z 541.1[M+H]+,RT＝1.81min.
Compound 33: (S) -N- ((R) -1- (tert-butylformyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
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),7.25–7.17(m,2H),7.13–7.06(m,1H),5.30–5.21(m,1H),4.57–4.48(m,1H),2.95–2.70(m,2H),2.63–2.46(m,2H),2.38–2.19(m,2H),2.08–1.87(m,2H),1.21(s,4H),1.21(s,5H).
LCMS:m/z 541.1[M+H]+,RT＝1.8min.
Example 15: compound 34
The same procedure as in example 1 was followed, using imine intermediate A2, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was reacted with 2-chloropyrimidine to give compound 34.
Compound 34: (2S) -N- (1- (4, 4-Difluorocyclohexyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxo-1- (pyrimidin-2-yl) pyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 579.2[M+H]+,RT＝1.61min.
Example 16: compound 35
The same procedure as in example 1 was repeated except that the product obtained by the reaction of imine intermediate A2, isocyanide intermediate B2 and L-pyroglutamic acid was reacted with 3-chlorobenzonitrile to obtain compound 35.
Compound 35: (2S) -1- (3-cyanophenyl) -N- (1- (N- (4, 4-difluorocyclohexyl) formyl) -2, 3-dihydro-1H-inden-1 yl) -N- (5-fluoro-3-pyridinyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 602.2[M+H]+,RT＝1.74min.
Example 17: compound 36 and compound 37
The same procedure as in example 1 was followed using imine intermediate A10, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 36 and compound 37.
Compound 36: (S) -N- ((S) -1- ((4, 4-Difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (3-chlorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 590.1(M+H)+,RT＝1.59min.
Compound 37: (S) -N- ((R) -1- ((4, 4-Difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (3-chlorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 590.1(M+H)+,RT＝1.606min.
Example 18: compound 39
The same procedure as in example 1 was followed, using imine intermediate A2, isocyanide intermediate B2 and L-pyroglutamic acid to give a product, which was reacted with 2-fluoropyridine to give compound 39.
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
1H 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),2.62–2.49(m,2H),2.47–2.29(m,1H),2.26–2.12(m,1H),2.10–1.68(m,8H),1.39–1.22(m,2H).
LCMS:m/z 596.2[M+H]+.
Example 19: compound 40
The same procedure as in example 1 was followed, using imine intermediate A11, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was reacted with 2-chloropyridine to give compound 40.
Compound 40: (2S) -N- (5-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 609.2[M+H]+,RT＝1.81min.
Example 20: compound 41 and Compound 42
The same procedure as in example 1 was followed using imine intermediate A2, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-bromo-4-chloropyridine to give compound 41 and compound 42.
Compound 41: (S) -1- (4-Chloropyridin-2-yl) -N- ((S) -1((3, 3-Difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -1-N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
1H 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),7.02–6.95(m,1H),5.96–5.85(m,1H),4.67–4.52(m,1H),4.23-4.21(m,1H),3.18–2.83(m,5H),2.67–2.41(m,3H),2.37–2.27(m,1H),2.25–2.14(m,1H),2.10–1.88(m,1H),1.72–1.57(m,1H).
LCMS:m/z 584.1[M+H]+,RT＝1.81min.
Compound 42: (S) -1- (4-Chloropyridin-2-yl) -N- ((R) -1((3, 3-Difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -1-N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
1H 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),4.19–4.05(m,1H),3.02–2.75(m,4H),2.66–2.49(m,2H),2.45–2.14(m,4H),2.10–1.94(m,2H).
LCMS:m/z 584.1[M+H]+,RT＝1.81min.
Example 21: compound 43 and compound 44
The same procedure as in example 1 was followed using imine intermediate A12, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloropyridine to give compounds 43 and 44.
Compound 43: (S) -N- ((S) -7-chloro-1- ((3, 3-difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1 yl) -1- (4-cyanopyridin-2-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
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),7.24–7.20(m,1H),7.16–7.11(m,1H),7.08–7.02(m,1H),7.00–6.92(m,1H),6.90–6.84(m,1H),6.83–6.70(m,1H),6.02–5.90(m,1H),4.69(dd,J＝6.3,3.0Hz,1H),4.36–4.20(m,1H),3.41–3.25(m,1H),3.23–3.10(m,1H),3.10–2.99(m,1H),2.99–2.84(m,3H),2.72–2.49(m,3H),2.48–2.17(m,3H),2.10–1.87(m,1H).
LCMS:m/z 608.2[M+H]+,RT＝1.84min.
Compound 44: (S) -N- ((R) -7-chloro-1- ((3, 3-difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1 yl) -1- (4-cyanopyridin-2-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 608.2[M+H]+,RT＝1.84min.
Example 22: compound 46 and Compound 47
The same procedure as in example 1 was followed using imine intermediate A13, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloropyridine to give compounds 46 and 47.
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
1H 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).
LCMS:m/z 608.2(M+H)+,RT＝1.90min.
Compound 47: (S) -N- ((R) -6-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 608.2(M+H)+,RT＝1.88min.
Example 23: compound 48 and compound 49
By the same method as in example 1, the product obtained by purification after the reaction using imine intermediate a14, isocyanide intermediate B1 and L-pyroglutamic acid was reacted, and then reacted with 2-chloropyridine, compound 48 and compound 49 were obtained.
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
1H 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).
LCMS:m/z 608.2(M+H)+,RT＝1.90min.
Compound 49: (S) -N- ((R) -5-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 608.2(M+H)+,RT＝1.90min.
Example 24: compound 50 and Compound 51
The same procedure as in example 1 was followed, using imine intermediate A2, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was reacted with 2-chloropyrazine, to give compound 50 and compound 51.
Compound 50: (S) -N- ((S) -1- ((3, 3-Difluorocyclobutyl) formyl) 2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxo-1- (pyrazin-2-yl) pyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 551.1[M+H]+,RT＝1.62min.
Compound 51: (S) -N- ((R) -1- ((3, 3-Difluorocyclobutyl) formyl) 2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -5-oxo-1- (pyrazin-2-yl) pyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 551.1[M+H]+,RT＝1.62min.
Example 25: compound 52 and Compound 53
Using the same procedure as in example 1, the product obtained by reacting imine intermediate A1, isocyanide intermediate B1 and L-pyroglutamic acid was reacted with 2-chloro-4-trifluoromethylpyridine to obtain Compound 52 and Compound 53
Compound 52: (S) -N- ((S) -1- (N- (3, 3-difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1 yl) -N- (3-fluorophenyl) -5-oxo-1- (4-trifluoromethylpyridin-2-yl) -pyrrolidine-2-carboxamide
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).
LCMS:m/z 617.2[M+H]+,RT＝1.93min.
Compound 53: (S) -N- ((R) -1- (N- (3, 3-difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1 yl) -N- (3-fluorophenyl) -5-oxo-1- (4-trifluoromethylpyridin-2-yl) -pyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 617.2[M+H]+,RT＝1.95min.
Example 26: compound 54 and compound 55
The same procedure as in example 1 was followed using imine intermediate A1, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-methoxypyridine to give compound 54 and compound 55.
