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

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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
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compound
unsubstituted
bases
alkyl
group
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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
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Shanghai Institute of Materia Medica of CAS
Shanghai Haihe Pharmaceutical Co Ltd
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Shanghai Institute of Materia Medica of CAS
Shanghai Haihe Pharmaceutical Co Ltd
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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
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    • 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

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, its preparation method with saltant type isocitric dehydrogenase inhibitory activity And purposes
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of compound with saltant type IDH inhibitory activity, its system Preparation Method and purposes.
Background technology
Isocitric dehydrogenase (IDH) is catalyzed isocitric acid ester oxidative decarboxylation to a-KG ester (α -one penta 2 Acid esters), while produce carbon dioxide and NADPH/NADH.This process has served important in the metabolic process of cell. According to the difference of electron accepting agent, these enzymes can divide into two kinds of different subclass, and one kind utilizes NAD (+) and another is sharp With NADP (+).It has been reported that 5 kinds of isocitric acid ester dehydrogenases in, 3 kinds are NAD (+) dependence isocitric acid ester dehydrogenases, It is primarily present in mitochondrial matrix；Other two kinds are NADP (+) dependence, i.e. isocitric acid ester dehydrogenase 1 and isocitric acid ester Dehydrogenase 2.Isocitric dehydrogenase 1 is primarily present in cytoplasm, and isocitric dehydrogenase 2 is primarily present in mitochondria In.The mutation of isocitric dehydrogenase betides many types of cancer, for example but is not limited to as follows, glioma, glue Matter blastoma, accessory nerve cytoma, acute leukemia, prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, epithelial duct Cancer, periphery T cell leukaemia, melanoma etc..
The mutational site of isocitric dehydrogenase 1 is normally at R100, R132, H133 and A134；Isocitric dehydrogenase 2 Mutational site be normally at R140 and R172.Not mutated IDH1 is catalyzed isocitric acid ester oxidative decarboxylation into α-ketoglutaric acid Ester, so as to reduce NAD+ (NADP+) to NADP (NADPH) in following forward reaction：
Isocitric acid ester+NAD+ (NADP+) → α-ketoglutaric acid ester+CO2+NADH (NADPH).
The isocitric dehydrogenase of saltant type loses this normal function, and has new ability, can be catalyzed α -one penta Two acid esters NAPH- dependences are reduced into R (-) -2- hydroxy-glutaric acid esters (2HG).Normal cell the inside 2HG concentration level is very It is low.And high concentration 2HG generation can help the formation and development of cancer.Such as in the acute leukemia people detection for thering is IDH to be mutated High concentration 2-HG is arrived.Good relevance be present with oncogene in the 2HG of high concentration.Therefore, the IDH of mutation and its new activity Suppression be potential therapeutic treatment for cancer.
In summary, the IDH inhibitor of development of mutant is badly in need of in this area.
The content of the invention
It is an object of the invention to provide a kind of saltant type IDH inhibitor, particularly IDH1, IDH2 saltant type inhibitor.
The first aspect of the present invention, there is provided the compound shown in a kind of Formulas I, its pharmaceutically acceptable salt or its Enantiomter, diastereoisomer, dynamic isomer, solvate, polymorph or prodrug,
Wherein,
W1、W2It is each independently selected from N or CRb；
W and W' is separately selected from CRaRb；
RaSelected from H, C1-C6Alkyl；
RbSelected from H, C1-C6 alkyl, C1-C6 haloalkyls, halogen, cyano group, phenyl, C1-C6 alkoxies；
N is 1,2,3,4 or 5；N ' is 0 or 1；
R1For substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl, substitution Or unsubstituted 4-8 circle heterocycles base, substituted or unsubstituted 4-8 members carbocylic radical, substituted or unsubstituted C5-20 aryl, substitution Or unsubstituted 5-10 unit's heteroaryls；Wherein, described heterocyclic radical or heteroaryl include the 1-3 hetero atoms being selected from the group：N、 O, S or P；
R2For substituted or unsubstituted C5-C20 aryl, substituted or unsubstituted 5-10 unit's heteroaryls, substitution or unsubstituted 5-10 members aryl and heterocyclic radical, wherein, described heteroaryl includes the hetero atoms that 1-3 is selected from the group：N, O or S；Described Aryl and heterocyclic radical include the 1-3 hetero atoms being selected from the group：N, O or S；
R3It is C1-C6 alkoxies, cyano group, hydroxyl, substituted or unsubstituted for halogen, substituted or unsubstituted C1-C6 alkyl 5-10 member aryl；
R4For-(CH2)mR11；
Wherein, m is 0-5 integer；Preferably 0-3 integer；
R11ForSubstituted or unsubstituted 5-10 unit's heteroaryls, substitution or Unsubstituted 5-10 members aryl, substituted or unsubstituted 5-10 circle heterocycles base；Wherein；X is selected from O, N or S；M is 0-5 integer； Rc is selected from H, substituted or unsubstituted 5-10 unit's heteroaryls, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 members Aryl；Rd is selected from H, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl-carbonyls；Or Rc is connected with Rd Form 4-8 members saturation or undersaturated heterocyclic radical or heteroaryl；Wherein, described heteroaryl includes 1-4 selected from as follows miscellaneous Atom：N, O, S or P；Described heterocyclic radical includes the 1-4 hetero atoms being selected from the group：N, O, S or P；
Above-mentioned any " substitution " refers to the substituent that one or more hydrogen atoms on group are selected from the group and substituted：-D、 Halogen ,-OH ,-NO2、-NH2,-N (unsubstituted C1-C6 alkyl)2,-CN, unsubstituted or halo C1-C8 alkyl, it is unsubstituted or C1-C8 alkoxyl-C1-C8 the alkyl of halo, unsubstituted or halo C3-C8 cycloalkyl, unsubstituted or halo C3-C8 cycloalkanes Base-C1-C8 alkyl, unsubstituted or halo C1-C8 alkoxyl, unsubstituted or halo C1-C6 alkyl-carbonyls, unsubstituted or halogen It is the C1-C6 alkoxy carbonyls in generation, hydroxamic acid base, unsubstituted or halo 5~8 yuan of aryl, unsubstituted or halo 5~8 yuan Heteroaryl, unsubstituted or halo 4~8 yuan of saturated heterocyclics or carbocyclic ring；Wherein, described heteroaryl includes 1-4 and is selected from the group Hetero atom：N, O or S, described heterocycle include the 1-4 hetero atoms being selected from the group：N, O or S；
In another preference, W CRaRb, and n is preferably 1-4 integer.
In another preference, W ' is CRaRb, and n ' is preferably 1.
In another preference, R2It is selected from the group：Wherein Rm is selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxies.
In another preference, R4For-(CH2)mR11；M is preferably 0,1 or 2.
In another preference, R11It is selected from the group： Wherein, X is O or N；V1, V2 and V3 are respectively selected from CRa or N；M is 0-4 integer； Ra is selected from H, C1-C6Alkyl, halogen, cyano group；Rc is selected from H, substituted or unsubstituted 5-10 unit's heteroaryls, substitution or unsubstituted C1- C6 alkyl, substituted or unsubstituted 5-10 members aryl；Rd is selected from H, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl-carbonyls；Wherein, described heteroaryl includes 1-4 and is selected from following hetero atom：N, O or S；Described heterocyclic radical Include the 1-4 hetero atoms being selected from the group：N, O or S.
In another preference, R4For-(CH2)mR11；M is preferably 0 or 1.
In another preference, R11Preferably Wherein, m is 0-4 integer；Rc is selected from H, substituted or unsubstituted 5-10 members heteroaryl Base, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 members aryl；Rd is selected from H, substitution or unsubstituted C1-C6 alkane Base, substituted or unsubstituted C1-C6 alkyl-carbonyls；Wherein, described heteroaryl includes 1-4 and is selected from following hetero atom：N、O Or S；Described heterocyclic radical includes the 1-4 hetero atoms being selected from the group：N, O or S.
In another preference, Rc is selected from the group： Wherein, R' or R " is independently selected from-CN ,-OH, hydroxamic acid base, C1-C6 alkyl-carbonyls ,-NO2, halogen, substitution or halogen For C1-C6 alkyl, C1-C6 alkoxies.
In another preference, described compound has the structure as shown in following formula I -1：
Wherein, each group is as defined above described in text.
In another preference, described compound has the structure as shown in following formula I -2：
Wherein, each group is as defined above described in text.
In another preference, described compound is selected from compound 1-133.
The second aspect of the present invention, there is provided a kind of method for preparing compound of formula I as described in the first aspect of the invention, 1) or 2) methods described comprises the following steps：
1) compound 1a and compoundIt is coupled under the reaction condition of atent solvent, so as to Form compound of formula I；
In formula, the definition of each group is as described in second aspect of the present invention；
2) compound 1a and compoundIt is coupled under the reaction condition of atent solvent, so Afterwards again withReaction generation compound of formula I；
In formula, the definition of each group is as described in second aspect of the present invention.
In another preference, the reaction is carried out in a solvent, and the solvent is selected from the group：Water, methanol, ethanol, Isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, Acetonitrile, DMF, DMA, dioxane, or its composition.
The third aspect of the present invention, there is provided a kind of purposes of compound of formula I as described in the first aspect of the invention, use In：
(a) medicine for treating the disease related to saltant type IDH is prepared；
(b) saltant type IDH inhibitor is prepared；
(c) suppress IDH mutation external non-therapeutic；
(d) suppress tumor cell proliferation external non-therapeutic；And/or
(e) disease related to saltant type IDH is treated.
In another preference, disease related described saltant type IDH is selected from the group：Cancer；Preferably leukaemia, brain Glioma, cholangiocarcinoma cells, cartilage joint sarcoma, fibrosarcoma, intrahepatic cholangiocarcinoma, the carcinoma of the rectum.
In another preference, the saltant type IDH is selected from the group：IDH1, IDH2, or its combination.
The fourth aspect of the present invention, there is provided a kind of pharmaceutical composition, described pharmaceutical composition include：
(i) compound of formula I of effective dose, or its pharmaceutically acceptable salt or its enantiomter, diastereo-isomerism Body, dynamic isomer, solvate, polymorph or prodrug；With
(ii) pharmaceutically acceptable carrier.
The fifth aspect of the present invention, there is provided a kind of method of suppression IDH mutation, methods described include step：To suppressing Object applies the compound of formula I as described in the first aspect of the invention or its pharmaceutically acceptable salt for suppressing effective dose, or right Suppress object and apply the pharmaceutical composition as described in third aspect present invention for suppressing effective dose.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical scheme.As space is limited, exist This no longer tires out one by one states.
Embodiment
The present inventor's in-depth study by long-term, a kind of compound with structure shown in Formulas I is prepared for, and found It has saltant type IDH inhibitory activity.And described compound is under extremely low concentration (can as little as≤100nmol/L), i.e., to one Series mutation type IDH produces inhibitory action, and inhibitory activity is quite excellent, thus it is related to saltant type IDH to can be used for treatment Disease such as tumour.Based on above-mentioned discovery, inventor completes the present invention.
Term
Unless otherwise defined, the connotation that otherwise all scientific and technical terminologies have herein and claim theme art technology The connotation that personnel are generally understood that is identical.Unless otherwise indicated, all patents, patent application, the open material being cited in full text herein It is integrally incorporated by reference herein.
It should be understood that above-mentioned summary and being specified as exemplary and being only used for explaining hereafter, without appointing to present subject matter What is limited.In this application, unless otherwise expressly specified, it is otherwise plural using also including during odd number.It has to be noticed that unless in text Separately there is clear explanation, otherwise singulative used includes the plural shape of referents in the present specification and claims Formula.It shall yet further be noted that unless otherwise stated, "or" used, "or" represent "and/or".In addition, term " comprising " used with And other forms, such as it is "comprising", " containing " and " containing " and non-limiting.
Can be in bibliography (including Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY4TH ED. " Vols.A (2000) and B (2001), Plenum Press, New York) in find definition to standard chemistry terms. Unless otherwise stated, using the conventional method in the range of art technology, as mass spectrum, NMR, IR and UV/VIS spectroscopic methodology and Pharmacological method.Unless propose to be specifically defined, otherwise herein in analytical chemistry, Synthetic Organic Chemistry and medicine and pharmaceutical chemistry Relevant description in the term that uses be known in the art.In chemical synthesis, chemical analysis, medicine preparation, preparation and it can pass Send, and to using standard technique in the treatment of patient.For example, using manufacturer to the operation instruction of kit, or according to The explanation of mode well known in the art or the present invention are implemented to react and purified.Generally can according in this specification quote and Description in the multiple summary and more specific document that discuss, according to conventional method well known in the art implement above-mentioned technology and Method.In this manual, group and its substituent can be selected by those skilled in the art with provide stable structure division and Compound.
