CN107987006A - Indoles or azaindole analog derivative, its preparation method and application - Google Patents

Indoles or azaindole analog derivative, its preparation method and application Download PDF

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Publication number
CN107987006A
CN107987006A CN201711386216.6A CN201711386216A CN107987006A CN 107987006 A CN107987006 A CN 107987006A CN 201711386216 A CN201711386216 A CN 201711386216A CN 107987006 A CN107987006 A CN 107987006A
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bases
sulfydryl
pyrrolo
pyridine
naphthalene
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CN107987006B (en
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杨琰
王奇昌
扈占坤
秦至臻
卞德乾
刘海云
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China Resources Saike Pharmaceutical Co Ltd
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China Resources Saike Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention belongs to field of medicaments, specifically, the purposes the present invention relates to a series of indoles or preparation method of azaindole analog derivative and its officinal salt, the pharmaceutical composition comprising the derivative and derivative and pharmaceutical composition in preparing anti-gout drugs and treating relevant disease.The structural formula of compound of the present invention is as follows：

Description

Indoles or azaindole analog derivative, its preparation method and application
Technical field
The invention belongs to field of medicaments, and specifically, the present invention relates to a series of indoles or azaindole analog derivative And its preparation method of officinal salt, the pharmaceutical composition comprising the derivative and the derivative and pharmaceutical composition Purposes in preparing anti-gout drugs and treating relevant disease.
Background technology
Gout is due to internal purine metabolic disturbance, and uric acid is excessive in blood, causes lithate in joint, kidney and connective tissue Middle precipitation, so as to cause urarthritis, gouty nephropathy and calculosis etc., is medically referred to as gout.This disease is with joint It is its feature that single water Monosodium urate that can be found in liquid and tophus has two-fold photosensitiveness, which crystallizes,.Its Clinical symptoms is：Hyperuricemia And urate crystal, deposit caused by characteristic acute arthritis, tophus, interstitial nephritis, severe patient see joint deformity and Dysfunction, often with uric acid lithangiuria, is more common in the middle-aging male and postmenopausal women of bodily form obesity.
Gout medication generally can be divided into 3 classes by its action character：
The medicine first, antigout breaks out.This kind of medicine has Indomethacin (indocin) and colchicines tablets.
Indomethacin has slight uricotelism, caused pain when can eliminate gout breaking-out.It is usually used in gout hair Make caused Bones and joints disease.Patient wants full wafer to swallow when taking this product, prohibits with the patient of gastric ulcer, epilepsy, mental disease Only take this medicine, this similar drug is unsuitable long-term use of.
The toxic side effect of colchicines tablets is larger, is only limited to the gouty attack,acute phase at present, and some patientss are taking this product When there is also the reaction such as vomiting, diarrhea, the optimal dose of colchicin antigout need further to study.
Second, uricosuric drug.Probenecid just belongs to this kind of medicine, it mainly suppresses reabsorption of the renal tubule to lithate, Increase the excretion of lithate, reduce the concentration of lithate in blood, prevent the generation of urate crystal, support the operation in joint, also Established lithate can be promoted to dissolve.This product is generally used for the treatment of chronic gout without anti-inflammatory and analgesic effect, or gout is extensive It is multiple.
Third, uric acid synthesizes blocking agent.Allopurinol belongs to this kind of medicine, it mainly by suppressing xanthine oxidase, prevents body Interior hypoxanthine and xanthine are metabolized as uric acid, so that the generation of uric acid is reduced, available for primary, Secondary cases and chronic gout The acute inflammation when treatment of disease, this product cannot control the gout to break out, and must be two weeks or so after the disappearance of the acute stage of gout It can use.
Uric acid is the result of xanthine oxidation.Uric acid metabolism illness include but not limited to polycythemia, myeloid metaplasia, Gout, repeatedly gout breaking-out, urarthritis, hyperuricemia, hypertension, angiocardiopathy, coronary heart disease, Lay-naphthalene Er Shi Syndrome, it is triumphant-match two Cotards, nephrosis, kidney stone, renal failure, arthritis, arthritis, urolithiasis, lead poisoning, The uric acid metabolism exception relevant disease such as sarcoidosis.
It is a kind of orally active URAT1 inhibitor to carry out Si Nuolei (Lesinurad).In I phases and II phase clinical research knots Fruit shows, carrys out Si Nuolei (Lesinurad) and is combined with xanthine oxidase inhibitor, can effectively adjust uric acid level, and have Higher-security, its molecular structure are as follows：
Lesinurad is weaker there are drug activity, and dosage is big, the problems such as bringing renal toxicity high, clinically needs to develop medicine Imitate the URAT1 inhibitor of higher.To have surprisingly found that a kind of sulfur heterocyclic ring and its derivative have good studying for we URAT1 inhibitory action, in-vitro screening and pharmacological research are superior to carry out Si Nuolei, therefore the present invention develops a kind of therapeutic effect more Good anti-gout drugs.
The content of the invention
It is an object of the invention to provide the indoles or azaindole analog derivative shown in a kind of formula I, it pharmaceutically may be used The salt of receiving, solvate, hydrate or pharmaceutically acceptable prodrug, its structure are as follows：
Wherein：
X1, X2, X3, X4Independently selected from CH or N；
It is N to be up to one in X1, X2, X3, X4；
R1Selected from H or C1-3Alkyl；
W is represented：
Wherein：
R2Selected from H, cyano group, halogen, C1-6 alkyl or cycloalkyls；
Work as R1For H when, W works as R at 11For C1-3During alkyl, W is at 3；
Y is represented at 2 or 3：
Wherein：
R3, R4Independently selected from H or methyl；
M1Represent H or pharmaceutically acceptable cation.