Compound 54: (S) -N- ((S) -1- ((3,3, -Difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -1- (4-methoxypyridin-2-yl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 579.2[M+H]+,RT＝1.84min.
Compound 55: (S) -N- ((R) -1- ((3,3, -Difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -1- (4-methoxypyridin-2-yl) -5-oxopyrrolidine-2-carboxamide
1H NMR(400MHz,CDCl3)δ8.06(d,J＝2.1Hz,1H),7.97–7.87(m,1H),7.46–7.26(m,4H),7.24–7.19(m,1H),7.14–6.96(m,3H),6.67–6.53(m,1H),5.73–5.54(m,1H),4.70–4.60(m,1H),4.15–4.00(m,1H),3.87(s,3H),2.95–2.75(m,4H),2.68–2.58(m,1H),2.56–2.45(m,1H),2.45–2.35(m,1H),2.35–2.23(m,2H),2.20–2.10(m,1H),2.07–1.89(m,2H).
LCMS:m/z 579.2[M+H]+,RT＝1.84min.
Example 27: compound 56 and compound 57
The same procedure as in example 1 was followed using imine intermediate A15, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyridine to give compound 56 and compound 57.
Compound 56 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3,3, -difluorocyclobutyl) formyl) -4-chloro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 609.2[M+H]+；RT＝1.89min.
Compound 57 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3,3, -difluorocyclobutyl) formyl) -4-chloro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
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),5.49(d,J＝6.1Hz,1H),4.62(dd,J＝9.3,3.0Hz,1H),4.18-3.97(m,1H),2.98-2.81(m,3H),2.72-2.59(m,1H),2.61-2.48(m,1H),2.47-2.15(m,4H),2.13-1.92(m,2H).
LCMS:m/z 609.2[M+H]+；RT＝1.89min
Example 28: compound 58 and compound 59
The same procedure as in example 1 was followed using imine intermediate A16, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 58 and compound 59.
Compound 58 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3,3, -difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-chloro-5-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-NMR(CDCl3 400MHz):δ8.74(m,1H),8.54-8.50(m,1H),7.30(m,1H),7.24-7.13(m,4H),7.10-7.01(m,3H),5.76(m,1H),4.67-4.65(m,1H),4.30-4.12(m,1H),2.95-2.87(m,2H),2.57-2.55(m,2H),2.44-2.37(m,2H),2.18-2.13(m,1H),2.04-2.00(m,1H),1.59-1.27(m,2H),0.98-0.85(m,2H).
LCMS:m/z 608.2[M+H]+,RT＝1.748min.
Compound 59 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3,3, -difluorocyclobutyl) formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-chloro-5-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-NMR(CDCl3 400MHz):δ8.77(s,1H),8.23-8.18(m,1H),7.48-7.39(m,1H),7.38-7.29(m,3H),7.23-7.10(m,3H),5.49(m,1H),4.65-4.63(m,1H),4.08(s,1H),2.92-2.77(m,2H),2.65-2.54(m,2H),2.31-2.27(m,2H),2.08-1.97(m,2H),1.27-1.25(m,2H),0.98-0.85(m,2H).
LCMS:m/z 608.2[M+H]+,RT＝1.75min.
Example 28: compound 60 and compound 61
The same procedure as in example 1 was followed using imine intermediate A1, isocyanide intermediate B4 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 60 and compound 61.
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
1H NMR(MeOD-d4,400MHz):δ8.73(s,1H),8.58-8.54(m,1H),7.41-7.29(m,9H),7.08-7.01(m,6H),4.73-4.71(m,1H),2.98-2.88(m,3H),2.61-2.55(m,3H),2.17-1.98(m,2H).
LCMS:m/z 560.2(M+H)+；RT＝1.72min.
Compound 61 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- (phenylcarbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 560.2(M+H)+；RT＝1.72min.
Example 29: compound 62 and compound 63
The product obtained by the reaction of imine intermediate a1, isocyanide intermediate B1 and acid intermediate C5 was further reacted with 2-chloro-4-cyanopyridine by the same method as in example 1 to obtain compound 62 and compound 63.
Compound 62 (S) -3- (4-cyanopyridin-2-yl) -N- ((S) -1- (3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) 2-oxooxazolidine-4-carboxamide
1H 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).
LCMS:m/z 576.2(M+H)+；RT＝1.66min.
Compound 63 (S) -3- (4-cyanopyridin-2-yl) -N- ((R) -1- (3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -2-oxooxazolidine-4-carboxamide
1H 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).
LCMS:m/z 576.2(M+H)+；RT＝1.66min.
Example 30: compound 64 and compound 65
The same procedure as in example 1 was followed using imine intermediate A17, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 64 and compound 65.
Compound 64 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -6-fluoro-2, 3-dihydro-1H-inden-1-yl-N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 592.2(M+H)+；RT＝1.83min.
Compound 65 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -6-fluoro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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),6.89(dd,J＝43.0,8.6Hz,1H),5.57(d,J＝5.7Hz,1H),4.67-4.60(m,1H),4.17-3.94(m,1H),2.95-2.62(m,4H),2.59-2.13(m,5H),2.05-1.83(m,3H).
LCMS:m/z 592.2(M+H)+；RT＝1.84min.
Example 31: compound 66
The same procedure as in example 1 was followed using imine intermediate A18, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 66.
Compound 66 (2S) -1- (4-cyanopyridin-2-yl) -N- (1- ((3, 3-difluorocyclobutyl) carbamoyl) -4- (trifluoromethyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 642.2(M+H)+；RT＝1.92min.
Example 32: compound 67 and compound 68
The same procedure as in example 1 was followed using imine intermediate A19, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 67 and compound 68.
Compound 67 (S) -N- (4-chloro-3-fluorophenyl) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxopyrrole-2-carboxamide
1H-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).
LCMS:m/z 608.2(M+H)+,RT＝1.75min.
Compound 68 (S) -N- (4-chloro-3-fluorophenyl) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxopyrrole-2-carboxamide
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).
LCMS:m/z 608.2(M+H)+；RT＝1.76min.
Example 33: compound 69 and compound 70
The same procedure as in example 1 was followed using imine intermediate A20, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 69 and compound 70.
Compound 69 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxo-N-phenylpyrrole-2-carboxamide
1H-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),5.81-5.80(d,J＝5.6Hz,1H),4.68-4.66(d,J＝6.0Hz,1H),4.11(s,1H),2.91-2.83(m,5H),2.55-2.26(m,1H),2.16-2.10(m,1H),1.98-1.88(m,1H).
LCMS:m/z 556.2(M+H)+；RT＝1.64min.
Compound 70 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxo-N-phenylpyrrole-2-carboxamide
1H-NMR(DMSO-d6,400MHz):δ8.76(s,1H),8.20-8.21(d,J＝4.0Hz,1H),7.58-7.60(d,J＝6.8Hz,1H),7.47-7.48(d,J＝7.2Hz,2H),7.40(t,1H),7.31-7.33(d,J＝6.4Hz,2H),7.20-7.23(m,2H),7.11(s,2H),5.53-5.54(d,J＝4.8Hz,1H),4.62-4.64(d,J＝8.4Hz,1H),4.09(m,1H),2.82-2.88(m,3H),2.71-2.78(m,1H),2.54-2.55(m,2H),2.27-2.37(m,4H),1.95-2.04(m,2H).
LCMS:m/z 556.2(M+H)+；RT＝1.66min.
Example 34: compound 71 and compound 72
The same procedure as in example 1 was followed using imine intermediate A21, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 71 and compound 72.
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
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).
LCMS:m/z 592.2(M+H)+；RT＝1.69min.
Compound 72 (S) -N- (3, 4-difluorophenyl) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxopyrrole-2-carboxamide
1H 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).
LCMS:m/z 592.2(M+H)+；RT＝1.691min.
