CN108689938A - Polysubstituted indazole compounds and its purposes as IDO inhibitor - Google Patents
Polysubstituted indazole compounds and its purposes as IDO inhibitor Download PDFInfo
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses polysubstituted indazole compounds shown in a kind of formula (I), also disclose the preparation method of the compound and the purposes as IDO inhibitor.The compound of the present invention can be used for preventing and/or treat a variety of diseases, such as Alzheimer disease, cataract, cellular immunity activate relevant infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism abnormal.
Description
Technical field
The present invention relates to indazole compounds, further relate to preparation method and the purposes as IDO inhibitor.
Background technology
Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) is the indoles such as catalysis tryptophan
Indole ring oxicracking in amine molecule makes it by the rate-limiting enzyme of kynurenine approach catabolism.
IDO plays an important role in tumour immunity exemption and tumour generating process.Under normal circumstances, IDO is in vivo
Low expression level, and the high expression IDO that most of tumour cells can then form, convert L-Trp to N- formyl dog urinary ammonias
Acid reduces the Tryptophan concentration in cell micro-environment so that the T cell synthesis that tryptophan relies on was stagnated in the G1 phases, and T cell increases
It grows and is suppressed, to inhibit lethal effect of the body immune system to tumor tissues.Meanwhile the lower tryptophan of IDO effects
There are cytotoxicities for metabolite, can generate direct dissolution to T cell.
Therefore, inhibit the activity of IDO that can effectively prevent the degradation of near tumor cells tryptophan, promote T cell
Proliferation, to enhance attacking ability of the body to tumour cell.Also, IDO inhibitor can also be shared with chemotherapeutics, be reduced
The drug resistance of tumour cell, to enhance the antitumor activity of conventional cytotoxic therapy.Simultaneously IDO inhibitor is taken also to can be improved
The effect of therapeutic vaccine of cancer patient.
In addition to being played an important role in terms of tumor cell drug resistance, IDO also to it is a variety of related with cellular immunity activation
Disease pathogenesis it is closely related.IDO have been found be with cellular immunity activate relevant infection, malignant tumour, itself
The target of the major diseases such as immunity disease, AIDS.Meanwhile inhibiting IDO still for suffering from the nervous system disease such as depression
Disease, the critical treatment strategy of the patient of Alzheimer disease.Therefore, IDO inhibitor has wide potential applicability in clinical practice.
Invention content
To solve the above problems, the present invention provides a kind of compounds or its optical isomer or its racemic modification to mix
Object or its pharmaceutically acceptable salt or its solvate, shown in the structure such as formula (I) of the compound:
Wherein,
R1Selected from hydrogen or C1~C6Alkyl;
R2Selected from hydrogen or-NH-R6;
R3Selected from hydrogen or halogen;
R4Selected from hydrogen or halogen;
R5Selected from hydrogen or-NH-R6;
R6Selected from hexamethylene ketone group ,-CH2-R7Or-CH2-CH(R8)-R9;
R7,R9Selected from-CON (OH)-R10, substitution or non-substituted 4~6 yuan of naphthenic base or 4~6 circle heterocyclic ring bases, it is described
Substituted naphthenic base or heterocycle is by selected from hydroxyl ,-COOH or-COOR11Substituent group replaced;
R8Selected from C1~C6Alkyl or the C of hydroxyl substitution1~C6Alkyl;
R10Selected from 4~6 circle heterocyclic ring bases;
R11Selected from C1~C6Alkyl;
Wherein, only work as R2Selected from-NH-R6When, R5Selected from hydrogen.
Further, R2Selected from hydrogen, R3Selected from halogen, R4Selected from hydrogen, R5Selected from-NH-R6;
Alternatively, R2Selected from-NH-R6,R3Selected from hydrogen, R4Selected from halogen, R5Selected from hydrogen.
Further, the hetero atom of the heterocycle is nitrogen or oxygen.
Further, the naphthenic base is cyclohexyl.
Further, the halogen is selected from fluorine, chlorine or bromine.
Further, the R6Selected from one of following group:
Further, the compound is selected from one of following compound:
The present invention also provides aforesaid compound or its prodrug or its optical isomer or its raceme mixture,
Or the purposes of its pharmaceutically acceptable salt or its solvate on preparing IDO inhibitor class drug.
Further, the drug is to prevent and/or treat Alzheimer disease, cataract, cellular immunity activation correlation
Infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception drug.
The present invention also provides a kind of pharmaceutical compositions, it is compound above-mentioned or its prodrug or its optical siomerism
Body or its raceme mixture or its pharmaceutically acceptable salt or its solvate are active constituent, in addition pharmaceutically
The preparation that acceptable auxiliary material is prepared.
The C1~C6Alkyl refers to C1,C2,C3,C4,C5,C6Alkyl, i.e., with 1~6 carbon atom linear chain or branched chain
Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, sec-butyl, amyl, hexyl etc..
The prodrug is the derivative of aforesaid compound, and their own may have weaker activity or even without work
Property, but upon administration, (such as passing through metabolism, solvolysis or other mode) is converted to accordingly in physiological conditions
Biologically active form.