Preferably, the indoles of the invention or azaindole analog derivative, its pharmaceutically acceptable salt, solvent Compound, hydrate or pharmaceutically acceptable prodrug, structural formula are as follows：
Wherein,
X1, X2, X3, X4, R2, R3, R4, M1Substitution mode be same as above,
Alternatively, structural formula is as follows：
Wherein,
X1, X2, X3, X4, R2, R3, R4, M1Substitution mode be same as above,
Alternatively, structural formula is as follows：
Wherein,
X1, X2, X3, X4, R2, R3, R4, M1Substitution mode be same as above,
It is further preferred that the compound of the present invention is：
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid (I 1)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] sodium acetate (I 2)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] acetic acid (I 3)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] sodium acetate (I 4)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] acetic acid (I 5)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] sodium acetate (I 6)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] acetic acid (I 7)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] sodium acetate (I 8)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] acetic acid (I 9)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] sodium acetate (I 10)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indol-3-yls] sulfydryl] propionic acid (I 11)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indol-3-yls] sulfydryl] potassium propionate (I 12)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] propionic acid (I 13)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] potassium propionate (I 14)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] propionic acid (I 15)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] potassium propionate (I 16)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] propionic acid (I 17)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] potassium propionate (I 18)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] propionic acid (I 19)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] potassium propionate (I 20)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] -2 Methylpropionic acid (I 21)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] -2 Methylpropionic acid lithium (I 22)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 23)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ24)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 25)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ26)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 27)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ28)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 29)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ30)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] acetic acid (I 31)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] sodium acetate (I 32)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] acetic acid (I 33)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] sodium acetate (I 34)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] acetic acid (I 35)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] sodium acetate (I 36)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] acetic acid (I 37)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] sodium acetate (I 38)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] acetic acid (I 39)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] sodium acetate (I 40)；
2- [[3- (4- bromonaphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] propionic acid (I 41)；
2- [[3- (4- bromonaphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] potassium propionate (I 42)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] propionic acid (I 43)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] potassium propionate (I 44)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] propionic acid (I 45)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] potassium propionate (I 46)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] propionic acid (I 47)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] potassium propionate (I 48)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] propionic acid (I 49)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] potassium propionate (I 50)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] -2 Methylpropionic acid (I 51)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 52)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid (I 53)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid lithium (I 54)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid (I 55)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid lithium (I 56)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid (I 57)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid lithium (I 58)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid (I 59)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2- methyl Propionic acid lithium (I 60)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] acetic acid (I 61)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] sodium acetate (I 62)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] acetic acid (I 63)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] sodium acetate (I 64)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] acetic acid (I 65)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] sodium acetate (I 66)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] acetic acid (I 67)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] sodium acetate (I 68)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] acetic acid (I 69)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] sodium acetate (I 70)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] propionic acid (I 71)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] potassium propionate (I 72)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] propionic acid (I 73)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] potassium propionate (I 74)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] propionic acid (I 75)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] potassium propionate (I 76)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] propionic acid (I 77)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] potassium propionate (I 78)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] propionic acid (I 79)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] potassium propionate (I 80)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] -2 Methylpropionic acid (I 81)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 82)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 83)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ84)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 85)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ86)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 87)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ88)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 89)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (Ⅰ90)；
Compound of the present invention, corresponding structural formula are as follows：
Compound of the present invention and its pharmaceutically acceptable salt, its pharmaceutical salts are Na, K, Li, Ca, Mg salt.It is preferred that For Na salt.
The invention further relates to the pharmaceutically acceptable prodrug of the compound, includes but not limited to：Ester, carbonic ester, grace that Card is than ester, sulfocarbonate, N- acyl derivatives, N- acyloxy derivatives, amino acid conjugates etc..
It is a further object of the invention to provide the indoles representated by formula I or azaindole analog derivative or its can The preparation method of pharmaceutical salts or prodrug.
The preparation method of the following compound of structural formula of the present invention, comprises the following steps：
Wherein, substituent is same as above.
(1) compound is reacted under the action of thiocarbamide, iodine and potassium iodide shown in formula II, is added shown in NaOH and formula III Compound, compound shown in production IV：
(2) compound shown in formula IV reacts the institute of production VI with compound shown in formula V under the action of catalyst and alkali Show compound：
(3) compound hydrolyzes compound shown in production VII in alkaline conditions shown in formula VI：
(4) compound shown in formula VII and compound, M shown in corresponding alkali reaction production VIII1Represent it is pharmaceutically acceptable sun from Son：
The preparation method of the following compound of structural formula of the present invention, comprises the following steps：
Wherein, substituent is same as above.
(1) compound shown in formula II and compound shown in iodomethane reaction production Ⅸ：
(2) compound shown in formula Ⅸ is under the action of halogenating agent, compound shown in production Ⅹ：
(3) compound shown in formula Ⅹ reacts the institute of production Ⅻ with compound shown in formula Ⅺ under the action of catalyst and alkali Show compound：
(4) compound is reacted under the action of thiocarbamide, iodine and potassium iodide shown in formula Ⅻ, is added shown in NaOH and formula III Compound, compound shown in production XIII：
(5) compound shown in Formula XIII is made to hydrolyze compound shown in production XIV in alkaline conditions：
(6) compound shown in Formula XIV is made to react compound shown in production XV, M with corresponding alkali1Represent it is pharmaceutically acceptable sun from Son：
The preparation method of the following compound of structural formula of the present invention, comprises the following steps：
Wherein, substituent is same as above.
(1) compound shown in Formula XVI and compound shown in the reaction production of compound shown in Formula XVI I XVIII are made：
(2) compound shown in formula XVIII and compound shown in the reaction production of compound shown in Formula V XIX：
(3) compound hydrolyzes compound shown in production XX in alkaline conditions shown in formula XIX：
(4) compound shown in formula XX and compound, M shown in corresponding alkali reaction production XXI1Represent it is pharmaceutically acceptable sun from Son：
Compound according to the present invention, belongs to known compound, can commercially buy or by Know that technology is prepared.
It is another object of the present invention to provide provide a kind of pharmaceutical composition.
The pharmaceutical composition of the present invention, at least containing the indoles or azaindole analog derivative representated by a kind of formula I, or Its officinal salt.
As needed, pharmaceutical composition of the invention can also add one or more pharmaceutically acceptable carriers or tax Shape agent.
The pharmaceutical composition of the present invention, shared by the indoles or azaindole analog derivative or its officinal salt shown in formula I Percentage by weight can be 0.1-99.9%, remaining is pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention can be prepared into any pharmaceutically useful formulation, these formulations include：Tablet, sugar coated tablet Agent, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, mouth containing agent, granule, electuary, Pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, ointment, emplastrum, creme, spray, Drops, patch.The preparation of the present invention, preferably peroral dosage form, such as：Capsule, tablet, oral liquid, granule, pill, dissipate Agent, sublimed preparation, paste etc..
Method of administration of the present invention can be take orally, non-bowel or local administration, preferably oral and injection form administration.It is suitable for Medicinal oral Preparation can be tablet, capsule, granule or other preparation such as solution suitable for medicinal liquid form, Lotion, suspending agent etc..Preferable oral formulations are tablets, and the tablet can be made coating, enteric, sustained release or quantitatively release The form put.
The pharmaceutical composition of the present invention, its preparation being administered orally can contain common excipient, such as adhesive, filling Agent, diluent, tablet agent, lubricant, disintegrant, colouring agent, flavor enhancement and wetting agent, if necessary can be coated tablet.
Applicable filler includes cellulose, mannitol, lactose and other similar fillers.Suitable disintegrant bag Include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycollate.Suitable lubricant includes, such as firmly Fatty acid magnesium.Suitable pharmaceutically acceptable wetting agent includes lauryl sodium sulfate.
Solid oral composition can be prepared by common methods such as mixing, filling, tablettings.Work can be made by carrying out mixing repeatedly Property material be distributed in entirely using a large amount of fillers those compositions in.
The form of oral liquid for example can be water-based or oily suspensions, solution, emulsion, syrup or elixir, Or can be a kind of dry products that water or other suitable carriers can be used to compound before use.This liquid preparation can contain Conventional additive, such as suspending agent, such as sorbierite, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl are fine Dimension element, aluminium stearate gel or hydrogenated edible fats, emulsifying agent, such as lecithin, anhydro sorbitol monooleate or Arab Glue；Non-aqueous carrier (they can include edible oil), such as the oily ester of the ester of apricot kernel oil, fractionated coconut oil, such as glycerine, Propane diols or ethanol；Preservative, such as para hydroxybenzene methyl esters or propylparaben or sorbic acid, and if desired, Contain conventional flavouring agent or colouring agent.
For injection, the fluid unit dosage form of preparation contains the active material and sterile carrier of the present invention.According to carrier And concentration, this compound can be suspended or be dissolved.The preparation of solution is dissolved in a kind of load typically by by active material In body, disinfection is filtered before a kind of suitable bottle or ampoule is loaded into, is then sealed.For example a kind of local anaesthesia of auxiliary material Agent, preservative and buffer can also be dissolved in this carrier., can be after bottle be loaded by this in order to improve its stability Kind composition frost, and under vacuo remove water.
The pharmaceutical composition of the present invention, suitable pharmaceutically acceptable load is optionally added when being prepared into medicament Body, the pharmaceutically acceptable carrier are selected from：Mannitol, sorbierite, sodium pyrosulfite, sodium hydrogensulfite, sodium thiosulfate, salt Sour cysteine, thioacetic acid, methionine, injection Vitamin B_6 DTA disodiums, Ethylenediaminetetraacetic Acid Calcium Salt, carbonate, the acetic acid of monovalence alkali metal Salt, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, wheat Bud sugar, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and its Derivative, alginates, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, calcium bicarbonate, surface-active Agent, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid material, kaolin, talcum powder, calcium stearate, magnesium stearate etc..
The compounds of this invention or its officinal salt can be administered individually or in the form of pharmaceutical composition.Medicine group of the present invention Compound can be made into various suitable dosage forms according to method of administration.Using one or more physiologically acceptable carriers, tax is included Shape agent and auxiliary agent, they are conducive to for reactive compound to be processed into the preparation that can pharmaceutically use.Appropriate dosage form Depending on selected method of administration, can be prepared according to general knowledge well known in the art.
It is an object of the invention to provide the indoles shown in formula I or azaindole analog derivative or its officinal salt to exist Prepare the application in the medicine for adjusting uric acid level and/or treating gout and related indication.
It is an object of the invention to provide the indoles shown in formula I or azaindole analog derivative or its officinal salt or Prodrug pharmaceutical composition as active component is preparing adjusting uric acid level and/or is treating the medicine of gout and related indication In application.
Wherein, related indication includes：Hyperuricemia, urarthritis, inflammatory arthritis, nephrosis, renal lithiasis, Arthritis, urate crystal deposit in joint, urolithiasis, urate crystal deposit in kidney essence, gout is broken out, gout Stone gout or its combination.
Compound of the present invention or its pharmaceutically acceptable salt can be used as Unit Therapy, also can with it is another Kind or a variety of therapies are administered in combination.Play a role extremely for preventing or treating uric acid level in the mankind or other mammals The method of any disease or illness, the disease or illness include but not limited to：Hyperuricemia, gout, urarthritis, inflammation Disease property arthritis, nephrosis, renal lithiasis, arthritis, urate crystal deposit in joint, urolithiasis, urate crystal are in kidney Deposition, gout breaking-out, chalky gout or its combination in essence.
Compound and other therapeutic agents of the present invention it is specifically chosen by depending on the diagnosis of attending doctor and its a The judgement of the symptom of body and appropriate therapeutic scheme.Other medicaments are URAT1 inhibitor, xanthine oxidase inhibitor, Huang Purine dehydrogenase, xanthine oxidoreductase inhibitors, purine nucleoside phosphorylase inhibitor, uric acid transporter body inhibitor, Portugal Grape sugar transporters inhibitor, organic anion transporter (OAT) inhibitor, OAT-4 inhibitor or combination.Second medicament is preferably Allopurinol, Febuxostat, Topiroxostat or its combination.
Compound of the present invention, notable with therapeutic effect, side effect is low, and synthetic route is simple, and cost is low, product The features such as stable quality.
Embodiment
Technical scheme is further described below by specific embodiment, but not as the present invention Limitation.
1 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid (I 1)
Step 1：2- [(1H- indol-3-yls) sulfydryl] acetic acid
Indoles (2.9g) is dissolved in methanol (30mL), adds thiocarbamide (12g), iodine (6.4g) and potassium iodide are added dropwise at room temperature The mixed aqueous solution (50mL) of (4.2g), lower stirring reaction at room temperature, TLC monitoring is after the reaction was complete.Add NaOH solution (2M, 125mL), 100oC stirs 10min.Add methyl bromoacetate (4.9g), at room temperature stirring reaction 2h.TLC is after the reaction was complete.Acetic acid Ethyl ester (300mL) and water (100mL) extraction, ethyl acetate phase wash (100mL*4) with saturated common salt, and organic phase is through anhydrous slufuric acid Sodium is dried, and filtering, is concentrated under reduced pressure, column chromatography purifying (eluant, eluent, dichloromethane: methanol=10: 1, v: v), sterling 800mg is obtained, Yield 15.6%.
Step 2：2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid (I 1)
By 2- [(1H- indol-3-yls) sulfydryl] acetic acid (200mg), the bromo- 1- naphthonitriles (230mg) of 4-, CuI (100mg), Cs2CO3 (300mg), dimethylglycine (50mg) are added in DMSO (4mL), displacement argon gas protection, 130 DEG C of stirring reactions The reaction was complete for 12h, TLC detection, is cooled to room temperature, and adds ethyl acetate and saturated sodium bicarbonate solution, liquid separation, ethyl acetate phase Washed 3~5 times with saturated salt solution, dried with anhydrous sodium sulfate, filtered, be concentrated under reduced pressure, column chromatography purifying (eluant, eluent, dichloro Methane: methanol=10: 1, v: v), obtain sterling 80mg, yield 23.1%.LC-MS：m/z 359.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.59 (s, 1H), 8.38 (d, J=8,0Hz, 1H), 8.31 (d, J= 8.0Hz, 1H), 7.92 (t, J=7.2Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J= 7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 3.58 (s, 2H)
2 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] sodium acetate (I 2)
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid (100mg, 0.279mmol) is dissolved in In 5mL methanol, sodium hydroxide solution (1M, 0.279mL) is added, is stirred at room temperature 10 minutes, is concentrated under reduced pressure into dry, obtains white solid 106mg, yield 100%, LC-MS：m/z 359.1[M+H]+。
3 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] acetic acid (I 3)
Indoles is substituted by raw material of 7- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 1, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J= 7.6Hz,1H),3.79(s,2H).
4 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] sodium acetate (I 4)
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
5 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] acetic acid (I 5)
Indoles is substituted by raw material of 6- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 1, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.41 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 3.79(s,2H).
6 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] sodium acetate (I 6)
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
7 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] acetic acid (I 7) (Ⅰ7)
Indoles is substituted by raw material of 5- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 1, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.41 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 3.78(s,2H).
8 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] sodium acetate (I 8)
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
9 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] acetic acid (I 9)
Indoles is substituted by raw material of 4- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 1, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J= 7.6Hz,1H),3.78(s,2H).
10 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] sodium acetate (Ⅰ10)；
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
11 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- indol-3-yls] sulfydryl] propionic acid (I 11)
Substitute the bromo- 1- naphthonitriles of 4- and 2- methyl bromoacetates respectively using Isosorbide-5-Nitrae-dibromine naphthalene and 2 bromopropionic acid methyl esters as raw material, Synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 426.0[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.60 (s, 1H), 8.39 (d, J=8,0Hz, 1H), 8.34 (d, J= 8.0Hz, 1H), 7.92 (t, J=7.2Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J= 7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 4.48 (s, 1H), 1.76 (s, 3H)
12 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- indol-3-yls] sulfydryl] potassium propionate (I 12)
2- [[1- (4- cyano group is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- indol-3-yls] sulfydryl] propionic acid Naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, sodium hydroxide is substituted with potassium hydroxide, synthetic method is the same as described in embodiment 2 The preparation method of compound, LC-MS：m/z 426.0[M+H]+。
13 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] propionic acid (I 13)
Indoles is substituted by raw material of 7- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 427.0[M+H ]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J= 7.6Hz,1H),4.54(s,1H),1.79(s,3H).
14 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] potassium propionate (I 14)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
15 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] propionic acid (I 15)
Indoles is substituted by raw material of 6- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 427.0[M+H ]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.41 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 4.56(s,1H),1.77(s,3H).
16 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] potassium propionate (I 16)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
17 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] propionic acid (I 17)
Indoles is substituted by raw material of 5- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 427.0[M+H ]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.42 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 4.59(s,1H),1.80(s,3H).
18 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] potassium propionate (I 18)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
19 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] propionic acid (I 19)
Indoles is substituted by raw material of 4- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 427.0[M+H ]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J= 7.6Hz,1H),4.57(s,1H),1.79(s,3H).
20 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] potassium propionate (I 20)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
21 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] -2 Methylpropionic acid (I 21)
The bromo- 1- naphthonitriles of 4- and 2- bromine second are substituted as raw material using the bromo- 4- cyclopropyl naphthalenes of 1- and 2- isobutyl bromides methyl esters respectively Sour methyl esters, synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 402.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.51 (s, 1H), 8.39 (d, J=8,0Hz, 1H), 8.34 (d, J= 8.0Hz, 1H), 7.92 (t, J=7.2Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J= 7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 2.53-2.60 (m, 1H), 1.45 (s, 6H), 1.13-1.17 (m, 2H), 0.84-0.87(m,2H).
22 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] -2 Methylpropionic acid lithium (I 22)
2- is substituted by raw material of 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] -2 Methylpropionic acids [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with lithium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 402.1[M+H]+。
23 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] -2- first Base propionic acid (I 23)
Indoles is substituted by raw material of 7- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J= 7.6Hz,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
24 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] -2- first Base propionic acid lithium (I 24)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+。
25 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] -2- first Base propionic acid (I 25)
Indoles is substituted by raw material of 6- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.40 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.32 (d, J=8.4Hz, 1H), 7.96 (s, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
26 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] -2- first Base propionic acid lithium (I 26)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+。
27 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] -2- first Base propionic acid (I 27)
Indoles is substituted by raw material of 5- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.42 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
28 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] -2- first Base propionic acid lithium (I 28)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+。
29 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] -2- first Base propionic acid (I 29)
Indoles is substituted by raw material of 4- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 1, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.31 (d, J= 7.6Hz,1H),2.53-2.61(m,1H),1.46(s,6H),1.13-1.18(m,2H),0.83-0.86(m,2H).
30 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] -2- first Base propionic acid lithium (I 30)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+。
31 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] acetic acid (I 31)
Step 1：N- methyl indols
Indoles (1.2g, 10mmol) is added in 20mL DMF, adds potassium carbonate (2.8g, 20mmol) and iodomethane (2.8g, 20mmol), is heated to 40 DEG C of reaction 3h, is cooled to room temperature, add water and ethyl acetate extraction, ethyl ester is mutually washed with water two It is secondary, it is concentrated to dryness, post separation (eluant, eluent PE：EA=5:1) 1.0g oily liquids, yield 77%, are obtained
Step 2：1- methyl -3- bromo indoles
N- methyl indols (1.0g, 76mmol) are dissolved in 10mL DMF, NBS (1.1g, 92mmol) is added, is stirred at room temperature 2h, adds water and ethyl acetate extraction, and organic phase is washed with water twice, is concentrated to dryness, post separation post separation (eluant, eluent PE：EA= 5:1) 1.5g oily liquids, yield 94%, are obtained.
Step 3：4- (1- Methyl-1H-indole -3- bases) -1- naphthonitriles
By 1- methyl -3- bromo indoles (1.4g, 5mmol), 4- cyano group naphthalene -1- pinacol borates (1.5g, 5.5mmol), Potassium acetate (1.5g, 15mmol) and Pd (dppf) Cl2 (0.4g, 0.5mmol) are added in 10mL dioxane, are added 4mL water, are put Argon gas protection to be changed, 90 DEG C of reaction 3h is heated to, is cooled to room temperature, add water and ethyl acetate extraction, ethyl acetate phase is concentrated to dryness, Post separation (eluant, eluent PE：EA=3:1) solid 1.1g, yield 80%, are obtained.
Step 4：2- [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] acetic acid (I 31)
4- (1- Methyl-1H-indole -3- bases) -1- naphthonitriles (1.1g) are dissolved in methanol (10mL), add thiocarbamide (1.9g), is added dropwise iodine (1.0g) and the mixed aqueous solution (15mL) of potassium iodide (0.64g) at room temperature, at room temperature lower stirring reaction, TLC monitoring is after the reaction was complete.Add NaOH solution (2M, 10mL), 100oC stirrings 10min.Add methyl bromoacetate (0.78g), room temperature Lower stirring reaction 2h.TLC is after the reaction was complete.Ethyl acetate (100mL) and water (70mL) extraction, ethyl acetate phase are eaten with saturation Salt washes (50mL*4), and organic phase is dried over anhydrous sodium sulfate, and filtering, is concentrated under reduced pressure, column chromatography purifying (eluant, eluent, dichloromethane Alkane: methanol=10: 1, v: v), obtain sterling 196mg, yield 13.5%, LC-MS：m/z 373.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.60 (s, 1H), 8.39 (d, J=8,0Hz, 1H), 8.32 (d, J= 8.0Hz, 1H), 7.93 (t, J=7.2Hz, 1H), 7.84 (d, J=7.6Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 3.58 (s, 2H), 2.90 (s, 3H)
32 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] sodium acetate (I 32)
2- [[1- are substituted by raw material of 2- [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] acetic acid (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, synthetic method with compound described in embodiment 2 preparation method, LC-MS：m/z 373.1[M+H]+。
33 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] Acetic acid (I 33)
Indoles is substituted by raw material of 7- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 31, LC- MS：m/z 374.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.71 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.52 (t, J= 7.6Hz, 1H), 8.39 (d, J=8.4Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.34 (d, J=7.6Hz, 1H), 3.79 (s,2H).3.10(s,3H).
34 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] Sodium acetate (I 34)
Using 2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] acetic acid as Raw material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, and synthetic method is the same as change described in embodiment 2 The preparation method of compound, LC-MS：m/z 374.1[M+H]+。
35 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] Acetic acid (I 35)
Indoles is substituted by raw material of 6- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 31, LC- MS：m/z 374.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.41 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 3.79 (s, 2H) .3.11(s,3H).
36 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] Sodium acetate (I 36)
Using 2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] acetic acid as Raw material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, and synthetic method is the same as change described in embodiment 2 The preparation method of compound, LC-MS：m/z 374.1[M+H]+。
37 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] Acetic acid (I 37)；
Indoles is substituted by raw material of 5- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 31, LC- MS：m/z 374.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.40 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 3.78 (s, 2H), 3.11(s,3H).
38 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] Sodium acetate (I 38)
Using 2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] acetic acid as Raw material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, and synthetic method is the same as change described in embodiment 2 The preparation method of compound, LC-MS：m/z 374.1[M+H]+。
39 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] Acetic acid (I 39)
Indoles is substituted by raw material of 4- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 31, LC- MS：m/z 374.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 3.78 (s,2H),3.10(s,3H).
40 2- of embodiment [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] Sodium acetate (I 40)
Using 2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] acetic acid as Raw material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, and synthetic method is the same as change described in embodiment 2 The preparation method of compound, LC-MS：m/z 374.1[M+H]+。
41 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] propionic acid (I 41)
The bromo- 1- naphthonitriles of 4- are substituted by raw material of Isosorbide-5-Nitrae-dibromine naphthalene, 2- methyl bromoacetates are substituted with 2 bromopropionic acid methyl esters, are closed Preparation method into method with compound described in embodiment 31, LC-MS：m/z 440.0[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.60 (s, 1H), 8.39 (d, J=8,0Hz, 1H), 8.34 (d, J= 8.0Hz, 1H), 7.92 (t, J=7.2Hz, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 4.48 (s, 1H), 2.90 (s, 3H), 1.76 (s, 3H)
42 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] potassium propionate (I 42)
2- [[1- are substituted by raw material of 2- [[3- (4- bromonaphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] propionic acid (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, sodium hydroxide is substituted with potassium hydroxide, synthetic method is the same as implementation The preparation method of compound, LC-MS described in example 2：m/z 440.0[M+H]+。
43 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] third Sour (I 43)
Indoles is substituted by raw material of 7- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 441.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 4.54 (s,1H),3.14(s,3H).1.79(s,3H).
44 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] third Sour potassium (I 44)
Using 2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] propionic acid as original Material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide with potassium hydroxide, closes Preparation method into method with compound described in embodiment 2, LC-MS：m/z 441.0[M+H]+。
45 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] third Sour (I 45)
Indoles is substituted by raw material of 6- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 441.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.42 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 4.56 (s, 1H), 3.13(s,3H),1.77(s,3H).
46 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] third Sour potassium (I 46)
Using 2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] propionic acid as original Material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide with potassium hydroxide, closes Preparation method into method with compound described in embodiment 2, LC-MS：m/z 441.0[M+H]+。
47 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] third Sour (I 47)
Indoles is substituted by raw material of 5- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 441.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.42 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 4.59 (s, 1H), 3.14(s,3H),1.80(s,3H).
48 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] third Sour potassium (I 48)
Using 2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] propionic acid as original Material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide with potassium hydroxide, closes Preparation method into method with compound described in embodiment 2, LC-MS：m/z 441.0[M+H]+。
49 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] third Sour (I 49)
Indoles is substituted by raw material of 4- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 441.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 4.57 (s,1H),3.12(s,3H),1.79(s,3H).
50 2- of embodiment [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] third Sour potassium (I 50)
Using 2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] propionic acid as original Material substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide with potassium hydroxide, closes Preparation method into method with compound described in embodiment 2, LC-MS：m/z 441.0[M+H]+。
51 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] -2 Methylpropionic acid (Ⅰ51)
The bromo- 1- naphthonitriles of 4- and 2- bromine second are substituted as raw material using the bromo- 4- cyclopropyl naphthalenes of 1- and 2- isobutyl bromides methyl esters respectively Sour methyl esters, synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 416.2[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.51 (s, 1H), 8.39 (d, J=8,0Hz, 1H), 8.34 (d, J= 8.0Hz, 1H), 7.92 (t, J=7.2Hz, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 2.92 (s, 3H), 2.53-2.60 (m, 1H), 1.45 (s, 6H), 1.13-1.17 (m, 2H), 0.84- 0.87(m,2H).
52 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] -2 Methylpropionic acid Lithium (I 52)
Using 2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] -2 Methylpropionic acid as raw material 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted, sodium hydroxide, synthesis are substituted with lithium hydroxide Method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 416.2[M+H]+。
53 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid (I 53)
Indoles is substituted by raw material of 7- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 417.2[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 3.14 (s,3H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
54 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid lithium (I 54)
With 2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2- first Base propionic acid substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid for raw material, and hydrogen is substituted with lithium hydroxide Sodium oxide molybdena, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 417.2[M+H]+。
55 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid (I 55)
Indoles is substituted by raw material of 6- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 417.2[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.40 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.32 (d, J=8.4Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 3.13 (s, 3H), 2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
56 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid lithium (I 56)
With 2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2- first Base propionic acid substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid for raw material, and hydrogen is substituted with lithium hydroxide Sodium oxide molybdena, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 417.2[M+H]+。
57 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid (I 57)
Indoles is substituted by raw material of 5- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 417.2[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.42 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 3.13 (s, 3H), 2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
58 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid lithium (I 58)
With 2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2- first Base propionic acid substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid for raw material, and hydrogen is substituted with lithium hydroxide Sodium oxide molybdena, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 417.2[M+H]+。
59 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid (I 59)
Indoles is substituted by raw material of 4- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 31, LC-MS：m/z 417.2[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 3.15 (s,3H),2.53-2.61(m,1H),1.46(s,6H),1.13-1.18(m,2H),0.83-0.86(m,2H).
60 2- of embodiment [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] mercaptos Base] -2 Methylpropionic acid lithium (I 60)
With 2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2- first Base propionic acid substitutes 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid for raw material, and hydrogen is substituted with lithium hydroxide Sodium oxide molybdena, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 417.2[M+H]+。
61 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] acetic acid (I 61)
Step 1：2- [(1H- indoles -2- bases) sulfydryl] methyl acetate
2- chloro-indoles (3.0g, 20mmol), Anhydrous potassium carbonate (4.1g, 30mmol) are added in 50mL DMF, under stirring 2- methyl thioglycolates (2.7g, 25mmol) are added, being heated to 50 DEG C of reaction 2h, TLC detections, the reaction was complete, is cooled to room temperature, adds Enter ethyl acetate and water extraction, ethyl acetate phase is washed with water 2 times, is concentrated to dryness, column separating purification (eluant, eluent PE：EA=2:1), Obtain 3.1g oily liquids, yield 70%.
Step 2：2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] methyl acetate
By 2- [(1H- indoles -2- bases) sulfydryl] methyl acetate (2.2g), the bromo- 1- naphthonitriles (2.3g) of 4-, CuI (1.0g), Cs2CO3 (3.0g), dimethylglycine (500mg) are added in DMSO (50mL), displacement argon gas protection, 130 DEG C of stirring reactions 12h, is cooled to room temperature, and adds ethyl acetate and saturated water, liquid separation, and ethyl acetate phase is washed 2 times with saturated salt solution, and use is anhydrous Sodium sulphate is dried, and filtering, is concentrated under reduced pressure, column chromatography purifying (eluant, eluent, dichloromethane: methanol=10: 1, v: v), obtain sterling 0.9g, yield 24%.