Example 35: compound 73 and compound 74
The same procedure as in example 1 was followed using imine intermediate A22, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 73 and compound 74.
The compound 73(S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- (3, 3-difluorocyclobutylamido-formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 5921[M+H]+；RT＝1.8min.
Compound 74 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- (3, 3-difluorocyclobutylamido-formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 5921[M+H]+；RT＝1.7min.
Example 36: compound 75 and compound 76
The same procedure as in example 1 was followed using imine intermediate A23, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 75 and compound 76.
Compound 75 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3,3, -difluorocyclobutyl) formyl) -5-fluoro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 592.1[M+H]+；RT＝1.85min.
Compound 76 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3,3, -difluorocyclobutyl) formyl) -5-fluoro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 592.1[M+H]+；RT＝1.86min.
Example 37: compound 77 and Compound 78
The same procedure as in example 1 was followed using imine intermediate A24, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 77 and compound 78.
Compound 77 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3, 3-difluorocyclobutyl) carbamoyl-4-fluoro-2, 3-dihydro-1H-inden-1-yl-) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 592.2[M+H]+；RT＝1.86min.
Compound 78 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -4-fluoro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 592.1[M+H]+；RT＝1.87min.
Example 37: compound 79 and Compound 80
The same procedure as in example 1 was followed using imine intermediate A25, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 79 and compound 80.
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
1H 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,1H),7.10-6.90(m,2H),5.84(m,1H),4.63-4.49(m,1H),4.22-4.15(m,1H),3.11-2.82(m,5H),2.63-2.45(m,2H),2.26-2.20(m,2H),2.08-1.96(m,2H).
LCMS:m/z 609.1[M+H]+；RT＝1.80min.
Compound 80 (S) -N- ((R) -4-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-cyanopyridin-2-yl) -N- (5-fluoropyridin-3-yl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 609.1[M+H]+；RT＝1.81min.
Example 39: compound 81 and Compound 82
The same procedure as in example 1 was followed using imine intermediate A26, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 81 and compound 82. Compound 81 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- (3, 3-difluorocyclobutylamido-formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (2, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 592.1[M+H]+；RT＝1.8min.
Compound 82 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- (3, 3-difluorocyclobutylamido-formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (2, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 592.1[M+H]+；RT＝1.82min.
Example 40: compound 83
The same procedure as in example 1 was followed using imine intermediate A27, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 83.
Compound 83 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3,3, -difluorocyclobutyl) formyl) -7-fluoro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 592.1[M+H]+；RT＝1.83min.
Example 40: compound 84 and compound 85
The same procedure as in example 1 was followed, using imine intermediate A28, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyridine to give compound 84 and compound 85.
Compound 84 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (2, 3-difluorophenyl) -5-oxopyrrole-2-carboxamide
1H-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).
LCMS:m/z 592.2[M+H]+；RT＝1.67min.
Compound 85 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (2, 3-difluorophenyl) -5-oxopyrrole-2-carboxamide
1H-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).
LCMS:m/z 592.2[M+H]+；RT＝1.67min.
Example 41: compound 88 and compound 89
The same procedure as in example 1 was followed using imine intermediate A29, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 88 and compound 89.
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
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).
LCMS:m/z 604.2[M+H]+；RT＝1.64min.
Compound 89 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -4-methoxy-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrole-2-carboxamide
1H-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).
LCMS:m/z 604.2[M+H]+；RT＝1.65min.
Example 42: compound 90
The same procedure as in example 1 was followed using imine intermediate A22, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyrimidine to give compound 90.
Compound 90 (S) -1- (4-cyanopyrimidin-2-yl) -N- ((S) -1- (3, 3-difluorocyclobutylamido-formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-NMR(CDCl3,400MHz):δ8.90(s,1H),7.29-6.85(m,7H),6.65-6.63(m,1H),5.73(s,1H),4.52-4.49(m,1H),4.09(s,1H),2.9-2.6(m,5H),2.51-1.98(m,7H).
LCMS:m/z 593.3[M+H]+；RT＝1.3min.
Example 43: compound 91
The product obtained by reacting imine intermediate a22, isocyanide intermediate B1 and acid intermediate C5 was reacted with 2-chloro-4-cyanopyridine by the same method as in example 1 to obtain compound 91.
Compound 91 (S) -3- (4-cyanopyridin-2-yl) -N- ((S) -1- (3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -2-oxooxazolidine-4-carboxamide
1H 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).
LCMS:m/z 594.2[M+H]+；RT＝1.7min.
Example 44: compound 92 and compound 93
The same procedure as in example 1 was followed using imine intermediate A30, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compounds 92 and 93.
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
1H 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).
LCMS:m/z 626.1[M+H]+；RT＝1.91min.
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
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).
LCMS:m/z 626.2[M+H]+；RT＝1.93min.
Example 44: compound 96 and compound 97
The same procedure as in example 1 was followed, using imine intermediate A1, isocyanide intermediate B6 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyridine to give compound 96 and compound 97.
Compound 96 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- (cyclopropylmethylaminoformyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 538.6(M+H)+；RT＝1.79min.
Compound 97 (S) -1- (4-cyanopyridin-2-yl) -N- ((R) -1- (cyclopropylmethylaminoformyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 538.6[M+H]+；RT＝1.81min.
Example 46: compound 98 and compound 99
The same procedure as in example 1 was followed using imine intermediate A1, isocyanide intermediate B5 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 98 and compound 99.
Compound 98 (S) -1- (4-cyanopyridin-2-yl) -N- (3-fluorophenyl) -N- ((S) -1- (4, 4-dimethylcyclohexanoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 594.2[M+H]+；RT＝1.83min.
Compound 99 (S) -1- (4-cyanopyridin-2-yl) -N- (3-fluorophenyl) -N- ((R) -1- (4, 4-dimethylcyclohexanoyl) -2, 3-dihydro-1H-inden-1-yl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 594.2[M+H]+；RT＝1.86min.