The preparation may include injection or oral preparation.
Key intermediate and compound in the present invention are detached and are purified, and used mode is normal in organic chemistry
Isolation and purification method.
One or more compounds of the present invention can be used in conjunction with one another, and also be may be selected the compound of the present invention and appointed
What other active agent is used in combination, and is used to prepare IDO inhibitor.It, can be by these if using one group of compound
Compound is administered simultaneously, respectively or in an orderly manner to study subject.
Pharmaceutically acceptable auxiliary material of the present invention refers to the substance being included in addition to the active ingredient (s in dosage form.
Tests prove that indazole compounds provided by the invention have excellent inhibiting effect to IDO, can be used for pre-
A variety of diseases are prevented and/or treat, such as Alzheimer disease, cataract, the relevant infection of cellular immunity activation, autoimmune disease
Disease, AIDS, cancer, depression or tryptophan metabolism exception etc..
Obviously, the above according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific implementation mode of form by the following examples remakes further specifically the above of the present invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
In the present invention, the connotation of english abbreviation is as follows:
DCM:Dichloromethane, dichloromethane.
DMAP:4-Dimethylaminopyridine, 4-dimethylaminopyridine.
DIBAL-H:Diisobutylaluminum hydride, diisobutyl aluminium hydride.
MeOH:Methyl alcohol, methanol.
EA:Ethyl acetate, ethyl acetate.
Et3N:Triethylamine, triethylamine.
SOCl2:Thionyl chloride, thionyl chloride.
PE:Petroleum ether, petroleum ether.
TFA:Tallow Fatty Acid, trifluoroacetic acid.
THF:Tetrahydrofuran, tetrahydrofuran.
Specific implementation mode
The preparation method of key intermediate LWQ-148, LWQ-193 are that laboratory voluntarily synthesizes, used in remaining present invention
Reagent and initial feed are cheap and easy to get, are purchased from Chengdu Ke Long chemical reagents corporations unless otherwise specified.
(1) synthesis of compound L WQ-148
The synthesis of 1 compound 4a:
At room temperature, raw material TCCA (640mg, 2.74mmol) is slowly added into the concentrated sulfuric acid of 2d (1g, 5.49mmol)
It in (25mL) solution, finishes, opens to 130 DEG C of stirring 4h;TLC shows raw material, and the reaction was complete, finally obtains white powder
872.6mg, yield:73.6%.
The synthesis of 2 compound 5a:
Raw material 4a (5.9g, 23.60mmol) methanol (10mL) Isosorbide-5-Nitrae-dioxane (5mL) is dissolved, is added under ice bath
10N HCl (12mL) Fe (3.96g, 70.80mmol), finishes, and 80 DEG C of stirring 3h, TLC shows raw material, and the reaction was complete.Finally receive
Pale yellow powder 3.55g, yield:68.4%.
The synthesis of 3 compound L WQ-147:
Raw material 5a (3.55g, 16.13mmol) AcOH (15mL) are dissolved, be added at 0 DEG C sodium nitrite (2.23g,
Aqueous solution (5mL) 32.26mmol), finishes, and rt stirs 6h;TLC shows raw material, and the reaction was complete, finally receives crocus powder
2.7g, yield:72.5%.
1H NMR(400MHz,CDCl3,ppm):δ14.04(s,1H),8.56(s,1H),8.23(s,1H),8.13(s,
1H,);13C NMR(300MHz,CDCl3,ppm):δ140.3,133.3,133.1,130.4,118.9,118.0,114.8;HRMS
(AP-ESI)Calcd.for C7H4ClN3O2:219.9890(M+Na)+.Found:219.0458.
The synthesis of 4 compound L WQ-148
Raw material LWQ-147 (3.4g, 14.05mmol) ethyl alcohol (20mL) and water (10mL) are dissolved, chlorination is added under rt
Ammonium (376mg, 7.02mmol) and Fe (3.9g, 70.25mmol), finish, 80 DEG C of stirring 4h;TLC shows raw material, and the reaction was complete, most
After receive crocus powder 2.73g, yield:70.2%.
1H NMR(400MHz,DMSO,ppm)δ12.75(s,1H),8.10(s,1H),6.62(s,1H),6.13(s,1H)
.13C NMR(300MHz,d6-DMSO,ppm):δ145.0,143.6,131.9,127.8,112.0,107.1,100.4;HRMS
(AP-ESI)Calcd.for C7H6ClN3:190.0148(M+Na)+.Found:190.0677.
(2) synthesis of compound L QW-193
The synthesis of 1 compound 11:
By raw material 10 (1.00g, 4.32mmol) 15mL AcOH dissolving, be added at 0 DEG C sodium nitrite (0.66mg,
Aqueous solution (2mL) 9.52mmol).It finishes, rt stirs 6h.TLC monitors raw material, and the reaction was complete, is spin-dried for reaction solution, extracts, crude product
It is purified through column chromatography, obtains crocus powder compounds (0.5mg, 2.07mmol), yield:47.7%.