When the conventional chemical formulas by writing from left to right describes substituent, the substituent is similarly included from right to left Write substituent equivalent in chemistry resulting during structural formula.For example ,-CH2O- is equal to-OCH2-.
Chapter title used herein is only used for the purpose of organizational, and is not necessarily to be construed as the limit to the theme System.All documents or literature department quoted in the application point include but is not limited to patent, patent application, article, books, manipulator Volume and paper, it is integrally incorporated by reference herein.
The some chemical groups defined herein represent carbon atom present in the group previously by symbol is simplified Sum.For example, C1-6 alkyl refers to the alkyl as defined below with 1 to 6 carbon atom altogether.Simplify the carbon in symbol Total atom number does not include the carbon being likely to be present in the substituent of the group.
In addition to foregoing, when in for the description of the present application and claims, unless otherwise specified, otherwise Following term has implication as follows.
In this application, term " halogen " refers to fluorine, chlorine, bromine or iodine.
" hydroxyl " refers to-OH groups.
" hydroxy alkyl " refers to the alkyl as defined below substituted by hydroxyl (- OH).
" carbonyl " refers to-C (=O)-group.
" nitro " refers to-NO2.
" cyano group " refers to-CN.
" amino " refers to-NH2.
" substituted amino " refers to by one or two alkyl, alkyl-carbonyl, aralkyl, heteroaryl alkane as defined below The amino of base substitution, for example, alkyl monosubstituted amino, dialkyl amido, alkyl amido, aryl alkyl amino, heteroarylalkyl amino.
" carboxyl " refers to-COOH.
In this application, (groups such as the alkyl of halogen substitution are used for example in as a part for group or other groups In), term " alkyl " means only to be made up of carbon atom and hydrogen atom, without unsaturated bond, to have such as 1 to 12 (be preferably 1 To 8, more preferably 1 to 6) carbon atom and by the remainder of singly-bound and molecule connect straight or branched hydrocarbon chain base Group.The example of alkyl include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, N-pentyl, 2- methyl butyls, 2,2- dimethyl propyls, n-hexyl, heptyl, 2- methylhexyls, 3- methylhexyls, octyl group, nonyl With decyl etc..
In this application, the part as group or other groups, term " alkenyl " mean only by carbon atom and hydrogen Atom composition, containing at least one double bond, there are such as 2 to 14 (be preferably 2 to 10, more preferably 2 to 6) carbon atoms And the hydrocarbon chain radical of the straight or branched connected by the remainder of singly-bound and molecule, such as, but not limited to vinyl, propylene Base, pi-allyl, but-1-ene base, but-2-ene base, amyl- 1- alkenyls, amyl- 1,4- dialkylenes etc..
In this application, the part as group or other groups, term " alkynyl " mean only by carbon atom and hydrogen Atom composition, containing at least one three key and optional one or more double bonds, to have such as 2 to 14 (be preferably 2 to 10 Individual, more preferably 2 to 6) hydrocarbon chain radical of carbon atom and the straight or branched connected by the remainder of singly-bound and molecule, Such as, but not limited to acetenyl, propyl- 1- alkynyls, butyl- 1- alkynyls, amyl- 1- alkene -4- alkynyls etc..
In this application, the part as group or other groups, term " cycloalkyl " mean only by carbon atom and The non-aromatic monocyclic or multi-ring alkyl of the stabilization of hydrogen atom composition, it may include fused ring system, bridged-ring system or loop coil body System, has 3 to 15 carbon atoms, preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms, and it is saturation It is or unsaturated and the connection of the remainder of singly-bound and molecule can be passed through via any suitable carbon atom.It is unless another in this specification Specialize outside, the carbon atom in cycloalkyl can be optionally oxidized.The example of cycloalkyl includes but is not limited to cyclopropyl, ring Butyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cyclooctyl, 1H- indenyls, 2,3- bis- Hydrogenated indenyl, 1,2,3,4- tetrahydro-naphthalenyls, 5,6,7,8- tetrahydro-naphthalenyls, 8,9- dihydro -7H- benzo ring heptene -6- bases, 6,7, 8,9- tetrahydrochysene -5H- benzocycloheptas alkenyl, 5,6,7,8,9,10- hexahydros-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptyl, The ring of 7,7- dimethyl-two [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl group, two rings [3.1.1] heptyl, Two rings [3.2.1] octyl group, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro -4,7- methylene - 1H- indenyls and octahydro -2,5- methylene-pentalene base etc..
In this application, the part as group or other groups, term " heterocyclic radical " mean by 2 to 14 carbon originals 3 yuan to 20 yuan non-aromatic cyclic groups of the stabilization of son and 1 to 6 hetero atom composition selected from nitrogen, phosphorus, oxygen and sulphur.Remove Specialized in addition in non-this specification, otherwise heterocyclic radical can be the member ring systems of monocyclic, bicyclic, three rings or more ring, and it can Including fused ring system, bridged-ring system or spiro ring system；Nitrogen, carbon or sulphur atom in its heterocyclic radical are optionally oxidized；Nitrogen Atom is optionally quaternized；And heterocyclic radical can be partially or completely saturation.Heterocyclic radical can be via carbon atom or miscellaneous original Son is simultaneously connected by singly-bound with molecule remainder.In the heterocyclic radical comprising condensed ring, one or more rings can be hereafter institute The aryl or heteroaryl of definition, it with the tie point of molecule remainder is non-aromatic annular atom that condition, which is,.With regard to the mesh of the present invention For, heterocyclic radical is preferably 4 yuan to 11 yuan nonaro-maticity lists for including 1 to 3 heteroatomic stabilization selected from nitrogen, oxygen and sulphur Ring, bicyclic, bridged ring or spiro-cyclic groups, more preferably include 1 to 34 yuan to 8 of heteroatomic stabilization selected from nitrogen, oxygen and sulphur First non-aromatic monocyclic, bicyclic, bridged ring or spiro-cyclic groups.The example of heterocyclic radical includes but is not limited to：Pyrrolidinyl, morpholinyl, Piperazinyl, homopiperazine base, piperidyl, thio-morpholinyl, 2,7- diaza-spiros [3.5] nonane -7- bases, 2- oxa- -6- azepines - Spiral shell [3.3] heptane -6- bases, 2,5- diazas-bicyclic [2.2.1] heptane -2- bases, azetidinyl, pyranose, oxinane Base, thiapyran base, tetrahydrofuran base, oxazinyls, dioxy cyclopenta, tetrahydro isoquinolyl, Decahydroisoquinolinpreparation base, imidazolinyl, miaow Oxazolidinyl, quinolizine base, thiazolidinyl, isothiazole alkyl, isoxazole alkyl, indolinyl, octahydro indyl, octahydro iso-indoles Base, pyrrolidinyl, pyrazolidinyl, phthaloyl imino etc..
In this application, the part as group or other groups, term " aryl " mean there is 6 to 18 carbon originals The conjugated hydrocarbon member ring systems group of sub (preferably with 6 to 10 carbon atoms).For purposes of the invention, aryl can be single The member ring systems of ring, bicyclic, three rings or more ring, it can also be condensed with cycloalkyl defined above or heterocyclic radical, condition is virtue Base is connected via the atom on aromatic rings by the remainder of singly-bound and molecule.The example of aryl include but is not limited to phenyl, Naphthyl, anthryl, phenanthryl, fluorenyl, 2,3- dihydro -1H- isoindolyls, 2- benzoxazolinones, 2H-1,4- benzoxazines -3 (4H) -one -7- bases etc..
In this application, term " aryl alkyl " refers to the alkane defined above substituted by aryl defined above Base.
In this application, the part as group or other groups, term " heteroaryl " mean there is 1 to 15 in ring Individual carbon atom (preferably with 1 to 10 carbon atom) and 1 to 6 heteroatomic 5 yuan to 16 yuan conjugate ring for being selected from nitrogen, oxygen and sulphur It is group.Unless being specialized in addition in this specification, otherwise heteroaryl can be the ring body of monocyclic, bicyclic, three rings or more ring System, it can also be condensed with cycloalkyl defined above or heterocyclic radical, condition is that heteroaryl passes through via the atom on aromatic rings The remainder of singly-bound and molecule connects.Nitrogen, carbon or sulphur atom in heteroaryl are optionally oxidized；Nitrogen-atoms is optionally It is quaternized.For purposes of the invention, heteroaryl is preferably comprising 1 to 5 heteroatomic stabilization for being selected from nitrogen, oxygen and sulphur 5 yuan to 12 yuan aromatic radicals, more preferably include 1 to 45 yuan to 10 of heteroatomic stabilization selected from nitrogen, oxygen and sulphur First aromatic radical includes 1 to 3 heteroatomic 5 yuan to 6 yuan aromatic radical for being selected from nitrogen, oxygen and sulphur.Heteroaryl Example include but is not limited to thienyl, imidazole radicals, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyls, pyridine radicals, Pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazoles base, indyl, furyl, pyrrole radicals, triazolyl, tetrazolium Base, triazine radical, indolizine base, isoindolyl, indazolyl, iso indazolyl, purine radicals, quinolyl, isoquinolyl, phenodiazine naphthyl, naphthalene Piperidinyl, quinoxalinyls, pteridyl, carbazyl, carboline base, phenanthridinyl, phenanthroline, acridinyl, phenazinyl, isothiazolyl, benzene It is benzothiazolyl, benzothienyl, oxatriazoles base, cinnolines base, quinazolyl, thiophenyl, indolizine base, phenanthrolene base, different Oxazolyl, phenoxazine groups, phenothiazinyl, 4,5,6,7- tetrahydro benzos [b] thienyl, naphtho- pyridine radicals, [1,2,4] triazol [4,3-b] pyridazine, [1,2,4] triazol [4,3-a] pyrazine, [1,2,4] triazol [4,3-c] pyrimidine, [1,2,4] triazol [4,3-a] pyridine, imidazo [1,2-a] pyridine, imidazo [1,2-b] pyridazine, imidazo [1,2-a] pyrazine etc..
In this application, term " heteroaryl alkyl " refers to be substituted by heteroaryl defined above defined above Alkyl.
In this application, " optional " or " optionally " represent the event then described or situation may occur may not also Occur, and the situation that the description occurs and do not occurred including the event or situation simultaneously.For example, " aryl being optionally substituted " Represent that aryl is substituted or unsubstituted, and the description is simultaneously including substituted aryl and unsubstituted aryl.
Terms used herein " part ", " structure division ", " chemical part ", " group ", " chemical group " refer in molecule Specific fragment or functional group.Chemical part is typically considered the chemical entities being embedded or attached on molecule.
" stereoisomer " refers to be made up of same atoms, is bonded by identical key, but with different three-dimensional structures Compound.The present invention will cover various stereoisomers and its mixture.
When containing alkene double bond in the compound of the present invention, unless otherwise stated, the compound of the present invention is intended to wrap Containing E- and Z- geometric isomers.
" dynamic isomer " refers to that proton is formed from an atom transfer of molecule to another atom of identical molecule Isomers.All tautomeric forms of the compound of the present invention also will be contained in the scope of the present invention.
The compound or its pharmaceutically acceptable salt of the present invention may contain one or more asymmetric carbon atoms, and therefore Enantiomter, diastereoisomer and other stereoisomeric forms in any ratio can be produced.Each asymmetric carbon atom can be based on three-dimensional Learn and be defined as (R)-or (S)-.It is contemplated that including all possible isomers, and its racemic modification and optical voidness Form.The preparation of the compound of the present invention racemic modification, diastereoisomer or enantiomter can be selected as raw material or Intermediate.Optically active isomers can be prepared using chiral synthon or chiral reagent, or be entered using routine techniques Row is split, the methods of for example with crystallization and chiral chromatogram.
The routine techniques of preparation/separation individual isomeric includes being synthesized by the chirality of suitable optical voidness precursor, or makes With such as chiral hplc resolution of racemic body (or racemic modification of salt or derivative), Gerald see, for example, Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols, Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations, Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128.
In this application, term " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically may be used The base addition salts of receiving.
" pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects , the salt formed with inorganic acid or organic acid.Inorganic acid salt includes but is not limited to hydrochloride, hydrobromate, sulfate, nitric acid Salt, phosphate etc.；Acylate includes but is not limited to formates, acetate, 2,2- dichloroacetates, trifluoroacetate, propionic acid Salt, caproate, caprylate, caprate, undecylenate, glycollate, gluconate, lactate, sebacate, adipic acid Salt, glutarate, malonate, oxalates, maleate, succinate, fumarate, tartrate, citrate, palm Hydrochlorate, stearate, oleate, cinnamate, laruate, malate, glutamate, pyroglutamate, aspartic acid Salt, benzoate, mesylate, benzene sulfonate, tosilate, alginate, ascorbate, salicylate, 4- ammonia Base salicylate, napadisilate etc..These salt can be prepared by method known in the art.
" pharmaceutically acceptable base addition salts " be refer to keep free acid biological effectiveness and without other side effects , the salt formed with inorganic base or organic base.Salt derived from inorganic base includes but is not limited to sodium salt, sylvite, lithium salts, ammonium Salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc..Preferable inorganic salts are ammonium salt, sodium salt, sylvite, calcium salt and magnesium Salt.Salt derived from organic base includes but is not limited to following salt：Primary amine class, secondary amine class and tertiary amines, substituted amine, bag Include natural substituted amine, cyclic amine and deacidite, such as ammonia, isopropylamine, trimethylamine, diethylamine, three Ethamine, tripropyl amine (TPA), monoethanolamine, diethanol amine, triethanolamine, dimethylethanolamine, DMAE, 2- lignocaine second Alcohol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, procaine, choline, glycine betaine, ethylenediamine, gucosamine, Methyl glucose osamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamino resin etc..Preferable organic base includes isopropyl Amine, diethylamine, monoethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.These salt can pass through method known in the art Prepare.
" polymorph " refers to some compounds of the present invention in the solid state due to two or more be present not The caused different solid crystal phases with molecules align.Some compounds of the present invention may have more than one crystal formation, this hair It is bright to be intended to include various crystal formations and its mixture.
Generally, crystallization effect can produce the solvate of the compounds of this invention.Term " the solvation used in the present invention Thing " refers to the aggregation with one or more solvent molecules comprising one or more the compounds of this invention molecules.Solvent can be Water, solvate in this case is hydrate.Or solvent can be organic solvent.Therefore, compound of the invention can be with Exist with hydrate, including monohydrate, dihydrate, semihydrate, times semihydrate, trihydrate, tetrahydrate etc., with And corresponding solvation form.The compounds of this invention can form real solvate, but in some cases, can also only protect Indefinite water or water is stayed to add the mixture of the indefinite solvent in part.The present invention compound can react in a solvent or from Precipitation or crystallized out in solvent.The solvate of the compounds of this invention is also contained within the scope of the present invention.
Present invention additionally comprises the prodrug of above-claimed cpd.In this application, term " prodrug " expression can be in physiological conditions Compound lower or that the bioactive compound of the present invention is converted to by solvolysis.Therefore, term " prodrug " refers to The pharmaceutically acceptable metabolic precursor thereof of the compound of the present invention.When being given in need individual, prodrug can not have Activity, but the reactive compound of the present invention is converted in vivo.Prodrug generally rapid conversion in vivo, and produce the present invention's Parent compound, such as realized by hydrolyzing in blood.Prodrug compound generally provides molten in mammalian organism The advantages of Xie Du, histocompatbility or sustained release.Prodrug includes known amino protecting group and carboxyl-protecting group.Specific prodrug system Preparation Method can refer to Saulnier, M.G., et al., Bioorg.Med.Chem.Lett.1994,4,1985-1990； Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
In this application, " pharmaceutical composition " refers to that the compounds of this invention is used to live biology with what this area generally received Property compound is delivered to the preparation of the medium of mammal (such as people).The medium includes pharmaceutically acceptable carrier.Medicine The purpose of composition is to promote the administration of organism, the absorption beneficial to active component and then performance bioactivity.
Terms used herein " pharmaceutically acceptable " refers to the bioactivity for not influenceing the compounds of this invention or property Material (such as carrier or diluent), and relative nontoxic, the i.e. material can be applied to individual without causing bad biological respinse Or interacted in a manner of bad with any component included in composition.
In this application, " pharmaceutically acceptable carrier " include but is not limited to it is any by correlation government administration section permitted Can be the acceptable adjuvant used for the mankind or domestic animal, carrier, excipient, glidant, sweetener, diluent, preservative, dye Material/colouring agent, flavouring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent.
" tumour " of the present invention, " cell proliferative disorder relevant disease " etc. includes but is not limited to leukaemia, gastro-intestinal stromal Knurl, histiocytic lymphoma, non-small cell lung cancer, ED-SCLC, cancer of pancreas, lung squamous cancer, adenocarcinoma of lung, breast cancer, forefront Gland cancer, liver cancer, cutaneum carcinoma, cell carcinoma, cervical carcinoma, oophoroma, intestinal cancer, nasopharyngeal carcinoma, the cancer of the brain, osteocarcinoma, cancer of the esophagus, melanin The diseases such as knurl, kidney, carcinoma of mouth.
Terms used herein " prevention ", " prevention " and " preventing " includes generation or the evil for sufferer is reduced disease or illness The possibility of change.
Term " treatment " used herein includes following meanings with other similar synonyms：
(i) prevention disease or illness occur in mammal, particularly when this kind of mammal be susceptible to the disease or Illness, but when being not yet diagnosed as suffering from the disease or illness；
(ii) suppress disease or illness, that is, contain its development；
(iii) disease or illness are alleviated, i.e. the state of the disease or illness is disappeared；Or
(iv) symptom caused by the disease or illness is mitigated.
Term " effective dose ", " therapeutically effective amount " or " pharmacy effective dose " used herein refers to take metapedes with certain Alleviate at least one medicament of one or more symptoms or the amount of compound of treated disease or illness in degree.Its result Can be sign, the abatement of symptom or the cause of disease and/or alleviation, or biosystem it is any other needed for change.For example, for controlling " effective dose " treated is clinically to provide the composition for including compound disclosed herein needed for significant remission effect Amount.The technology of such as dose escalation trial can be used to determine the effective dose being suitable in any individual case.
Terms used herein " taking ", " administration ", " administration " etc. are to refer to compound or composition being delivered to progress The method in the required site of biological agent.These methods include but is not limited to oral route, through intraduodenal routes, parenteral note Penetrate (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration and per rectum administration.This area The known application technique available for Compounds and methods for described herein of technical staff, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s, Discussed in Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa Those.In preferred embodiments, the compound and composition being discussed herein are by orally administering.
Term " drug regimen " used herein, " drug combination ", " drug combination ", " applying other treatments ", " apply it Its therapeutic agent " etc. refers to that it includes active component by mixing or combining more than one active component the drug therapy that obtains Fixation and non-fixed Combination.Term " fixed Combination " refers to be administered simultaneously to patient in the form of single entity or single formulation At least one compound as described herein and at least one collaboration medicament.Term " not fixed Combination " refers to the shape with corpus separatum Formula is administered simultaneously to patient, share or at least one compound as described herein is sequentially applied with variable interval time and at least One kind collaboration preparation.These are also applied in HAART, such as using three or more active components.
It should also be appreciated by one skilled in the art that in method discussed below, midbody compound functional group may need To be protected by appropriate protection group.Such functional group includes hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protecting group bag Include trialkylsilkl or diarylalkyl-silyl (such as t-butyldimethylsilyl, tert-butyl diphenyl first Silylation or trimethyl silyl), THP trtrahydropyranyl, benzyl etc..The protection group of suitable amino, amidino groups and guanidine radicals includes uncle Butoxy carbonyl, benzyloxycarbonyl group etc..Suitable sulfhydryl protected base includes-C (O)-R " (wherein R " is alkyl, aryl or aralkyl), To methoxy-benzyl, trityl etc..Suitable carboxyl-protecting group includes alkyl, aryl or aralkyl esters.
Protection group can be introduced and removed according to standard technique well known by persons skilled in the art and as described herein.Protect The use of shield base is specified in Greene, T.W. and P.G.M.Wuts, Protective Groups in Organi Synthesis, (1999), in 4th Ed., Wiley.Protection group can also be fluoropolymer resin.
Compound of formula I
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,
In another preference, described W, W ', W1、W2、n、n’、R1、R2、R3、R4、m、R11, X, Rc, Rd independently of one another For the group corresponding to following compound.
The preparation of compound of formula I
The compound of formula I provided by the invention, can be by following method 1) or 2) prepare：
1) compound 1a and compoundIt is coupled under the reaction condition of atent solvent, so as to Form compound of formula I；
In formula, each group is as defined above described in text；
2) compound 1a and compoundIt is coupled under the reaction condition of atent solvent, then Again withReaction generation compound of formula I；
In formula, each group is as defined above described in text.
In another preference, the reaction is carried out in a solvent, and the solvent is selected from the group：Water, methanol, ethanol, Isopropanol, ethylene glycol, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, Acetonitrile, DMF, DMA, dioxane, or its composition.
Main advantages of the present invention include：
1. provide a kind of compound shown in formula I.
2. providing a kind of novel saltant type IDH inhibitor of structure and its preparation and application, described inhibitor is to prominent Modification IDH has higher inhibitory activity.
3. provide a kind for the treatment of and the pharmaceutical composition of saltant type IDH relevant diseases.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Intermediate A 1：The synthesis of N- (2,3- dihydro -1H- indenes -1- bases) -3- fluoroanilines
Sequentially add 1- indones (2g, 15mmol) in dry 50ml single port bottle, m-fluoroaniline (2.2g, 19.7mmol), the 4A molecular sieves (20g) activated, 1, the 2- dichloroethanes 40ml dried, flow back 36h under nitrogen protection, TLC is monitored, and generates product 60%-70%, there is starting material left, is filtered, and is collected filtrate and is spin-dried for obtaining product 2.3g.Crude product is not purified Directly use.
Using as above method, with substituted or unsubstituted (miscellaneous) aromatic ring and naphthenic one, and substituted or unsubstituted aniline, Heterocyclic aromatic amine reacts, and solvent could alternatively be toluene either dioxane or other atent solvents, obtain imine intermediate A2, A3, A4, A5, A6, A8, A9, A10, A16, A19, A20, A21, A22, A26, A28, A29, A31, A33, A34 and A35. its Middle A2, A3, A4, A5, A6, A8, A9, A10, A16, A28, A29, A31, A33, A34, A35 is not purified to be directly used in next step Reaction；A19, A20, A21, A22, A26 purify through column chromatography.
The intermediate structure is as follows：
Intermediate A 19:N- (2,3- dihydro -1H- indenes -1- bases) -3 fluoro- 4 chloroanilines
1H-NMR(d6-DMSO,400MHz)：δ 7.91-7.75 (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 A 20:N- (2,3- dihydro -1H- indenes -1- bases) aniline
LCMS:m/z 208.2(M+H)+, RT=1.5min.
Intermediate A 21:N- (2,3- dihydro -1H- indenes -1- bases) -2,5- difluoroanilines
LCMS:m/z 244.1(M+H)+, RT=1.7min.
Intermediate A 22:N- (2,3- dihydro -1H- indenes -1- bases) -3,5- difluoroanilines
1H-NMR(CDCl3,400MHz)：δ 7.88 (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 A 26:(N- (2,3- dihydro -1H- indenes -1- bases) -2,5- difluoroanilines
1H-NMR(CDCl3,400MHz):δ 7.93 (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- (the chloro- 2,3- dihydros -1H- indenes -1- bases of 5-) -5- fluoro-3-pyridine amine
The chloro- 1- indones (333mg, 2mmol) of 5- and 3- amino-5-fluorines pyridine (222mg, 2mmol) are in 10mL reaction bulb In test tube, 120 DEG C of reactions are heated under the protection of tube sealing nitrogen.TLC/LCMS detect to product be not further added by when, add dichloromethane Alkane dissolves, and adds anhydrous sodium sulfate drying, filtering, is spin-dried for obtaining schiff bases crude product stand-by.
Using as above method, with substituted or unsubstituted (miscellaneous) aryl simultaneously cycloalkyl ketone compounds, and substitute or do not take The aniline in generation, heterocyclic aromatic amine reaction, obtain imine intermediate A7, A11, A13, A14, A15, A17, A18, A23, A24, A25, A27,A30。
Intermediate A 12：N- (the chloro- 2,3- dihydros -1H- indenes -1- bases of 7-) -3- fluoroanilines
Sequentially add 7- chlorine indone (2.5g, 15mmol) in dry 50ml single port bottle, m-fluoroaniline (2.2g, 19.7mmol), the 4A molecular sieves (20g) activated, 1, the 2- dichloroethanes 40ml dried, instillation titanium tetrachloride (142mg, 0.05equiv) it is catalyzed, flows back under nitrogen protection, TLC, which is monitored to product, is no longer increased, and filtering, filtrate is spin-dried for obtaining crude product 2.5g is directly used in react in next step.