Example 47: compound 100
The product obtained by the reaction of imine intermediate a12, isocyanide intermediate B1 and acid intermediate C5 was reacted with 2-chloro-4-cyanopyridine in the same manner as in example 1 to obtain compound 100.
Compound 100 (S) -1- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3,3, -difluorocyclobutyl) formyl) -7-chloro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -2-oxooxazolidine-4-carboxamide
1H NMR(400MHz,DMSO):δ8.73(dd,J＝23.0,4.9Hz,1H),8.28(s,1H),8.16(d,J＝6.6Hz,1H),7.65-7.56(m,1H),7.55-7.48(m,1H),7.40-7.24(m,2H),7.21-7.02(m,2H),6.89-6.80(m,1H),6.73-6.53(m,1H),4.65-4.53(m,2H),4.40-4.22(m,1H),4.21-4.08(m,1H),3.30-3.20(m,1H),3.17-3.05(m,1H),3.02-2.92(m,1H),2.91-2.77(m,2H),2.74-2.50(m,3H).
LCMS:m/z＝611.1[M+H]+；RT＝1.84min.
Example 48: compound 101
The product obtained by the reaction of imine intermediate A1, isocyanide intermediate B1 and L-pyroglutamic acid and 2-chloro-4-cyanopyrimidine were reacted by the same method as in example 1 to obtain compound 101 (a pair of diastereomeric mixtures was not separated).
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
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).
LCMS:m/z 575.6[M+H]+；RT＝1.44min.
Example 49: compound 102 and compound 103
The same procedure as in example 1 was followed, using imine intermediate A12, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyrimidine to give compound 102 and compound 103.
Compound 102 (S) -1- (4-cyanopyrimidin-2-yl) -N- ((S) -1- ((3,3, -difluorocyclobutyl) formyl) -7-chloro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H NMR(400MHz,CDCl3):δ8.94(d,J＝4.3Hz,1H),7.62-7.46(m,1H),7.35-7.28(m,1H),7.25-7.17(m,1H),7.13-7.02(m,2H),6.99-6.90(m,1H),6.90-6.77(m,2H),6.03-5.84(m,1H),4.53(d,J＝8.3Hz,1H),4.40-4.18(m,1H),3.52-3.24(m,2H),3.15-2.78(m,4H),2.71-2.23(m,5H),2.13-1.91(m,1H).
LCMS:m/z＝610.2[M+H]+；RT＝1.81min.
Compound 103 (S) -1- (4-cyanopyrimidin-2-yl) -N- ((R) -1- ((3,3, -difluorocyclobutyl) formyl) -7-chloro-2, 3-dihydro-1H-inden-1-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z＝610.2[M+H]+；RT＝1.81min.
Example 50: compound 104
The same procedure as in example 1 was followed, using imine intermediate A30, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyrimidine to give compound 104.
Compound 104: (S) -N- (S) -4-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -1- (4-aminopyrimidin-2-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide cyclobutylbutyl
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＝34.9,8.9Hz,1H),6.78(t,J＝8.7Hz,1H),5.88-5.47(m,1H),4.62–4.50(m,1H),4.12(s,1H),3.16–3.00(m,1H),2.97–2.54(m,5H),2.50-2.0(m 5H),2.10–1.97(m,1H).
LCMS:m/z 627.0[M+H]+；RT＝1.80min.
Example 51: compound 105 and compound 106
The same procedure as in example 1 was followed using imine intermediate A2, isocyanide intermediate B1 and acid intermediate C5 to give a product, which was reacted with 2-chloro-4-cyanopyridine to give compound 105 and compound 106.
Compound 105 (S) -3- (4-cyanopyridin-2-yl) -N- ((S) -1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -2-oxooxazolidine-4-carboxamide
1H-NMR(CDCl3400MHz):δ8.51-8.38(m,4H),7.88(m,1H),7.27-7.17(m,2H),7.05-6.96(m,3H),5.99-5.89(m,1H),4.73-4.72(m,1H),4.47(s,1H),4.26-4.12(m,2H),2.99-2.88(m,2H),2.62-2.61(m,3H),2.03(m,1H),1.23-1.27(m,1H),0.85-0.87(m,1H).
LCMS:m/z577.3[M+H]+；RT＝1.70min.
Compound 106 (S) -3- (4-cyanopyridin-2-yl) -N- ((R) -1- ((3, 3-difluorocyclobutane) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -N- (5-fluoropyridin-3-yl) -2-oxooxazolidine-4-carboxamide
1H-NMR(CDCl3400MHz):δ8.59-8.53(m,2H),8.29-8.17(m,1H),7.48-7.46(m,1H),7.40-7.36(m,2H),7.30-7.28(m,2H),7.27-7.25(m,1H),7.23-7.15(m,1H),5.62(m,1H),4.47(m,1H),4.31-4.27(m,1H),4.14-4.12(m,1H),4.11(m,1H),2.91-2.90(m,2H),2.53-2.51(m,1H),2.39-2.29(m,2H),2.04(m,1H),1.76m,1H),1.27-1.24(m,1H).
LCMS:m/z 577.3[M+H]+；RT＝1.69min.
Example 52: compound 107 and compound 108
The same procedure as in example 1 was followed, using imine intermediate A22, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-nitropyridine, to give compound 107 and compound 108.
Compound 107 (S) -1- (4-nitropyridin-2-yl) -N- ((S) -1- (3, 3-difluorocyclobutylamido-formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
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).
LCMS:m/z 612.2[M+H]+；RT＝1.60min.
Compound 108 (S) -1- (4-Nitropyridin-2-yl) -N- ((R) -1- (3, 3-Difluorocyclobutylamido-formyl) -2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z 612.2[M+H]+；RT＝1.61min.
Example 53: compound 109 and compound 110
The same procedure as in example 1 was followed using imine intermediate A33, isocyanide intermediate B1 and the acid L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyrimidine to give compound 109 and compound 110.
Compound 109 (S) -1- (4-cyanopyrimidin-2-yl) -N- ((S) -1- (3, 3-difluorocyclobutylamido-formyl) -7-methyl-2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z＝607.6[M+H]+；RT＝1.52min.
Compound 110 (S) -1- (4-cyanopyrimidin-2-yl) -N- ((R) -1- (3, 3-difluorocyclobutylamido-formyl) -7-methyl-2, 3-dihydro-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H-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).
LCMS:m/z＝607.6[M+H]+；RT＝1.51min.
Example 54: compound 111 and compound 112
The same procedure as in example 1 was followed using imine intermediate A35, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was then reacted with 2-chloro-4-cyanopyridine to give compound 111 and compound 112.
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-cyclopentapyridine-7-carboxamide
1H-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).
LCMS:m/z＝593.0[M+H]+；RT＝1.59 min.
Compound 112: (R) -7- ((S) -1- (4-cyanopyridin-2-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide) -N- (3, 3-difluorocyclobutyl) -6, 7-dihydro-5H-cyclopentapyridine-7-carboxamide
1H-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).
LCMS:m/z＝593.0[M+H]+；RT＝1.58 min.
Example 55: compound 113 and compound 114
The same procedure as in example 1 was followed, using imine intermediate A32, isocyanide intermediate B1 and L-pyroglutamic acid to give a product, which was reacted with 2-chloro-4-cyanopyridine, to give compound 113 and compound 114.
Compound 113: (S) -N- ((S) -7-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-indene-1- (4-cyanopyridin-2-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z＝626.2[M+H]+；RT＝1.85 min.
Compound 114: (S) -N- ((R) -7-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-indene-1- (4-cyanopyridin-2-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
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),4.80–4.60(m,1H),4.11–3.93(m,1H),3.2-2.58(m,6H),2.40–1.90(m,6H).
LCMS:m/z＝626.2[M+H]+；RT＝1.85 min.
Example 56: compound 115
The product obtained by the reaction of imine intermediate A22, isocyanide intermediate B7 and L-pyroglutamic acid and 2-chloro-4-cyanopyridine were reacted by the same method as in example 1 to obtain compound 115 (a pair of diastereomeric mixtures was not separated).
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
1H 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.
Example 57: compound 116