The synthesis of 2 compound L QW-193:
Compound 11 (0.34g, 1.40mmol) ethyl alcohol (10mL) water (5mL) is dissolved, lower addition chlorination is stirred at room temperature
Ammonium (38mg, 0.70mmol) and Fe (0.39g, 7.02mmol), finish, and are warming up to 80 DEG C of stirring 4h;TLC shows that raw material has reacted
Entirely, the solid in reaction solution is filtered off, filter cake is washed repeatedly with EA, and filtrate is spin-dried for, and residue is diluted with water, and EA is extracted 3 times, saturation
Brine It 3 times, dry concentration.Crude product is through column chromatography (PE:EA=1:1) pale yellow powder compound L QW-193 is obtained
(0.15mg, 0.71mmol), yield:50.5%.
1H NMR (400MHz, DMSO) δ 12.76 (s, 1H), 7.90 (s, 1H), 7.11 (d, J=1.1Hz, 1H), 6.58
(d, J=0.9Hz, 1H), 5.67 (s, 1H)13C NMR(101MHz,DMSO)δ139.9,133.4,125.8,122.8,120.4,
120.1,110.0.ESI-MS:211.9745[M+H].
The synthesis of embodiment 1 compound L WQ-136, LWQ-138, LWQ-156, LWQ-167, LWQ-223
Synthetic route is as follows:
The synthesis of 1 raw material LWQ-221:
Dry 50mL pear shape bottles are taken, with the 30mL concentrated sulfuric acids by 2- methyl-1s, 3- dinitrobenzenes (CAS:606-20-2,
5.00g, 27.45mmol are purchased from Chengdu Rui Ouke Reagent Companies) it dissolves, it is slowly added to 1,3-, bis- bromo- 5,5- bis- under ice bath stirring
Methyl hydantoin (CAS:77-48-5,4.29g, 15.00mmol are purchased from Chengdu Rui Ouke Reagent Companies), it is added dropwise, room temperature is stirred
Reaction 15h is mixed, TLC shows raw material, and the reaction was complete, and reaction solution is poured slowly into ice water, filters, and filter cake vacuum drying obtains white
Bromo- 2 methyl-1s of solid powder 5-, 3- dinitrobenzenes (6.59g, yield 92%).
Dry 50mL pear shape bottles are taken, with 20mL methanol and 10mL dioxane by bromo- 2 methyl-1s of 5-, 3- dinitrobenzenes
(5.00g, 19.16mmol) dissolves, and is stirred at room temperature down and is slowly added to 16.48mL concentrated hydrochloric acids and iron powder (3.22g, 57.47mmol),
It finishes, rises to 80 DEG C and be stirred at reflux and react 12h, TLC shows that raw material fundamental reaction is complete, reaction solution is concentrated, crude product is through column layer
Analyse (PE:EA=5:1) the bromo- 2- methyl-3-nitros aniline of faint yellow solid powder 5- ((2.74g, yield 62%) is purified to obtain.
The 25mL pear shape bottles for taking a drying, with 7mL glacial acetic acid by the bromo- 2- methyl-3-nitros aniline of 5- (0.40g,
It 1.73mmol) dissolves, 2mL sodium nitrites (0.24g, 3.46mmol) solution is slowly dropped to reaction solution under 0 DEG C of mechanical agitation
In, it finishing, is warmed to room temperature and is stirred to react 12h, TLC shows raw material, and the reaction was complete, and solid precipitation has been diluted with water into reaction solution,
Filtering, filter cake vacuum drying, then through column chromatography (PE:EA=5:1) the bromo- 4 nitro -1H- indazoles of yellow solid powder 6- are purified to obtain
LWQ-221 (0.40g, yield 96%).
Structural Identification:With mutually isostructural reference substance CAS:885518-46-7 (is purchased from the limited public affairs of Nantong biotechnology
Department) comparison HPLC collection of illustrative plates, it is completely the same.Purity is 98% through HPLC tests;1H-NMR(400MHz,d6-DMSO,ppm):δ
12.46(br,1H),8.30(s,1H),8.20(s,1H),8.12(s,1H),4.60(br,2H).
The synthesis of 2 compounds 33:
Raw material LWQ-221 (30mg, 0.1239mmol) is dissolved in THF (5ml), at 0 DEG C be added sodium hydride (10mg,
0.1488mmol), it finishes, stirs 3h, add methyl iodide (8.5 μ L, 0.1325mmol), finish, move to rt stirrings 3h.TLC
Show that the reaction was complete for raw material.Finally take faint yellow solid 19mg, yield:67.9%.
The synthesis of 3 compounds 34:
By raw material 33 (19mg, 0.0745mmol), ammonium chloride (5mg, 0.0372mmol) is dissolved in second alcohol and water (3ml:
In 1.5ml), it is added with stirring Fe (21mg, 0.357mmol), is finished, opens to 80 DEG C and is stirred at reflux 4h.TLC shows raw material reaction
Completely, faint yellow solid 12mg, yield are finally taken:74%;
1H NMR(400MHz,CDCl3) δ 7.88 (d, J=0.9Hz, 1H), 6.98 (d, J=1.1Hz, 1H), 6.49 (d, J
=1.3Hz, 1H), 4.30-4.09 (m, 1H), 4.00 (s, 1H)
The synthesis of 4 compound L WQ-136
By raw material 34 (70mg, 0.2431mmol) and raw material 35 (50mg, 0.3159mmol) and dihydropyridine ester (109mg,
0.4298mmol) it is dissolved in DCM;MeOH=6:In 2ml, it is added with stirring TFA (23ul, 0.2431mmol).It finishes, opens to 40
DEG C it is stirred at reflux 3h.TLC shows raw material, and the reaction was complete, finally takes weak yellow foam shape solid 23mg.Yield:22.1%.