Step 3：2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] acetic acid (I 61)
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] methyl acetate (0.5g, 1.3mmol) is dissolved in In 20mL THF, LiOH solution (1M, 20mL) is added, 2h is stirred at room temperature, TLC detects the dilute hydrochloric acid for without starting material left, adding 2N Adjust pH to 4~5, add ethyl acetate extraction, organic phase is washed with water 2 times, be concentrated under reduced pressure into it is dry, column chromatography purifying (eluant, eluent, Dichloromethane: methanol=10: 1, v: v), obtain sterling 0.4g, yield 83%, LC-MS：m/z 359.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.61 (s, 1H), 8.35 (d, J=8,0Hz, 1H), 8.30 (d, J= 8.0Hz, 1H), 7.91 (t, J=7.2Hz, 1H), 7.83 (d, J=7.6Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.22 (t, J=8.0Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 6.80 (s, 1H), 3.58 (s, 2H)
62 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] sodium acetate (I 62)
2- [[1- (4- cyano group is substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] acetic acid Naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS： m/z 359.1[M+H]+。
63 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] acetic acid (I 63)
Indoles is substituted by raw material of 7- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 61, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.90 (s,1H),3.79(s,2H).
64 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] sodium acetate (Ⅰ64)
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
65 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] acetic acid (I 65)
Indoles is substituted by raw material of 6- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 61, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.41 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.90 (s, 1H), 3.79(s,2H).
66 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] sodium acetate (Ⅰ66)
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
67 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] acetic acid (I 67)
Indoles is substituted by raw material of 5- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 61, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.41 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.92 (s, 1H), 3.78(s,2H).
68 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] sodium acetate (Ⅰ68)
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
69 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] acetic acid (I 69)
Indoles is substituted by raw material of 4- azaindoles, synthetic method is the same as the preparation method of compound described in embodiment 61, LC- MS：m/z 360.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.91 (s,1H),3.78(s,2H).
70 2- of embodiment [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] sodium acetate (Ⅰ70)
Substituted by raw material of 2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] acetic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, system of the synthetic method with compound described in embodiment 2 Preparation Method, LC-MS：m/z 360.1[M+H]+。
71 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] propionic acid (I 71)
Substitute the bromo- 1- naphthonitriles of 4- and 2- methyl bromoacetates respectively using Isosorbide-5-Nitrae-dibromine naphthalene and 2 bromopropionic acid methyl esters as raw material, Synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 426.0[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.60 (s, 1H), 8.39 (d, J=8,0Hz, 1H), 8.34 (d, J= 8.0Hz, 1H), 7.92 (t, J=7.2Hz, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 6.80 (s, 1H), 4.48 (s, 1H), 1.76 (s, 3H)
72 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] potassium propionate (I 72)
2- [[1- (4- cyano group is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] propionic acid Naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, sodium hydroxide is substituted with potassium hydroxide, synthetic method is the same as described in embodiment 2 The preparation method of compound, LC-MS：m/z 426.0[M+H]+。
73 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] propionic acid (I 73)
Indoles is substituted by raw material of 7- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 427.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.92 (s,1H),4.54(s,1H),1.79(s,3H).
74 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] potassium propionate (I 74)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
75 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] propionic acid (I 75)
Indoles is substituted by raw material of 6- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 427.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.41 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.92 (s, 1H), 4.56(s,1H),1.77(s,3H).
76 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] potassium propionate (I 76)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
77 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] propionic acid (I 77)
Indoles is substituted by raw material of 5- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 427.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.42 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.96 (s, 1H), 4.59(s,1H),1.80(s,3H).
78 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] potassium propionate (I 78)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
79 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] propionic acid (I 79)
Indoles is substituted by raw material of 4- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with Isosorbide-5-Nitrae-dibromine naphthalene, with 2 bromopropionic acid first Ester substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 427.0[M+ H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.96 (s,1H),4.57(s,1H),1.79(s,3H).
80 2- of embodiment [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] potassium propionate (I 80)
2- is substituted by raw material of 2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] propionic acid [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with potassium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 427.0[M+H]+。
81 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] -2 Methylpropionic acid (I 81)
The bromo- 1- naphthonitriles of 4- are substituted by raw material of the bromo- 4- cyclopropyl naphthalenes of 1-, 2- bromoacetic acids are substituted with 2- isobutyl bromides methyl esters Methyl esters, synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 402.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.51 (s, 1H), 8.39 (d, J=8,0Hz, 1H), 8.34 (d, J= 8.0Hz, 1H), 7.92 (t, J=7.2Hz, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.27 (t, J=8.0Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 7.03 (d, J=8.0Hz, 1H), 6.80 (s, 1H), 2.53-2.60 (m, 1H), 1.45 (s, 6H), 1.13-1.17 (m, 2H), 0.84- 0.87(m,2H).
82 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 82)
2- is substituted by raw material of 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] -2 Methylpropionic acids [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid, substitutes sodium hydroxide, synthetic method is same with lithium hydroxide The preparation method of compound, LC-MS described in embodiment 2：m/z 402.1[M+H]+。
83 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2- first Base propionic acid (I 83)
Indoles is substituted by raw material of 7- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.70 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (t, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 7.98 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.50 (t, J=8.0Hz, 1H), 7.45 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.93 (s,1H),2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
84 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2- first Base propionic acid lithium (I 84)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+。
85 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2- first Base propionic acid (I 85)
Indoles is substituted by raw material of 6- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.78 (s, 1H), 9.40 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.32 (d, J=8.4Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 6.95 (s, 1H), 2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
86 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2- first Base propionic acid lithium (I 86)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+。
87 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2- first Base propionic acid (I 87)
Indoles is substituted by raw material of 5- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.77 (s, 1H), 9.42 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.96 (s, 1H), 2.52-2.60(m,1H),1.44(s,6H),1.13-1.17(m,2H),0.83-0.87(m,2H).
88 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2- first Base propionic acid lithium (I 88)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+。
89 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2- first Base propionic acid (I 89)
Indoles is substituted by raw material of 4- azaindoles, the bromo- 1- naphthonitriles of 4- are substituted with the bromo- 4- cyclopropyl naphthalenes of 1-, with 2- bromines Methyl isobutyrate substitutes 2- methyl bromoacetates, and synthetic method is the same as the preparation method of compound described in embodiment 61, LC-MS：m/z 403.1[M+H]+。
1H NMR(400MHz,DMSO-d6)：δ=12.87 (s, 1H), 8.58 (d, J=6,4Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.33 (t, J=8.4Hz, 1H), 8.18 (d, J=7.6Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.73 (t, J=8.0Hz, 1H), 7.51 (t, J=8.0Hz, 1H), 7.44 (d, J=6.4Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 6.93 (s,1H),2.53-2.61(m,1H),1.46(s,6H),1.13-1.18(m,2H),0.83-0.86(m,2H).
90 2- of embodiment [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2- first Base propionic acid lithium (I 90)
With 2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid 2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid is substituted for raw material, hydroxide is substituted with lithium hydroxide Sodium, synthetic method is the same as the preparation method of compound described in embodiment 2, LC-MS：m/z 403.1[M+H]+.In vitro biological activity Evaluation
Test example 1,
The plasmid (EX-T4563-M03, GeneCopoeia) that total length human URAT 1 gene (SLC22A12) will be contained is transfected into In Flp-In T-REx-293 cells, URAT1 high expressing cell 293/hURAT1 are built, measure transfectional cell intake radioactivity is same The ability of position element mark uric acid.The work of compound is evaluated by measuring the ability of compounds block transfectional cell intake uric acid Property.
293/hURAT1 cells are inoculated in coated 96 orifice plate of poly D-Lys with the density of 40000 cells/wells It is incubated overnight in (BD, 356461).Culture medium is removed, adds reaction buffer (125mM sodium gluconates, the 4.8mM Portugals of preheating Grape saccharic acid potassium, 1.3mM calcium gluconates, 1.2mM potassium dihydrogen phosphates, 1.2mM magnesium sulfate, 5.6mM glucose, 25mM HEPES, PH7.4), it is incubated 10 minutes for 37 DEG C.Buffer solution is removed, addition contains 50 μM of 14C- uric acid (American Radiolabeled Chemicals, ARC0513) and the reaction buffer of compound or solvent, 37 DEG C are incubated 5 minutes.Buffer solution is removed, with slow Fliud flushing is washed 3 times.Add 100mM NaOH cell lysis 20 minutes.Cell pyrolysis liquid is transferred to Isoplate-96 orifice plates In (PerkinElmer, 6005040), scintillation fluor liquid is added, is counted in MicroBeta2 (PerkinElmer) counter.
Testing compound is dissolved in DMSO, and using the DMSO of same concentrations as the solvent control without compound. Using the intake of uric acid in the cell for containing DMSO solvent controls as 100%, cellular uptake in each test compound well is calculated The inhibiting rate percentage of uric acid, absorbs inhibiting rate by the uric acid of compound under various concentrations and calculates IC50 values.
Compound of the present invention is detected according to as above scheme, and partial results are shown in following table, wherein：
A represents that IC50 exists>In the range of 10 μM；
B represents IC50 in the range of 2 μM -10 μM；
C represents IC50 in the range of 0.1 μM -2 μM
Test example 2,
Biological acdtivity in vivo is evaluated
1) experiment material
Experimental animal：SD rats, male, weight ♂ 180-200g, 6-8 week old during reception.Animal adapts to 5 days in the environment After start to test.Weight ♂ 220-250g during experiment.It is purchased from Beijing HFK Bio-Technology Co., Ltd., SPF grades.
Test specimen：Compound of the present invention, Lesinurad (positive control), 0.5%CMC-Na are ground into homogeneous mixed Suspension.
Experiment reagent：
Oteracil Potassium, BJ140984206E, Hua Maike imports packing, room temperature preserve.Weighed with 1mg accuracy electronic balances Oteracil Potassium 12.5g, is put into mortar, adds a small amount of 0.5%CMC-Na to be ground dissolving, pours into graduated cylinder, adds 0.5% repeatedly CMC-Na carries out rinse to mortar, finally fills up 0.5%CMC-Na and is settled to 250ml (50mg/mL concentration).Refrigerator preserves.
Chloraldurate, lot number：20130116, Sinopharm Chemical Reagent Co., Ltd., room temperature preserves.With 1mg accuracy Electronic balance weighs chloraldurate 3.5g, is put into small beaker, with a small amount of physiological saline solution, is transferred in graduated cylinder, uses physiology Brine is settled to 100ml.Refrigerator preserves.For anaesthetizing.
Instrument and equipment：
Plum Teller ALC-210.3 electronic balances, precision 0.001mg, Beijing Sai Duolisi instrument systems Co., Ltd.Electronics Scale：Heng Xin Electronics Co., Ltd.s of Zhongshan city, model ACS, precision 0.1g
Rat metabolism cage：Suzhou City Feng Laboratory Animal Equipment Co., Ltd
Thunder Du's automatic clinical chemistry analyzer, Shenzhen Lei Du Instrument Ltd.
2) experimental method
Oteracil Potassium, which is given, using continuous gavage induces rat hyperuricemia model.Experimental animal divides at random according to weight Group, successive administration 7 days.Daily gavage give after all modeling of rat Oteracil Potassium 5mL/kg, 1h respectively gavage to each by reagent, Model group gavage gives equivalent solvent.It is administered after the 5th day medicine and metabolic cage is transferred to after 1h, after adapting to 1 day, 24h urine was collected in the 6th day Liquid, measures volume, and centrifuges 10min in 2000r/min room temperature, takes supernatant 1mL to carry out blood biochemistry detection.7th day administration 1h The eye corner of the eyes takes blood afterwards, and 5000r/min centrifugation 5min, take 4 DEG C of preservations of blood plasma, for Biochemical Indexes.
Measure uric acid (Urine in blood uric acid in serum (Serum Uric acid, SUA) and urine respectively using kit Uric Acid, UUA) it is horizontal.
3) data statistics
Enumeration data carries out statistical test using Radit methods, and measurement data is counted using Student t methods of inspection Learn and examine, judge significant difference between group.
4) experimental result
The result shows that compared with model group, after 7 days, serum Uric Acid Concentration significantly drops Oral Administration in Rats compound of the present invention Low, urine uric acid concentration dramatically increases, and shows that it has and promotes uric acid excretion, reduces the effect of serum uric acid level, and in the present invention The effect of I2, I8 under 40mg/kg dosage is suitable with Lesinurad 40mg/kg effects, prompts its internal anti-trioxypurine effect can Lesinurad can be better than.
1 blood uric acid of table and urine uric acid testing result
Note：Compared with model group, * P<0.05,**P<0.01
Due to being limited be subject to application documents length, in above-mentioned experiment, the present invention only enumerates section Example as experiment Medicine, but in fact, the compound being related in the scope of the present invention, can obtain same or similar beneficial effect Fruit.

Claims (15)

1. indoles or azaindole analog derivative shown in a kind of formula I, its pharmaceutically acceptable salt, solvate, hydration Thing or pharmaceutically acceptable prodrug, its structure are as follows：
Wherein：
X1, X2, X3, X4Independently selected from CH or N；
It is N to be up to one in X1, X2, X3, X4；
R1Selected from H or C1-3Alkyl；
W is represented：
Wherein：
R2Selected from H, cyano group, halogen, C1-6Alkyl or cycloalkyl；
Work as R1For H when, W works as R at 11For C1-3During alkyl, W is at 3；
Y is represented at 2 or 3：
Wherein：
R3, R4Independently selected from H or methyl；
M1Represent H or pharmaceutically acceptable cation.
2. indoles according to claim 1 or azaindole analog derivative, its pharmaceutically acceptable salt, solvation Thing, hydrate or pharmaceutically acceptable prodrug, it is characterised in that the structural formula of the compound is as follows：
Wherein,
X1, X2, X3, X4, R2, R3, R4, M1With claim 1.
3. indoles according to claim 1 or azaindole analog derivative, its pharmaceutically acceptable salt, solvation Thing, hydrate or pharmaceutically acceptable prodrug, it is characterised in that the structural formula of the compound is as follows：
Wherein,
X1, X2, X3, X4, R2, R3, R4, M1With claim 1.
4. indoles according to claim 1 or azaindole analog derivative, its pharmaceutically acceptable salt, solvation Thing, hydrate or pharmaceutically acceptable prodrug, it is characterised in that the structural formula of the compound is as follows：
Wherein,
X1, X2, X3, X4, R2, R3, R4, M1With claim 1.
5. indoles according to claim 1 or azaindole analog derivative, its pharmaceutically acceptable salt, solvation Thing, hydrate or pharmaceutically acceptable prodrug, it is characterised in that its pharmaceutical salts is Na, K, Li, Ca, Mg salt.
6. indoles according to claim 1 or azaindole analog derivative, its pharmaceutically acceptable salt, solvation Thing, hydrate or pharmaceutically acceptable prodrug, it is characterised in that the compound pharmaceutically acceptable salt is Na salt.