Using the same procedure as in example 1, the product obtained by reacting imine intermediate A12, isocyanide intermediate B1 and L-pyroglutamic acid was reacted with 2-chloropyrimidine to obtain compound 116
Compound 116: (S) -N- ((S) -7-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-indene-1- (pyrimidin-2-yl) -N- (3-fluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z＝584.0[M+H]+；RT＝1.67min
Example 58: compound 117 and compound 118
The same procedure used in example 1 was repeated to obtain a product obtained by reacting imine intermediate A22, isocyanide intermediate B1 and D-pyroglutamic acid, and further reacting the product with 4-cyano-2-chloropyridine, thereby obtaining compound 117 and compound 118.
Compound 117: (R) -1- (4-Aminopyridin-2-yl) -N- ((S) -1- ((3, 3-Difluorocyclobutane) carbamoyl) -2, 3-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
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＝6.2Hz,1H),4.68(dd,J＝9.2,3.4Hz,1H),4.18-4.09(m,1H),3.00–2.82(m,5H),2.62–2.52(m,2H),2.45–2.25(m,3H),2.22-2.14(m,1H),2.09–1.97(m,1H).
LCMS:m/z 592.1(M+H)+,RT＝1.80min.
Compound 118: (R) -1- (4-Aminopyridin-2-yl) -N- ((R) -1- ((3, 3-Difluorocyclobutane) carbamoyl) -2, 3-1H-inden-1-yl) -N- (3, 5-difluorophenyl) -5-oxopyrrolidine-2-carboxamide
1H 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).
LCMS:m/z 592.1(M+H)+,RT＝1.80min.
Example 59: compound 119 and compound 120
The same procedure as in example 1 was followed using imine intermediate A12, isocyanide intermediate B1 and acid intermediate C5 to give a product, which was reacted with 4-cyano-2-chloropyrimidine to give compound 119 and compound 120.
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
1H 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).
LCMS:m/z＝611.1[M+H]+；RT＝1.74min
Compound 120: (S) -N- ((R) -7-chloro-1- ((3, 3-difluorocyclobutyl) carbamoyl) -2, 3-dihydro-1H-inden-1-yl) -3- (4-cyanopyrimidin-2-yl) -N- (3-fluorophenyl) -2-oxooxazolidine-4-carboxamide
1H 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).
LCMS:m/z＝611.1[M+H]+；RT＝1.74min
Example 60: compound 5
The method comprises the following steps: chloroacetic acid (190mg,2mmol) was weighed into a microwave reaction tube, Schiff base was dissolved in 1mL of anhydrous methanol and injected into the microwave tube, after stirring for 30 minutes, cyclohexyl isonitrile (220mg,2mmol) was added, and the microwave tube was sealed and reacted at 30 ℃ overnight. The reaction was quenched with 10mL of water and extracted with ethyl acetate (3 x 15mL), the combined ethyl acetate was washed several times with brine, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried and isolated by column chromatography (eluent dichloromethane: 50:1) to give intermediate 5-1(200mg, white solid) in 23.3% yield.
1H NMR(DMSO-d6,400MHz):δ7.39-7.33(m,1H),7.27-7.22(m,2H),7.12-7.03(m,6H),3.90-3.82(m,2H),3.81-3.49(m,3H),3.07-3.00(m,2H),1.72-1.68(m,4H),1.59-1.54(m,1H),1.31-1.07(m,5H).
LCMS:m/z 451.3[M+Na]+；RT＝2.0min.
Step two: intermediate 5-1(100mg,0.23mmoL) and a 100mL reaction flask were charged with 2-methylimidazole (19mg,0.23mmoL), triethylamine (46mg,0.46mmoL) and 5mL of dichloromethane, respectively, and the mixture was heated under reflux under nitrogen overnight. The reaction solution was filtered with celite, and the filtrate was spin-dried and then isolated by column chromatography (eluent dichloromethane: 20:1) to give compound 5(80mg, white solid) in 73% yield. Compound 5: n-cyclohexyl-1- (N- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) acetamide) -2, 3-dihydro-1H-indene-1-carboxamide.
1H NMR(600MHz,MeOD):δ7.40-7.35(m,1H),7.30-7.03(m,5H),7.01-6.93(m,1H),6.88(s,2H),6.77(d,J＝1.3Hz,1H),5.50-5.49(m,1H),4.51-4.35(m,2H),3.75-3.61(m,1H),2.86-2.57(m,2H),2.22(s,3H),1.87-1.58(m,6H),1.40-1.28(m,4H),1.27-1.05(m,2H).
LCMS:m/z 475.3(M+H)+；RT＝1.64min.
Example 61: compound 6
Using the same procedure as in example 54, imine intermediate A3, a product obtained by reacting cyclohexylisocyanide with chloroacetic acid, and substitution reaction with 2-methylimidazole were further carried out to obtain compound 6.
Compound 6N-cyclohexyl-2- (N- (3-fluorophenyl) -2- (2-methyl-1H-imidazol-1-yl) acetamide) -2, 3-dihydro-1H-indene-2-carboxamide
1HNMR(400MHz,DMSO):δ7.44-7.37(m,1H),7.30-7.24(m,1H),7.23-7.07(m,6H),7.06-7.00(m,2H),6.84(d,J＝1.1Hz,1H),6.63(d,J＝1.1Hz,1H),4.29(q,J＝17.3Hz,3H),3.62-3.47(m,3H),3.10-3.01(m,2H),2.05(s,3H),1.69-1.44(m,5H),1.30-1.11(m,5H).
LCMS:m/z 475.2(M+H)+；RT＝1.65min.
Example 62: compound 11
By the same procedure as in example 54, using imine intermediate A5, a product obtained by reacting cyclohexylisocyanide with chloroacetic acid, and further carrying out substitution reaction with 2-methylimidazole, compound 11 was obtained.
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
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).
LCMS:m/z 461.2[M+H]+；RT＝1.58min.
Example 63: compound 16
The same procedure used in example 54 was repeated to give compound 16, using imine intermediate A1, isocyanide intermediate B2 and chloroacetic acid as the reaction product, followed by substitution with piperidine.
Compound 16, N- (4, 4-difluorocyclohexyl) -1- (N-3-fluorophenyl) -2- (piperidin-1-yl) acetamido) -2, 3-dihydro-1H-indene-1-carboxamide
1H-NMR(MeOD 400MHz):δ7.47-7.36(m,1H),7.24-6.93(m,6H),6.81(d,1H)3.88(s,1H),3.76-3.61(m,2H),3.52-3.45(m,2H),3.01-2.79(m,6H),2.02-.199(m,2H),1.88-1.50(m,9H),1.47-1.43(m,4H).
LCMS:m/z 514.2[M+H]+；RT＝1.057min.
Example 64: compound 25
By the same procedure as in example 54, the product obtained by reacting imine intermediate A1, isocyanide intermediate B2 and chloroacetic acid was subjected to substitution reaction with dimethylbenzimidazole to obtain compound 25.
Compound 25, N- (4, 4-difluorocyclohexyl) -1- (N-3-fluorophenyl) 2- (2-methyl-1H-benzimidazol-1-yl) acetamido) -2, 3-dihydro-1H-indene-1-carboxamide
1H-NMR(MeOD 400MHz):δ7.90-7.88(m,1H),7.49-7.42(m,5H),7.35-7.32(m,3H),7.23-7.17(m,2H),6.98-6.93(m,1H),5.40-5.39(m,1H),4.60-4.54(m,2H),3.82(s,1H),2.82-2.73(m,3H),2.71-2.67(m,2H),2.33-2.29(m,2H),1.96-1.72(m,6H),1.39-1.29(m,2H).
LCMS:m/z 561.2[M+H]+；RT＝1.124min.
Example 65: compound 28
The same procedure used in example 54 was repeated except for using imine intermediate A2, isocyanide intermediate B1 and chloroacetic acid to obtain a product, and carrying out substitution reaction with 2-methylimidazole to obtain compound 28.
Compound 28, N- (4, 4-difluorocyclobutyl) -1- (N- (5-pyridin-3-yl) -2- (2-methylimidazol-1-yl) acetylamino) -2, 3-dihydro-1H-inden-1-yl-carboxamide
1H-NMR(MeOD 400MHz):δ8.70-8.42(m,1H),8.38-8.04(m,1H),7.42-739(m,3H),7.26-7.16(m,2H),6.95-6.87(m,2H),4.90-4.75(m,2H),4.25(m,1H),3.07-3.05(m,2H),2.93-2.86(m,4H),2.74-2.59(m,1H),2.57(s,3H),2.56-2.50(m,1H).
LCMS:m/z 484.3[M+H]+；RT＝0.937min.
Example 66: compound 45
By the same procedure as in example 54, a substitution reaction was carried out using the product obtained by reacting imine intermediate A1, isocyanide intermediate B1 and chloroacetic acid, and intermediate D1 to give compound 45.
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
1H-NMR(MeOD 400MHz):δ8.45(s,1H),8.34(s,1H),7.45-7.43(m,1H),7.26-7.15(m,2H),7.09-6.96(m,5H),4.92(m,1H),4.81(m,1H),4.10-4.08(m,1H),2.98(m,2H),2.86-2.79(m,4H),2.74(s,3H),2.69-2.46(m,2H).