Above method, titanium tetrachloride can be substituted for other lewis acids (BFEE, alchlor etc.), molten Agent can be replaced toluene, dioxane.
Using as above method, reacted with 7- chlorine indone and 3,5- difluoroaniline, obtain imine intermediate A32.
Intermediate B 1:The synthesis of the fluoro- 3- cyclobutyl isocyanides of 1,1- bis-
Step 1：In clean 250ml tube sealings, B1-1 (25g, 175mmol) and Ethyl formate 140ml, stirring are added Triethylamine (53g, 525mmol) is added under state, at 110 DEG C of oil bath, is stirred overnight, is cooled to room temperature, is filtered, filter cake second Acetoacetic ester is washed 2-3 times, and filtrate is spin-dried for, is obtained compound 2 (22g, yield with saturated common salt water washing 2 times: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 2：In dry 1L single port bottle, compound B-11-2 (22g, 163mmol), triphenyl phosphorus are sequentially added (47g, 179mmol), carbon tetrachloride (25g, 163mmol), triethylamine (16.5g, 163mmol) and 500ml dichloromethane, 45 DEG C flow through night next time, are spin-dried under cold bath, add 500ml ether and are beaten 1 hour, filtering, are washed with ether, filtrate silicon Glue mixes sample, is spin-dried under cold bath, and target compound (11.8g, 62%) is purified to obtain by silicagel column (ether).
1H-NMR(DMSO 400MHz):δ4.28-4.26(m,1H),3.19-3.08(m,2H),2.97-2.87(m,2H)。
Using as above method, different isocyanide intermediate Bs 2, B3, B5, B6, B7 are made with different amine.
Intermediate B 2:The fluoro- 3- cyclohexyls isocyanides of 1,1- bis-
1H-NMR(CDCl 400MHz):δ3.84(s,1H),1.93-2.17(m,8H)
Intermediate B 3：4- isocyanides-oxinane
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 B 5：4,4- Dimethylcyclohexyl isocyanides
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 B 6：Ether dope is not spin-dried for, not separation of intermediates, is directly used in and is reacted in next step.
Intermediate B 7：Ether dope is not spin-dried for, not separation of intermediates, is directly used in and is reacted in next step.
Intermediate B 4:The synthesis of phenyl isocyanide
Sequentially add aniline (5.0g, 53.69mmol, 1.0eq), the tetrabutyl at room temperature in dry 500mL there-necked flasks Ammonium hydrogen sulfate (1.82g, 5.37mmol, 0.1eq), dichloromethane (160mL), sodium hydrate aqueous solution (50%, 80mL).0 Chloroform (9.61g, 80.54mmol, 1.5eq) is slowly added dropwise at DEG C, is stirred at room temperature 18 hours.After completion of the reaction, will react Liquid is poured into water (500mL), is extracted with dichloromethane (500mL).Organic phase is dried with sodium sulphate, is concentrated under reduced pressure.Pass through silica gel Post obtains product phenyl isocyanide (3.0g, yellow oily liquid), yield 55%.
1H NMR(CDCl3-d1,400MHz)：δ7.39(m,5H).
Intermediate C1：(S) synthesis of -1- (4- cyanopyridine -2- bases) pyrrolidines -2- carboxylic acids
Step 1：By compound L-proline methyl ester hydrochloride (4.98 grams, 30 mMs, CAS:2133-40-6) and 2- Bromo- 4- cyanopyridines (2.28 grams, 20 mMs) are dissolved in you), Xantphos (5.78 grams, 10 mMs) and cesium carbonate (19.56 Gram, 60 mMs), in 1 dioxane (80 milliliters), add at room temperature Pd2 (dba) 3 (1.83 grams, 2 00 degree Celsius of mmoles The lower reaction of nitrogen protection 12 hours.After completion of the reaction, 50 milliliters of ethyl acetate are added.Organic phase washed with water (20 milliliters × 1), Saturated aqueous common salt (20 milliliters × 1) washs.Collect organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration.Cross pillar (petroleum ether：Ethyl acetate=20：1,10：1) purify, obtain product (S)-methyl 1- (4- cyanopyridine -2- bases) pyrrolidines -2- Carboxylic acid (1.34 grams, yellow solid), yield：29%.LCMS:m/z232.1(M+H)+；RT=1.387min.
Step 2：C1-1 (460 milligrams, 2 mMs) is dissolved in tetrahydrofuran/water (15 milliliters/8 milliliters), in room temperature Lower addition lithium hydroxide (84 milligrams, 2 mMs), reacts 4 hours at room temperature.After completion of the reaction, addition is adjusted with watery hydrochloric acid PH to 2, add 15 milliliters of ethyl acetate.Organic phase washed with water (20 milliliters × 1), saturated aqueous common salt (20 milliliters × 1) washing. Organic phase is collected, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated to give product C1：(S) -1- (4- cyanopyridine -2- bases) Pyrrolidines -2- carboxylic acids (310 milligrams, yellow solid), yield：78.3%.
LCMS:m/z 218.1(M+H)+；RT=1.076min.
Intermediate C2：The synthesis of 2- ((4- cyano-phenyls) amino) acetic acid
Step 1：Compound C2-1 (1g, 8.5mmol), sodium acetate are sequentially added in dry 50ml single port bottles (1.4g, 17mmol), bromoacetate (1.7g, 10mmol) and 30ml ethanol, flow back 36 hours, be spin-dried for solvent, add 50ml Ethyl acetate, it is spin-dried for saturated common salt water washing, anhydrous sodium sulfate drying, filtering, with (petroleum ether：Ethyl acetate=2:1) mistake Silicagel column purifies to obtain intermediate C2-2 (300mg, yield：17.4%) LCMS:m/z 205.2(M+H)+, RT=1.37min.
Step 2：Compound C2-2 (300mg, 1.47mmol), hydroxide are sequentially added in dry 50ml single port bottles Sodium (118mg, 2.94mmol), water 3ml and 12ml methanol, it is stirred at room temperature 3 hours, is spin-dried for solvent, PH is adjusted about etc. with watery hydrochloric acid In 5, white solid C2 (120mg, yield are obtained by preparative separation：46.3%).
LCMS:M/z=175.2 (M-1)-, RT=1.07min.
Intermediate C4:2- ((2- fluorine pyridin-3-yl) amino) acetic acid
Intermediate C4. is prepared using with intermediate C2 identical methods
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：The synthesis of 2- (methyl (phenyl) amino) acetic acid
Step 1：Compound C3-1 (3g, 16.7mmol, CAS23284-84- are sequentially added in dry 50ml tube sealings 6), iodomethane (7.1g, 50mmol), 20ml toluene, 80 degrees Celsius are stirred overnight, and cooling, add 30ml water, are extracted with ethyl acetate Take (50ml*2), anhydrous sodium sulfate drying, saturated common salt water washing, be spin-dried for, crude product passes through silicagel column (petroleum ether：Acetic acid second Ester=20:1) yellow oil product 2- (methyl (phenyl) amino) ethyl acetate (C3-2) 1.2g. yields are obtained：37%.LCMS:m/ Z 194.3 (M-1) R=1.616.
Step 2：Compound C3-2 (1.2g, 6.2mmol) sodium hydroxide is sequentially added in dry 25ml single port bottles (0.62g, 15mmol) and 5ml water, 15ml methanol, it is stirred at room temperature three hours, spins off organic solvent, regulation PH is approximately equal to 4, uses second Acetoacetic ester extracts (50ml*2), anhydrous sodium sulfate drying, is spin-dried for obtaining yellow oil 2- (methyl (phenyl) amino) acetic acid (C3) 420mg, yield：41%.
LCMS:m/z 166.3(M-1)-, RT=1.2min.
Intermediate C5：(S) synthesis of -2- oxos oxazolidine -4- carboxylic acids
Step 1：Sequentially added at room temperature in dry 500mL single port bottles Serine (10.0g, 95.2mmol, 1.0eq), sodium acid carbonate (20g, 238.0mmol, 2.5eq) and water (30mL).At 0 DEG C add benzyl chloroformate (2.0mL, 142.8mmol, 1.5eq), it is stirred at room temperature 18 hours.After completion of the reaction, reaction solution is poured into water (200), uses ethyl acetate (300mL) extracting impurities.It is 1 that aqueous phase is acidified to pH value with concentrated hydrochloric acid, then is extracted 3 times with ethyl acetate (300mL).Organic phase is revolved Dry, residue washs mashing with ethyl acetate, filtering, obtains products C 5-1：(S) -2- (((benzyloxy) carbonyl) amino) -3- hydroxyls Base propionic acid (10g, white solid), yield 45%.LCMS:m/z 238.2(M-H)-；RT=1.047min
Step 2：Sequentially added at room temperature at 0 DEG C, in 100mL single port bottles C5-1 (2.5g, 10.45mmol, 1.0eq), Water (10mL) and sodium hydroxide (0.84g, 20.91mmol, 2.0eq).It is stirred at room temperature 1 hour.After completion of the reaction, will react Liquid is poured into water (20), with ether (300mL) extracting impurities.It is 1 that aqueous phase is acidified to pH value with concentrated hydrochloric acid, then uses ethyl acetate (300mL) is extracted 5 times.Obtain product (S) -2- oxo oxazolidine -4- carboxylic acids (600mg, white solid), yield 86%.
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).
Intermediate D1:The synthesis of 2- methyl isophthalic acid H- imidazos [4,3-b] pyrazine
2,3- diaminopiperazines (200mg, 1.82mmol), acetic anhydride are sequentially added in dry 50ml single port bottles (445.4mg, 4.36mmol), reacted 2 hours at 140 DEG C, be cooled to room temperature, be spin-dried for acetic anhydride, add the 10N of heat NaOH Solution 1ml, 2ml acetic acid is added, refrigerator is put and stands overnight, separated out solid, filtering, be washed with water, it is dry that brown color solid produces Thing 90mg.
LCMS:m/z 135.2(M+H)+；RT=0.53min.
Intermediate D2：The synthesis of 2- (2- methyl isophthalic acid H- imidazoles -5- bases) pyrimidine
Step 1：30ml anhydrous tetrahydro furans are added in dry 100ml there-necked flasks, ventilation, nitrogen protection, are cooled to 0 DEG C, 2mol/L LDA (10.5ml, 22.7mmol) and tri-butyl tin hydride (5.64ml, 22.7mmol) are slowly added to, at 0 DEG C Lower stirring 15 minutes, is then cooled to -78 DEG C, and the tetrahydrofuran solution (20ml) of 2- chlorine pyrimidine (2g, 17.5mmol) is added dropwise, adds It is complete to be slowly raised to room temperature, it is stirred overnight, adds 30ml water, be extracted with ethyl acetate (50mlx3), anhydrous sodium sulfate drying, revolves Dry, crude product passes through silicagel column (PE:EA=10：1) purifying obtains yellow oily liquid product D2-1：2.15g (yield：35%).
Step 2：In dry 100ml single port bottles, the bromo- 2- methyl isophthalic acids H- imidazoles (CAS of 5- are added:16265-11-5, 1g, 6.25mmol), and tetrahydrofuran 20ml, 0 DEG C is cooled to, NaH (0.375g, 9.4mmol) is added portionwise, is slowly raised to room Temperature, stir 1 hour, add SEM-Cl (1.25g, 7.5mmol), be stirred overnight at room temperature, be quenched with water, ethyl acetate extraction (50mlx3), saturated common salt water washing, anhydrous sodium sulfate drying, is spin-dried for, and crude product passes through silicagel column (PE:EA=1:1) purify To faint yellow oily product D2-2:1.4g (yields：78%).LCMS:m/z 293.1[M+H]+, RT=1.34min.
Step 3：Sequentially add D2-2 (1g, 3.43mmol) in dry 50ml single port bottles, D2-1 (1.18g, 4.12mmol) with tetra-triphenylphosphine palladium (300mg), dry DMF 20ml are added, three times, nitrogen is protected, at 120 DEG C for ventilation Stirring 4 hours, dry solvent is drawn with oil pump, adds 20ml water, is extracted with ethyl acetate, anhydrous sodium sulfate drying, be spin-dried for, crude product passes through Silicagel column (PE:EA=1：1) red solid D2-3 is obtained:0.97g (yields：95%).LCMS:m/z 291.2[M+H]+, RT= 0.980min。
Step 4：D2-3 (500mg, 1.72mmol) is added in dry 50ml single port bottles and adds 20ml DCM, and 10ml trifluoroacetic acids, are stirred overnight at room temperature, and are spin-dried for solvent, are washed with saturated sodium bicarbonate aqueous solution, ethyl acetate extraction, rotation Dry, crude product passes through silicagel column (PE:EA=1：1) red solid product D2 is obtained:160mg (yield 58%)
LCMS:m/z 161.2[M+H]+, RT=0.445min.