7. indoles according to claim 1 or azaindole analog derivative, its pharmaceutically acceptable salt, solvation Thing, hydrate or pharmaceutically acceptable prodrug, it is characterised in that the compound is selected from：
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] acetic acid (I 1)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] sodium acetate (I 2)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] acetic acid (I 3)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] sodium acetate (I 4)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] acetic acid (I 5)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] sodium acetate (I 6)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] acetic acid (I 7)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] sodium acetate (I 8)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] acetic acid (I 9)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] sodium acetate (I 10)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indol-3-yls] sulfydryl] propionic acid (I 11)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indol-3-yls] sulfydryl] potassium propionate (I 12)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] propionic acid (I 13)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] potassium propionate (I 14)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] propionic acid (I 15)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] potassium propionate (I 16)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] propionic acid (I 17)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] potassium propionate (I 18)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] propionic acid (I 19)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] potassium propionate (I 20)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] -2 Methylpropionic acid (I 21)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indol-3-yls] sulfydryl] -2 Methylpropionic acid lithium (I 22)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 23)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (I 24)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 25)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (I 26)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 27)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (I 28)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid (I 29)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridin-3-yl] sulfydryl] -2 Methylpropionic acid lithium (I 30)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] acetic acid (I 31)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] sodium acetate (I 32)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] acetic acid (I 33)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] sodium acetate (I 34)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] acetic acid (I 35)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] sodium acetate (I 36)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] acetic acid (I 37)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] sodium acetate (I 38)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] acetic acid (I 39)；
2- [[3- (4- cyano group naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] sodium acetate (I 40)；
2- [[3- (4- bromonaphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] propionic acid (I 41)；
2- [[3- (4- bromonaphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] potassium propionate (I 42)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] propionic acid (I 43)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] potassium propionate (I 44)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] propionic acid (I 45)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] potassium propionate (I 46)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] propionic acid (I 47)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] potassium propionate (I 48)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] propionic acid (I 49)；
2- [[3- (4- bromonaphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] potassium propionate (I 50)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] -2 Methylpropionic acid (I 51)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- Methyl-1H-indole -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 52)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (Ⅰ53)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid Lithium (I 54)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (Ⅰ55)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid Lithium (I 56)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (Ⅰ57)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid Lithium (I 58)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (Ⅰ59)；
2- [[3- (4- cyclopropyl naphthalene -1- bases) -1- methyl isophthalic acid H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid Lithium (I 60)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] acetic acid (I 61)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] sodium acetate (I 62)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] acetic acid (I 63)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] sodium acetate (I 64)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] acetic acid (I 65)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] sodium acetate (I 66)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] acetic acid (I 67)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] sodium acetate (I 68)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] acetic acid (I 69)；
2- [[1- (4- cyano group naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] sodium acetate (I 70)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] propionic acid (I 71)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] potassium propionate (I 72)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] propionic acid (I 73)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] potassium propionate (I 74)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] propionic acid (I 75)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] potassium propionate (I 76)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] propionic acid (I 77)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] potassium propionate (I 78)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] propionic acid (I 79)；
2- [[1- (4- bromonaphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] potassium propionate (I 80)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] -2 Methylpropionic acid (I 81)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- indoles -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 82)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 83)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 84)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 85)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [2,3-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 86)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 87)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-c] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 88)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid (I 89)；
2- [[1- (4- cyclopropyl naphthalene -1- bases) -1H- pyrrolo-es [3,2-b] pyridine -2- bases] sulfydryl] -2 Methylpropionic acid lithium (I 90)。
8. indoles or azaindole analog derivative described in claim 2, its pharmaceutically acceptable salt, solvate, water The preparation method of compound or pharmaceutically acceptable prodrug, it is characterised in that comprise the following steps：
(1) compound is reacted under the action of thiocarbamide, iodine and potassium iodide shown in formula II, adds chemical combination shown in NaOH and formula III Thing, compound shown in production IV：
(2) compound shown in formula IV reacts VI shownization of production with compound shown in formula V under the action of catalyst and alkali Compound：
(3) compound hydrolyzes compound shown in production VII in alkaline conditions shown in formula VI：
(4) compound shown in formula VII and compound, M shown in corresponding alkali reaction production VIII1Represent pharmaceutical acceptable cation：
9. indoles or azaindole analog derivative described in claim 3, its pharmaceutically acceptable salt, solvate, water The preparation method of compound or pharmaceutically acceptable prodrug, it is characterised in that comprise the following steps：
(1) compound shown in formula II and compound shown in iodomethane reaction production Ⅸ：
(2) compound shown in formula Ⅸ is under the action of halogenating agent, compound shown in production Ⅹ：
(3) compound shown in formula Ⅹ reacts Ⅻ shownization of production with compound shown in formula Ⅺ under the action of catalyst and alkali Compound：
(4) compound is reacted under the action of thiocarbamide, iodine and potassium iodide shown in formula Ⅻ, adds chemical combination shown in NaOH and formula III Thing, compound shown in production XIII：
(5) compound shown in Formula XIII is made to hydrolyze compound shown in production XIV in alkaline conditions：
(6) compound shown in Formula XIV is made to react compound shown in production XV, M with corresponding alkali1Represent pharmaceutical acceptable cation：
10. indoles or azaindole analog derivative described in claim 3, its pharmaceutically acceptable salt, solvate, water The preparation method of compound or pharmaceutically acceptable prodrug, it is characterised in that comprise the following steps：
(1) compound shown in Formula XVI and compound shown in the reaction production of compound shown in Formula XVI I XVIII are made：
(2) compound shown in formula XVIII and compound shown in the reaction production of compound shown in Formula V XIX：
(3) compound hydrolyzes compound shown in production XX in alkaline conditions shown in formula XIX：
(4) compound shown in formula XX and compound, M shown in corresponding alkali reaction production XXI1Represent pharmaceutical acceptable cation：
11. a kind of pharmaceutical composition, it is characterised in that with claim 1-7 any one of them indoles or Azaindoles Derivative, its pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable prodrug as pharmaceutical activity into Point.
12. the pharmaceutical composition described in claim 11, it is characterised in that the medicine of other antigouts can also be added, other Medicine is selected from：URAT1 inhibitor, xanthine oxidase inhibitor, xanthine dehydrogenase, xanthine oxidoreductase inhibitors, Purine nucleoside phosphorylase inhibitor, uric acid transporter body inhibitor, glucose transporter inhibitor, organic anion transporter (OAT) inhibitor, OAT-4 inhibitor or combination, second medicament are preferably Allopurinol, Febuxostat, Topiroxostat or its combination.
13. indoles or azaindole analog derivative described in claim 1, its pharmaceutically acceptable salt, solvate, water Compound or pharmaceutically acceptable prodrug, in the medicine for preparing the related indication for adjusting uric acid level and/or treating gout Application.
14. the pharmaceutical composition described in claim 11 is preparing adjusting uric acid level and/or is treating the related indication of gout Medicine in application.
15. the application according to claim 13 or 14, it is characterised in that its related indication is hyperuricemia, gout Property arthritis, inflammatory arthritis, urate crystal deposits in joint, urolithiasis, urate crystal deposit in kidney essence, Gout breaking-out, chalky gout or its combination.
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