LCMS:m/z 535.2[M+H]+；RT＝1.44min.
Example 67: compound 86
By the same procedure as in example 54, a substitution reaction was carried out using the product obtained by reacting imine intermediate A1, isocyanide intermediate B2 and chloroacetic acid, and intermediate D2 to give compound 86.
Compound 86N- (3, 3-difluorocyclobutyl) -1- (N- (3-fluorophenyl) -2- (2-methyl-4- (pyrimidin-2-yl) -1H-imidazol-1-yl) acetamido) -2, 3-dihydro-1H-inden-1-ylcarboxamide
H-NMR(CDCl3 400MHz):δ8.74(m,1H),7.65(m,1H),7.57-7.45(m,2H),7.38-7.33(m,3H),7.28(m,1H),7.23-7.19(m,2H),6.89-6.82(m,1H),5.50(m,1H),4.51-4.44(m,2H),3.88-3.87(m,1H),2.81-2.77(m,2H),2.69(s,3H),2.33-2.32(m,1H),1.98-1.73(m,6H),1.44-1.37(m,2H).
LCMS:m/z 589.2[M+H]+；RT＝1.056min.
Example 68: compound 87
The same procedure used in example 54 was repeated except for using imine intermediate A2, isocyanide intermediate B2 and chloroacetic acid to obtain a product, and carrying out substitution reaction with 2-methylimidazole to obtain compound 87.
Compound 87, N- (4, 4-Difluorocyclohexyl) -1- (N- (5-Fluoropyridin-3-yl) -2- (2-methylimidazol-1-yl) acetamido) -2, 3-dihydro-1H-inden-1-ylcarboxamide
1H-NMR(CDCl3 400MHz):δ8.56-8.48(m,1H),8.37-8.34(m,1H),7.65-7.63(m,1H),7.40-7.28(m,2H),7.21-7.08(m,3H),7.03-7.00(m,1H),5.80-5.63(m,1H),4.48-4.40(m,2H),3.88-3.84(m,1H),2.92-2.72(m,2H),2.56(s,3H),2.38(s,1H),2.01-1.74(m,7H),1.50-1.41(m,2H).
LCMS:m/z 512.3[M+H]+；RT＝0.944min.
Example 69: compound 18
N- (4, 4-Difluorocyclohexyl) -1- (N- (3-fluorophenyl) -2- (methyl (phenyl) amino) acetamido) -2, 3-dihydro-1-indene-1-carboxamide
Compound C3(165mg,1mmol), a1(225mg,1mmol), and 2ml of anhydrous methanol were added sequentially in a dry 25ml single-necked flask, and after stirring for 4 hours at room temperature, B2(145mg,1mmol) was added and stirring was continued overnight to prepare by isolation the product N- (4, 4-difluorocyclohexyl) -1- (N- (3-fluorophenyl) -2- (methyl (phenyl) amino) acetamido) -2, 3-dihydro-1-indene-1-carboxamide as a gray solid in 19mg yield: 3.6 percent.
1H-NMR(CDCl3 400MHz):δ7.23-7.19(m,1H),7.15-7.05(m,5H),7.03-6.86(m,4H),6.78-6.68(m,3H),3.89-3.78(m,2H),3.06(s,3H),2.94-2.79(m,2H),2.58-2.56(m,1H),2.02-1.59(m,7H),1.48-1.44(m,3H).
LCMS:m/z 536.2[M+H]+；RT＝1.84min.
Example 70: compound 17
Compound 17 is obtained by the same procedure as in example 62, using imine intermediate A1, isocyanide intermediate B2 and acid intermediate C3.
Compound 17, 1- (2- ((4-cyanophenyl) amino) -N- (3-fluorophenyl) acetylamino) -N- (4, 4-difluorocyclohexyl) -2, 3-dihydro-1-indene-1-carboxamide
1H-NMR(CDCl3400MHz):δ7.49-7.45(m,2H),7.25(s,1H),7.12-7.07(m,4H),6.99-6.93(m,3H),6.75(s,2H),6.56(d,1H),3.41-3.78(m,3H),2.91-3.27(m,4H),2.09-1.82(m,4H),1.69-1.52(m,4H).
LCMS:m/z 569.2[M+2]+；RT＝1.71min.
Example 71: compound 24
Compound 24 was obtained by the same procedure as in example 62, using imine intermediate A1, isocyanide intermediate B2 and 4-pyridineacetic acid.
Compound 24, N- (4, 4-difluorocyclohexyl) -1- (N- (3-fluorophenyl) -2- (pyridin-4-yl) acetamido) -2, 3-dihydro-1H-indene-1-carboxamide
1H-NMR(CDCl3 400MHz):δ8.74(s,2H),7.64-7.58(m,3H),7.36-7.29(m,3H),7.23-7.13(m,3H),6.72-6.68(m,1H),5.46-5.44(m,1H),3.91-3.90(m,1H),3.59-3.55(m,2H),2.76(m,1H),2.61(m,1H),2.28(s,2H),2.00-1.78(m,6H),1.45-1.37(m,2H).
LCMS:m/z 508.2[M+H]+；RT＝1.116min.
Example 72: compound 26
Compound 26 was obtained by the same procedure as in example 62 using imine intermediate a1, isocyanide intermediate B2 and acid intermediate C4.
Compound 26, N- (4, 4-difluorocyclohexyl) -1- (N- (3-fluorophenyl) -2- ((2-fluoropyridin-3-yl) amino) acetamido) -2, 3-dihydro-1H-indene-1-carboxamide
1H 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).
LCMS:m/z 541.2[M+H]+；RT＝1.678min.
The control compound AGI-5198, CAS:1355326-35-0, was purchased from Selleck, Inc.
Test example 1 Effect of the Compounds of the present invention on the enzymatic Activity of IDH1 at molecular level
Reagents, consumables and instruments:
the enzymes used in the experiments were purchased from cayman.
the substrates α -KG, NADPH and Diaphorase were purchased from Sigma, Resazurin was purchased from carbofuran, and the remaining reagents were purchased from national pharmaceutical group Chemicals, Inc.
Reaction microplates (6008260) were purchased from Perkinelmer.
The multifunctional microplate reader for the experimental reading plate is a PerkinElmer product, and the model is as follows: EnVison.
The experimental water is distilled water produced by national medicine group.
Compound preparation: centrifuging compound 12000g for 5min, adding DMSO to prepare 10mM stock solution, vortexing uniformly, and then performing ultrasonic treatment for 10min for later use, and storing at-40 ℃. For testing, the samples were first diluted to 10. mu.M in DMSO and then diluted 3X-fold in a gradient to different test solubilities.
the enzymatic activity of IDH1 converting α -KG to 2HG was measured by NADPH consumption after the end of the enzymatic reaction, adding catalytic excess diaphorase and reazurin, producing a fluorescent signal reflecting the amount of residual NADPH, 384 well plates, 5. mu.L of enzyme system (150mM NaCl,20mM Tris pH 7.5,10mM MgCl.) was added20.05% (w/v) bone serum album min, 0.012 μ L enzyme), 2.5 μ L compound, 2.5 μ L mixed solution of substrate α -KG and NADPH (substrate α -KG final concentration 1mM, NADPH final concentration 4 μ M), incubation at room temperature in the dark for 60min, detection reaction:mu.L of 1 × detection buffer diluted 0.01unit diaphorase and 5. mu.M resazurin was added to each well and incubated at room temperature in the dark for 10 min. Reading a plate: by PerkinElmerat Ex 544Em 590 test panel. IC (integrated circuit)50Values were calculated using GraphPad Prism software.
Results
Table 1 shows the IC of some of the compounds of the invention50The value is obtained.
Letter A stands for IC50Less than 100 nm;
letter B stands for IC50From 100nm to 1000 nm;
letter C stands for IC501uM to 10 uM;
letter D stands for IC50Is 10uM or more.
TABLE 1 IC of some of the compounds of the invention50Value of
The results show that the compounds of the invention are effective in inhibiting IDH1 activity at very low concentrations (< 10uM, preferably < 100 nm).
Test example 2: proliferation inhibition determination of compound on malignant glioma cell strain U87
The proliferation inhibitory activity of the compound of the present invention on malignant glioma cell line U87 was determined in the following manner.
The determination method comprises the following steps: u87 cells (cell bank of the China academy of sciences type culture Collection) were first adaptedPreferably, the cells are seeded at a cell concentration of 2000 cells/well in a 96-well culture plate, 90. mu.L of the medium per well is incubated overnight at 37 ℃ in a carbon dioxide incubator, and then test compounds at different concentrations are added for 96 hours, and a solvent control group (negative control) is set. After 96 hours, the compound can be tested for Cell proliferation inhibitory activity by the CCK8(Cell Counting Kit-8) method. IC (integrated circuit)50Values can be calculated from the inhibition of cells by the test compound at a range of different concentrations.
