CN107033087B - 1H-indazole-4-amine compounds and use thereof as IDO inhibitors - Google Patents
1H-indazole-4-amine compounds and use thereof as IDO inhibitors Download PDFInfo
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- CN107033087B CN107033087B CN201610081017.3A CN201610081017A CN107033087B CN 107033087 B CN107033087 B CN 107033087B CN 201610081017 A CN201610081017 A CN 201610081017A CN 107033087 B CN107033087 B CN 107033087B
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 12
- MDELYEBAXHZXLZ-UHFFFAOYSA-N 1h-indazol-4-amine Chemical class NC1=CC=CC2=C1C=NN2 MDELYEBAXHZXLZ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000005934 immune activation Effects 0.000 claims abstract description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 7
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 7
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- 208000030159 metabolic disease Diseases 0.000 claims abstract description 6
- 208000030507 AIDS Diseases 0.000 claims abstract description 5
- 201000011510 cancer Diseases 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims description 23
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- 229940079593 drug Drugs 0.000 claims description 9
- 230000001413 cellular effect Effects 0.000 claims description 7
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- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- -1 1H-indazole-4-amine compound Chemical class 0.000 abstract description 7
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- 230000002829 reductive effect Effects 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- NMEMXQPAMKMVJY-UHFFFAOYSA-N 6-bromo-N-[(2-nitrophenyl)methyl]-1H-indazol-4-amine Chemical compound BrC=1C=C(C=2C=NNC=2C=1)NCC1=C(C=CC=C1)[N+](=O)[O-] NMEMXQPAMKMVJY-UHFFFAOYSA-N 0.000 description 4
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- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical group N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical group C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical group CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
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- AHEMYGJJCOXPSP-UHFFFAOYSA-N 6-bromo-4-nitro-1h-indazole Chemical compound [O-][N+](=O)C1=CC(Br)=CC2=C1C=NN2 AHEMYGJJCOXPSP-UHFFFAOYSA-N 0.000 description 1
- VCUKKMIXURRDKL-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-ethylphenyl)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(CC)=CC=C1N1C(=O)C(SC=2C3=C(N(C)C)C=CN=2)=C3N=C1 VCUKKMIXURRDKL-UHFFFAOYSA-N 0.000 description 1
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- FBKMWOJEPMPVTQ-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide Chemical compound NS(=O)(=O)NCCNC1=NON=C1C(=NO)NC1=CC=C(F)C(Br)=C1 FBKMWOJEPMPVTQ-UHFFFAOYSA-N 0.000 description 1
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- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a 1H-indazole-4-amine compound, a preparation method of the compound and application of the compound as an IDO inhibitor. The compound of the present invention can be used for preventing and/or treating various diseases, such as Alzheimer disease, cataract, infection related to cell immune activation, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism disorder, etc.
Description
Technical Field
The invention relates to 1H-indazol-4-amine compounds, to a method for the production thereof and to the use thereof as IDO inhibitors.
Background
Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme which catalyzes the epoxidation and cleavage of indole in Indoleamine molecules such as tryptophan and the like so as to decompose and metabolize the indole according to the canine uric acid pathway.
IDO plays an important role in the process of tumor immune exemption and tumorigenesis. Under normal conditions, IDO is expressed at a low level in vivo, most tumor cells form high-expression IDO, L-tryptophan is converted into N-formyl kynurenine, the tryptophan concentration in the microenvironment of the cells is reduced, the synthesis of tryptophan-dependent T cells is stopped at G1, and the proliferation of the T cells is inhibited, so that the killing effect of the immune system of the body on tumor tissues is inhibited. Meanwhile, the metabolite of tryptophan has cytotoxicity under the action of IDO, and can directly dissolve T cells.
Therefore, inhibiting the activity of IDO can effectively prevent the degradation of tryptophan around tumor cells and promote the proliferation of T cells, thereby enhancing the attack capability of the body on the tumor cells. Moreover, the IDO inhibitor can be used together with chemotherapeutic drugs to reduce drug resistance of tumor cells, thereby enhancing the antitumor activity of conventional cytotoxic therapy. The administration of an IDO inhibitor also enhances the therapeutic efficacy of the therapeutic vaccine in cancer patients.
Besides playing an important role in tumor cell resistance, IDO is also closely associated with the pathogenesis of a variety of diseases associated with cellular immune activation. IDO has been shown to be a target for serious diseases associated with cellular immune activation, such as infections, malignancies, autoimmune diseases, aids, and the like. Meanwhile, IDO inhibition is an important treatment strategy for patients suffering from nervous system diseases such as depression and Alzheimer's disease. Therefore, the IDO inhibitor has wide clinical application prospect.
Disclosure of Invention
In order to solve the problems, the invention mainly provides a novel IDO inhibitor medicament which is a 1H-indazole-4-amine compound.
The invention provides a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the structure of the compound is shown as the formula (I):
wherein,
y represents-NH-),
R1Selected from H, X, -CX3、-CHX2、-CH2X、-(CH2)aCH3；
R2Is selected from- (CH)2)b-R3、-CH2NHR3、-CH2CONH-R3、-CH(CH2OH)R3or-CH2CH(OH)R3，
R3Selected from substituted or unsubstituted aryl, cycloalkyl or heterocyclyl, each of which is independently substituted by one or more substituents selected from- (CH)2)cCOOH、-(CH2)dCOOR4、X、-(CH2)cOH、-(CH2)cNH2Nitro and C1-C6 alkyl;
R4selected from methyl or ethyl;
x represents F, Cl, Br or I, a ═ 0 or 1, b ═ 0 or 1, c ═ 0 or 1, and d ═ 0 or 1.
The alkyl group having C1-C6 is a straight or branched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like.
Further, said R1Selected from H, Br, -CF3、-CH3or-CH2CH3。
Further, said R1Is selected from Br.
Further, the structure of the compound is shown as formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII):
further, the cycloalkyl group is cyclohexyl; the substituted cycloalkyl is cycloalkyl substituted with one hydroxyl group.
Further, the heterocyclic group is tetrahydropyranyl.
Further, the substituted aryl is selected from the group consisting of substituted aryl substituted by one- (CH)2) Phenyl substituted with cCOOH, chlorine, amino, hydroxyl, nitro or methyl.