Intermediate D3：2- (2- methyl isophthalic acid H- imidazoles -5- bases) pyrazine
Using the above method, set out to obtain 2- (2- methyl isophthalic acid H- imidazoles -5- bases) pyrazine with 2- chloropyrazines.
Embodiment 1：Compound 1 and compound 2
Step 1：Intermediate A 1 is added in microwave reaction pipe, L-Glutimic acid (260mg, 2mmol), it is anhydrous to inject 2mL Methanol dissolving adds intermediate B 1 (240mg, 2mmol) after being stirred at room temperature 15 minutes, and tube sealing reacted after in 40 DEG C of oil baths Night.It is extracted with ethyl acetate (3*10mL) three times after adding 10mL water, combined ethyl acetate mutually uses saturated common salt water washing for several times, With being spin-dried for obtaining crude reaction after anhydrous sodium sulfate drying, separated using positive column chromatography (methylene chloride/methanol=95/5) It is (2S)-N- (1- (3,3- difluoro cyclobutylmethyls acyl group) -2,3- dihydro -1H- indenyls)-N-3- fluorobenzene to light tan solid Base -5- oxo-pyrroli -2- formamides (intermediate 1-1,140mg, yield=15%),
LCMS:m/z 943.4(2M+H)+, RT=1.64min.
Step 2：The intermediate 1-1 (140mg, 0.3mmol) that step 1 obtains, cesium carbonate are added in microwave reaction pipe (145mg,0.45mmol),Pd2(dba)3(14mg, 0.015mmol), Xant-phos (9mg, 0.015mmol) and the chloro- 4- of 2- Cyanopyridine (50mg, 0.36mmol), the anhydrous Isosorbide-5-Nitrae-dioxane of 5mL is injected, is placed in after tube sealing at 70 DEG C and reacts 3h.Filtering, Filtrate uses the crude product of the isolated compound 1 of chromatography post separation (petrol ether/ethyl acetate=4/1) and compound 2 after being spin-dried for, It is further purified respectively using efficient liquid phase preparative liquid chromatography afterwards to obtain target compound 1 and 2.
Compound 1：(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) formoxyl) -2, 3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutyl) formoxyl) -2, 3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.73 (d, J=0.9Hz, 1H), 8.56-8.51 (m, 1H), 7.33-7.11 (m, 7H),7.08–6.94(m,2H),5.83–5.71(m,1H),4.72–4.62(m,1H),4.18-4.08(m,1H),2.98-2.84 (m,5H),2.65–2.07(m,6H),2.03–1.90(m,1H).
LCMS:m/z 574.1(M+H)+, RT=1.84min.
Embodiment 2：Compound 3 and compound 4
Using method same as Example 1, using imine intermediate A2, isocyanide intermediate B 1 and L-Glutimic acid are carried out Obtained product is reacted, then is reacted with the chloro- 4- cyanopyridines of 2-, purifying obtains compound 3 and compound 4.
Compound 3：(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbonyl) -2,3- Dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutyl) carbonyl) -2,3- Dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.76 (d, J=7.9Hz, 1H), 8.65-8.16 (m, 3H), 7.77-7.32 (m, 3H),7.32–7.07(m,3H),5.60-5.54(m,1H),4.59-4.52(m,1H),4.16-4.05(m,1H),2.97–2.71 (m,4H),2.68–2.47(m,2H),2.45–2.14(m,4H),2.12–1.83(m,2H).
LCMS:m/z 575.2(M+H)+, RT=1.74min.
Embodiment 3：Compound 7 and compound 8
Using method same as Example 1, using imine intermediate A2, isocyanide intermediate B 2 and L-Glutimic acid are carried out Obtained product is reacted, then is reacted with the chloro- 4- cyanopyridines of 2-, purifying obtains compound 7 and compound 8.
Compound 7：(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((4,4- difluorocyclohex alkane) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- ((4,4- difluorocyclohex alkane) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 4：Compound 9 and compound 10
Using method same as Example 1, using imine intermediate A4, cyclohexyl isocyanide and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, purifying obtains compound 9 and compound 10.
Compound 9：(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- (cyclohexyl formoxyl) -1,2,3,4- tetrahydrochysenes Naphthalene -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- (cyclohexyl formoxyl) -1,2,3,4- tetrahydrochysenes Naphthalene -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 5：Compound 12 and compound 13
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, purifying obtains compound 12 and compound 13.
Compound 12：(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((4,4- difluorocyclohex alkane) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.74 (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- cyanopyridine -2- bases)-N- ((R) -1- ((4,4- difluorocyclohex alkane) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 6：Compound 14 and compound 15
Using the identical method of embodiment 1, using imine intermediate A1, cyclohexyl isocyanide and L-Glutimic acid are reacted The product obtained afterwards, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 14 and compound 15.
Compound 14：(S) -1- (4- cyanopyridine -2- bases)-N- ((R) -1- (cyclohexyl carboxyamide base) -2,3- two Hydrogen -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.73 (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- cyanopyridine -2- bases)-N- ((S) -1- (cyclohexyl carboxyamide base) -2,3- two Hydrogen -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.76 (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.
Embodiment 7：Compound 19 and compound 20
Using the identical method of embodiment 1, using imine intermediate A31, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 19 and compound 20.
Compound 19：(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -4- methyl -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.73 (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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -4- methyl -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 8：Compound 21
Using the identical method of embodiment 1, using imine intermediate A22, isocyanide intermediate B 2 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyrimidines of 2-, obtain compound 21.
Compound 21：(2S) -1- (4- cyanopyrimidine -2- bases)-N- (1- ((4,4- difiuorocyclohexyls) carbamoyl) - 2,3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyl) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 9：Compound 22
Using the identical method of embodiment 1, using imine intermediate A16, isocyanide intermediate B 1 and sour intermediate C5 are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyrimidines of 2-, obtain compound 22.
Compound 22：(2S)-3- (4- cyanopyrimidine-2- bases)-N- (1-(3,3- difluoros cyclobutyl) carbamoyl)-2, 3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -2- oxooxazolidine -4- formamides
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.
Embodiment 10：Compound 23
Using the identical method of embodiment 1, using imine intermediate A6, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 23.
Compound 23：(2S) -1- (4- cyanopyridine -2- bases)-N- (7- ((4,4- difluorocyclohex alkane) carbamoyl) two Ring [4.2.0] octyl- 1 (6), 2,4- triolefin -7- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.76 (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.
Embodiment 11：Compound 27
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 3 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 27.
Compound 27：(2S) -1- (4- cyanopyridine -2- bases)-N- (3- fluorophenyls) -5- oxos-N- (1- ((tetrahydrochysene -2H- Pyrans -4- bases) carbamoyl) -2,3- dihydro -1H- indenes -1- bases) pyrrolidines -2- formamides.
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.
Embodiment 12：Compound 28 and compound 29
Using the identical method of embodiment 1, using imine intermediate A7, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 28 and compound 29.
Compound 28：(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((4,4- difiuorocyclohexyls) carbamyls Base) the fluoro- bases of 2,3- dihydros -1H- indenes -1 of -6-)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- ((4,4- difiuorocyclohexyls) carbamyls Base) the fluoro- bases of 2,3- dihydros -1H- indenes -1 of -6-)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 13：Compound 30
Using the identical method of embodiment 1, using imine intermediate A8, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 30.
Compound 30：(2S)-1- (4- cyanopyridine-2- bases)-N- (1- (4,4-difiuorocyclohexyl) carbamoyl)-2, 3- dihydro -1H- indenes -1- bases) -5- oxos-N- (3- methoxyphenyls) pyrrolidines -2- formamides
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.
Embodiment 14：Compound 31
Using the identical method of embodiment 1, using imine intermediate A9, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 31.
Compound 31：(2S)-1- (4- cyanopyridine-2- bases)-N- (1- (4,4-difiuorocyclohexyl) carbamoyl)-2, 3- dihydro -1H- indenes -1- bases) -5- oxos-N- (3- tolyls) pyrrolidines -2- formamides
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.
Embodiment 14：Compound 32 and compound 33
Using the identical method of embodiment 1, using imine intermediate A2, tert-butyl group isocyanide and L-Glutimic acid are reacted The product obtained afterwards, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 32 and compound 33.
Compound 32：(S)-N- ((S) -1- (tert-butyl group formoxyl) -2,3- dihydro -1H- indenes -1- bases) -1- (4- cyano group pyrroles Pyridine -2- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3) δ 8.74 (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-butyl group formoxyl) -2,3- dihydro -1H- indenes -1- bases) -1- (4- cyano group pyrroles Pyridine -2- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3) δ 8.74 (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.
Embodiment 15：Compound 34
Using the identical method of embodiment 1, using imine intermediate A2, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with 2- chlorine pyrimidines, obtain compound 34.
Compound 34：The base of (2S)-N- (1- (4,4- difiuorocyclohexyls) formoxyl) -2,3- dihydro -1H- indenes -1)-N- (5- Fluorine pyridin-3-yl) -5- oxos -1- (pyrimidine -2-base) pyrrolidines -2- formamides
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.
Embodiment 16：Compound 35
Using the identical method of embodiment 1, using imine intermediate A2, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with 3- chlorobenzene cyanogen, obtain compound 35.
Compound 35：(2S) -1- (3- cyano-phenyls)-N- (1- (N- (4,4- difiuorocyclohexyls) formoxyl) -2,3- two The base of hydrogen -1H- indenes -1)-N- (5- fluoro-3-pyridines base) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 17：Compound 36 and compound 37
Using the identical method of embodiment 1, using imine intermediate A10, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 36 and compound 37.
Compound 36：(S)-N- ((S) -1- ((4,4- difluoros cyclobutyl) formoxyl) -2,3- dihydro -1H- indenes -1- bases) - 1- (4- cyanopyridine -2- bases)-N- (3- chlorphenyls) -5- oxo-pyrrolidine -2- formamides
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- difluoros cyclobutyl) formoxyl) -2,3- dihydro -1H- indenes -1- bases) - 1- (4- cyanopyridine -2- bases)-N- (3- chlorphenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 18：Compound 39
Using the identical method of embodiment 1, using imine intermediate A2, isocyanide intermediate B 2 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with 2- fluorine pyridines, obtain compound 39.
Compound 39：(2S)-N- (1- ((4,4- difiuorocyclohexyls) formoxyl) -2,3- dihydro -1H- indenes -1- bases) -1- (4- fluorine pyridine -2- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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]+.
Embodiment 19：Compound 40
Using the identical method of embodiment 1, using imine intermediate A11, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with 2- chloropyridines, obtain compound 40.
Compound 40：(2S)-N- (the chloro- 1- of 5- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydro -1H- indenes - 1- yls) -1- (4- cyanopyridine -2- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 20：Compound 41 and compound 42
Using the identical method of embodiment 1, using imine intermediate A2, isocyanide intermediate B 1 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the bromo- 4- chloropyridines of 2-, obtain compound 41 and compound 42.
Compound 41：(S) -1- (4- chloropyridine -2- bases)-N- ((S) -1 ((3,3- difluoros cyclobutyl) formoxyl) -2,3- Dihydro -1H- indenes -1- bases) -1-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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- chloropyridine -2- bases)-N- ((R) -1 ((3,3- difluoros cyclobutyl) formoxyl) -2,3- Dihydro -1H- indenes -1- bases) -1-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 21：Compound 43 and compound 44
Using the identical method of embodiment 1, using imine intermediate A12, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with 2- chloropyridines, obtain compound 43 and compound 44.
Compound 43：(S)-N- (the chloro- 1- of (S) -7- ((3,3- difluoros cyclobutyl) formoxyl) -2,3- dihydro -1H- indenes -1 Base) -1- (4- cyanopyridine -2- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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- (the chloro- 1- of (R) -7- ((3,3- difluoros cyclobutyl) formoxyl) -2,3- dihydro -1H- indenes -1 Base) -1- (4- cyanopyridine -2- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 22：Compound 46 and compound 47
Using the identical method of embodiment 1, using imine intermediate A13, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with 2- chloropyridines, obtain compound 46 and compound 47.
Compound 46：(S)-N- (the chloro- 1- of (S) -6- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.73 (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- (the chloro- 1- of (R) -6- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.77 (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.