1H NMR(400MHz,DMSO)δ9.32(s,1H),8.18(s,1H),7.22–7.15(m,3H),6.98(s,1H),
6.74 (d, J=8.5Hz, 2H), 6.11 (d, J=1.1Hz, 1H), 4.30 (s, 1H), 3.91 (s, 3H)13C NMR(101MHz,
DMSO)δ143.88,141.87,131.60,122.30,112.86,100.66,99.18,71.71,46.19,44.60,
35.84,31.17,29.63,25.47,24.94.HRMS(AP-ESI)Calcd.for C16H22BrN3O 374.0844(M+Na
)+.Found:374.0677.
Compound L WQ-138, LWQ-156 are respectively raw material, reference with compound L WQ-148, LWQ-193 and compound 35
The synthetic method of compound L WQ-136 is made.
LWQ-156:1H NMR(400MHz,CDCl3)δ7.94(s,1H),6.96(s,1H),6.33(s,1H),3.53(dt,
J=14.3,4.9Hz, 1H), 3.30 (m, 2H), 2.07-1.95 (m, 1H), 1.91-1.65 (m, 4H), 1.44-1.19 (m, 3H)
.13C NMR(101MHz,CDCl3)δ142.78,141.80,131.87,123.05,112.67,102.78,101.12,49.34,
44.08,36.09,30.95,29.66,25.22,24.56.ESI-MS:346.0525[M+Na]
LWQ-138:Yield:52.8%;White-yellowish solid;1H NMR(400MHz,DMSO)δ12.77(s,1H),8.19
(s, 1H), 6.64 (s, 1H), 6.59 (s, 1H), 6.06 (s, 1H), 4.75 (d, J=5.2Hz, 1H), 3.78-3.50 (m, 1H),
3.18 (dd, J=9.8,4.9Hz, 1H), 2.91-2.83 (m, 1H), 1.93 (d, J=12.7Hz, 1H), 1.69-1.46 (m,
1H),1.32-0.90(m,1H).HRMS(AP-ESI)Calcd.for C14H18ClN3O 302.1036(M+Na)+.Found:
302.0978.
LWQ-167 is using compound 7 and compound 35a as raw material.The synthetic method of reference compound LWQ-136 is made.1H
NMR(400MHz,DMSO)δ11.97(s,1H),8.12(s,1H),6.34(s,1H),6.79(s,1H),6.16(s,1H),4.72
(d, J=5.2Hz, 1H), 3.78-3.50 (m, 1H), 3.18 (dd, J=9.8,4.9Hz, 1H), 2.91-2.83 (m, 1H), 1.93
(d, J=12.7Hz, 1H), 1.69-1.46 (m, 1H), 1.32-0.90 (m, 1H) .HRMS (AP-ESI) Calcd.for
C14H18BrN3O 346.0633(M+Na)+.Found:346.0778.
LWQ-223 is using compound 7 and compound 35b as raw material.The synthetic method of reference compound LWQ-136 is made.
LWQ-223:Yield:77.8%;Bright-yellow solid;1H NMR(400MHz,DMSO)δ13.31(s,2H),9.15(s,3H),
8.10 (s, 3H), 7.54 (s, 2H), 7.04 (s, 2H), 5.33 (s, 2H), 2.52 (s, 7H), 2.22 (d, J=5.6Hz, 4H),
1.96 (d, J=5.6Hz, 5H), 1.25 (s, 1H) .HRMS (AP-ESI) Calcd.for C13H14BrN3O 331.0218(M+Na
)+.Found:331.0129.
The structure of aforesaid compound is as follows:
The synthesis of embodiment 2 compound L WQ-154, LWQ-155, LWQ-158, LWQ-159, LWQ-165, LWQ-166
Synthetic route is as follows:
The synthesis of 1 intermediate 37b
Under Ar gas shieldeds, by triphenyl phosphorus methyl bromide (5.34g, 15.06mmol) with THF dissolvings are steamed again, it is cooled to -78
℃.The n-BuLi (6.00mL, 15.06mmol) of 2.5M is slowly added dropwise, finishes, equality of temperature stirs 1h, and compound 36 is added
The THF solution of (2.00g, 10.04mmol) stirs 1h, is gradually increased to 0 DEG C.Saturated aqueous ammonium chloride is added and stops reaction, rotation
Dry reaction liquid is diluted with water residue, and EA is extracted 3 times, and saturated sodium-chloride water solution washs 2 times, dry, concentration.Crude product is through column
Chromatograph (PE:EA=20:1) colourless oil liquid compound 37b (600g, 3.04mmol), yield 30% are purified to obtain.