Through determination, the tested compounds 1-133 have an inhibiting effect on malignant glioma cell line U87.
Test example 3: measurement of proliferation inhibitory Activity of the Compound of the present invention on tumor cell lines other than malignant glioma cell line U87
The present invention also measured the proliferation inhibitory activity of some compounds on tumor cell lines other than those in test example 2, such as HT1080, MCF-7, T47D, ZR-75, MAD-MB-468, etc., in the same manner as in test example 2.
Cell line name Tumor cell type
HT1080 Human fibrosarcoma cell
MCF-7 Human breast cancer cell
T47D Human breast cancer cell line
ZR-75 Human breast cancer cell line
MAD-MB-468 Human breast cancer cell line
Through detection, the tested compound 1-133 has inhibition effect on different tumor cell strains HT1080, MCF-7, T47D, ZR-75 and MAD-MB-468.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof,
wherein,
W1、W2each independently selected from N or CRb；
W and W' are givenIs independently selected from CRaRb；
RaSelected from H, C1-C6An alkyl group;
Rbselected from H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, phenyl, C1-C6 alkoxy;
n is 1,2,3,4 or 5; n' is 0 or 1;
R1is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl, substituted or unsubstituted 4-8 membered heterocyclic group, substituted or unsubstituted 4-8 membered carbocyclic group, substituted or unsubstituted C5-20 aryl, substituted or unsubstituted 5-10 membered heteroaryl; wherein said heterocyclyl or heteroaryl group contains 1 to 3 heteroatoms selected from the group consisting of: n, O, S or P;
R2is a substituted or unsubstituted C5-C20 aryl, a substituted or unsubstituted 5-to 10-membered heteroaryl, a substituted or unsubstituted 5-to 10-membered arylheterocyclo, wherein said heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of: n, O or S; said aryl-and heterocyclyl-group contains 1 to 3 heteroatoms selected from the group consisting of: n, O or S;
R3is halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy, substituted or unsubstituted 5-to 10-membered aryl;
R4is- (CH)2)mR11；
Wherein m is an integer of 0 to 5; preferably an integer of 0 to 3;
R11is composed ofSubstituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocyclyl; wherein; x is selected from O, N or S; m is an integer of 0 to 5; rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; or Rc and Rd are joined to form a 4-8 membered saturated or unsaturated heterocyclyl or heteroaryl; wherein, theThe heteroaryl group of (a) comprises 1 to 4 heteroatoms selected from: n, O, S or P; said heterocyclyl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O, S or P;
any "substitution" described above means that one or more hydrogen atoms on the group is substituted with a substituent selected from the group consisting of: -D, halogen, -OH, -NO2、-NH2N (unsubstituted C1-C6 alkyl)2CN, -CN, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy-C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C3-C8 cycloalkyl-C1-C8 alkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C1-C6 alkylcarbonyl, unsubstituted or halogenated C1-C6 alkoxycarbonyl, hydroxamic acid groups, unsubstituted or halogenated 5-to 8-membered aryl, unsubstituted or halogenated 5-to 8-membered heteroaryl, unsubstituted or halogenated 4-to 8-membered saturated heterocyclic or carbocyclic ring; wherein said heteroaryl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O or S, the heterocycle comprising 1 to 4 heteroatoms selected from the group consisting of: n, O or S.
2. A compound of formula I according to claim 1, wherein R is2Selected from the group consisting of: wherein Rm is selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy.
In another preferred embodiment, R4Is- (CH)2)mR11(ii) a m is preferably 0, 1 or 2.
3. A compound of formula I according to claim 1, wherein R is11Selected from the group consisting of: wherein X is O or N; v1, V2 and V3 are respectively selected from CRa or N; m is an integer of 0 to 4; ra is selected from H, C1-C6Alkyl, halogen, cyano; rc is selected from H, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl; rd is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylcarbonyl; wherein said heteroaryl group contains 1 to 4 heteroatoms selected from: n, O or S; said heterocyclyl group contains 1 to 4 heteroatoms selected from the group consisting of: n, O or S.
4. The compound of formula I according to claim 1, wherein Rc is selected from the group consisting of: wherein R 'or R' are each independently selected from the group consisting of-CN, -OH, hydroxamic acid group, C1-C6 alkylcarbonyl, -NO2Halogen, substituted or halogenated C1-C6 alkyl, C1-C6 alkoxy.
5. The compound of formula I according to claim 1, selected from the following structures:
6. a process for the preparation of a compound of formula I according to any one of claims 1 to 5, comprising the following steps 1) or 2):
1) compound 1a and compoundCoupling under reaction conditions in an inert solvent to form a compound of formula I;
wherein each group is as defined in any one of claims 1 to 5;
2) compound 1a and compoundCoupling under the reaction conditions of an inert solvent and then reacting withReacting to generate a compound shown in the formula I;
wherein each group is as defined in any one of claims 1 to 5.
7. Use of a compound of formula I according to claim 1 for:
(a) preparing a medicament for treating a disease associated with mutant IDH;
(b) preparing a mutant IDH inhibitor;
(c) non-therapeutically inhibiting IDH mutations in vitro;
(d) non-therapeutically inhibiting tumor cell proliferation in vitro; and/or
(e) Treating a disease associated with mutant IDH.
8. The use of claim 7, wherein the mutant IDH is selected from the group consisting of: IDH1, IDH2, or a combination thereof.
9. A pharmaceutical composition, comprising:
(i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph, or prodrug thereof; and
(ii) a pharmaceutically acceptable carrier.
10. A method of inhibiting IDH mutation comprising the steps of: administering to a subject an inhibitory effective amount of a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, or administering to a subject an inhibitory effective amount of a pharmaceutical composition as described in claim 7.
CN201610506631.XA 2016-06-30 2016-06-30 Compound, preparation method and the usage with saltant type isocitric dehydrogenase inhibitory activity Pending CN107556366A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201610506631.XA CN107556366A (en) 2016-06-30 2016-06-30 Compound, preparation method and the usage with saltant type isocitric dehydrogenase inhibitory activity
PCT/CN2017/090909 WO2018001332A1 (en) 2016-06-30 2017-06-29 Compound having inhibitory activity against mutant isocitrate dehydrogenase, preparation method therefor and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610506631.XA CN107556366A (en) 2016-06-30 2016-06-30 Compound, preparation method and the usage with saltant type isocitric dehydrogenase inhibitory activity