Embodiment 23：Compound 48 and compound 49
Using the identical method of embodiment 1, using imine intermediate A14, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction through purifying, then reacted with 2- chloropyridines, obtain compound 48 and compound 49.
Compound 48：(S)-N- (the chloro- 1- of (S) -5- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.73 (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- (the chloro- 1- of (R) -5- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.76 (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.
Embodiment 24：Compound 50 and compound 51
Using the identical method of embodiment 1, using imine intermediate A2, isocyanide intermediate B 1 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with 2- chloropyrazines, obtain compound 50 and compound 51.
Compound 50：(S)-N- ((S) -1- ((3,3- difluoros cyclobutyl) formoxyl) 2,3- dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -5- oxos -1- (pyrazine -2- bases) pyrrolidines -2- formamides
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- difluoros cyclobutyl) formoxyl) 2,3- dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -5- oxos -1- (pyrazine -2- bases) pyrrolidines -2- formamides
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.
Embodiment 25：Compound 52 and compound 53
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 1 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- trifluoromethyl pyridines of 2-, obtain compound 52 and compound 53
Compound 52：(S)-N- ((S) -1- (N- (3,3- difluoro cyclobutyl) the formoxyl)-base of 2,3- dihydro -1H- indenes -1) - N- (3- fluorophenyls) -5- oxos -1- (4- trifluoromethyl pyridine -2- bases)-pyrrolidines -2- formamides
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- difluoro cyclobutyl) the formoxyl)-base of 2,3- dihydro -1H- indenes -1) - N- (3- fluorophenyls) -5- oxos -1- (4- trifluoromethyl pyridine -2- bases)-pyrrolidines -2- formamides
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.
Embodiment 26：Compound 54 and compound 55
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 1 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with 2- chloro-4-methoxy pyridines, obtain compound 54 and compound 55.
Compound 54：(S)-N- ((S) -1- ((3,3,-difluoro cyclobutyl) formoxyl) -2,3- dihydro -1H- indenes -1- bases) - N- (3- fluorophenyls) -1- (4-methoxypyridine -2- bases) -5- oxo-pyrrolidine -2- formamides
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,-difluoro cyclobutyl) formoxyl) -2,3- dihydro -1H- indenes -1- bases) - N- (3- fluorophenyls) -1- (4-methoxypyridine -2- bases) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3) δ 8.06 (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.
Embodiment 27：Compound 56 and compound 57
Using the identical method of embodiment 1, using imine intermediate A15, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 56 and compound 57.
Compound 56:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The chloro- 2,3- dihydros -1H- indenes -1- bases of 4-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The chloro- 2,3- dihydros -1H- indenes -1- bases of 4-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.7 (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
Embodiment 28：Compound 58 and compound 59
Using the identical method of embodiment 1, using imine intermediate A16, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 58 and compound 59.
Compound 58:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - 2,3- dihydro -1H- indenes -1- bases)-N- (the chloro- 5- fluorophenyls of 3-) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - 2,3- dihydro -1H- indenes -1- bases)-N- (the chloro- 5- fluorophenyls of 3-) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 28：Compound 60 and compound 61
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 4 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 60 and compound 61.
Compound 60:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- (phenylcarbamoyl) -2,3- dihydros - 1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- (phenylcarbamoyl) -2,3- dihydros - 1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 29：Compound 62 and compound 63
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 1 and sour intermediate C5 are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 62 and compound 63.
Compound 62:(S) -3- (4- cyanopyridine -2- bases)-N- ((S) -1- (3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) 2- oxooxazolidine -4- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- (3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -2- oxooxazolidine -4- formamides
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.
Embodiment 30：Compound 64 and compound 65
Using the identical method of embodiment 1, using imine intermediate A17, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 64 and compound 65.
Compound 64:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -6- fluoro- 2,3- dihydros -1H- indenes -1- bases-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.73 (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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) the fluoro- 2,3- dihydros -1H- indenes -1- bases of -6-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.71 (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.
Embodiment 31：Compound 66
Using the identical method of embodiment 1, using imine intermediate A18, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 66.
Compound 66:(2S) -1- (4- cyanopyridine -2- bases)-N- (1- ((3,3- difluoros cyclobutyl) carbamoyl) - 4- (trifluoromethyl) -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 32：Compound 67 and compound 68
Using the identical method of embodiment 1, using imine intermediate A19, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 67 and compound 68.
Compound 67:(S)-N- (the chloro- 3- fluorophenyls of 4-) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- bis- Fluorine cyclobutyl) carbamoyl) -2,3- dihydro -1H- indenes -1- bases) -5- oxo pyrroles's -2- formamides
1H-NMR(DMSO-d6,400MHz):δ 8.74 (s, 1H), 8.53-8.48 (dd, J 1=4.8Hz, J 2=15.2Hz 1H), 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- (the chloro- 3- fluorophenyls of 4-) -1- (4- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- bis- Fluorine cyclobutyl) carbamoyl) -2,3- dihydro -1H- indenes -1- bases) -5- oxo pyrroles's -2- formamides
1H-NMR(DMSO-d6,400MHz)：δ 8.77 (s, 1H), 8.20-8.16 (dd, J 1=4.0Hz, J 2=12.8Hz 1H),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.
Embodiment 33：Compound 69 and compound 70
Using the identical method of embodiment 1, using imine intermediate A20, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 69 and compound 70.
Compound 69:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases) -5- oxo-N-phenyl pyrroles's -2- formamides
1H-NMR(DMSO-d6,400MHz):δ 8.72 (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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases) -5- oxo-N-phenyl pyrroles's -2- formamides
1H-NMR(DMSO-d6,400MHz):δ 8.76 (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.
Embodiment 34：Compound 71 and compound 72
Using the identical method of embodiment 1, using imine intermediate A21, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 71 and compound 72.
Compound 71:(S)-N- (3,4- difluorophenyls) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros Cyclobutyl) carbamoyl) -2,3- dihydro -1H- indenes -1- bases) -5- oxo pyrroles's -2- formamides
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- difluorophenyls) -1- (4- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros Cyclobutyl) carbamoyl) -2,3- dihydro -1H- indenes -1- bases) -5- oxo pyrroles's -2- formamides
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.
Embodiment 35：Compound 73 and compound 74
Using the identical method of embodiment 1, using imine intermediate A22, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 73 and compound 74.
Compound 73 (S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- (3,3- difluoro cyclobutyl carbamoyl) -2, 3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
1H-NMR(CDCl3,400MHz):δ 8.74 (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- cyanopyridine -2- bases)-N- ((R) -1- (3,3- difluoro cyclobutyl carbamoyl) -2, 3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
1H-NMR(CDCl3,400MHz):δ 8.77 (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.
Embodiment 36：Compound 75 and compound 76
Using the identical method of embodiment 1, using imine intermediate A23, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 75 and compound 76.
Compound 75:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The fluoro- 2,3- dihydros -1H- indenes -1- bases of 5-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3) δ 8.73 (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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The fluoro- 2,3- dihydros -1H- indenes -1- bases of 5-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 37：Compound 77 and compound 78
Using the identical method of embodiment 1, using imine intermediate A24, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 77 and compound 78.
Compound 77:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbamyls The fluoro- 2,3- dihydros -1H- indenes -1- bases-of base -4-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.73 (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- cyanopyridine -2- bases)-N-((R) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) the fluoro- 2,3- dihydros -1H- indenes -1- bases of -4-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.76 (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.
Embodiment 37：Compound 79 and compound 80
Using the identical method of embodiment 1, using imine intermediate A25, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 79 and compound 80.
Compound 79:(S)-N- (the chloro- 1- of (S) -4- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.75 (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- (the chloro- 1- of (R) -4- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (5- fluorine pyridin-3-yl) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.76 (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.
Embodiment 39：Compound 81 and compound 82
Using the identical method of embodiment 1, using imine intermediate A26, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 81 and compound 82.Compound 81: (S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- (3,3- difluoro cyclobutyl carbamoyl) -2,3- dihydro -1H- indenes -1- Base)-N- (2,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- (3,3- difluoro cyclobutyl carbamoyl) -2, 3- dihydro -1H- indenes -1- bases)-N- (2,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
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.
Embodiment 40：Compound 83
Using the identical method of embodiment 1, using imine intermediate A27, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 83.
Compound 83:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The fluoro- 2,3- dihydros -1H- indenes -1- bases of 7-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.75 (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.
Embodiment 40：Compound 84 and compound 85
Using the identical method of embodiment 1, using imine intermediate A28, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 84 and compound 85.
Compound 84:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (2,3- difluorophenyls) -5- oxo pyrroles's -2- formamides
1H-NMR(DMSO-d6, 400MHz)：δ 8.74 (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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (2,3- difluorophenyls) -5- oxo pyrroles's -2- formamides
1H-NMR(DMSO-d6,400MHz):δ 8.75 (s, 1H), 8.35-8.22 (dd, J 1=4.8Hz, J 2=9.6Hz 1H),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.
Embodiment 41：Compound 88 and compound 89
Using the identical method of embodiment 1, using imine intermediate A29, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 88 and compound 89.
Compound 88:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -4- methoxyl group -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo pyrroles's -2- formamides
1H-NMR(DMSO-d6,400MHz):δ 8.72 (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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -4- methoxyl group -2,3- dihydro -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxo pyrroles's -2- formamides
1H-NMR(DMSO-d6,400MHz):δ 8.76 (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.
Embodiment 42：Compound 90
Using the identical method of embodiment 1, using imine intermediate A22, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyrimidines of 2-, obtain compound 90.
Compound 90:(S) -1- (4- itrile groups pyrimidine -2-base)-N- ((S) -1- (3,3- difluoro cyclobutyl carbamoyl) -2, 3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
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.
Embodiment 43：Compound 91
Using the identical method of embodiment 1, using imine intermediate A22, isocyanide intermediate B 1 and sour intermediate C5 are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 91.
Compound 91:(S) -3- (4- cyanopyridine -2- bases)-N- ((S) -1- (3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -2- oxooxazolidine -4- formamides
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.
Embodiment 44：Compound 92 and compound 93
Using the identical method of embodiment 1, using imine intermediate A30, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 92 and compound 93.
Compound 92:(S)-N- (the chloro- 1- of (S) -4- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (3,5- difluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.74 (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- (the chloro- 1- of (R) -4- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- cyanopyridine -2- bases)-N- (3,5- difluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.77 (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.
Embodiment 44：Compound 96 and compound 97
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 6 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 96 and compound 97.
Compound 96:(S) -1- (4- itrile group pyridine -2- bases)-N- ((S) -1- (Cvclopropvlmethvl amido formyl) -2,3- two Hydrogen -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxygen pyrrolidines -2- formamides
1H NMR(400MHz,CDCl3):δ 8.8 (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- itrile group pyridine -2- bases)-N- ((R) -1- (Cvclopropvlmethvl amido formyl) -2,3- two Hydrogen -1H- indenes -1- bases)-N- (3- fluorophenyls) -5- oxygen pyrrolidines -2- formamides
1H NMR(400MHz,CDCl3):δ 8.7 (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.
Embodiment 46：Compound 98 and compound 99
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 5 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 98 and compound 99.
Compound 98:(S) -1- (4- itrile group pyridine -2- bases)-N- (3- fluorophenyls)-N- ((S) -1- (4,4- diformazan basic rings Base formoxyl) -2,3- dihydro -1H- indenes -1- bases) -5- oxo-pyrrolidine -2- formamides
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- itrile group pyridine -2- bases)-N- (3- fluorophenyls)-N- ((R) -1- (4,4- diformazan basic rings Base formoxyl) -2,3- dihydro -1H- indenes -1- bases) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 47：Compound 100
Using the identical method of embodiment 1, using imine intermediate A12, isocyanide intermediate B 1 and sour intermediate C5 are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 100.
Compound 100:(S) -1- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The chloro- 2,3- dihydros -1H- indenes -1- bases of 7-)-N- (3- fluorophenyls) -2- oxo oxazolidine -4- formamides
1H NMR(400MHz,DMSO):δ 8.73 (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.
Embodiment 48：Compound 101
Using the identical method of embodiment 1, using imine intermediate A1, isocyanide intermediate B 1 and L-Glutimic acid are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyrimidines of 2-, obtaining compound 101, (a pair of mixture of diastereomers do not divide Open).
Compound 101:(2S)-N- (1- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydro -1H- indenes -1- Base) -1- (4- cyanopyrimidine pyridine -2- bases)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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.
Embodiment 49：Compound 102 and compound 103
Using the identical method of embodiment 1, using imine intermediate A12, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyrimidines of 2-, obtain compound 102 and compound 103.
Compound 102:(S) -1- (4- cyanopyrimidine -2- bases)-N- ((S) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The chloro- 2,3- dihydros -1H- indenes -1- bases of 7-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.94 (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- cyanopyrimidine -2- bases)-N- ((R) -1- ((3,3,-difluoro cyclobutyl) formoxyl) - The chloro- 2,3- dihydros -1H- indenes -1- bases of 7-)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3):δ 8.94 (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.
Embodiment 50：Compound 104
Using the identical method of embodiment 1, using imine intermediate A30, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyrimidines of 2-, obtain compound 104.
Compound 104：(S)-N-chloro- 1- of (S) -4- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -1- (4- aminopyrimidine -2- bases)-N- (3,5- difluorophenyls) -5- oxo-pyrrolidine -2- formamide cyclobutyl
1H NMR(400MHz,CDCl3) δ 8.96 (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.
Embodiment 51：Compound 105 and compound 106
Using the identical method of embodiment 1, using imine intermediate A2, isocyanide intermediate B 1 and sour intermediate C5 are carried out instead Should after obtained product, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 105 and compound 106.
Compound 105:(S) -3- (4- cyanopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutyl) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -2- oxo oxazolidine -4- formamides
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- cyanopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutane) carbamyls Base) -2,3- dihydro -1H- indenes -1- bases)-N- (5- fluorine pyridin-3-yl) -2- oxo oxazolidine -4- formamides
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.
Embodiment 52：Compound 107 and compound 108
Using the identical method of embodiment 1, using imine intermediate A22, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- nitropyridines of 2-, obtain compound 107 and compound 108.
Compound 107:(S) -1- (4- nitropyridine -2- bases)-N- ((S) -1- (3,3- difluoro cyclobutyl carbamoyl) - 2,3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
1H-NMR(CDCl3,400MHz):δ 9.18 (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- nitropyridine -2- bases)-N- ((R) -1- (3,3- difluoro cyclobutyl carbamoyl) - 2,3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
1H-NMR(CDCl3,400MHz):δ 9.21 (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.
Embodiment 53：Compound 109 and compound 110
Using the identical method of embodiment 1, using imine intermediate A33, isocyanide intermediate B 1 and sour L-Glutimic acid enter The product obtained after row reaction, then reacted with the chloro- 4- cyanopyrimidines of 2-, obtain compound 109 and compound 110.
Compound 109:(S) -1- (4- cyanopyrimidine -2- bases)-N- ((S) -1- (3,3- difluoro cyclobutyl carbamoyl) - 7- methyl -2,3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
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- cyanopyrimidine -2- bases)-N- ((R) -1- (3,3- difluoro cyclobutyl carbamoyl) - 7- methyl -2,3- dihydro -1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxygen pyrrolidines -2- formamides
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.
Embodiment 54：Compound 111 and compound 112
Using the identical method of embodiment 1, using imine intermediate A35, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 111 and compound 112.
Compound 111：(S) -7- ((S) -1- (4- cyanopyridine -2- bases)-N- (3,5- difluorophenyls) -5- oxo pyrroles Alkane -2- formamides)-N- (3,3- difluoros cyclobutyl) -6,7- dihydro -5H- pentamethylene pyridine -7- formamides
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- cyanopyridine -2- bases)-N- (3,5- difluorophenyls) -5- oxo pyrroles Alkane -2- formamides)-N- (3,3- difluoros cyclobutyl) -6,7- dihydro -5H- pentamethylene pyridine -7- formamides
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.
Embodiment 55：Compound 113 and compound 114
Using the identical method of embodiment 1, using imine intermediate A32, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtain compound 113 and compound 114.
Compound 113：(S)-N- (the chloro- 1- of (S) -7- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- (4- cyanopyridine -2- bases)-N- (3,5- difluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400 MHz,CDCl3) δ 8.77 (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- (the chloro- 1- of (R) -7- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- (4- cyanopyridine -2- bases)-N- (3,5- difluorophenyl) -5- oxo-pyrrolidine -2- formamides
1H NMR(400 MHz,CDCl3) δ 8.73 (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.
Embodiment 56：Compound 115
Using the identical method of embodiment 1, using imine intermediate A22, isocyanide intermediate B 7 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with the chloro- 4- cyanopyridines of 2-, obtaining compound 115, (a pair of mixture of diastereomers are not Separate).
Compound 115：(2S) -1- (4- cyanopyridine -2- bases)-N- (3,5- difluorophenyls) -5- oxos-N-1- ((3,3, 3- trifluoro propyls) carbamoyl) -2,3- dihydro -1H- indenes -1- bases) pyrrolidines -2- formamides
1H NMR(400MHz,CDCl3) δ 8.80 (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.
Embodiment 57：Compound 116
Using the identical method of embodiment 1, using imine intermediate A12, isocyanide intermediate B 1 and L-Glutimic acid are carried out The product obtained after reaction, then reacted with 2- chlorine pyrimidines, obtain compound 116
Compound 116：(S)-N- (the chloro- 1- of (S) -7- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- (pyrimidine -2-base)-N- (3- fluorophenyls) -5- oxo-pyrrolidine -2- formamides
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
Embodiment 58：Compound 117 and compound 118
Using the identical method of embodiment 1, using imine intermediate A22, isocyanide intermediate B 1 and D- pyroglutamic acids are carried out The product obtained after reaction, then reacted with 4- cyano group -2- chloropyridines, obtain compound 117 and compound 118.
Compound 117：(R) -1- (4-aminopyridine -2- bases)-N- ((S) -1- ((3,3- difluoros cyclobutane) carbamyls Base) -2,3-1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3) δ 8.75 (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-aminopyridine -2- bases)-N- ((R) -1- ((3,3- difluoros cyclobutane) carbamyls Base) -2,3-1H- indenes -1- bases)-N- (3,5- difluorophenyls) -5- oxo-pyrrolidine -2- formamides
1H NMR(400MHz,CDCl3) δ 8.74 (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.
Embodiment 59：Compound 119 and compound 120
Using the identical method of embodiment 1, using imine intermediate A12, isocyanide intermediate B 1 and sour intermediate C5 are carried out The product obtained after reaction, then reacted with 4- cyano group -2- chlorine pyrimidines, obtain compound 119 and compound 120.
Compound 119：(S)-N- (the chloro- 1- of (S) -7- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -3- (4- cyanopyrimidine -2- bases)-N- (3- fluorophenyls) -2- oxo oxazolidine -4- formamides
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- (the chloro- 1- of (R) -7- ((3,3- difluoros cyclobutyl) carbamoyl) -2,3- dihydros -1H- Indenes -1- bases) -3- (4- cyanopyrimidine -2- bases)-N- (3- fluorophenyls) -2- oxo oxazolidine -4- formamides
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
Embodiment 60：Compound 5
Step 1：Monoxone (190mg, 2mmol) is weighed in microwave reaction pipe, schiff bases is dissolved simultaneously with 1mL absolute methanols Inject in microwave tube, stirring adds cyclohexyl isonitrile (220mg, 2mmol) after 30 minutes, sealing microwave tube reacted at 30 DEG C Night.Add 10mL water quenchings and go out and react and be extracted with ethyl acetate (3*15mL), the ethyl acetate of merging after salt washed several times with water with using Anhydrous sodium sulfate drying, filtering, filtrate are spin-dried for rear column chromatography (eluant dichloromethane：50:1) isolated intermediate 5-1 (200mg, white solid), yield 23.3%.
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 2：Intermediate 5-1 (100mg, 0.23mmol) is with 100mL reaction bulbs, being separately added into 2-methylimidazole (19mg, 0.23mmoL), it is heated to reflux under the protection of nitrogen after triethylamine (46mg, 0.46mmol) and 5mL dichloromethane Reaction is overnight.Reaction solution is filtered with diatomite, and filtrate uses column chromatography (eluant dichloromethane after being spin-dried for：20:1) it is isolated Compound 5 (80mg, white solid), yield 73%.Compound 5：N- cyclohexyl -1- (N- (3- fluorophenyls) -2- (2- methyl - 1H- imidazoles -1- bases) acetamide) -2,3- dihydro -1H- indenes -1- formamides.
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.
Embodiment 61：Compound 6
Using the identical method of embodiment 54, using imine intermediate A3, after cyclohexyl isocyanide and monoxone are reacted Obtained product, then substitution reaction is carried out with 2-methylimidazole, obtain compound 6.
Compound 6:N- cyclohexyl -2- (N- (3- fluorophenyls) -2- (2- methyl-1 H-imidazole-1-groups) acetamide) -2,3- Dihydro -1H- indenes -2- formamides
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.
Embodiment 62：Compound 11
Using the identical method of embodiment 54, using imine intermediate A5, after cyclohexyl isocyanide and monoxone are reacted Obtained product, then substitution reaction is carried out with 2-methylimidazole, obtain compound 11.
Compound 11:N- cyclohexyl -7- (N- (3- fluorophenyls) -2- (2- methyl-1 H-imidazole-1-groups) acetamide) two rings [4.2.0] octyl- 1 (6), 2,4- triolefin -7- formamides
1HNMR(400MHz,CDCl3):δ 7.30-7.16 (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.
Embodiment 63：Compound 16
Using the identical method of embodiment 54, using imine intermediate A1, isocyanide intermediate B 2 and monoxone are reacted The product obtained afterwards, then substitution reaction is carried out with piperidines, obtain compound 16.
Compound 16:N- (4,4- difluoros cyclohexyl) -1- (N-3- fluorophenyls) -2- (piperidin-1-yl) acetylamino) -2, 3- dihydro -1H- indenes -1- formamides
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.
Embodiment 64：Compound 25
Using the identical method of embodiment 54, using imine intermediate A1, isocyanide intermediate B 2 and monoxone are reacted The product obtained afterwards, then substitution reaction is carried out with dimethylbenzimidazole, obtain compound 25.
Compound 25:N- (4,4- difluoros cyclohexyl) -1- (N-3- fluorophenyls) 2- (2- methyl isophthalic acid H- benzimidazole -1- bases) Acetylamino) -2,3- dihydro -1H- indenes -1- formamides
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.
Embodiment 65：Compound 28
Using the identical method of embodiment 54, using imine intermediate A2, isocyanide intermediate B 1 and monoxone are reacted The product obtained afterwards, then substitution reaction is carried out with 2-methylimidazole, obtain compound 28.
Compound 28:N- (4,4- difluoros cyclobutyl)-1- (N- (5- pyridin-3-yls)-2-(2-methylimidazole-1- bases) second Acylamino-) -1 base of -2,3- dihydro -1H- indenes-formamide
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.
Embodiment 66：Compound 45
Using the identical method of embodiment 54, using imine intermediate A1, isocyanide intermediate B 1 and monoxone are reacted The product obtained afterwards, then substitution reaction is carried out with intermediate D1, obtain compound 45.
Compound 45：N- (4,4- difluoro cyclohexyl) -1- (N-3- fluorophenyls) 2- (2- methyl isophthalic acid H- imidazos [4,5-b] Pyrazine -1- bases) acetylamino) -2,3- dihydro -1H- indenes -1- formamides
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.
Embodiment 67：Compound 86
Using the identical method of embodiment 54, using imine intermediate A1, isocyanide intermediate B 2 and monoxone are reacted The product obtained afterwards, then substitution reaction is carried out with intermediate D2, obtain compound 86.
Compound 86:N- (3,3- difluoros cyclobutyl) -1- (N- (3- fluorophenyls) -2- (2- methyl -4- (pyrimidine -2-base) - 1H- imidazoles -1- bases) acetamido) -2,3- dihydro -1H- indenes -1- base formamides
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.
Embodiment 68：Compound 87
Using the identical method of embodiment 54, using imine intermediate A2, isocyanide intermediate B 2 and monoxone are reacted The product obtained afterwards, then substitution reaction is carried out with 2-methylimidazole, obtain compound 87.
Compound 87:N- (4,4- difiuorocyclohexyls) -1- (N- (5- fluorine pyridin-3-yl) -2- (2-methylimidazole -1- bases) Acetylamino) -2,3- dihydro -1H- indenes -1- base formamides
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.
Embodiment 69：Compound 18
N- (4,4- difiuorocyclohexyls) -1- (N- (3- fluorophenyls) -2- (methyl (phenyl) amino) acetylamino) -2,3- two Hydrogen -1- indenes -1- formamides
Compound C3 (165mg, 1mmol), A1 (225mg, 1mmol) are sequentially added in dry 25ml single port bottles, and 2ml absolute methanols, after being stirred at room temperature 4 hours, add B2 (145mg, 1mmol) and continue to be stirred overnight, be prepared by separation Gray solid product N- (4,4- difiuorocyclohexyls) -1- (N- (3- fluorophenyls) -2- (methyl (phenyl) amino) acetylamino) -2, 3- dihydro -1- indenes -1- formamide 19mg, yield：3.6%.
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.
Embodiment 70：Compound 17
Using the identical method of embodiment 62, using imine intermediate A1, isocyanide intermediate B 2 and sour intermediate C3 are carried out Compound 17 is obtained after reaction.
Compound 17:1- (2- ((4- cyano-phenyls) amino)-N- (3- fluorophenyls) acetylamino)-N- (4,4- difluoro rings Hexyl) -2,3- dihydro -1- indenes -1- formamides
1H-NMR(CDCl3 400MHz):δ7.49-7.45(m,2H),7.25(s,1H),7.12-7.07(m,4H),6.99- 6.93(m,3H),6.75(s,2H),6.56(d,1H),3.41-3.78(m,3H),2.91-3.27(m,4H),2.09-1.82(m, 4H),1.69-1.52(m,4H).
LCMS:m/z 569.2[M+2]+；RT=1.71min.
Embodiment 71：Compound 24
Using the identical method of embodiment 62, using imine intermediate A1, isocyanide intermediate B 2 and 4- pyridylacetic acids are carried out Compound 24 is obtained after reaction.
Compound 24:N- (4,4- difiuorocyclohexyls) -1- (N- (3- fluorophenyls) -2- (pyridin-4-yl) acetylamino) -2, 3- dihydro -1H- indenes -1- formamides
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.
Embodiment 72：Compound 26
Using the identical method of embodiment 62, using imine intermediate A1, isocyanide intermediate B 2 and sour intermediate C4 are carried out Compound 26 is obtained after reaction.
Compound 26:N- (4,4- difiuorocyclohexyls)-1-(N- (3- fluorophenyls)-2- ((2- fluorine pyridin-3-yl) amino) second Acylamino-) -2,3- dihydro -1H- indenes -1- formamides
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.
Control compound AGI-5198, CAS:1355326-35-0, bought from Selleck companies.
The compounds of this invention of test case 1 is in influence of the molecular level to IDH1 enzymatic activitys
Reagent, consumptive material and instrument：
Enzyme used is purchased from cayman companies in experiment.
Substrate α-KG, NADPH and Diaphorase are purchased from Sigma；Resazurin is purchased from lark prestige；Remaining examination used Agent is purchased from Chemical Reagent Co., Ltd., Sinopharm Group.
Reaction microwell plate (6008260) is purchased from PerkinElmer companies.
Experiment read plate is PerkinElmer Products with multi-function microplate reader, model：EnVison.
Experimental water is that Chinese medicines group produces distilled water.
Compound is prepared：Compound 12000g centrifuges 5min, adds DMSO and is configured to 10mM liquid storages, ultrasound after being vortexed uniformly 10min is stand-by, -40 DEG C of preservations.It is diluted to 10 μM of solution during test with DMSO first, then gradient dilution 3 × times to not again Same test solubility.
Test method：IDH1 conversions α-KG to 2HG enzyme activity function is measured with NADPH consumption.In enzymatic reaction knot Shu Hou, adds catalysis excessive diaphorase and reazurin, and caused fluorescence signal can reflect remaining NADPH's Amount.In 384 orifice plates, 5 μ L enzyme systems (150mM NaCl, 20mM Tris pH=7.5,10mMMgCl are added2, 0.05% (w/v) Bovine serum albumin, 0.012 μ L enzymes), 2.5 μ L compounds, 2.5 μ L substrate α-KG and NADPH mixed liquor (bottom 4 μM of thing α-KG final concentrations 1mM, NADPH final concentration), room temperature lucifuge is incubated 60min.Detection reaction：Added per hole 5 μ L 1 × The 0.01unit diaphroase and 5 μM of resazurin of detection buffer dilutions, room temperature lucifuge are incubated 10min.Read Plate：Use PerkinElmerThe drafting boards of at Ex 544Em 590..IC50Value uses GraphPad Prism software meters Try to achieve.
As a result
Table 1 shows the IC of part of compounds of the present invention50Value.
Alphabetical A represents IC50Less than 100nm；
Letter b represents IC50For 100nm to 1000nm；
Letter C represents IC50For 1uM to 10uM；
Alphabetical D represents IC50For more than 10uM.
The IC of 1 part of compounds of the present invention of table50Value
As a result show, the compounds of this invention is under extremely low concentration (≤10uM, preferably≤100nm), you can effectively suppress IDH1 activity.
Test case 2：The compounds of this invention determines to Malignant glioma cells strain U87 Proliferation Ability
This experiment determines the compounds of this invention and Malignant glioma cells strain U87 Proliferation Ability is lived with the following method Property.
Assay method：First by U87 cells (the American Type Culture Collection committee of Chinese Academy of Sciences cell bank) with suitable thin 2000/hole of born of the same parents' concentration is seeded on 96 well culture plates, per the μ L culture mediums of hole 90, is cultivated for 37 DEG C in carbon dioxide incubator After night, the test-compound for adding various concentrations acts on 96 hours, and setting solvent control group (negative control).After 96 hours, Test compound can be carried out with CCK8 (Cell Counting Kit-8) method for suppressing cell-proliferation activity.IC50Value can lead to Cross under a series of various concentrations, suppression numerical value of the test-compound for cell calculates.
After measured, test-compound 1-133 is respectively provided with inhibitory action for Malignant glioma cells strain U87.
Test case 3：The compounds of this invention is lived to the Proliferation Ability of the tumor cell line beyond Malignant glioma cells strain U87 The measure of property
Using with the identical method of test case 2, the present invention also measured were part of compounds to beyond test case 2 other are swollen The proliferation inhibition activity of tumor cell strain, such as HT1080, MCF-7, T47D, ZR-75, MAD-MB-468 etc..
Cell line title Tumor cell type
HT1080 Human fibrosarcoma cell
MCF-7 Human breast cancer cell
T47D Breast cancer lines
ZR-75 Breast cancer lines
MAD-MB-468 Breast cancer lines
After measured, test-compound 1-133 is for different tumor cell line HT1080, MCF-7, T47D, ZR-75, MAD-MB-468 is respectively provided with inhibitory action.
All it is incorporated as referring in this application in all documents that the present invention refers to, it is independent just as each document It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited Enclose.

Claims (10)

1. the compound shown in a kind of Formulas I, or its pharmaceutically acceptable salt or its enantiomter, diastereoisomer, mutually Tautomeric, solvate, polymorph or prodrug,
Wherein,
W1、W2It is each independently selected from N or CRb；
W and W ' is separately selected from CRaRb；
RaSelected from H, C1-C6Alkyl；
RbSelected from H, C1-C6 alkyl, C1-C6 haloalkyls, halogen, cyano group, phenyl, C1-C6 alkoxies；
N is 1,2,3,4 or 5；N ' is 0 or 1；
R1Do not take for substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C4 alkyl, substitution or The 4-8 circle heterocycles base in generation, substituted or unsubstituted 4-8 members carbocylic radical, substituted or unsubstituted C5-20 aryl, substitution do not take The 5-10 unit's heteroaryls in generation；Wherein, described heterocyclic radical or heteroaryl include the 1-3 hetero atoms being selected from the group：N, O, S or P；
R2For substituted or unsubstituted C5-C20 aryl, substituted or unsubstituted 5-10 unit's heteroaryls, substituted or unsubstituted 5-10 First aryl and heterocyclic radical, wherein, described heteroaryl includes the 1-3 hetero atoms being selected from the group：N, O or S；Described aryl is simultaneously Heterocyclic radical includes the 1-3 hetero atoms being selected from the group：N, O or S；
R3For halogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxies, cyano group, hydroxyl, substituted or unsubstituted 5-10 First aryl；
R4For-(CH2)mR11；
Wherein, m is 0-5 integer；Preferably 0-3 integer；
R11ForSubstituted or unsubstituted 5-10 unit's heteroaryls, substitution or Unsubstituted 5-10 members aryl, substituted or unsubstituted 5-10 circle heterocycles base；Wherein；X is selected from O, N or S；M is 0-5 integer； Rc is selected from H, substituted or unsubstituted 5-10 unit's heteroaryls, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 members Aryl；Rd is selected from H, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl-carbonyls；Or Rc is connected with Rd Form 4-8 members saturation or undersaturated heterocyclic radical or heteroaryl；Wherein, described heteroaryl includes 1-4 selected from as follows miscellaneous Atom：N, O, S or P；Described heterocyclic radical includes the 1-4 hetero atoms being selected from the group：N, O, S or P；
Above-mentioned any " substitution " refers to the substituent that one or more hydrogen atoms on group are selected from the group and substituted：- D, halogen Element ,-OH ,-NO2、-NH2,-N (unsubstituted C1-C6 alkyl)2,-CN, unsubstituted or halo C1-C8 alkyl, unsubstituted or halogen C1-C8 alkoxyl-C1-C8 the alkyl in generation, unsubstituted or halo C3-C8 cycloalkyl, unsubstituted or halo C3-C8 cycloalkanes Base-C1-C8 alkyl, unsubstituted or halo C1-C8 alkoxyl, unsubstituted or halo C1-C6 alkyl-carbonyls, unsubstituted or halogen It is the C1-C6 alkoxy carbonyls in generation, hydroxamic acid base, unsubstituted or halo 5~8 yuan of aryl, unsubstituted or halo 5~8 yuan Heteroaryl, unsubstituted or halo 4~8 yuan of saturated heterocyclics or carbocyclic ring；Wherein, described heteroaryl includes 1-4 and is selected from the group Hetero atom：N, O or S, described heterocycle include the 1-4 hetero atoms being selected from the group：N, O or S.
2. compound of formula I as claimed in claim 1, it is characterised in that R2It is selected from the group： Wherein Rm is selected from H, D, halogen, C1-C6 alkyl, C1-C6 alkoxies.
In another preference, R4For-(CH2)mR11；M is preferably 0,1 or 2.
3. compound of formula I as claimed in claim 1, it is characterised in that R11It is selected from the group： Wherein, X O Or N；V1, V2 and V3 are respectively selected from CRa or N；M is 0-4 integer；Ra is selected from H, C1-C6Alkyl, halogen, cyano group；Rc be selected from H, Substituted or unsubstituted 5-10 unit's heteroaryls, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 members aryl；Rd Selected from H, substitution or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl-carbonyls；Wherein, described heteroaryl includes 1-4 are selected from following hetero atom：N, O or S；Described heterocyclic radical includes the 1-4 hetero atoms being selected from the group：N, O or S.
4. compound of formula I as claimed in claim 1, it is characterised in that Rc is selected from the group： Wherein, R ' or R " are independently selected from-CN ,-OH, hydroxamic acid base, C1-C6 alkyl Carbonyl ,-NO2, halogen, substitution or halo C1-C6 alkyl, C1-C6 alkoxies.
5. compound of formula I as claimed in claim 1, it is characterised in that described compound is selected from following structure：
A kind of 6. method for preparing the compound of formula I as described in claim 1-5 is any, it is characterised in that methods described includes Following steps 1) or 2)：
1) compound 1a and compoundIt is coupled under the reaction condition of atent solvent, so as to be formed Compound of formula I；
In formula, the definition of each group as claim 1-5 it is any described in；
2) compound 1a and compoundIt is coupled under the reaction condition of atent solvent, Ran Houzai WithReaction generation compound of formula I；
In formula, the definition of each group as claim 1-5 it is any described in.
7. the purposes of compound of formula I as claimed in claim 1, it is characterised in that be used for：
(a) medicine for treating the disease related to saltant type IDH is prepared；
(b) saltant type IDH inhibitor is prepared；
(c) suppress IDH mutation external non-therapeutic；
(d) suppress tumor cell proliferation external non-therapeutic；And/or
(e) disease related to saltant type IDH is treated.
8. purposes as claimed in claim 7, it is characterised in that the saltant type IDH is selected from the group：IDH1, IDH2, or its group Close.
9. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes：
(i) compound of formula I of effective dose, or its pharmaceutically acceptable salt or its enantiomter, diastereoisomer, mutually Tautomeric, solvate, polymorph or prodrug；With
(ii) pharmaceutically acceptable carrier.
A kind of 10. method of suppression IDH mutation, it is characterised in that including step：To suppress object apply suppress effective dose as Compound of formula I or its pharmaceutically acceptable salt described in claim 1, or to suppression object administration suppression effective dose such as power Profit requires the pharmaceutical composition described in 7.
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