The synthesis of 2 intermediate 38a
Compound 37a (1.00g, 9.04mmol) is dissolved in dichloromethane, addition metachloroperbenzoic acid (2.82g,
16.35mmol), it finishes, is warming up to return stirring 4h.It is cooled to room temperature, is spin-dried for reaction solution, crude product is through column chromatography (PE:EA=
20:1) colourless oil liquid 38a (0.93g, 7.33mmol), yield 81% are purified to obtain.
Using compound 37b as raw material, the synthetic method of reference compound 38a carries out, and colourless oil liquid compound is made
38b, yield 80%.
The synthesis of 3 compound L WQ-159
Compound 7 (0.1g, 0.47mmol) and compound 38a (59mg, 0.47mmol) are dissolved in second alcohol and water (2:1)
In the mixed solvent adjusts pH to 10~11 with sodium hydrate aqueous solution.It is warming up to 110 DEG C of return stirring 3h.In reaction process, note
Meaning maintains the pH to 10~11 of reaction solution.It is spin-dried for reaction solution, crude product is through column chromatography (PE:EA=1:1) yellow oily half is purified to obtain
Solid chemical compound LWQ-159 (73mg, 0.22mmol), yield 47%.
1H NMR(400MHz,CDCl3)δ7.89(s,1H),6.98(s,1H),6.48(s,1H),4.25(s,1H),4.22-
4.12(m,2H),3.88-3.84(m,1H),1.82–1.70(m,4H),1.51-1.43(m,1H),1.30-1.11(m,6H)
.ESI-MS:338.0790[M+H].
Compound L WQ-158 and compound L WQ-166 is the reference compound using compound 7 and compound 38b as raw material
The synthetic method of LWQ-159 carries out, and weak yellow foam shape solid chemical compound LWQ-158 and tan solid Compound LWQ- is made
166.Yield is respectively 45% and 40%.
Compound L WQ-158:1H NMR(400MHz,CDCl3)δ7.91(s,1H),6.96(s,1H),6.48(s,1H),
4.33(s,2H),4.21-4.11(m,2H),4.03-3.98(m,1H),3.63-3.48(m,2H),3.31–3.09(m,2H),
2.29-2.20(m,8.3Hz,1H),1.98-1.87(m,2H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ154.5,
142.1,141.1,130.9,122.4,113.1,107.2,101.7,79.4,73.3,72.3,60.4,52.9,50.6,48.6,
47.7,45.8,45.4,42.6,41.6,41.2.ESI-MS:425.1110[M+H].
Compound L WQ-166:1H NMR (400MHz, DMSO) δ 8.33 (s, 1H), 6.88 (s, 1H), 6.11 (d, J=
1.5Hz, 1H), 6.02 (s, 1H), 5.29 (d, J=5.7Hz, 1H), 4.40-4.18 (m, 2H), 3.84 (s, 1H), 3.19-2.93
(m,2H),2.16-2.10(m,2H),1.92–1.88(m,1H),1.80–1.55(m,2H),1.40(s,9H).ESI-MS:
425.1110[M+H].
Compound L WQ-154 and compound L WQ-155 is using compound L WQ-193 and compound 38a as raw material, referenceization
The synthetic method for closing object LWQ-159 carries out, and weak yellow foam shape solid chemical compound LWQ-154 and tan solid Compound is made
LWQ-155.Yield is respectively 45% and 40%.
LWQ-154:1H NMR (400MHz, DMSO) δ 8.10 (s, 1H), 7.01 (d, J=1.6Hz, 1H), 6.28 (t, J=
30.2Hz, 1H), 5.65 (s, 2H), 4.90 (d, J=5.9Hz, 1H), 3.73 (s, 1H), 2.10 (s, 1H), 1.89-0.97 (m,
11H).ESI-MS:338.0790[M+H].
LWQ-155:1H NMR (400MHz, DMSO) δ 7.87 (s, 1H), 7.18 (d, J=1.7Hz, 1H), 6.70 (d, J=
1.7Hz, 1H), 5.66 (s, 2H), 5.54 (d, J=5.2Hz, 1H), 3.65-3.51 (m, 1H), 3.18 (d, J=5.3Hz, 1H),
1.96–0.93(m,11H).ESI-MS:338.0790[M+H].
The synthesis of 4 compound L WQ-165
Compound L WQ-158 (50mg, 0.12mmol) is dissolved in 3mLDCM, 150 μ LTFA are added with stirring.It finishes, room
Temperature stirring 1h.It is spin-dried for reaction solution, EA is added to dissolve residue, saturated sodium bicarbonate aqueous solution adjusts pH to alkalinity, saturated sodium-chloride
Aqueous solution washs 3 times, dry, concentration.Crude product is through column chromatography (DCM:MeOH=20:1) faint yellow oily semisolid is purified to obtain
Close object LWQ-165 (21mg, 0.06mmol), yield 50%.
1H NMR (400MHz, DMSO) δ 8.11 (s, 1H), 6.97 (d, J=5.2Hz, 1H), 6.28 (s, 1H), 6.18 (s,
2H),4.25-4.23(m,2H),3.93-3.88(m,1H),3.19-2.98(m,3H),2.22-2.16(m,1H),2.00-1.82
(m,2H).ESI-MS:325.0586[M+H].
The synthesis of embodiment 3 compound L WQ-162, LWQ-163
Synthetic route is as follows:
The preparation of 1 intermediate 40
3- azetidinecarboxylic acids 39 (2.47g, 24.46mmol) are dissolved in 30mL methanol, SOCl is slowly added dropwise at 0 DEG C2
(8.87mL,122.3mmol).It finishes, is warming up to and 10h is stirred at room temperature.It is spin-dried for reaction solution, the rotation of residue dichloromethane band goes it
In SOCl2, band rotation 3 times, it is colorless viscous shape liquid to obtain crude product, because the water solubility of compound 40 is very good, therefore without
Further work-up directly casts step, quantitative yield.
The preparation of 2 intermediates 41
Compound 40 (3.68g, 24.46mmol) is dissolved in acetonitrile, Et is sequentially added3N(3.39mL,
24.46mmol),(Boc)2The acetonitrile solution and DMAP (0.30g, 2.45mmol) of O (5.87g, 26.91mmol).It finishes, room temperature
Stir 5h.The reaction was complete for TLC detections, filters off the solid in reaction solution, is spin-dried for filtrate and obtains crude product.Crude product is through column chromatography (PE:EA=
40:1) colourless oil liquid compound 41 (3.00g, 14.02mmol), yield 57% are purified to obtain.
The preparation of 3 intermediates 42
Compound 41 (1.00g, 5.30mmol) is dissolved in dichloromethane, Ar protections are lower to be added in three-necked bottle, be cooled to-
After 78 DEG C, DIBAL-H (11.7mL, 11.7mmol) is slowly added dropwise, finishes, 0 DEG C is slowly increased to after equality of temperature stirring 30min.It is added
2mL absolute methanols stop reaction, and 200mL10% aqueous citric acid solutions are added.There is white solid precipitation at this time, keeps temperature stirring
It disappears to white solid.It is extracted 3 times with dichloromethane, dry, concentration crude product is through column chromatography (PE:EA=5:1) it obtains colourless slightly viscous
Thick liquid compound 42 (0.57g, 3.24mmol), yield 61%.
The synthesis of 4 compound L WQ-163
By compound 7 (0.1g, 0.47mmol), compound 42 (0.18g, 0.94mmol) and dihydropyridine ester (0.17g,
It 0.66mmol) is dissolved in the in the mixed solvent of DCM/MeOH, is added with stirring TFA (5 μ L, 0.05mmol).It finishes, is warming up to 45 DEG C
React 4h.It is spin-dried for reaction solution, is diluted with EA, saturated sodium bicarbonate adjusts pH to 8~9.It is dry, it concentrates, crude product is pure through column chromatography
Change to obtain tan solid Compound LWQ-163 (0.1g, 0.26mmol), yield 54%.1H NMR(400MHz,CDCl3)δ10.41
(s, 1H), 7.96 (d, J=0.9Hz, 1H), 7.05 (d, J=1.0Hz, 1H), 6.34 (d, J=1.1Hz, 1H), 4.43-4.40
(m,1H),4.15-4.11(m,2H),3.76-3.72(m,2H),3.53-3.50(m,2H),2.96-2.87(m,1H),1.48
(s,9H).ESI-MS:381.0848[M+H].
The synthesis of 5 compound L WQ-162
Compound L WQ-163 (50mg, 0.13mmol) is dissolved in the dioxane hydrochloride of 1M, 1h is stirred at room temperature.Rotation
Dry reaction liquid, is diluted with sodium bicarbonate aqueous solution, and EA is extracted 3 times, and saturated sodium-chloride water solution washs 1 time, dry, concentration, slightly
Product obtain yellow solid compound LWQ-162 (20mg, 0.07mmol), yield 53% through column chromatography.
1H NMR(400MHz,CDCl3)δ8.00(s,1H),6.98(s,1H),6.45(s,1H),6.30(s,1H),6.14
(s,1H),4.24-4.20(m,1H),4.08-4.04(m,2H),3.69-3.66(m,2H),3.44–3.41(m,2H).13C NMR
(101MHz,DMSO)δ145.8,137.6,127.8,121.7,110.1,107.2,101.7,55.2,48.9.ESI-MS:
281.0392[M+H]
The synthesis of 4 compound L WQ-192 of embodiment
Synthetic route is as follows:
The synthesis of 1 intermediate 44
Intermediate 7 (300mg, 1.41mmol), 43 (422mg, 2.12mmol) dihydropyridine esters (358mg, 1.41mmol)
It is added in reaction bulb, with 10mL dichloromethane and methyl alcohol mixed liquor (1:1) dissolve, be slowly added dropwise trifluoroacetic acid (10 μ L,
0.14mmol), the reaction was complete for 45 DEG C of reflux 3h, TLC detections, dichloromethane and methanol is spin-dried for, crude product is through column chromatography (DCM:
MeOH=80:1→40:1) yellow solid 432mg intermediates 44, yield 77% are purified to obtain.
1H NMR(400MHz,CDCl3) δ 10.41 (s, 1H), 7.96 (d, J=0.9Hz, 1H), 7.05 (d, J=1.0Hz,
1H), 6.34 (d, J=1.1Hz, 1H), 4.43-4.40 (m, 1H), 4.15-4.11 (m, 2H), 3.76-3.72 (m, 2H), 3.43-
3.51(m,2H),2.96-2.87(m,2H),1.38(s,9H).HRMS(AP-ESI)Calcd.For
C13H15BrN4O2339.0378(M+H)+.Found:339.0354.
The synthesis of 2 compound L WQ-192
Intermediate 44 (35mg, 0.09mmol), palladium carbon (5%) (10mg) are added in three-necked bottle, dissolved with 5mL methanol,
It is filled with hydrogen by threeway, three times, the reaction was complete for TLC detections after reacting at room temperature 1h, palladium carbon is filtered to remove, first is gone in rotation for ventilation
Alcohol obtains compound L WQ-192 28mg, yield 93%.
1H NMR(400MHz,DMSO)δ12.67(s,1H),11.23(s,1H)8.01(s,1H),6.94(s,1H),6.74
(s, 1H), 4.72 (m, 1H), 3.78-3.50 (m, 4H), 3.18 (dd, J=9.8,4.9Hz, 2H), 1.83 (m, 1H), 1.39 (m,
2H).13C NMR(300MHz,d6-DMSO)δ160.42,148.43,128.0,124.8,110.25,108.75,59.44,
35.16,46.46,37.64,30.53.
The synthesis of 5 compound L WQ-186 of embodiment
Synthetic route is as follows:
The synthesis of 1 intermediate 46
Pyridinium chloro-chromate (445mg) is added in reaction bulb, is dissolved with 5mL dichloromethane, 45 (200mg) are slow
It being added drop-wise in the dichloromethane solution of pyridinium chloro-chromate, reacts at room temperature 1.5h, the reaction was complete for TLC detections, is filtered with diatomite,
Through column chromatography (PE:EA=5:1) colourless transparent liquid 124mg, yield 63% are obtained.
The synthesis of 2 intermediates 47
Compound 46 (100mg, 0.90mmol), azanol hydrochloric acid are added in reaction bulb, it is molten with 10mL (90% ethyl alcohol)
Solution, is slowly added portionwise sodium hydroxide (327mg, 8.17mmol), 30min is stirred at room temperature, and then rises to 80 DEG C of reflux 1h, TLC
The reaction was complete for detection, waits for that reaction solution is cooled to room temperature, 10mL dilute hydrochloric acid is added, is extracted with dichloromethane, drying is concentrated to give intermediate
47 be colourless transparent liquid 123mg, yield 100%.
The synthesis of 3 intermediates 48
Compound 47 (210mg, 1.63mmol) 5mL methanol is dissolved, 0 DEG C is added with stirring sodium cyanoborohydride
(174mg, 2.77mmol) and then the concentrated hydrochloric acid that 12N is slowly added dropwise, reacts 4h at room temperature.Waiting for raw material, the reaction was complete, with the hydrogen of 6N
Aqueous solution of sodium oxide tune pH to 9, then uses dichloromethane:Isopropanol=3:1 extraction obtains crude product 100mg after dry concentration, is light
Yellow liquid, yield 47%.
The synthesis of 4 compound L WQ-186
Intermediate 29 (50mg, 0.18mmol) 3mL n,N-Dimethylformamide is dissolved, by 1- (3- dimethylaminos
Propyl) -3- ethyl carbodiimides (45mg, 0.23mmol), 2- (7- azos benzotriazole)-N, N, N',N'Tetramethylurea six
Fluorophosphoric acid ester (85mg, 0.22mmol), n,N-diisopropylethylamine (60 μ L, 0.36mmol) are separately added into reaction bulb, finally
Intermediate 48 (50mg, 0.36mmol) is added in mixed liquor, 3h is reacted at room temperature, the reaction was complete for TLC detections, and a large amount of water are added,
It is extracted with ethyl acetate, saturated common salt water washing, dry, concentrate thick crude product, crude product is through column chromatography (DCM:MeOH=80:1→
40:1) yellow solid LWQ-186 37mg, yield 53% are purified to obtain.
1H NMR(400MHz,DMSO)δ10.02(s,1H),8.07(s,1H),6.77(s,1H),6.29(s,1H),6.16
(s, 2H), 5.25 (s, 2H), 3.85 (d, J=13.2Hz, 2H), 3.42 (d, J=7.2Hz, 2H), 3.29 (t, J=11.2Hz,
2H), 2.06-1.80 (m, 1H), 1.57 (d, J=12.9Hz, 2H), 1.24-1.05 (m, 2H) .HRMS (AP-ESI)
Calcd.For C16H20BrN3O3 404.0688(M+H)+.Found:404.1054.