Publications (1)

Publication Number Publication Date
CN107556366A true CN107556366A (en) 2018-01-09

Family

ID=60785883

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610506631.XA Pending CN107556366A (en) 2016-06-30 2016-06-30 Compound, preparation method and the usage with saltant type isocitric dehydrogenase inhibitory activity

Country Status (2)

Country Link
CN (1) CN107556366A (en)
WO (1) WO2018001332A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114667167A (en) * 2019-08-09 2022-06-24 阿提奥斯医药有限公司 Heterocyclic compounds for the treatment of cancer

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202120486A (en) * 2019-08-09 2021-06-01 英商阿帝歐斯製藥有限公司 Novel compounds
KR20240021774A (en) * 2021-06-15 2024-02-19 위겐 바이오메더슨 테크널러지 (상하이) 컴퍼니 리미티드 IDH mutation inhibitors and uses thereof
CN116730979A (en) * 2022-03-11 2023-09-12 武汉人福创新药物研发中心有限公司 Pol theta inhibitor

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2736125A1 (en) * 2008-09-03 2010-03-11 The Johns Hopkins University Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma
US20140100223A1 (en) * 2011-03-29 2014-04-10 President & Fellows Of Harvard College Compounds and methods for the treatment of isocitrate dehydrogenase related diseases
WO2014147586A1 (en) * 2013-03-22 2014-09-25 Novartis Ag 1-(2-(ethylamino)pyrimidin-4-yl)pyrrolidin-2-ones as inhibitors of mutant idh
WO2015010297A1 (en) * 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015121209A1 (en) * 2014-02-11 2015-08-20 Bayer Pharma Aktiengesellschaft Benzimidazol-2-amines as midh1 inhibitors
AR101976A1 (en) * 2014-09-19 2017-01-25 Forma Therapeutics Inc DERIVATIVES OF PIRIDIN-2 (1H) -ON QUINOLINONE AS INHIBITORS OF MUTANT DEHYDROGENASE ISOCITRATE
US20190350920A1 (en) * 2018-05-16 2019-11-21 Forma Therapeutics, Inc. Solid forms of ((s)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
US20220204509A1 (en) * 2019-04-22 2022-06-30 Epitas Biosciences (shanghai) Co., Ltd. Pyrimido five-membered heterocyclic compound and use thereof as mutant idh2 inhibitor

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103304572A (en) * 2012-03-09 2013-09-18 上海医药集团股份有限公司 3-cyanoquinoline compound as well as pharmaceutical composition and application thereof
NZ706999A (en) * 2012-10-15 2018-12-21 Agios Pharmaceuticals Inc Inhibitors of mutant isocitrate dehydrogenase and therapeutical uses thereof
WO2015006591A1 (en) * 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as idh2 mutants inhibitors for the treatment of cancer
JP6471155B2 (en) * 2013-07-11 2019-02-13 アギオス ファーマシューティカルス，インコーポレーテッド N, 6-bis (aryl or heteroaryl) -1,3,5-triazine-2,4-diamine compounds as IDH2 variant inhibitors for the treatment of cancer

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2736125A1 (en) * 2008-09-03 2010-03-11 The Johns Hopkins University Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma
US20140100223A1 (en) * 2011-03-29 2014-04-10 President & Fellows Of Harvard College Compounds and methods for the treatment of isocitrate dehydrogenase related diseases
WO2014147586A1 (en) * 2013-03-22 2014-09-25 Novartis Ag 1-(2-(ethylamino)pyrimidin-4-yl)pyrrolidin-2-ones as inhibitors of mutant idh
WO2015010297A1 (en) * 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015121209A1 (en) * 2014-02-11 2015-08-20 Bayer Pharma Aktiengesellschaft Benzimidazol-2-amines as midh1 inhibitors
AR101976A1 (en) * 2014-09-19 2017-01-25 Forma Therapeutics Inc DERIVATIVES OF PIRIDIN-2 (1H) -ON QUINOLINONE AS INHIBITORS OF MUTANT DEHYDROGENASE ISOCITRATE
US20190350920A1 (en) * 2018-05-16 2019-11-21 Forma Therapeutics, Inc. Solid forms of ((s)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
US20220204509A1 (en) * 2019-04-22 2022-06-30 Epitas Biosciences (shanghai) Co., Ltd. Pyrimido five-membered heterocyclic compound and use thereof as mutant idh2 inhibitor

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MINDY I. DAVIS等: "Biochemical, Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1", 《MOLECULAR BASES OF DISEASE》 *
QIANGANGZHENG等: "Discovery and structure-activity-relationship study of novel conformationally restricted indane analogues for mutant isocitric dehydrogenase 1 (IDH1) inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
王莹莹等: "突变异柠檬酸脱氢酶1及其抑制剂的研究进展", 《广东化工》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114667167A (en) * 2019-08-09 2022-06-24 阿提奥斯医药有限公司 Heterocyclic compounds for the treatment of cancer
JP2022548822A (en) * 2019-08-09 2022-11-22 アルティオス ファーマ リミテッド Heterocyclic compounds for use in treating cancer
JP7401651B2 (en) 2019-08-09 2023-12-19 アルティオス ファーマ リミテッド Heterocyclic compounds for use in the treatment of cancer

Also Published As

Publication number Publication date
WO2018001332A1 (en) 2018-01-04

Similar Documents

Publication Publication Date Title
CN111153901B (en) Nitrogen-containing fused heterocyclic SHP2 inhibitor compound, preparation method and application
CN112142735B (en) Condensed cyanopyridine compound, preparation method and application
EP3207043B1 (en) Dihydropyrrolopyridine inhibitors of ror-gamma
AU2016311426B2 (en) Compounds and compositions useful for treating disorders related to NTRK
CN110156786B (en) Pyrimido-cyclic compounds, process for their preparation and their use
TWI751163B (en) Fgfr4 inhibitor, its preparation method and use thereof
CN111704611A (en) Aryl spiro SHP2 inhibitor compound, preparation method and application
IL262345A (en) Inhibitors of activin receptor-like kinase
WO2014134772A1 (en) Compounds inhibiting leucine-rich repeat kinase enzyme activity
CN109721600B (en) Nitrogen-containing fused ring compounds and preparation method and application thereof
CN114805361B (en) Amino substituted aromatic heterocyclic pyrazole compound, preparation method and application
CN107556366A (en) Compound, preparation method and the usage with saltant type isocitric dehydrogenase inhibitory activity
CN114685487A (en) Pyrimidine heterocyclic compound, preparation method and application
CN112778336B (en) Nitrogen-containing condensed ring STING regulator compound, preparation method and application
EP4074699A1 (en) Compound as cyclin-dependent kinase 9 inhibitor and use thereof
JP6718553B2 (en) Compound having mutant IDH inhibitory activity, method for producing the same and use thereof
JP2023522863A (en) Tricyclic compounds as EGFR inhibitors
CN110655520A (en) Pyrimido-cyclic compounds, process for their preparation and their use
CN114524810B (en) Pyrimidine heterocyclic compounds, preparation method and application
EP4206197A1 (en) Preparation method for novel rho-related protein kinase inhibitor and intermediate in preparation method
CN114805311A (en) Spirocyclic indenes
CN114907350B (en) Nitrogen-containing condensed ring compound, preparation method and application
CN110272416A (en) Pyrazolo [3,4-c] pyridine -7- amine derivative and its preparation method and application
CN112778308A (en) Fused tricyclic derivatives as FGFR4 inhibitors
JP2022528437A (en) Piperazine amide derivative, its manufacturing method and its use in medicine

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information
CB02 Change of applicant information

Address after: 201203 Shanghai city Pudong New Area Jing Road No. 351 Building No. 2 room A649-15

Applicant after: Shanghai Haihe pharmaceutical research and Development Co., Ltd

Applicant after: SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES

Address before: 201203 Shanghai city Pudong New Area Jing Road No. 351 Building No. 2 room A649-15

Applicant before: Shanghai Haihe Pharmaceutical Research and Development Co.,Ltd.

Applicant before: SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES