CN105968111A - Pyridino-imidazole derivatives as well as preparation method and application thereof - Google Patents

Pyridino-imidazole derivatives as well as preparation method and application thereof Download PDF

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Publication number
CN105968111A
CN105968111A CN201610552230.8A CN201610552230A CN105968111A CN 105968111 A CN105968111 A CN 105968111A CN 201610552230 A CN201610552230 A CN 201610552230A CN 105968111 A CN105968111 A CN 105968111A
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base
pyridine
imidazo
sulfydryl
methylpropionic acid
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杨琰
扈占坤
王奇昌
秦至臻
王文峰
刘蕴秀
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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
    • 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 the field of medicine, and in particular relates to a series of pyridino-imidazole derivatives as well as preparation methods of pharmaceutical salts and pharmaceutically acceptable pro-drugs thereof, pharmaceutical compositions containing the pyridino-imidazole derivatives, and use of the pyridino-imidazole derivatives and the pharmaceutical compositions in preparation of anti-gout drugs and treatment of related diseases.

Description

Pyridine-imidazole analog derivative, its preparation method and application
Technical field
The invention belongs to field of medicaments, specifically, the present invention relates to a series of pyridine-imidazole analog derivative and can Pharmaceutical salts and the preparation method of pharmaceutically acceptable prodrug, comprise the pharmaceutical composition of described derivant and described derivative Thing and pharmaceutical composition purposes in preparing anti-gout drugs and treatment relevant disease.
Background technology
Gout is due to internal purine metabolic disturbance, and in blood, uric acid is too much, causes urate in joint, kidney and connective tissue Middle precipitation, thus cause gouty arthritis, gouty nephropathy and calculosis etc., medically it is referred to as gout.Primary disease is with joint Can find the single water Monosodium urate crystallization having two-fold photosensitiveness in liquid and tophus is its feature.Its Clinical symptoms is: hyperuricemia And urate crystal, the characteristic acute arthritis caused by deposition, tophus, interstitial nephritis, severe patient see joint deformity and Dysfunction, often accompanies uric acid lithangiuria, is more common in the fat middle-aging male of the bodily form and postmenopausal women.
Gout medication generally can be divided into 3 classes by its action character:
One is gout outbreak medicine.This kind of medicine has indomethacin (indometacin) and colchicines tablets.
Indomethacin has slight uricotelism, the pain caused when can eliminate gout outbreak.It is usually used in gout to send out Osteoarthrosis disease caused by work.Patient wants full wafer to swallow when taking this product, prohibits with gastric ulcer, epilepsy, psychotic patient Only take this medicine, the unsuitable long-term taking of this quasi drugs.
The toxic and side effects of colchicines tablets is relatively big, is only limited to the gouty attack,acute phase at present, and some patients is taking this product Time there is also the reaction such as vomiting, diarrhoea, the optimal dose of colchicine gout need to study further.
Two is uricosuric drug.Probenecid just belongs to this kind of medicine, its mainly suppression renal tubules to uratic heavy absorption, Increase uratic excretion, reduce uratic concentration in blood, prevent the generation of urate crystal, support the operation in joint, also Can promote that established urate is dissolved.This product, without anti-inflammatory and analgesic effect, is generally used for the treatment of chronic gout, or gout is extensive Multiple.
Three is that uric acid synthesizes blocker.Allopurinol belongs to this kind of medicine, and it mainly by suppression xanthine oxidase, stops body Interior hypoxanthine and xanthine metabolism are uric acid, thus reduce the generation of uric acid, can be used for constitutional, Secondary cases and chronic gout Sick treatment, this product can not control acute inflammation during gout outbreak, and must be about the acute stage of gout disappears two weeks after Can use.
Uric acid is the result of xanthine oxidation.Uric acid metabolism disease include but not limited to erythrocytosis, myeloid metaplasia, The outbreak of gout, repeatedly gout, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lay naphthalene Er Shi Syndrome, triumphant match two Cotard, nephropathy, renal calculus, renal failure, arthritis, arthritis, urinary calculus, lead poisoning, The uric acid metabolism exception relevant diseases such as sarcoidosis.
Carrying out Si Nuolei (Lesinurad) is a kind of orally active URAT1 inhibitor.Tie in I phase and II phase clinical research Fruit shows, carrys out Si Nuolei (Lesinurad) and is combined with xanthine oxidase inhibitor, can effectively regulate uric acid level, and have Higher-security, its molecular structure is as follows:
It is more weak to there is drug activity in Lesinurad, and dosage is big, brings the problems such as nephrotoxicity is high, needs clinically to develop medicine Imitate higher URAT1 inhibitor.We have surprisingly found that a class sulfur heterocyclic ring and derivant thereof have good studying URAT1 inhibitory action, in-vitro screening and pharmacological research are superior to Si Nuolei, and therefore the present invention develops a kind of therapeutic effect more Good anti-gout drugs.
Summary of the invention
First purpose of the present invention there are provided the pyridine-imidazole analog derivative representated by formula I, and pharmaceutically Acceptable salt, solvate, hydrate and pharmaceutically acceptable prodrug, its structure is as follows:
Wherein:
X1, X2, X3, X4 independence selected from CH or N；At least one of which is N；
R1, R2 are independently selected from H, cyano group, halogen, C1-6 alkyl or cycloalkyl, CF3, methoxyl group, ethyoxyl, carboxyl, acyl Amine, sulfonamide；
M is that H, C1-3 alkyl, carbonic ester, En Naka are than ester or pharmaceutically acceptable cation.
Preferably, the compounds of this invention is:
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 1)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 2)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ3)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-miaow Azoles also [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 4)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 5)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 6)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 7)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ8)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-miaow Azoles also [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 9)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 10)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 11)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 12)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ13)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-miaow Azoles also [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 14)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 15)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 16)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 17)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ18)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-miaow Azoles also [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 19)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 20)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 21)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 22)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 23)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazoles And [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 24)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 25)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 26)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 27)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 28)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazoles And [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 29)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 30)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 31)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 32)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 33)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazoles And [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 34)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 35)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 36)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 37)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 38)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazoles And [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 39)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 40)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 41)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ42)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 43)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H- Imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 44)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 45)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 46)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ47)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 48)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H- Imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 49)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 50)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 51)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ52)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 53)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H- Imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 54)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 55)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 56)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ57)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 58)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H- Imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 59)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 60)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 61)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 62)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ63)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-miaow Azoles also [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 64)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 65)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 66)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 67)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ68)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-miaow Azoles also [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 69)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 70)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 71)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 72)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ73)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-miaow Azoles also [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 74)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 75)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 76)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 77)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ78)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-miaow Azoles also [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 79)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 80)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 81)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 82)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 83)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carbamoyl naphthalene-1-base)- 3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 84)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 85)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 86)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 87)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 88)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carbamoyl naphthalene-1-base)- 3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 89)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 90)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 91)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 92)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 93)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carbamoyl naphthalene-1-base)- 1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 94)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 95)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 96)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 97)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 98)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carbamoyl naphthalene-1-base)- 1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 99)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 100)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (Ⅰ101)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Sodium (I 102)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Methyl ester (I 103)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)- 3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 104)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 105)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (Ⅰ106)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Sodium (I 107)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Methyl ester (I 108)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)- 3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 109)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 110)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (Ⅰ111)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Sodium (I 112)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Methyl ester (I 113)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)- 1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 114)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 115)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (Ⅰ116)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Sodium (I 117)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Methyl ester (I 118)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)- 1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 119)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2- Base] sulfydryl]-2 Methylpropionic acid ester (I 120)；
Counter structure formula is as follows:
It is further preferred that compound of the present invention is selected from:
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 1)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 2)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 6)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 7)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 11)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 12)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 16)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 51)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 66)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 81)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 91)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 92)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (Ⅰ101)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (Ⅰ116)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid Sodium (I 117)；
The invention still further relates to the one-tenth salt research of compound by above-mentioned formula I, include but not limited to Na, K, Li, Mg, Ca, Zn salt.
The invention still further relates to the pharmaceutically acceptable prodrug of this compound, include but not limited to ester, carbonic ester, grace that Card is than ester, sulfocarbonate, N-acyl derivative, N-acyloxy derivative, amino acid conjugates etc..
The present invention relates to a kind of pharmaceutical composition, this pharmaceutical composition comprises the compound or its carried in claim 1 Pharmaceutically acceptable salt, prodrug, hydrate, for treating the disease of the mankind.
Compound of the present invention or its pharmaceutically acceptable salt, solvate, prodrug can be as Unit Therapy Use, it is possible to co-administered with another kind of or multiple therapy.For preventing or treat uric acid water in the mankind or other mammals Any disease that flat exception plays a role or the method for disease, this disease or disease include but not limited to: hyperuricemia, bitterly Wind, gouty arthritis, inflammatory arthritis, nephropathy, nephrolithiasis, arthritis, urate crystal deposit in joint, urinary calculi Disease, urate crystal deposit in excess of the kidney matter, gout outbreak, chalky gout or a combination thereof.
The compound that the present invention relates to and the specifically chosen diagnosis that will depend upon which attending doctor of other therapeutic agents and individual The judgement of the condition of illness of body and suitable 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 a combination thereof.
Second object of the present invention be to provide pyridine-imidazole analog derivative representated by formula I or its officinal salt and The preparation method of prodrug.
The preparation method of the present invention, comprises the following steps:
(1) compound shown in compound shown in formula II and formula III is made to generate compound shown in formula IV under the effect of alkali:
(2) compound shown in production V under reducing agent effect of compound shown in formula IV is made:
(3) compound and thiophosgene shown in formula V is made to react compound shown in production VI:
(4) compound shown in formula VI is made to react chemical combination shown in production VII with 2-isobutyl ethyl bromide in the basic conditions Thing:
(5) compound shown in formula VII is made to hydrolyze compound shown in production VIII in the basic conditions:
(6) compound shown in formula VIII and compound shown in corresponding alkali reaction production Ⅸ, M are made1Represent pharmaceutically acceptable sun from Son:
(7) make compound and oxalyl chloride shown in formula Ⅸ react acylated, then react production Ⅹ institute with corresponding alcohol or ammonia Show compound, M2Represent C1-3Alkyl, carbonic ester, En Naka compare ester
Third object of the present invention is to provide a kind of pharmaceutical composition, containing representated by least one formula I Pyridine-imidazole analog derivative and officinal salt thereof or pharmaceutically acceptable prodrug.
As required, the pharmaceutical composition of the present invention can also add one or more pharmaceutically acceptable carrier or taxes Shape agent.
Weight shared by the pharmaceutical composition of the present invention, pyridine-imidazole analog derivative representated by formula I or its officinal salt Percentage ratio can be 0.1-99.9%, and remaining is pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention can be prepared as any pharmaceutically useful dosage form, and these dosage forms include: tablet, coated tablet Agent, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, Pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spray, Drop, patch.The preparation of the present invention, preferably peroral dosage form, such as: capsule, tablet, oral liquid, granule, pill, dissipate Agent, sublimed preparation, unguentum etc..
Route of administration of the present invention can be administered orally, non-bowel or topical, preferred oral and injection form are administered.Be suitable to Medicinal oral Preparation can be tablet, capsule, granule or other be suitable to medicinal liquid form preparation such as solution, Emulsion, suspending agent etc..Preferably oral formulations is tablet, and described tablet can be made coating, enteric, slow release or quantitatively release The form put.
The pharmaceutical composition of the present invention, the preparation of its oral administration can be containing conventional excipient, such as binding agent, filling Agent, diluent, tablet agent, lubricant, disintegrating agent, coloring agent, flavoring agent and wetting agent, can be coated tablet if desired.
The filler being suitable for includes the filler that cellulose, mannitol, lactose are similar with other.Suitable disintegrating agent bag Include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycollate.Suitable lubricant includes, the most firmly Fatty acid magnesium.Suitable pharmaceutically acceptable wetting agent includes sodium lauryl sulphate.
Can be filled by mixing, the method that tabletting etc. is commonly used prepares solid oral composition.Repeatedly mix and can make to live Property material is distributed in those compositionss of a large amount of filler of whole use.
The form of oral liquid can be such as aqueous or oily suspensions, solution, Emulsion, syrup or elixir, Or can be the compounding dry products of a kind of available water before use or other suitable carrier.This liquid preparation can contain Conventional additive, such as suspending agent, such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl fibre 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), the oily ester of the such as ester of almond oil, fractionated coconut oil, such as glycerol, Propylene glycol or ethanol；Preservative, such as para hydroxybenzene methyl ester or propyl p-hydroxybenzoate or sorbic acid, and if it is required, Can be containing conventional flavouring agent or coloring agent.
For injection, the fluid unit dosage form of preparation contains active substance and the sterile carrier of the present invention.According to carrier And concentration, this compound can be suspended or dissolve.The preparation of solution is typically by active substance is dissolved in a kind of load In body, filter-sterilized before being loaded into a kind of suitable bottle or ampoule, then seal.Such as a kind of local anesthesia of adjuvant Agent, preservative and buffer agent can also be dissolved in this carrier.In order to improve its stability, can be by this after loading bottle Plant compositions frost, and under vacuo water is removed.
The pharmaceutical composition of the present invention, optionally adds applicable pharmaceutically acceptable load when being prepared as medicament Body, described pharmaceutically acceptable carrier is selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, salt Acid cysteine, TGA, methionine, injection Vitamin B_6 DTA disodium, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence, acetic acid Salt, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, wheat Bud sugar, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and Derivant, alginate, gelatin, polyvinylpyrrolidone, glycerol, POLYSORBATE 80, agar, calcium carbonate, calcium bicarbonate, surface activity Agent, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc..
The compounds of this invention or its officinal salt can be individually or to be administered with the form of pharmaceutical composition.Medicine group of the present invention Compound can be made into various suitable dosage forms according to route of administration.Use one or more physiologically acceptable carriers, comprise tax Shape agent and auxiliary agent, they are conducive to reactive compound is processed into the preparation that can pharmaceutically use.Suitable dosage form Depend on selected route of administration, can be prepared according to general knowledge well known in the art.
Fourth object of the present invention is to provide pyridine-imidazole analog derivative and officinal salt thereof or prodrug in preparation Application in the medicine of regulation uric acid level and/or treatment gout.
5th purpose of the present invention be to provide using pyridine-imidazole analog derivative and officinal salt thereof or prodrug as The pharmaceutical composition of active component answering in the medicine of preparation regulation uric acid level and/or the relevant indication for the treatment of gout With.
Its relevant indication be hyperuricemia, gout, gouty arthritis, inflammatory arthritis, nephropathy, nephrolithiasis, Arthritis, urate crystal deposit in joint, urinary calculus, urate crystal deposit in excess of the kidney matter, gout is shown effect, gout Stone gout or a combination thereof.
Specific embodiment
Below by specific embodiment, technical scheme is further described, the enforcement wherein enumerated Example is the description of the invention, and limits its protection domain never in any form.
Embodiment 1 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 1)
Step 1:4-[(4-nitropyridine-3-base) amino]-1-naphthonitrile
4-amino-1-naphthonitrile (4g, 23.8mmol) is dissolved in 120ml DMF, is cooled to less than 0 DEG C, add NaH (1.2g, 30.5mmol), is stirred at room temperature 30min, is again cooled to less than 0 DEG C, addition 3-fluoro-4-nitropyridine (3.4g, 23.8mmol), 1.5h is stirred at room temperature, adds saturated ammonium chloride solution (20ml) cancellation, add saturated aqueous common salt (150ml) and separate out Solid, filters, obtains yellow solid, washs with ethanol (20mL), and solid (weight in wet base 8.5g) is directly used in next step reaction.
Step 2:4-[(4-aminopyridine-3-base) amino]-1-naphthonitrile
By 4-[(4-nitropyridine-3-base) amino]-1-naphthonitrile (8.5g, 23.8mmol theoretical maximum) and 2-sulfydryl third Acetoacetic ester (15.5g, 238mmol) adds in 50mL THF, adds saturated ammonium chloride solution (150mL), heats 40 DEG C of stirrings 2 little Time.Reaction system being cooled to room temperature, adds ethyl acetate extraction (100ml*2 time), organic facies concentrates, and obtains 4.3g yellow solid, Two step yields 70%
Step 3:4-(2-sulfydryl-3H-imidazo [4,5-c] pyridin-3-yl)-1-naphthonitrile
4-[(4-aminopyridine-3-base) amino]-1-naphthonitrile (1.24g, 4.78mmol) is dissolved in ethyl acetate (30mL) in, adding triethylamine (1.45g, 14.34mmol), dropping thiophosgene (1.1g, 9.56mmol), the lower reaction 1 of room temperature is little Time.Add water (50mL) washing, and organic facies is concentrated to dryness, and obtains solid 1.1g, yield 76%.
Step 4:2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acetoacetic ester
4-(2-sulfydryl-3H-imidazo [4,5-c] pyridin-3-yl)-1-naphthonitrile (0.60g, 2.0mmol) is dissolved in DMF (30mL) in, add potassium carbonate (0.55g, 4.0mmol), add 2-isobutyl ethyl bromide (0.39g, 2.0mmol), anti-at 45-50 DEG C Answer 2 hours.TLC (PE:EA=2:1) monitoring raw material reaction is complete.Add ethyl acetate (100mL) extraction, organic phase washed with water (100mL*3), saturated aqueous common salt washing (50mL*2), anhydrous sodium sulfate is dried, and concentrates, and residue is isolated and purified through silicagel column (eluant, petroleum ether: ethyl acetate=2: 1, v: v) obtain white crystalline thing 0.48g, yield 58%.
Step 5:2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 1)
By 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid second Ester (0.42g, 1.0mmol) is dissolved in 5ml methanol, adds the lithium hydroxide aqueous solution 10ml of 1N, is stirred at room temperature 2 hours.TLC examines Survey raw material reaction is complete, adds 2N salt acid for adjusting pH value to 4～5, adds ethyl acetate extraction, concentrate, and residue separates through silicagel column (eluant, dichloromethane: methanol=10: 1, v: v) obtain yellow solid 310mg, yield 80%, LC-MS:m/z 389.1 to purification [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.33 (s, 1H), 8.79 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.51 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),1.74(s,6H).
Embodiment 2 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 2)
By 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (100mg, 0.257mmol) is dissolved in 5mL methanol, adds sodium hydroxide solution (1M, 0.257mL), is stirred at room temperature 10 minutes, subtracts Pressure is concentrated to dryness, and obtains white solid 106mg, yield 100%, LC-MS:m/z 389.1 [M+H]+。
Embodiment 3 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 3)
By 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (200mg, 0.515mmol) is dissolved in the dichloromethane that 10mL is dried, and adds oxalyl chloride (80mg, 0.702mmol) and 1 DMF Catalysis, is stirred at room temperature 1h, TLC and detects without starting material left, be evaporated to do.Add absolute methanol 5mL, be stirred at room temperature 30 points Clock, is evaporated to do, and obtains white solid 207mg, yield 100%, LC-MS:m/z 403.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.80 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.51 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.78 (s,3H)1.74(s,6H).
Embodiment 4 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group naphthalene-1- Base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 4)
By 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (100mg, 0.257mmol) is dissolved in the dichloromethane that 5mL is dried, and adds oxalyl chloride (45mg, 0.351mmol) and 1 DMF urges Change, 1h, TLC are stirred at room temperature and detect without starting material left, be evaporated to do, residue be dissolved in the dichloromethane that 5mL is dried, add Enter 4-(methylol)-5-methyl-[1,3] dioxole-2-ketone (46mg, 0.351mmol) and triethylamine (71mg, 0.702mmol), under nitrogen protection, it is heated to 40 DEG C, reacts 3 hours.By reaction system concentrating under reduced pressure, residue is through silicagel column It is isolated and purified that (eluant, petroleum ether: ethyl acetate=5: 1, v: v) obtain 77mg white solid, and yield is 60%, LC-MS:m/z 501.1[M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.78 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.50 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.85 (s,2H),2.67(s,3H),1.74(s,6H).
Embodiment 5 1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid ester (I 5)
Isobutyryl chloride (59mg, 0.554mmol) is dissolved in the dichloromethane that 5mL is dried, adds the zinc chloride of catalytic amount, Displacement argon shield, is cooled to-5 DEG C, adds acetaldehyde (26.8mg, 0.609mmol), is warmed to room temperature stirring 1 hour, in system Addition 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (100mg, 0.257mmol), add triethylamine (84mg, 0.831mmol), be heated to 40 DEG C, react 3h.It is evaporated to do by system, surplus Through silicagel column, isolated and purified (eluant, petroleum ether: ethyl acetate=10: 1, v: v) obtain 84mg white solid to excess, and yield is 65%, LC-MS:m/z 503.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.79 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.51 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.45- 6.50 (m, 1H), 2.76-2.80 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.74 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 6 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 6)
With 2-fluoro-3-nitropyridine for raw material substitution 3-fluoro-4-nitropyridine, synthetic method is with chemical combination described in embodiment 1 The preparation method of thing, LC-MS:m/z 389.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.02 (s, 1H), 8.43 (d, J=7.6Hz, 1H), 8.31 (d, J= 9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 1.67 (s, 6H).
Embodiment 7 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 7)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 389.1 [M+H]+。
Embodiment 8 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 8)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 403.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.46 (d, J=7.6Hz, 1H), 8.34 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.60 (s, 3H), 1.65 (s, 6H).
Embodiment 9 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group naphthalene-1- Base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 9)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 71%, LC-MS:m/z 501.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.47 (d, J=7.6Hz, 1H), 8.35 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.60 (s, 2H), 2.59 (s, 3H), 1.63 (s, 6H).
Embodiment 10 1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 10)；
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 65%, LC-MS:m/z 503.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.42 (d, J=7.6Hz, 1H), 8.32 (d, J=9.2Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.66 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 11 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 11)
With 4-fluoro-3-nitropyridine for raw material substitution 3-fluoro-4-nitropyridine, synthetic method is with chemical combination described in embodiment 1 The preparation method of thing, LC-MS:m/z 389.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.93 (s, 1H), 9.50 (s, 1H), 8.62 (d, J=6,0Hz, 1H), 8.51 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J= 8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),1.75(s,6H).
Embodiment 12 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 12)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 389.1 [M+H]+。
Embodiment 13 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 13)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 403.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.51 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.50 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.70 (s,3H),1.75(s,6H).。
Embodiment 14 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group naphthalene-1- Base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 14)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 67%, LC-MS:m/z 501.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.52 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.50 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.81 (s,2H),2.65(s,3H),1.74(s,6H)。
Embodiment 15 1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 15)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 61%, LC-MS:m/z 503.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.53 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.51 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.45- 6.50 (m, 1H), 2.75-2.80 (m, 1H), 1.74 (s, 6H), 1.67 (d, J=10.8Hz, 3H), 1.03 (d, J=9.6Hz, 6H)。
Embodiment 16 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 16)
With 3-fluoro-2-nitropyridine for raw material substitution 3-fluoro-4-nitropyridine, synthetic method is with chemical combination described in embodiment 1 The preparation method of thing, LC-MS:m/z 389.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.01 (s, 1H), 8.56 (d, J=7.2Hz, 1H), 8.41 (d, J= 9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J= 8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.66 (s, 6H).
Embodiment 17 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 17)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 389.1 [M+H]+。
Embodiment 18 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 18)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 403.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.57 (d, J=7.6Hz, 1H), 8.44 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.65 (s, 3H), 1.68 (s, 6H).
Embodiment 19 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group naphthalene-1- Base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 19)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 65%, LC-MS:m/z 501.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.62 (d, J=7.2Hz, 1H), 8.45 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.63 (s, 6H).
Embodiment 20 1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 20)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 60%, LC-MS:m/z 503.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.52 (d, J=7.2Hz, 1H), 8.42 (d, J=9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.66 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 21 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 21)
With the bromo-naphthalidine of 4-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 1 Preparation method, LC-MS:m/z 442.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.23 (s, 1H), 8.78 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),1.77(s,6H).
Embodiment 22 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 22)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 422.0 [M+H]+。
Embodiment 23 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 23)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 456.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.81 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.50 (d, J= 7.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.78 (s,3H)1.75(s,6H)。
Embodiment 24 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-bromonaphthalene-1-base)- 3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 24)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 62%, LC-MS:m/z 554.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.77 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.49 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.06-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.85 (s,2H),2.66(s,3H),1.73(s,6H).
Embodiment 25 1-(isobutyryl epoxide) ethyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid ester (I 25)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 556.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.77 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.48 (d, J= 7.6Hz, 1H), 8.35 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.97 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.44- 6.50 (m, 1H), 2.76-2.80 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.74 (s, 6H), 1.01 (d, J=9.6Hz, 6H)。
Embodiment 26 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 26)
With the bromo-naphthalidine of 4-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 6 Preparation method, LC-MS:m/z 442.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.11 (s, 1H), 8.45 (d, J=7.2Hz, 1H), 8.31 (d, J= 9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J= 8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.64 (s, 6H).
Embodiment 27 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 27)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 442.0 [M+H]+。
Embodiment 28 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 28)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 456.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.46 (d, J=7.6Hz, 1H), 8.33 (d, J=9.6Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.65 (s, 3H), 1.67 (s, 6H).
Embodiment 29 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-bromonaphthalene-1-base)- 3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 29)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 63%, LC-MS:m/z 554.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.43 (d, J=7.2Hz, 1H), 8.34 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.66 (s, 6H).
Embodiment 30 1-(isobutyryl epoxide) ethyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid ester (I 30)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 59%, LC-MS:m/z 556.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.42 (d, J=7.2Hz, 1H), 8.33 (d, J=9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.66 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 31 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 31)
With the bromo-naphthalidine of 4-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 11 Preparation method, LC-MS:m/z 442.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.99 (s, 1H), 9.51 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.52 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J= 8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),1.76(s,6H).
Embodiment 32 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 32)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 442.0 [M+H]+。
Embodiment 33 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 33)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 456.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.52 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.49 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.70 (s,3H),1.74(s,6H).。
Embodiment 34 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-bromonaphthalene-1-base)- 1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 34)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 69%, LC-MS:m/z 554.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.50 (s, 1H), 8.62 (d, J=6,0Hz, 1H), 8.51 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.81 (s,2H),2.66(s,3H),1.77(s,6H)。
Embodiment 35 1-(isobutyryl epoxide) ethyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid ester (I 35)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 60%, LC-MS:m/z 556.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.53 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.45- 6.50 (m, 1H), 2.75-2.80 (m, 1H), 1.74 (s, 6H), 1.67 (d, J=10.8Hz, 3H), 1.01 (d, J=9.6Hz, 6H)。
Embodiment 36 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 36)
With the bromo-naphthalidine of 4-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 16 Preparation method, LC-MS:m/z 442.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.21 (s, 1H), 8.55 (d, J=7.2Hz, 1H), 8.40 (d, J= 9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J= 8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.65 (s, 6H).
Embodiment 37 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid sodium (I 37)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 442.0 [M+H]+。
Embodiment 38 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid methyl ester (I 38)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 456.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.58 (d, J=7.6Hz, 1H), 8.46 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.69 (s, 3H), 1.69 (s, 6H).
Embodiment 39 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-bromonaphthalene-1-base)- 1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 39)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 554.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.61 (d, J=7.2Hz, 1H), 8.43 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.64 (s, 6H).
Embodiment 40 1-(isobutyryl epoxide) ethyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid ester (I 40)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto into Base]-2 Methylpropionic acid, yield 57%, LC-MS:m/z 556.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.54 (d, J=7.2Hz, 1H), 8.45 (d, J=9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.69 (s, 6H), 1.04 (d, J=9.6Hz, 6H).
Embodiment 41 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-first Base propanoic acid (I 41)
With 4-cyclopropyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with chemical combination described in embodiment 1 The preparation method of thing, LC-MS:m/z 404.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.43 (s, 1H), 8.88 (s, 1H), 8.59 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),1.77(s,6H).
Embodiment 42 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-first Base sodium propionate (I 42)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 404.1 [M+H]+。
Embodiment 43 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-first Base methyl propionate (I 43)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 418.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.84 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.49 (d, J= 7.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.78 (s,3H)1.78(s,6H)。
Embodiment 44 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyclopropyl naphthalene-1- Base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 44)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 62%, LC-MS:m/z 516.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.76 (s, 1H), 8.55 (d, J=6,4Hz, 1H), 8.49 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.06-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.85 (s,2H),2.66(s,3H),1.74(s,6H).
Embodiment 45 1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 45)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 556.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.75 (s, 1H), 8.54 (d, J=6,4Hz, 1H), 8.48 (d, J= 7.6Hz, 1H), 8.35 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.97 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.44- 6.50 (m, 1H), 2.76-2.80 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.74 (s, 6H), 1.02 (d, J=9.6Hz, 6H)。
Embodiment 46 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl-prop Acid (I 46)
With 4-cyclopropyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with chemical combination described in embodiment 6 The preparation method of thing, LC-MS:m/z 404.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.15 (s, 1H), 8.44 (d, J=7.2Hz, 1H), 8.31 (d, J= 9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J= 8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.65 (s, 6H).
Embodiment 47 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-first Base sodium propionate (I 47)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 404.1 [M+H]+。
Embodiment 48 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-first Base methyl propionate (I 48)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 418.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.45 (d, J=7.6Hz, 1H), 8.33 (d, J=9.6Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.65 (s, 3H), 1.66 (s, 6H).
Embodiment 49 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyclopropyl naphthalene-1- Base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 49)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 516.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.42 (d, J=7.2Hz, 1H), 8.32 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.66 (s, 6H).
Embodiment 50 1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 50)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 59%, LC-MS:m/z 518.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.44 (d, J=7.2Hz, 1H), 8.34 (d, J=9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.66 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 51 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-first Base propanoic acid (I 51)
With 4-cyclopropyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with chemical combination described in embodiment 11 The preparation method of thing, LC-MS:m/z 442.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.95 (s, 1H), 9.52 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.52 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J= 8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),1.78(s,6H).
Embodiment 52 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-first Base sodium propionate (I 52)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 404.1 [M+H]+。
Embodiment 53 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-first Base methyl propionate (I 53)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 417.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.51 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.49 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.70 (s,3H),1.74(s,6H).。
Embodiment 54 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyclopropyl naphthalene-1- Base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 54)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 69%, LC-MS:m/z 516.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.50 (s, 1H), 8.62 (d, J=6,0Hz, 1H), 8.51 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.81 (s,2H),2.66(s,3H),1.77(s,6H)。
Embodiment 55 1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 55)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 61%, LC-MS:m/z 518.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.54 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.45- 6.50 (m, 1H), 2.75-2.80 (m, 1H), 1.74 (s, 6H), 1.67 (d, J=10.8Hz, 3H), 1.03 (d, J=9.6Hz, 6H)。
Embodiment 56 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-first Base propanoic acid (I 56)
With 4-cyclopropyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with chemical combination described in embodiment 16 The preparation method of thing, LC-MS:m/z 404.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.21 (s, 1H), 8.55 (d, J=7.2Hz, 1H), 8.40 (d, J= 9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J= 8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.65 (s, 6H).
Embodiment 57 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-first Base sodium propionate (I 57)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 404.1 [M+H]+。
Embodiment 58 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-first Base methyl propionate (I 58)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 418.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.59 (d, J=7.6Hz, 1H), 8.45 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.69 (s, 3H), 1.69 (s, 6H).
Embodiment 59 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyclopropyl naphthalene-1- Base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 59)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 516.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.62 (d, J=7.2Hz, 1H), 8.46 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.65 (s, 6H).
Embodiment 60 1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 60)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-into Base] sulfydryl]-2 Methylpropionic acid, yield 57%, LC-MS:m/z 518.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.55 (d, J=7.2Hz, 1H), 8.43 (d, J=9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.69 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 61 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 61)
With 4-carboxyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 1 Preparation method, LC-MS:m/z 408.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.23 (s, 1H), 11.54 (s, 1H), 8.78 (s, 1H), 8.56 (d, J =6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4, 3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 1.77 (s, 6H).
Embodiment 62 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 62)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 408.1 [M+H]+。
Embodiment 63 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 63)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 422.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.59 (s, 1H), 8.81 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.50 (d, J=7.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),3.78(s,3H)1.75(s,6H)。
Embodiment 64 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carboxyl naphthalene-1- Base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 64)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 62%, LC-MS:m/z 520.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.56 (s, 1H), 8.77 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.49 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.06-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),4.85(s,2H),2.66(s,3H),1.73(s,6H).
Embodiment 65 1-(isobutyryl epoxide) ethyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 65)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 522.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.58 (s, 1H), 8.77 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.48 (d, J=7.6Hz, 1H), 8.35 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.97 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.44-6.50 (m, 1H), 2.76-2.80 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.74 (s, 6H), 1.01 (d, J= 9.6Hz,6H)。
Embodiment 66 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 66)
With 4-carboxyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 6 Preparation method, LC-MS:m/z 408.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.11 (s, 1H), 11.68 (s, 1H), 8.45 (d, J=7.2Hz, 1H), 8.31 (d, J=9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.64 (s, 6H).
Embodiment 67 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 67)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 408.1 [M+H]+。
Embodiment 68 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 68)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 422.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.67 (s, 1H), 8.46 (d, J=7.6Hz, 1H), 8.33 (d, J= 9.6Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.65 (s, 3H), 1.67 (s, 6H).
Embodiment 69 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carboxyl naphthalene-1- Base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 69)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 57%, LC-MS:m/z 520.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.64 (s, 1H), 8.43 (d, J=7.2Hz, 1H), 8.34 (d, J= 9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.66 (s, 6H).
Embodiment 70 1-(isobutyryl epoxide) ethyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 70)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 59%, LC-MS:m/z 522.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.65 (s, 1H), 8.42 (d, J=7.2Hz, 1H), 8.33 (d, J= 9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.66 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 71 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 71)
With 4-carboxyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 11 Preparation method, LC-MS:m/z 408.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.99 (s, 1H), 11.85 (s, 1H), 9.51 (s, 1H), 8.61 (d, J =6,0Hz, 1H), 8.52 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07- 8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J= 10.4,8,4Hz,1H),1.76(s,6H).
Embodiment 72 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 72)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 408.1 [M+H]+。
Embodiment 73 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 73)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 422.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.82 (s, 1H), 9.52 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.49 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J= 8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),3.70(s,3H),1.74(s,6H).。
Embodiment 74 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carboxyl naphthalene-1- Base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 74)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 61%, LC-MS:m/z 520.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.80 (s, 1H), 9.52 (s, 1H), 8.62 (d, J=6,0Hz, 1H), 8.51 (d, J=7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J= 8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H),4.81(s,2H),2.66(s,3H),1.77(s,6H)。
Embodiment 75 1-(isobutyryl epoxide) ethyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 75)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 56%, LC-MS:m/z 522.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.89 (s, 1H), 9.53 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.52 (d, J=7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J= 8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.45-6.50 (m, 1H), 2.75-2.80 (m, 1H), 1.74 (s, 6H), 1.67 (d, J=10.8Hz, 3H), 1.01 (d, J =9.6Hz, 6H).
Embodiment 76 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Propanoic acid (I 76)
With 4-carboxyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with compound described in embodiment 16 Preparation method, LC-MS:m/z 408.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.21 (s, 1H), 11.82 (s, 1H), 8.55 (d, J=7.2Hz, 1H), 8.40 (d, J=9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.65 (s, 6H).
Embodiment 77 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Sodium propionate (I 77)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 408.1 [M+H]+。
Embodiment 78 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2-methyl Methyl propionate (I 78)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 422.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.82 (s, 1H), 8.58 (d, J=7.6Hz, 1H), 8.46 (d, J= 9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.69 (s, 3H), 1.69 (s, 6H).
Embodiment 79 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carboxyl naphthalene-1- Base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 79)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 520.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.78 (s, 1H), 8.62 (d, J=7.2Hz, 1H), 8.43 (d, J= 9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.64 (s, 6H).
Embodiment 80 1-(isobutyryl epoxide) ethyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 80)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid changes 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] into Sulfydryl]-2 Methylpropionic acid, yield 57%, LC-MS:m/z 522.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=11.88 (s, 1H), 8.54 (d, J=7.2Hz, 1H), 8.45 (d, J= 9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.69 (s, 6H), 1.04 (d, J=9.6Hz, 6H).
Embodiment 81 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 81)
With 4-carbamoyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with described in embodiment 1 The preparation method of compound, LC-MS:m/z 407.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.23 (s, 1H), 8.78 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.53 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J= 10.4,8,4Hz,1H),1.77(s,6H).
Embodiment 82 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (I 82)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 83 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 83)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.81 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.50 (d, J= 7.6Hz, 1H), 8.38 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8, 4Hz,1H),3.78(s,3H)1.75(s,6H)。
Embodiment 84 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carbamoyl Naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 84)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 62%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.77 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.49 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.06-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8, 4Hz,1H),4.85(s,2H),2.66(s,3H),1.73(s,6H).
Embodiment 85 1-(isobutyryl epoxide) ethyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5- C] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 85)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 521.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.77 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.48 (d, J= 7.6Hz, 1H), 8.35 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.97 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8, 4Hz, 1H), 6.44-6.50 (m, 1H), 2.76-2.80 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.74 (s, 6H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 86 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 86)
With 4-carbamoyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with described in embodiment 6 The preparation method of compound, LC-MS:m/z 407.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.11 (s, 1H), 8.45 (d, J=7.2Hz, 1H), 8.31 (d, J= 9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.56 (t, J=8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.64 (s, 6H).
Embodiment 87 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (I 87)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 88 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 88)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.46 (d, J=7.6Hz, 1H), 8.33 (d, J=9.6Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.36 (t, J= 8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.65 (s, 3H), 1.67 (s, 6H).
Embodiment 89 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carbamoyl Naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 89)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 63%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.43 (d, J=7.2Hz, 1H), 8.34 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.66 (s, 6H).
Embodiment 90 1-(isobutyryl epoxide) ethyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5- B] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 90)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 59%, LC-MS:m/z 521.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.42 (d, J=7.2Hz, 1H), 8.33 (d, J=9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.66 (s, 6H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 91 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 91)
With 4-carbamoyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with described in embodiment 11 The preparation method of compound, LC-MS:m/z 407.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.99 (s, 1H), 9.51 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.52 (d, J=7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J= 8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.32-7.39 (dd, J= 10.4,8,4Hz,1H),1.76(s,6H).
Embodiment 92 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (I 92)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 93 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 93)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.52 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.49 (d, J= 7.6Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.32-7.39 (dd, J=10.4,8, 4Hz,1H),3.70(s,3H),1.74(s,6H).。
Embodiment 94 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carbamoyl Naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 94)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 65%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.50 (s, 1H), 8.62 (d, J=6,0Hz, 1H), 8.51 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.32-7.39 (dd, J=10.4,8, 4Hz,1H),4.81(s,2H),2.66(s,3H),1.77(s,6H)。
Embodiment 95 1-(isobutyryl epoxide) ethyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5- C] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 95)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 60%, LC-MS:m/z 521.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.53 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.52 (d, J= 7.6Hz, 1H), 8.37 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.60 (s, 2H), 7.32-7.39 (dd, J=10.4,8, 4Hz, 1H), 6.45-6.50 (m, 1H), 2.75-2.80 (m, 1H), 1.74 (s, 6H), 1.67 (d, J=10.8Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 96 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 96)
With 4-carbamoyl-naphthalidine for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with described in embodiment 16 The preparation method of compound, LC-MS:m/z 407.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.21 (s, 1H), 8.55 (d, J=7.2Hz, 1H), 8.40 (d, J= 9.6Hz, 1H), 8.18 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.55 (t, J=8.0Hz, 1H), 7.12 (d, J=8.8Hz, 1H), 1.65 (s, 6H).
Embodiment 97 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (I 97)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 98 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 98)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.58 (d, J=7.6Hz, 1H), 8.46 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.36 (t, J= 8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.69 (s, 3H), 1.69 (s, 6H).
Embodiment 99 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carbamoyl Naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 99)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 67%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.61 (d, J=7.2Hz, 1H), 8.43 (d, J=9.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63 (s, 2H), 2.59 (s, 3H), 1.64 (s, 6H).
Embodiment 100 1-(isobutyryl epoxide) ethyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4, 5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 100)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 57%, LC-MS:m/z 521.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.54 (d, J=7.2Hz, 1H), 8.45 (d, J=9.6Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.60 (s, 2H), 7.36 (t, J= 8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.69 (s, 6H), 1.04 (d, J=9.6Hz, 6H).
Embodiment 101 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 101)
With the 4-fluoro-naphthalidine of cyano group-5-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is changed with described in embodiment 1 The preparation method of compound, LC-MS:m/z 407.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.23 (s, 1H), 8.78 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74- 7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 1.77 (s, 6H).
Embodiment 102 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (I 102)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 103 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 103)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.81 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.38 (d, J= 8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.78 (s, 3H) 1.75 (s, 6H).
Embodiment 104 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group-5-fluorine Naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 104)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 65%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.77 (s, 1H), 8.56 (d, J=6,4Hz, 1H), 8.36 (d, J= 8.4Hz, 1H), 8.06-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.85 (s, 2H), 2.66 (s, 3H), 1.73 (s,6H).
Embodiment 105 1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5- C] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 105)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 61%, LC-MS:m/z 521.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.77 (s, 1H), 8.53 (d, J=6,4Hz, 1H), 8.35 (d, J= 8.4Hz, 1H), 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.97 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.55 (d, J=6.4Hz, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.44-6.50 (m, 1H), 2.76-2.80 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.74 (s, 6H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 106 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 106)
With the 4-fluoro-naphthalidine of cyano group-5-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is changed with described in embodiment 6 The preparation method of compound, LC-MS:m/z 407.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.11 (s, 1H), 8.45 (d, J=7.2Hz, 1H), 8.18 (d, J= 8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 7.12 (d, J= 8.8Hz,1H),1.64(s,6H)。
Embodiment 107 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (I 107)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 108 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 108)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.46 (d, J=7.6Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.65(s,3H),1.67(s,6H)。
Embodiment 109 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group-5-fluorine Naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 29)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.43 (d, J=7.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63(s,2H),2.59(s,3H),1.66(s,6H),.
Embodiment 110 1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5- B] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 110)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 59%, LC-MS:m/z 521.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.42 (d, J=7.2Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.66 (s, 6H), 1.02 (d, J= 9.6Hz,6H)。
Embodiment 111 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 111)
With the 4-fluoro-naphthalidine of cyano group-5-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with described in embodiment 11 The preparation method of compound, LC-MS:m/z 442.0 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.99 (s, 1H), 9.51 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.36 (d, J=8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J =7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 1.76 (s, 6H).
Embodiment 112 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (I 112)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 113 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 113)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.52 (s, 1H), 8.60 (d, J=6,0Hz, 1H), 8.36 (d, J= 8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 3.70 (s, 3H), 1.74 (s, 6H)..
Embodiment 114 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group-5-fluorine Naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 114)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 68%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.50 (s, 1H), 8.62 (d, J=6,0Hz, 1H), 8.37 (d, J= 8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 4.81 (s, 2H), 2.66 (s, 3H), 1.77 (s,6H)。
Embodiment 115 1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5- C] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 115)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 67%, LC-MS:m/z 521.2 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=9.53 (s, 1H), 8.61 (d, J=6,0Hz, 1H), 8.37 (d, J= 8.4Hz, 1H), 8.18 (d, J=6.4Hz, 1H) 8.07-8.10 (dd, J=8.4,3.6Hz, 1H), 7.98 (t, J=7.6Hz, 1H), 7.74-7.78 (m, 1H), 7.32-7.39 (dd, J=10.4,8,4Hz, 1H), 6.45-6.50 (m, 1H), 2.75-2.80 (m, 1H), 1.74 (s, 6H), 1.67 (d, J=10.8Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 116 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid (I 116)
With the 4-fluoro-naphthalidine of cyano group-5-for raw material substitution 4-amino-1-naphthonitrile, synthetic method is with described in embodiment 16 The preparation method of compound, LC-MS:m/z 407.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=13.21 (s, 1H), 8.55 (d, J=7.2Hz, 1H), 8.18 (d, J= 8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.61 (t, J=7.6Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 7.12 (d, J= 8.8Hz,1H),1.65(s,6H)。
Embodiment 117 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid sodium (117)
According to the method described in embodiment 2, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 407.1 [M+H]+。
Embodiment 118 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid methyl ester (I 118)
According to the method described in embodiment 3, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 100%, LC-MS:m/z 421.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.58 (d, J=7.6Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.24 (d, J=8.8Hz, 1H), 3.69(s,3H),1.69(s,6H)。
Embodiment 119 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group-5-fluorine Naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 119)
According to the method described in embodiment 4, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 64%, LC-MS:m/z 519.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.61 (d, J=7.2Hz, 1H), 8.16 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 4.63(s,2H),2.59(s,3H),1.64(s,6H),.
Embodiment 120 1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5- B] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 120)
According to the method described in embodiment 5, simply by 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyrrole Pyridine-2-base] sulfydryl]-2 Methylpropionic acid change into 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine- 2-yl] sulfydryl]-2 Methylpropionic acid, yield 57%, LC-MS:m/z 521.1 [M+H]+。
1H NMR(400MHz,DMSO-d6): δ=8.54 (d, J=7.2Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 7.91-7.94 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.22 (d, J=8.8Hz, 1H), 6.44-6.51 (m, 1H), 2.76-2.80 (m, 1H), 1.85 (d, J=12Hz, 3H), 1.69 (s, 6H), 1.04 (d, J= 9.6Hz,6H)。
In vitro biological activity is evaluated
Plasmid (EX-T4563-M03, GeneCopoeia) containing total length human URAT 1 gene (SLC22A12) is transfected into In Flp-In T-REx-293 cell, build URAT1 high expressing cell 293/hURAT1, measure transfectional cell picked-up radioactivity same The ability of position element labelling uric acid.The work of compound is evaluated by the ability measuring compounds block transfectional cell picked-up uric acid Property.
293/hURAT1 cell is inoculated in coated 96 orifice plates of poly D-Lys with the density of 40000 cells/well Overnight incubation in (BD, 356461).Remove culture medium, add reaction buffer (125mM sodium gluconate, the 4.8mM Portugal of preheating Grape saccharic acid potassium, 1.3mM calcium gluconate, 1.2mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 5.6mM glucose, 25mM HEPES, PH7.4), 10 minutes are hatched for 37 DEG C.Remove buffer, add containing 50 μMs of 14C-uric acid (American Radiolabeled Chemicals, ARC0513) and compound or the reaction buffer of solvent, hatch 5 minutes for 37 DEG C.Remove buffer, with slow Rush liquid and wash 3 times.Add 100mM NaOH cell lysis 20 minutes.Cell pyrolysis liquid is transferred to Isoplate-96 orifice plate In (PerkinElmer, 6005040), add scintillation fluor liquid, count in MicroBeta2 (PerkinElmer) enumerator.
Testing compound is dissolved in DMSO, and is the solvent control without compound with the DMSO of same concentrations. Using the intake of uric acid in the cell containing DMSO solvent control as 100%, calculate cellular uptake in each test compound well The suppression ratio percentage ratio of uric acid, calculates IC50 value by the uric acid picked-up suppression ratio of compound under variable concentrations.
Compound of the present invention detects according to as above scheme, and result is shown in following table, wherein:
A represents that IC50 exists > in the range of 10 μMs；
B represents that IC50 is in the range of 2 μMs-10 μMs；
C represents that IC50 is in the range of 0.1 μM-2 μMs.
Embodiment 242
Biological acdtivity in vivo is evaluated
1) experiment material
Laboratory animal: SD rat, male, body weight ♂ 180-198g, 6-8 week old during reception.Animal adapts to 5 days in the environment After start experiment.Body weight ♂ 220-252g during experiment.It is purchased from Beijing HFK Bio-Technology Co., Ltd., SPF level.
Test specimen: compound of the present invention, Lesinurad (positive control), 0.5%CMC-Na grinds to form homogeneous mixed Suspension.
Experiment reagent:
Oteracil Potassium, BJ140984206E, Hua Maike import subpackage, room temperature preserves.Weigh with 1mg degree of accuracy electronic balance Oteracil Potassium 12.5g, puts in mortar, adds a small amount of 0.5%CMC-Na and is ground dissolving, pours in graduated cylinder, repeatedly add 0.5% CMC-Na carries out rinse to mortar, finally fills up 0.5%CMC-Na and is settled to 250ml (50mg/mL concentration).Refrigerator store.
Chloral hydrate, lot number: 20130116, Chemical Reagent Co., Ltd., Sinopharm Group, room temperature preserves.With 1mg degree of accuracy Electronic balance weighs chloral hydrate 3.5g, puts in small beaker, uses a small amount of physiological saline solution, is transferred in graduated cylinder, uses physiology Saline is settled to 100ml.Refrigerator store.For anaesthetizing.
Instrument and equipment:
Prunus mume (sieb.) sieb.et zucc. Teller ALC-210.3 electronic balance, precision 0.001mg, Beijing Sai Duolisi instrument system company limited.
Electronic scale: Heng Xin Electronics Co., Ltd. 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 technique
Continuous gavage is used to give Oteracil Potassium induction rat hyperuricemia model.Experimental animal divides at random according to body weight Group, successive administration 7 days.Every day, gavage gave all rat Oteracil Potassium modeling 5mL/kg, and after 1h, gavage is given respectively by reagent respectively, Model group gavage gives equivalent solvent.Proceed to metabolic cage after being administered the 5th day medicine after 1h, after adapting to 1 day, collect 24h urine in the 6th day Liquid, measures volume, and is centrifuged 10min at 2000r/min room temperature, take supernatant 1mL and carry out blood biochemistry detection.Within 7th day, it is administered 1h The rear eye corner of the eyes takes blood, and 5000r/min is centrifuged 5min, takes blood plasma 4 DEG C preservation, for Biochemical Indexes.
Test kit is utilized to measure uric acid (Urine in blood uric acid in serum (Serum Uric acid, SUA) and urine respectively Uric Acid, UUA) level.
3) data statistics
Enumeration data uses Radit method to carry out statistical test, and measurement data uses Student t method of inspection to add up Learn inspection, it is judged that significant difference between group.
4) experimental result
Result shows, compared with model group, Oral Administration in Rats compound of the present invention is after 7 days, and serum Uric Acid Concentration significantly drops Low, acid concentration of urinating dramatically increases, and shows that it has promotion urate excretion, reduces the effect of serum uric acid level, and in the present invention I1, I11, I51 effect under 20mg/kg dosage is suitable with Lesinurad 40mg/kg effect, points out its internal uric acid resisting to make With being better than Lesinurad.
Table 1 blood uric acid and acid testing result of urinating
Note: compare with model group,*P<0.05,**P<0.01
Owing to being limited by application documents length, in above-mentioned experiment, the present invention only enumerates section Example as experiment Medicine, but it practice, other embodiments of the invention also can obtain same or like beneficial effect.

Claims (10)

1. there is a pyridine-imidazole analog derivative for general formula I, and pharmaceutically acceptable salt, solvate, water Compound and pharmaceutically acceptable prodrug, its planar structure is as follows:
Wherein:
X1, X2, X3, X4Independent selected from CH or N；X1, X2, X3, X4 at least one be N；
R1, R2Independently selected from H, cyano group, halogen, C1-6Alkyl or cycloalkyl, CF3, methoxyl group, ethyoxyl, carboxyl, amide, sulphur Amide；
M is H, C1-3Alkyl, carbonic ester, En Naka are than ester or pharmaceutically acceptable cation.
2. compound as claimed in claim 1, it is characterised in that the form of its pharmaceutical salts is Na, K, Li, Ca, Mg, preferably Na, K, Li salt.
3. compound as claimed in claim 1, it is characterised in that its pharmaceutically acceptable prodrug, include but not limited to ester, Carbonic ester, sulfocarbonate, N-acyl derivative, N-acyloxy derivative, amino acid conjugates.
Compound the most according to claim 1, it is characterised in that described compound is selected from:
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 1)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 2)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 3)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 4)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 5)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 6)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 7)；
2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 8)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 9)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 10)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 11)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 12)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 13)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 14)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 15)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 16)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 17)；
2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 18)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 19)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 20)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 21)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 22)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 23)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4, 5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 24)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2- Methylpropionate (I 25)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 26)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 27)；
2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 28)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4, 5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 29)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-bromonaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2- Methylpropionate (I 30)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 31)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 32)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 33)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4, 5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 34)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2- Methylpropionate (I 35)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 36)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 37)；
2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 38)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4, 5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 39)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-bromonaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2- Methylpropionate (I 40)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 41)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 42)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 43)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazoles And [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 44)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 45)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 46)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 47)；
2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 48)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazoles And [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 49)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyclopropyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 50)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 51)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 52)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 53)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazoles And [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 54)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 55)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 56)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 57)；
2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 58)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazoles And [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 59)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyclopropyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 60)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 61)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 62)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 63)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 64)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 65)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 66)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 67)；
2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 68)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 69)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carboxyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 70)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 71)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 72)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 73)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 74)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 75)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 76)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 77)；
2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (I 78)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 79)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carboxyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]- 2 Methylpropionic acid ester (I 80)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 81)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ82)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 83)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H- Imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 84)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 85)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 86)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ87)；
2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 88)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H- Imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 89)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-carbamoyl naphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 90)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 91)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ92)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 93)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H- Imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 94)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 95)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 96)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (Ⅰ97)；
2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid first Ester (I 98)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H- Imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 99)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-carbamoyl naphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] Sulfydryl]-2 Methylpropionic acid ester (I 100)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 101)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 102)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ103)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-miaow Azoles also [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 104)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 105)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 106)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 107)；
2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ108)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-miaow Azoles also [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 109)；
1-(isobutyryl epoxide) ethyl 2-[[3-(4-cyano group-5-fluoronaphthalene-1-base)-3H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 110)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 111)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 112)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ113)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-miaow Azoles also [4,5-c] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 114)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-c] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 115)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid (I 116)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid sodium (I 117)；
2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid methyl ester (Ⅰ118)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-miaow Azoles also [4,5-b] pyridine-2-base] sulfydryl]-2 Methylpropionic acid ester (I 119)；
1-(isobutyryl epoxide) ethyl 2-[[1-(4-cyano group-5-fluoronaphthalene-1-base)-1H-imidazo [4,5-b] pyridine-2-base] mercapto Base]-2 Methylpropionic acid ester (I 120).
5. pyridine-imidazole analog derivative described in claim 1 and pharmaceutically acceptable salt thereof and pharmaceutically acceptable The preparation method of prodrug, comprises the following steps:
(1) compound shown in compound shown in formula II and formula III is made to generate compound shown in formula IV under the effect of alkali:
(2) compound shown in production V under reducing agent effect of compound shown in formula IV is made:
(3) compound and thiophosgene shown in formula V is made to react compound shown in production VI:
(4) compound shown in formula VI is made to react compound shown in production VII in the basic conditions with 2-isobutyl ethyl bromide:
(5) compound shown in formula VII is made to hydrolyze compound shown in production VIII in the basic conditions:
(6) compound shown in formula VIII and compound shown in corresponding alkali reaction production Ⅸ, M are made1Represent pharmaceutical acceptable cation:
(7) make compound and oxalyl chloride shown in formula Ⅸ react acylated, then react production Ⅹ shownization with corresponding alcohol or ammonia Compound, M2Represent C1-3Alkyl, carbonic ester, En Naka compare ester
6. a pharmaceutical composition, it is characterised in that with the pyridine-imidazole analog derivative described in any one of claim 1-4 and Its pharmaceutically acceptable salt and pharmaceutically acceptable prodrug are as active constituents of medicine.
7. the pharmaceutical composition described in claim 6, it is also possible to add the medicine of other gouts,
Other drug is selected from: URAT1 inhibitor, xanthine oxidase inhibitor, xanthine dehydrogenase, xanthine oxidoreductase enzyme Inhibitor, purine nucleoside phosphorylase inhibitor, uric acid transporter body inhibitor, glucose transporter inhibitor, organic anion Transporter (OAT) inhibitor, OAT-4 inhibitor or combination, the second medicament be preferably allopurinol, Febuxostat, Topiroxostat or A combination thereof.
8. pyridine-imidazole analog derivative described in claim 1 and pharmaceutically acceptable salt thereof and pharmaceutically acceptable Prodrug application in the medicine of preparation regulation uric acid level and/or the relevant indication for the treatment of gout.
9. the pharmaceutical composition described in claim 6 preparation regulation uric acid level and/or treatment gout relevant indication Medicine in application.
Application the most according to claim 8 or claim 9, its relevant indication be hyperuricemia, gout, gouty arthritis, Inflammatory arthritis, nephropathy, nephrolithiasis, arthritis, urate crystal deposit in joint, urinary calculus, urate crystal exist Deposition, gout outbreak, chalky gout or a combination thereof in excess of the kidney matter.
CN201610552230.8A 2016-07-14 2016-07-14 Pyridino-imidazole derivatives as well as preparation method and application thereof Pending CN105968111A (en)

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CN108658879A (en) * 2017-03-29 2018-10-16 天津药物研究院有限公司 A kind of URAT1 inhibitor and its preparation method and application
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CN106083847A (en) * 2016-08-03 2016-11-09 山东大学 A kind of imidazopyridine mercapto phenylacetic acid derivative and preparation method and application
AU2016417542B2 (en) * 2016-08-03 2020-01-30 Shandong University Imidazopyridine thioglycolic acid derivative, preparation method therefor and application thereof
WO2018023851A1 (en) * 2016-08-03 2018-02-08 山东大学 Imidazopyridine thioglycolic acid derivative, preparation method therefor and application thereof
CN108658879A (en) * 2017-03-29 2018-10-16 天津药物研究院有限公司 A kind of URAT1 inhibitor and its preparation method and application
CN106943432B (en) * 2017-04-14 2020-06-05 广州市宙斯生物科技有限责任公司 Exosome derived from umbilical cord mesenchymal stem cells and application of exosome in preparation of liver cancer treatment drug
CN106974938A (en) * 2017-04-14 2017-07-25 南京盖斯夫医药科技有限公司 A kind of the excretion body and its pharmaceutical preparation in the mesenchymal stem cells MSCs source with antihepatocarcinoma effect
CN106943432A (en) * 2017-04-14 2017-07-14 南京盖斯夫医药科技有限公司 A kind of excretion body in umbilical cord mesenchymal stem cells source and its application in treatment liver-cancer medicine is prepared
CN106974938B (en) * 2017-04-14 2020-06-23 吉林市汇融再生医学有限公司 Exosome with anti-liver cancer effect and derived from mesenchymal stem cells and pharmaceutical preparation of exosome
CN109535405A (en) * 2017-09-21 2019-03-29 宁波聚嘉新材料科技有限公司 The preparation method of polyarylate of the one kind based on 2- (4- carboxyl phenyl) -5- pyridone and imidazoles
CN109535406A (en) * 2017-09-22 2019-03-29 宁波聚嘉新材料科技有限公司 The preparation method of polyarylate of the one kind based on 2- (3- hydroxy phenyl) -6- carboxyl pyridine and imidazoles
CN107987006A (en) * 2017-12-20 2018-05-04 华润赛科药业有限责任公司 Indoles or azaindole analog derivative, its preparation method and application
CN107987006B (en) * 2017-12-20 2021-06-01 华润赛科药业有限责任公司 Indole or azaindole derivatives, preparation method and application thereof
CN111943957A (en) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 Quinoline formamide compound and preparation method and application thereof

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