Further, said R3Selected from one of the following groups:
further, the compound is selected from one of the following compounds:
the invention also provides a method for preparing the compound of the formula (II) or a preparation intermediate thereof, which comprises the following steps:
the compound shown in the formula (II) or a preparation intermediate thereof is prepared by taking compounds shown in SM and S2 as raw materials and reacting under the action of a reducing agent.
In particular embodiments, the reaction may be carried out in the presence of an acidic catalyst.
The reducing agent is selected from DHP and NaBH4Or NaBH3(CN), most preferably DHP; the acidic catalyst can be TFA, formic acid, acetic acid or binaphthyl phosphoric acid, and TFA is the most preferable; the solvent is CH2Cl2MeOH or DMF, most preferably CH2Cl2。
In the preparation method provided by the invention, the preparation intermediate refers to a synthesis intermediate of a previous step of the target compound.
For example, when a certain compound R3Is selected from- (CH)2)dCOOR4When it is used as a drug, it may be used as a drug per se, or as another R3Is selected from- (CH)2)dCOOR4Intermediates for the preparation of the compounds. In a specific embodiment of the present invention, compound 1m may be used as a production intermediate for compound 1l, and compound 1o may be used as a production intermediate for compound 1 n. The compounds 1l and 1n can be prepared as preparation intermediates of the compounds 1m and 1o respectively, and further by ester hydrolysis reaction by the conventional ester hydrolysis technical means in the field.
Also for example, when R3When selected from nitro, it may be used as a drug per se or as another R3Is selected from-NH2Intermediates for the preparation of the compounds. In a specific embodiment of the present invention, compound 1p may be used as an intermediate for the preparation of compound 1q, 1q being prepared by reduction of the nitro group on 1 p.
The present invention also provides a process for producing the compound of formula (iii) or a production intermediate thereof, comprising the steps of:
the compound shown in the formula (III) or a preparation intermediate thereof is prepared by taking compounds shown in SM and S2 as raw materials and carrying out condensation reaction. The synthesized condensing agent can be EDCI or DCC, and the EDCI is optimal; the base can be HOBT or HATU, preferably HOBT.
The invention also provides a method for preparing the compound of the formula (IV) or a preparation intermediate thereof, which comprises the following steps:
(1)
reacting a compound shown as S4a and bis (trichloromethyl) carbonate serving as raw materials to prepare a compound shown as S4 b;
(2)
the compound shown in S4b and SM are used as raw materials to react to prepare the compound shown in the formula (IV) or a preparation intermediate thereof.
The invention also provides a method for preparing the compound of the formula (V) or the formula (VI) or a preparation intermediate thereof, which comprises the following steps:
the compound shown in S5 and SM is used as raw material to react to obtain the compound shown in formula (V) or formula (VI) or the intermediate thereof.
In particular embodiments, the pH of the synthesis reaction may be between 7 and 10, with a pH of 7 being most preferred. The reaction temperature may be in the range of 20-80 deg.C, most preferably 80 deg.C. The solvent is selected from EtOH, H2O、DMF、MeOH、THF、CH2Cl2、EtOAc orAny one or more of dioxane, most preferably EtOH and H2And (3) mixed solution of O.
The present invention also provides a process for preparing the compound of formula (vii) or a preparation intermediate thereof, comprising the steps of:
(1)
reacting a compound shown in SM and ethyl bromoacetate serving as raw materials to prepare a compound shown in S7 a;
in a particular embodiment of this reaction, it may be carried out in the presence of a base.
The base can be selected from K2CO3NaH, NaOH or KOH, most preferably K2CO3(ii) a The solvent is selected from CH2Cl2、MeOH,EtOH、THF、CH3COCH3EtOAc or DMF, most preferably DMF.
(2)
Hydrolyzing the compound shown as S7a, and reacting to obtain a compound shown as S7 b;
(3)
the compound shown in S7b and S7c are used as raw materials, and the compound shown in (VII) or a preparation intermediate thereof is prepared through condensation reaction.
The invention also provides application of the compound, or pharmaceutically acceptable salt thereof, or prodrug thereof, or solvate thereof in preparing IDO inhibitor medicines.
Further, the drug is a drug for preventing and/or treating alzheimer's disease, cataract, infection associated with cellular immune activation, autoimmune disease, aids, cancer, depression or tryptophan metabolism disorder.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Wherein the composition is a drug for treating or preventing and/or treating Alzheimer's disease, cataract, infection related to cellular immune activation, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism disorder
The prodrugs are derivatives of the aforementioned compounds which may themselves have poor activity or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The preparation can comprise injection or oral preparation.
Key intermediates and compounds of the present invention are isolated and purified by means of isolation and purification methods commonly used in organic chemistry.
One or more compounds of the present invention may be used in combination with each other, or alternatively, in combination with any other active agent, for the preparation of IDO inhibitors. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
The pharmaceutically acceptable auxiliary material of the invention refers to a substance contained in a dosage form except for an active ingredient.
Experiments prove that the 1H-indazole-4-amine compound provided by the invention has an excellent inhibiting effect on IDO, and can be used for preventing and/or treating various diseases, such as Alzheimer disease, cataract, infection related to cellular immune activation, autoimmune diseases, AIDS, cancers, depression or tryptophan metabolic disorder and the like.
In the present invention, the meanings of the acronyms are as follows:
and (3) DHP: 1,4-Dihydropyridine, Dihydropyridine.
DMF: dimethylformamide, Dimethylformamide.
DCC: dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide).
DIEA: n, N-Diisopropylethylamine, N, N-Diisopropylethylamine.
EA: ethyl acetate, Ethyl acetate.
EDCI: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
Et3N: triethylamine, Triethylamine.
HOBT: 1-Hydroxybenzotriazole, 1-Hydroxybenzotriazole.
HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
PE: petroleum ether, Petroleum ether.
TFA: tallow Fatty Acid, trifluoroacetic Acid.
THF: tetrahydrofuran, Tetrahydrofuran.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The reagents and starting materials were obtained from commercially available commercial sources, except for starting materials specifically labeled for the source, which were purchased from Douglas chemical company.
Example 1 Synthesis of intermediate starting Material
(1) Synthesis of 6a and 6b
The starting 4-nitro-1H-indazole 5a (CAS:2942-40-7,1.4g,8.26mmol, available from Annagel chemical Co., Ltd.) or 6-bromo-4-nitro-1H-indazole 5b (CAS:885518-46-7,2.0g,8.26mmol, available from Jiangsu Nantong Biotechnology Co., Ltd.) was dissolved in a mixed solvent of ethanol (20mL) and water (10mL), ammonium chloride (221.5mg,4.13mmol) was added, a portion of iron powder (1.3g,23.46mmol) was added thereto, the reaction was stirred at 80 ℃ for 5 minutes, the remaining iron powder (1.0g,17.86mmol) was added, and the reaction was continued for 20 minutes with stirring. After TLC detection of the reaction completion of the starting material, the reaction solution was filtered while hot, and the residue was washed with ethanol (10 mL). Ethanol was removed under reduced pressure and the aqueous layer was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, spin-dried and column-chromatographed (PE: EA ═ 8:1) to give a pale yellow solid in 92-94% yield. The yield of 6a was 94% and the yield of 6b was 92%.
(2) Synthesis of 6c
Synthesis of 2, 5-dimethyl-1, 3-dinitrobenzene (8)
Putting p-xylene (7) (360.0mg,3.40mmol) into a round-bottom flask, cooling to 0 ℃ in an ice bath, slowly dropwise adding, separating out a solid from a mixed acid solution (1mL) of 90% nitric acid solution and concentrated sulfuric acid (2:1), stirring at room temperature for reaction for 3h, detecting that the raw material (7) is completely reacted by TLC, pouring the reaction liquid into ice water, filtering, drying a filter cake in a vacuum drying oven for 12h to obtain a light yellow solid 545.8mg, wherein the yield is 82%.
Synthesis of 2, 5-dimethyl-3-nitroaniline (9)
2, 5-dimethyl-1, 3-dinitrobenzene (8) (196.0mg,1.00mmol) was dissolved in MeOH (6mL) and dioxane (3mL), concentrated hydrochloric acid (0.60mL) and Fe (168.90mg,3.00mmol) were added, and the reaction was stirred to 80 ℃ for 12 h. TLC detection raw material (8) is filtered after complete reaction, then reaction liquid is spin-dried, a small amount of water and saturated NaHCO are added3Adjusting the pH value of the solution to 7-8, extracting with ethyl acetate for three times, and washing the ethyl acetate layer with saturated saline solutionThe residue was dried over anhydrous magnesium sulfate and then spin-dried to obtain 142.8mg of a pale yellow solid with a yield of 86%.
Synthesis of 6-methyl-4-nitro-1H-indazole (10)
2, 5-dimethyl-3-nitroaniline (9) (83.0mg,0.50mmol) was dissolved in glacial acetic acid (3mL) and NaNO was added2(69.0mg,1.00mmol) was dissolved in water (0.5mL) and NaNO was added with stirring at room temperature2Slowly dripping the aqueous solution into a glacial acetic acid solution of 2, 5-dimethyl-3-nitroaniline (9), separating out solids, and stirring at room temperature for reaction for 13 hours. After TLC detection of the reaction of the raw material (9), the reaction solution was poured into ice water, filtered, and the filter cake was dried in a vacuum oven for 12 hours to obtain 79.6mg of a yellow solid with a yield of 90%.
Synthesis of 6-methyl-1H-indol-4-amine (6c)
Dissolving raw material 6-methyl-4-nitro-1H-indazole (10) (50mg,0.28mmol) in a mixed solvent of ethanol (2mL) and water (1mL), adding ammonium chloride (1.6mg,0.03mmol), adding iron powder (79.1mg,1.41mmol), heating to 80 ℃, stirring for reaction for 0.5H, detecting by TLC that the raw material (10) is completely reacted, filtering the reaction liquid while the reaction liquid is hot, and washing filter residues with ethanol. Ethanol was removed under reduced pressure and the aqueous layer was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, spun dry, and passed through a column (PE: EA ═ 10:1) to give 34.9mg of a pale yellow solid with a yield of 84%.
Example 2 Synthesis of Compounds 3a, 3b and 3c of the invention
Synthesis of ethyl 2- (6-bromo-1H-indazol-4-amino) acetate (11)
6-bromo-1H-indazol-4-amino 6b (212.0mg,1.00mmol) was dissolved in DMF (5mL) and potassium carbonate (345.0mg,2.50mmol) and potassium iodide (14.9mg,0.09mmol) were added. Ethyl bromoacetate (167.0. mu.L, 1.50mmol) was added under argon and reacted at 65 ℃ overnight. After TLC detection of the completion of the reaction of the starting material (6b), a large amount of DMF was pumped off, ethyl acetate (25mL) was added and washed three times with water (20 mL). The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried over a column (PE: EA ═ 15: 1). 206.9mg of a pale yellow solid were obtained in 70% yield.
Synthesis of 2- (6-bromo-1H-indazol-4-amino) acetic acid (12)
Ethyl 2- (6-bromo-1H-indazol-4-amino) acetate (11) (80.0mg,0.27mmol) was dissolved in ethanol (1.5mL) and water (1.5mL), sodium hydroxide (32.2mg,0.81mmol) was added, and the reaction was stirred at room temperature overnight. After TLC detection of the raw material reaction, adjusting pH to 5 with 1mol/L diluted hydrochloric acid, decompressing and spin-drying the reaction solution, directly using in the next reaction, the yield is 100%
Synthesis of 2- (6-bromo-1H-indazol-4-amino) -N-tetrahydro-2H-pyran-4-acetamide (3a)
Acid 12(50.0mg,0.19mmol) was dissolved in dichloromethane (3mL), placed in an ice bath, and tetrahydro-2H-pyran-4-amine 13(57uL,0.56mmol) was added dropwise, EDCI (42.6mg,0.22mmol), HoBt (32.4mg,0.22mmol), DIEA (61uL,0.37mmol) were added, and the mixture was reacted at 0 ℃ for 5 minutes, warmed to room temperature (25 ℃) and stirred overnight. After completion of the reaction of the starting material (12) by TLC, the reaction mixture was washed with saturated sodium bicarbonate (1.5mL), and the organic phase was spin-dried and passed through a column (PE: EA: 10:1) to obtain 42.1mg of a white powder with a yield of 65%.
1H-NMR(400MHz,d6-DMSO,ppm):8.22(d,1H,J＝7.5Hz,amide),8.07(s,1H,indazole-H3),6.87(s,1H,indazole-H7),6.29(d,1H,J＝1.1Hz,indazole-NH),6.14(s,1H,indazole-H5),4.90(s,1H,CH2),3.85-3.76(m,4H,pyran-H2and pyran-H6),3.52-3.48(m,1H,pyran-H4),3.42-3.34(m,4H,pyran-H3and pyran-H5).ESI-MS:375.0452[M+Na].
Synthesis of 2- (6-bromo-1H-indazol-4-amino) -N- (4-ethoxycarbonylphenyl) acetamide (3c)
Obtained by the preparation method of 3a using acid 12(50.0mg,0.19mmol) and ethyl 4-aminobenzoate 14(91.5mg,0.56mmol) as starting materials, to give 3c 46.4mg, yield 60%.1H-NMR(400MHz,d6-DMSO,ppm):10.67(s,1H,amide),8.13(s,1H,indazole-H3),7.82(d,2H,J＝8.7Hz,Ar-H2and Ar-H6),7.74(d,2H,J＝8.7Hz,Ar-H3and Ar-H5),6.98(s,1H,indazole-H7),6.32(d,1H,J＝1.2Hz,indazole-NH),6.18(s,1H,indazole-H5),5.21(s,2H,benzyl-CH2),4.48(q,2H,J＝6.8Hz,CH 2CH3),1.30(t,3H,J＝6.8Hz,CH2CH 3).ESI-MS:417.03[M+H].
Synthesis of 2- (6-bromo-1H-indazol-4-amino) -N- (4-carboxyphenyl) acetamide (3b)
Amide 3c (40.0mg,0.10mmol) was dissolved in ethanol (1.0mL) and water (1.0mL), and sodium hydroxide (11.5mg,0.29mmol) was added and stirred at room temperature overnight. TLC detection until the raw material reaction is complete, using 1mol/L dilute hydrochloric acid to adjust pH to 5, white solid is separated out, filtering, drying under reduced pressure to obtain 15.6mg white solid, yield 42%.
1H-NMR(400MHz,d6-DMSO,ppm):12.80(br,1H,COOH),10.67(s,1H,amide),8.13(s,1H,indazole-H3),7.91(d,2H,J＝8.7Hz,Ar-H2and Ar-H6),7.79(d,2H,J＝8.7Hz,Ar-H3and Ar-H5),6.98(s,1H,indazole-H7),6.32(d,1H,J＝1.2Hz,indazole-NH),6.18(s,1H,indazole-H5),5.21(s,2H,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):207.0,167.3,166.7,143.9,143.1,132.9,131.0,126.0,121.9,118.9,113.2,104.7,99.6,52.2.ESI-MS:389.03[M+H].
EXAMPLE 3 Synthesis of Compounds 1a, 1c-j and 1p of the invention
Dissolving amine 6b (0.28mmol) and benzaldehyde 16(0.24mmol) in dichloromethane (DCM, 3mL), adding dihydropyridine (DHP, 83.5mg,0.33mmol) and appropriate amount of 4A molecular sieve (840.2mg), dropwise adding trifluoroacetic acid (TFA, 17.6. mu.L, 0.24mmol), refluxing at 40 deg.C for 12h, filtering the reaction solution, spin-drying, and passing through the column to obtain compound 1 a.
4- ((6-bromo-1H-indazol-4-amino) methyl) benzoic acid (1a) yield 64%; a brown solid;1H-NMR(400MHz,d6-DMSO,ppm):12.80(br,2H,COOH and indazole-NH),8.22(s,1H,indazole-H3),7.91(d,2H,J＝8.3Hz,Ar-H2and Ar-H6),7.49(d,2H,J＝8.3Hz,Ar-H3and Ar-H5),6.64(s,1H,indazole-H7),6.01(s,1H,indazole-H5),4.53(s,2H,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):167.7,145.3,143.0,142.2,132.5,130.0,129.9,127.5,121.7,112.6,101.2,100.6,46.2.ESI-MS:344.0035[M-H].
the corresponding aldehyde starting materials were selected and prepared in a similar manner to give compounds 1c-j and 1p, with the following results and characterization:
N-benzyl-6-bromo-1H-indazol-4-amine (1c) yield 43%; a brown solid;1H-NMR(400MHz,d6-DMSO,ppm):12.83(s,1H,indazole-NH),8.23(s,1H,indazole-H3),7.40-7.23(m,5H,Ar-H),6.83(s,1H,indazole-H7),6.06(s,1H,indazole-H5),4.44(d,2H,J＝6.0Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):143.2,142.1,139.9,132.7,128.9,127.5,127.3,121.7,112.6,101.2,100.3,46.4.ESI-MS:302.02[M+H].
3- ((6-bromo-1H-indazol-4-amino) methyl) benzoic acid (1d) yield 60%; a brown solid;1H-NMR(400MHz,d6-DMSO,ppm):12.90(br,2H,COOH and indazole-NH),8.22(s,1H,indazole-H3),7.98(s,1H,Ar-H2),7.83(d,1H,J＝7.6Hz,Ar-H4),7.64(d,1H,J＝7.6Hz,Ar-H6),7.48(t,1H,J＝7.6Hz,Ar-H5),7.37(t,1H,J＝6.0Hz,NH),6.84(s,1H,indazole-H7),6.05(s,1H,indazole-H5),4.51(d,2H,J＝6.0Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):167.8,143.0,142.2,140.6,132.5,132.1,131.4,129.1,128.3,128.3,121.7,112.6,101.2,100.5,46.0.ESI-MS:344.00[M-H].
6-bromo-N- (4-methylbenzyl) -1H-indazol-4-amine (1e) yield 65%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):12.82(s,1H,indazole-NH),8.22(s,1H,indazole-H3),7.26(d,2H,J＝7.9Hz,Ar-H2and Ar-H6),7.14(d,2H,J＝7.9Hz,Ar-H3and Ar-H5),6.82(s,1H,indazole-H7),6.04(s,1H,indazole-H5),4.38(d,2H,J＝6.0Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):143.2,141.2,136.8,136.3,132.7,129.4,127.5,121.7,112.6,101.2,100.2,46.2,21.1.ESI-MS:316.03[M+H].
6-bromo-N- (4-chlorobenzyl) -1H-indazol-4-amine (1f) yield 71%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):12.85(s,1H,indazole-NH),8.21(s,1H,indazole-H3),7.40(s,4H,Ar-H),7.32(t,1H,J＝6.0Hz,NH),6.84(s,1H,indazole-H7),6.03(s,1H,indazole-H5),4.43(d,2H,J＝6.0Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):142.9,142.1,139.0,132.6,131.8,129.3,127.5,121.7,112.6,101.3,100.5,45.7.ESI-MS:335.97[M+H].
4- ((6-bromo-1H-indazol-4-amino) methyl) phenol (1g) yield 59%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):12.80(s,1H,indazole-NH),9.29(s,1H,indazole-H3),8.21(s,1H,OH),7.17(d,2H,J＝8.4Hz,Ar-H3and Ar-H5),6.81(s,1H,indazole-H7),6.72(d,2H,J＝8.4Hz,Ar-H2and Ar-H6),6.06(s,1H,indazole-H5),4.29(d,2H,J＝6.0Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):156.7,143.2,142.8,132.7,129.7,128.8,121.8,115.6,112.6,101.2,100.0,46.1.ESI-MS:318.03[M+H].
hydro xybenzoic acid (1H) 5- (((6-bromo-1H-indazol-4-amino) methyl) -2-hydroxybenzoic acid, yield 82%; brown solid;1H-NMR(400MHz,d6-DMSO,ppm):12.80(br,2H,COOH and indazole-NH),8.21(s,1H,indazole-H3),7.82(s,1H,Ar-H6),7.46(d,1H,J＝8.4Hz,Ar-H4),7.24(t,1H,J＝6.0Hz,NH),6.87(d,2H,J＝8.4Hz,Ar-H3),6.83(s,1H,indazole-H7),6.06(s,1H,indazole-H5),4.35(d,2H,J＝6.0Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):167.8,143.0,142.2,140.6,132.5,132.1,131.4,129.2,128.3,121.7,117.3,112.6,101.1,100.4,49.1.ESI-MS:360.02[M-H].
2- (4- ((6-bromo-1H-indazol-4-amino) methyl) phenyl) acetic acid (1i) yield 81%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):12.80(br,2H,COOH and indazole-NH),8.23(s,1H,indazole-H3),7.33(d,2H,J＝8.0Hz,Ar-H2and Ar-H6),7.23(d,2H,J＝8.0Hz,Ar-H3andAr-H5),6.83(s,1H,indazole-H7),6.05(s,1H,indazole-H5),4.40(s,2H,CH 2NH),3.18(s,2H,CH 2COOH).13C-NMR(100MHz,d6-DMSO,ppm):173.2,143.2,142.2,138.1,134.0,132.6,129.9,127.5,121.8,112.6,101.2,100.3,49.1,46.2.ESI-MS:358.03[M-H].
2- ((6-bromo-1H-indazol-4-amino) methyl) phenol (1j) yield 63%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):12.81(s,1H,indazole-NH),9.63(s,1H,indazole-H3),8.22(s,1H,indazole-H7),7.19-7.05(m,2H,Ar-H4and Ar-H6),6.87-6.72(m,2H,Ar-H3and Ar-H5),6.05(s,1H,indazole-H5),4.34(d,2H,J＝5.8Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):155.4,143.4,142.1,132.7,128.5,128.2,125.3,121.8,119.4,115.4,112.5,100.9,100.0,49.1.ESI-MS:318.02[M+H].
6-bromo-N- (2-nitrobenzyl) -1H-indazol-4-amine (1p) yield 70% as a yellow solid.1H-NMR(400MHz,d6-DMSO,ppm):12.20(s,1H,indazole-NH),8.31(s,1H,indazole-H3),7.98-7.55(m,4H,Ar-H),6.69(d,1H,J＝7.9Hz,indazole-H7),6.01(d,1H,J＝7.1Hz,indazole-H5),4.56(s,2H,benzyl-CH2).ESI-MS:346.11[M+H]。
EXAMPLE 4 Synthesis of Compound 1b of the present invention
Compound 1b was synthesized in a similar manner to that in example 3, except that compound 6b was replaced with compound 6a to give compound 1 b.
4- ((1H-indazol-4-amino) methyl) benzoic acid (1b) yield 62%; a brown solid;1H-NMR(400MHz,d6-DMSO,ppm):12.79(br,2H,COOH and indazole-NH),8.22(s,1H,indazole-H3),7.90(d,2H,J＝7.4Hz,Ar-H2and Ar-H6),7.50(d,2H,J＝7.4Hz,Ar-H3and Ar-H5),6.99-6.96(m,1H,indazole-H6),6.66(d,1H,J＝7.9Hz,indazole-H7),5.90(d,1H,J＝7.1Hz,indazole-H5),4.52(s,2H,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):167.7,146.1,142.0,141.7,132.1,129.9,129.7,128.0,127.5,113.8,98.2,98.1,46.5.ESI-MS:266.11[M-H].
EXAMPLE 5 Synthesis of Compound 1k of the present invention
Synthesis of (1S,2S) -2-hydroxycyclohexanecarboxaldehyde (17)
Heptanedial (40.0mg,0.31mmol) was dissolved in DCM (2mL), L-proline (3.6mg,0.031mmol) was added, and the reaction was stirred at room temperature for two hours. And (4) detecting by TLC until the raw material heptadialdehyde completely reacts. Spin-dry and column-pass (PE: EA ═ 6:1) to give 34.5mg of white liquid, 86% yield.
Synthesis of (1S,2R) -2- ((6-bromo-1H-indazol-4-amino) methyl) cyclohexanol (1k)
Preparation of compound 1k (56.3mg,0.17mmol, yield 62%): obtained by the method of preparation of 1a starting from amine 6b (60.0mg,0.28mmol) and aldehyde 17(30.7mg,0.24 mmol).
Yellow solid.1H-NMR(400MHz,CDCl3,ppm):7.94(s,1H,indazole-H3),6.96(s,1H,indazole-H7),6.33(s,1H,indazole-H5),3.56-3.50(m,1H,cyclohexanol-H1),3.35-3.25(m,2H,CH2NH),2.03-2.00(m,1H,cyclohexanol-H3),1.88-1.71(m,4H,cyclohexanol-H3and H6),1.39-1.25(m,4H,cyclohexanol-H4and H5).13C-NMR(100MHz,d6-DMSO,ppm):142.8,141.8,131.9,123.0,112.7,102.8,101.1,49.3,44.1,36.1,30.9,29.7,25.2,24.6.ESI-MS:346.0498[M+Na].
EXAMPLE 6 Synthesis of Compounds 1l, 1m, 1n and 1o of the invention
The synthetic route is as follows:
(1) synthesis of methyl 4- (1- ((6-bromo-1H-indazol-4-amino) -2-hydroxyethyl) benzoate (1m) and methyl 4- (2- ((6-bromo-1H-indazol-4-amino) -1-hydroxyethyl) benzoate (1o)
Epoxy 18(229.2mg,1.42mmol) and aniline 6b (300.0mg,1.42mmol) were dissolved in a 1:1 mixture of ethanol and water (20mL) and the reaction was refluxed at 100 ℃ overnight. After the raw material (18) completely reacted by TLC detection, ethanol was removed by swirling under reduced pressure, the reaction solution was extracted with ethyl acetate (15mL) 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, spun-dried, and subjected to column chromatography. The small polar impurities were first washed off with PE: EA ═ 15:1, then compound 1m was eluted with PE: EA ═ 6:1, and finally compound 1o was eluted with PE: EA ═ 3:1 (total yield 43%).
Compound 1m, yield 20%; a brown solid;1H-NMR(400MHz,d6-DMSO,ppm):12.87(s,1H,indazole-NH),8.33(s,1H,indazole-H3),7.92(d,2H,J＝8.3Hz,Ar-H2and Ar-H6),7.57(d,2H,J＝8.3Hz,Ar-H3and Ar-H5),6.94(d,1H,J＝6.8Hz,NH),6.82(s,1H,indazole-H7),5.88(s,1H,indazole-H5),5.11(t,1H,J＝5.3Hz,OH),4.69-4.64(m,1H,NHCH),3.83(s,3H,OCH3),3.76-3.71(m,2H,OHCH 2).
compound 1o, yield 23%; a brown solid;1H-NMR(400MHz,d6-DMSO,ppm):12.81(s,1H,indazole-NH),8.18(s,1H,indazole-H3),7.94(d,2H,J＝8.3Hz,Ar-H2and Ar-H6),7.56(d,2H,J＝8.3Hz,Ar-H3and Ar-H5),6.83(s,1H,indazole-H7),6.67(t,1H,J＝5.7Hz,NH),6.19(s,1H,indazole-H5),5.77(d,1H,J＝4.4Hz,OH),4.93-4.89(m,1H,OHCH),3.86(s,3H,OCH3),3.34(m,2H,NHCH 2).
(2) synthesis of 4- (1- ((6-bromo-1H-indazol-4-amino) -2-hydroxyethyl) benzoic acid (1l) and 4- (2- (6-bromo-1H-indazol-4-amino) -1-hydroxyethyl) benzoic acid (1n)
Using ester 1m (45.0mg,0.11mmol) as a starting material, the preparation of 3b in example 2 was carried out to give compound 1l (38mg,0.10mmol) as a brown solid.
1H-NMR(400MHz,d6-DMSO,ppm):12.87(br,2H,COOH and indazole-NH),8.35(s,1H,indazole-H3),7.91(d,2H,J＝8.2Hz,Ar-H2and Ar-H6),7.54(d,2H,J＝8.2Hz,Ar-H3and Ar-H5),6.97(d,1H,J＝6.7Hz,NH),6.81(s,1H,indazole-H7),5.89(s,1H,indazole-H5),5.13(br,1H,OH),4.68-4.63(m,1H,NHCH),3.75-3.71(m,2H,OHCH 2).13C-NMR(100MHz,d6-DMSO,ppm):167.7,147.0,142.5,142.2,132.7,131.0,129.9,127.5,121.5,112.7,101.9,100.6,65.8,59.8,49.1.ESI-MS:376.0299[M+H].
Using the ester 1o (45.0mg,0.11mmol) as a starting material, the preparation method of 3b in example 2 was carried out to give compound 1n (38mg, yield 87%) as a brown solid.
1H-NMR(400MHz,d6-DMSO,ppm):12.85(br,2H,COOH and indazole-NH),8.20(s,1H,indazole-H3),7.92(d,2H,J＝8.3Hz,Ar-H2and Ar-H6),7.53(d,2H,J＝8.3Hz,Ar-H3and Ar-H5),6.84(s,1H,indazole-H7),6.71(t,1H,J＝5.7Hz,NH),6.19(s,1H,indazole-H5),5.78(br,1H,OH),4.91(m,1H,OHCH),4.13(m,1H,NHCH).13C-NMR(100MHz,d6-DMSO,ppm):167.8,149.4,143.2,142.2,132.6,129.6,126.7,121.9,112.6,100.8,100.2,70.6,51.2.ESI-MS:376.0293[M+H].
EXAMPLE 7 Synthesis of Compound 1q of the present invention
Nitro compound 1p (2.9g,8.26mmol) was dissolved in a mixed solvent of ethanol (20mL) and water (10mL), ammonium chloride (221mg,4.13mmol) was added, a portion of iron powder (1.314g,23.46mmol) was added thereto, the reaction was stirred at 80 ℃ for 5 minutes, and another portion of iron powder (1g,17.86mmol) was added, and the reaction was continued for 20 minutes. After TLC detection of the completion of the reaction of the starting material 1p, the reaction solution was filtered while it was hot, and the residue was washed with ethanol (10 mL). Ethanol was removed under reduced pressure and the aqueous layer was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and spin-dried, and passed through a column ((PE: EA ═ 3:1)) to give 2.4g of a pale yellow solid in a yield of 92.1%.
1H-NMR(400MHz,d6-DMSO,ppm):12.21(s,1H,indazole-NH),8.30(s,1H,indazole-H3),6.69(d,1H,J＝7.9Hz,indazole-H7),6.91-6.01(m,5H,Ar-H,indazole-H5),4.35(s,2H,benzyl-CH2).ESI-MS:316.13[M+H].
EXAMPLE 8 Synthesis of Compound 1r of the present invention
Compound 1r was synthesized in a similar manner to that in example 3, except that compound 6b was replaced with compound 6c to give compound 1 r.
4- ((6-methyl-1H-indazol-4-amino) methyl) benzoic acid (1r) yield 70%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):12.79(br,2H,COOH and indazole-NH),8.23(s,1H,indazole-H3),7.91(d,2H,J＝7.4Hz,Ar-H2and Ar-H6),7.43(d,2H,J＝7.4Hz,Ar-H3and Ar-H5),6.62(d,1H,J＝7.9Hz,indazole-H7),5.84(d,1H,J＝7.1Hz,indazole-H5),4.48(s,2H,benzyl-CH2),2.38(s,3H,CH3).13C-NMR(100MHz,d6-DMSO,ppm):167.7,146.1,142.0,141.7,132.1,129.9,129.7,128.0,127.5,113.8,98.2,98.1,46.5,21.5.ESI-MS:281.12[M+H].
EXAMPLE 9 Synthesis of Compounds 2a-d of the invention
The starting material (6b) (50mg,0.185mmol) was dissolved in dichloromethane (3mL), and compound 21(97.6mg,0.708mmol) was added dropwise under an ice bath, EDCI (62.4mg,0.329mmol), HOBT (48mg,0.329mmol), DIEA (77.5uL,0.470mmol) were added, and the mixture was reacted at 0 ℃ for 5 minutes, and then warmed to room temperature (30 ℃ C.) and stirred overnight. After the starting material (6a) reacted completely by TLC, the reaction mixture was washed with water (1mL), then with saturated sodium bicarbonate (1.5mL), and the organic phase was spin-dried and passed through the column to give 2 a. 27.1mg of a yellow solid, the structure is characterized as follows:
3- ((6-bromo-1H-indazole-4-carbamoyl)) phenol (2a)
1H-NMR(400MHz,d6-DMSO,ppm):12.83(br,2H,indazole-NH and Ar-OH),8.52(s,1H,indazole-H3),7.62(s,1H,indazole-H7),6.76-8.09(m,4H,Ar-H),7.15(m,1H,Ar-H5),6.76(s,1H,indazole-H5),6.26(s,1H,NHCO).ESI-MS:332.01[M+H].
In a similar manner, benzoic acid of the corresponding substituent was selected to give 35.3mg of 2b as a yellow solid in 45.3% yield. Tan solid 2c, 36.3mg, yield 41.5%. The structure is characterized as follows:
3- ((6-bromo-1H-indazole-4-carbamoyl)) aniline (2b)
1H-NMR(400MHz,d6-DMSO,ppm):12.75(s,1H,indazole-NH),8.50(s,1H,indazole-H3),7.64(s,1H,indazole-H7),7.18(d,1H,J＝7.9Hz,Ar-H6),7.15(m,1H,Ar-H5),7.13(s,1H,indazole-H5),7.12(s,1H,Ar-H2),7.05(d,1H,J＝7.6,Ar-H4),6.54(s,1H,NHCO).ESI-MS:331.01[M+H].
4- ((6-bromo-1H-indazole-4-carbamoyl)) benzoic acid (2c)
1H-NMR(400MHz,d6-DMSO,ppm):13.12(br,2H,COOH and indazole-NH),8.56(s,1H,indazole-H3),8.07(d,2H,J＝8.3Hz,Ar-H2and Ar-H6),8.03(d,2H,J＝8.5Hz,Ar-H3and Ar-H5),7.67(s,1H,indazole-H7),6.70(s,1H,indazole-H5),6.62(s,1H,NHCO).ESI-MS:359.98[M+H].
EXAMPLE 10 Synthesis of Compounds 4a and 4b of the invention
Compound (22) (0.63mmol) and triethylamine (0.27ml, 1.95mmol) were dissolved in 5ml of THF, and compound (23) (0.06g, 0.20mmol) was added under stirring at 0 ℃ and after 3 hours of reaction with stirring at the same temperature, compound (6b) (0.09g, 0.42mmol) was added and after the addition, the reaction was stirred at room temperature for 12 hours and TCL showed complete reaction. The reaction solution was directly spin-dried to obtain a crude product, which was purified by column chromatography (PE: EA ═ 2:1) to obtain 0.07g of white solid powder with a yield of 41%.
Compound 4 a:1H-NMR(400MHz,d6-DMSO,ppm):12.40(s,1H,indazole-NH),10.12(br,1H,OH),8.90(s,1H,NHCONH),8.35(s,1H,NHCONH),8.20(s,1H,indazole-H3),7.31-7.68(m,4H,Ar-H),6.87(d,1H,J＝7.9Hz,indazole-H7),5.99(d,1H,J＝7.1Hz,indazole-H5).ESI-MS:347.11[M+H].
compound 4b was synthesized in a similar manner except that compound 22 was replaced with compound 3-aminophenol to give compound 4b as a white solid powder in 45% yield.
4b:1H-NMR(400MHz,d6-DMSO,ppm):12.40(s,1H,indazole-NH),10.12(br,1H,OH),8.90(s,1H,NHCONH),8.65(s,1H,NHCONH),8.20(s,1H,indazole-H3),7.38(d,2H,J＝7.4Hz,Ar-H2and Ar-H6),6.87(d,1H,J＝7.9Hz,indazole-H7),6.73(d,2H,J＝7.4Hz,Ar-H3and Ar-H5),5.99(d,1H,J＝7.1Hz,indazole-H5).ESI-MS:347.11[M+H].
EXAMPLE 11 Synthesis of Compounds 4c and 4d of the invention
With 4mLCH2Cl2And 4mL of saturated NaHCO3Compound (25) (0.34mmol) was dissolved in a round-bottom flask, and compound (23) (0.03g, 0.10mmol) was added with stirring at 0 ℃ and after 15min with stirring at the same temperature TCL showed complete reaction. The reaction solution was poured into a separatory funnel, and the organic layer was collected, dried, concentrated, and directly put into the next step without purification.
With 5mLCH2Cl2Compound (26) (0.34mmol) and compound (6b) (0.06g, 0.28mmol) were dissolved and left to react at 0 ℃ with stirring for 10h, after which TCL showed complete reaction. The reaction solution was directly spin-dried to obtain a crude product, which was purified by column chromatography (PE: EA ═ 3:1) to obtain 0.05g of a white solid powder with a yield of 51%.
4c:1H-NMR(400MHz,d6-DMSO,ppm):12.40(s,1H,indazole-NH),10.12(br,1H,OH),8.90(s,1H,NHCONH),7.62(s,1H,NHCONH),8.20(s,1H,indazole-H3),6.95(d,2H,J＝7.4Hz,Ar-H2and Ar-H6),6.71(d,1H,J＝7.9Hz,indazole-H7),6.73(d,2H,J＝7.4Hz,Ar-H3and Ar-H5),5.99(d,1H,J＝7.1Hz,indazole-H5),4.25(s,2H,benzyl-CH2).ESI-MS:361.01[M+H].
Compound 4d was synthesized in a similar manner except that compound 25 was replaced with 3-hydroxybenzylamine to give compound 4d as a white solid powder in 55% yield
4d:1H-NMR(400MHz,d6-DMSO,ppm):12.40(s,1H,indazole-NH),10.12(br,1H,OH),8.90(s,1H,NHCONH),7.62(s,1H,NHCONH),8.20(s,1H,indazole-H3),6.71(d,1H,J＝7.9Hz,indazole-H7),5.99(d,1H,J＝7.1Hz,indazole-H5),7.10-6.72(m,4H,Ar-H),4.43(s,2H,benzyl-CH2).ESI-MS:361.01[M+H].
EXAMPLE 12 inhibitory Activity of Compounds of the present invention on IDO protein
The recombinant human IDO protein is obtained by expressing through escherichia coli and purifying through nickel affinity chromatography. The compound has IDO inhibitory activity, and L-tryptophan is used as a substrate. The test compound was dissolved in 10% DMSO to prepare a dilution. 5uL of the dilution was added to 100. mu.L of the reaction. The 100. mu.L reaction contained 0.5% DMSO, 40nmol/L IDO, 900. mu. mol/L L-tryptophan, and other reaction co-products (potassium phosphate buffer, ascorbic acid, catalase, methylene blue). The reaction mixture was incubated at 37 ℃ for 180 minutes and stopped by the addition of trichloroacetic acid. The inhibitory activity of the compounds on IDO was evaluated by measuring the concentration of N-formyl kynurenine produced at 321nm using a Tecan Infinite M1000 microplate reader. The negative control was 5. mu.L of buffer instead of IDO. Clinical stage III IDO inhibitor INCB024360 was used as positive control to verify whether the IDO activity detection system established in this experiment was effective.
Three replicates of wells were set for each concentration. Data analysis was performed using software Graphpad Prism. Absorbance (A) in the reaction solution containing no test compoundt) Defined as 100% activity. Absorbance (A) in the reaction solution containing no IDOb) Defined as 0% activity. For the test compounds, the activity is calculated as: % activity ═ A-Ab)/(At-Ab)]× 100, wherein A is the absorbance of the reaction solution containing the compound to be tested, the inhibition rate is calculated by the formula that the% inhibition is 100-% activity.
By the above experimental method, the inhibitory activity against IDO of some of the compounds of the present invention was tested. The inhibitory activity of specific compounds at concentrations of 1. mu.M, 10. mu.M and 100. mu.M is shown in Table 1.
Wherein A represents that the inhibition rate is more than 90 percent, B represents that the inhibition rate is 70-90 percent, and C represents that the inhibition rate is 50-69 percent; d represents that the inhibition rate is 10-49%, E represents that the inhibition rate is less than 10%; the inhibition of the positive control at a concentration of 0.05. mu.M was 46%.
TABLE 1 inhibitory Activity of the Compounds of the present invention on IDO
The structure-activity relationship shows that: when R is1When the compound is a substituent containing halogen, the IDO enzyme inhibition activity of the compound is obviously increased; and R is1In the case of H or methyl, the activity is significantly reduced. When Y is an amino group linkage, the activity of the compound is significantly increased. When R is2When the structure contains a functional group capable of forming a hydrogen bond, the activity of the compound is remarkably increased.
Experiments prove that the 1H-indazole-4-amine compound provided by the invention has an excellent inhibiting effect on IDO, and can be used for preventing and/or treating various diseases, such as Alzheimer disease, cataract, infection related to cellular immune activation, autoimmune diseases, AIDS, cancers, depression or tryptophan metabolic disorder and the like.
Claims (9)
1. A compound selected from one of the following compounds:
2. a process for preparing a compound of claim 1, comprising the steps of:
the compound shown in the claim 1 is prepared by taking compounds shown in SM and S2 as raw materials and reacting under the action of a reducing agent;
wherein R is1、R3A corresponding radical as in claim 1.
3. A process for preparing a compound of claim 1, comprising the steps of:
condensing compounds shown in SM and S2 as raw materials to prepare a compound shown in claim 1;
wherein R is1、R3A corresponding radical as in claim 1.
4. A process for preparing a compound of claim 1, comprising the steps of:
(1)
reacting a compound shown as S4a and bis (trichloromethyl) carbonate serving as raw materials to prepare a compound shown as S4 b;
(2)
taking compounds shown in S4b and SM as raw materials, and reacting to prepare the compound shown in claim 1;
wherein R is1、R3A corresponding radical as in claim 1.
5. A process for preparing a compound of claim 1, comprising the steps of:
taking compounds shown as S5 and SM as raw materials, and reacting to prepare the compound shown as the claim 1;
wherein R is1、R3A corresponding radical as in claim 1.
6. A process for preparing a compound of claim 1, comprising the steps of:
(1)
reacting a compound shown in SM and ethyl bromoacetate serving as raw materials to prepare a compound shown in S7 a;
(2)
hydrolyzing the compound shown as S7a, and reacting to obtain a compound shown as S7 b;
(3)
carrying out condensation reaction on compounds shown in S7b and S7c as raw materials to obtain a compound shown in claim 1;
wherein R is1、R3A corresponding radical as in claim 1.
7. Use of a compound according to claim 1 for the manufacture of a medicament of the IDO inhibitor class.
8. Use according to claim 7, characterized in that: the drug is a drug for preventing and/or treating Alzheimer's disease, cataract, infection related to cellular immune activation, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism disorder.
9. A pharmaceutical composition characterized by: the compound is a preparation prepared by taking the compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
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| CN110382500B (en) * | 2017-03-21 | 2021-08-10 | 正大天晴药业集团股份有限公司 | Urea compounds for dual IDO and TDO inhibitors |
| CN108689938B (en) * | 2017-04-10 | 2021-07-30 | 西华大学 | Polysubstituted indazoles and their use as IDO inhibitors |
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| CN111285808B (en) * | 2018-12-07 | 2023-06-23 | 西华大学 | 4-aromatic heterocycle substituted indazole compound and application thereof as IDO/TDO dual inhibitor |
| CN111689901A (en) * | 2019-03-13 | 2020-09-22 | 西华大学 | Compound with TDO and IDO1 dual inhibitory activity and application thereof in preparing medicament for treating neurodegenerative diseases |
| CN111039790B (en) * | 2019-11-29 | 2022-04-19 | 浙江工业大学 | Synthesis method of 2, 6-dinitroterephthalic acid |
| CN114760994A (en) * | 2019-12-04 | 2022-07-15 | 艾库斯生物科学有限公司 | Inhibitors of HIF-2 alpha |
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