Inhibitory activity of 6 the compounds of this invention of embodiment to IDO albumen
Recombined human IDO albumen through Bacillus coli expression, nickel affinity chromatographic purifying and obtain.Compound is real to IDO inhibitory activity
It tests using L-Trp as substrate.Untested compound is dissolved in 10%DMSO solution and is configured to dilution.Take 5uL dilutions
It is added in 100 μ L reaction systems.Contain 0.5%DMSO, 40nmol/L IDO, 900 μm of ol/L L- in 100 μ L reaction systems
Tryptophan and other reaction concurrents (kaliumphosphate buffer, ascorbic acid, catalase, methylene blue).Reaction mixing
Object is cultivated 180 minutes under 37 degree, is added trichloroacetic acid and is terminated reaction.Existed using Tecan Infinite M1000 microplate reader
The concentration that the N- formoxyl kynurenins generated are measured at 321nm, to evaluate inhibitory activity of the compound to IDO.It is negative right
It is that IDO is replaced with the buffer solution of 5 μ L according to object.The IDO inhibitor INCB024360 of clinical III phases is as positive control, and verification is originally
Whether effective test the IDO Activity determinations system established.
Each concentration sets up three wells.Data analysis is carried out using software Graphpad Prism.Without test compounds
In the reaction solution of object, absorbance (At) it is defined as 100% activity.In the reaction solution without IDO, absorbance (Ab) it is defined as 0%
Activity.For untested compound, active calculation formula is:%activity=[(A-Ab)/(At-Ab)]× 100, wherein A are
The absorbance of reaction solution containing untested compound.The calculation formula of inhibiting rate is:%inhibition=100-%activity.
By the above experimental method, the inhibitory activity that the part of compounds in the present invention is directed to IDO is tested.Specific portion
It closes inhibitory activity of the object under 10 μM, concentration and is shown in Table 1.
Wherein A indicates that inhibiting rate is more than 80%, B and indicates that inhibiting rate is 60-79%, and C indicates that inhibiting rate is 30-59%;D tables
Show that inhibiting rate is 10-39%, E indicates that inhibiting rate is less than 10%;Inhibiting rate of the positive control at a concentration of 0.05 μM be
46%.
1 the compounds of this invention of table is classified the inhibitory activity of IDO
Tests prove that indazole compounds provided by the invention have excellent inhibiting effect to IDO, can be used for pre-
A variety of diseases are prevented and/or treat, such as Alzheimer disease, cataract, the relevant infection of cellular immunity activation, autoimmune disease
Disease, AIDS, cancer, depression or tryptophan metabolism exception etc..
Claims (10)
1. a kind of compound or its optical isomer or its raceme mixture or its pharmaceutically acceptable salt or its is molten
Object is closed in agent, shown in the structure such as formula (I) of the compound:
Wherein,
R1Selected from hydrogen or C1~C6Alkyl;
R2Selected from hydrogen or-NH-R6;
R3Selected from hydrogen or halogen;
R4Selected from hydrogen or halogen;
R5Selected from hydrogen or-NH-R6;
R6Selected from hexamethylene ketone group ,-CH2-R7Or-CH2-CH(R8)-R9;
R7,R9Selected from-CON (OH)-R10, substitution or non-substituted 4~6 yuan of naphthenic base or 4~6 circle heterocyclic ring bases, it is described substituted
Naphthenic base or heterocycle are by selected from hydroxyl ,-COOH or-COOR11Substituent group replaced;
R8Selected from C1~C6Alkyl or the C of hydroxyl substitution1~C6Alkyl;
R10Selected from 4~6 circle heterocyclic ring bases;
R11Selected from C1~C6Alkyl;
Wherein, only work as R2Selected from-NH-R6When, R5Selected from hydrogen.
2. compound according to claim 1, it is characterised in that:R2Selected from hydrogen, R3Selected from halogen, R4Selected from hydrogen, R5Selected from-
NH-R6;
Alternatively, R2Selected from-NH-R6,R3Selected from hydrogen, R4Selected from halogen, R5Selected from hydrogen.
3. compound according to claim 1, it is characterised in that:The hetero atom of the heterocycle is nitrogen or oxygen.
4. compound according to claim 1, it is characterised in that:The naphthenic base is cyclohexyl.
5. compound according to claim 1, it is characterised in that:The halogen is selected from fluorine, chlorine or bromine.
6. according to claim 1-5 any one of them compounds, it is characterised in that:The R6Selected from one of following group:
7. compound according to claim 1, it is characterised in that:The compound is selected from one of following compound:
8. any one of the claim 1-7 compounds or its prodrug or its optical isomer or its raceme mixture,
Or the purposes of its pharmaceutically acceptable salt or its solvate on preparing IDO inhibitor class drug.
9. purposes according to claim 8, it is characterised in that:The drug be prevent and/or treatment Alzheimer disease,
Cataract, cellular immunity activate relevant infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism different
Normal drug.
10. a kind of pharmaceutical composition, it is characterised in that:It is with before claim 1-7 any one of them compound or its
Medicine or its optical isomer or its raceme mixture or its pharmaceutically acceptable salt or its solvate are activity
Ingredient, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
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