CN106146533A - Sulfur heterocyclic ring carboxylic acid derivative, its preparation method and application - Google Patents
Sulfur heterocyclic ring carboxylic acid derivative, its preparation method and application Download PDFInfo
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- CN106146533A CN106146533A CN201610556049.4A CN201610556049A CN106146533A CN 106146533 A CN106146533 A CN 106146533A CN 201610556049 A CN201610556049 A CN 201610556049A CN 106146533 A CN106146533 A CN 106146533A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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Abstract
The invention belongs to field of medicaments, specifically, the present invention relates to the derivant of a series of sulfur heterocyclic ring carboxylic acid and officinal salt thereof and the preparation method of pharmaceutically acceptable prodrug, the pharmaceutical composition comprising described derivant and described derivant and the pharmaceutical composition purposes in preparing anti-gout drugs and treatment relevant disease.
Description
Technical field
The invention belongs to field of medicaments, specifically, the present invention relates to a series of sulfur heterocyclic ring carboxylic acid derivant and
Officinal salt and the preparation method of pharmaceutically acceptable prodrug, the pharmaceutical composition comprising described derivant and described in spread out
Biological and that pharmaceutical composition is in preparing anti-gout drugs and treatment relevant disease purposes.
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.
By its action character, one can be divided into 3 classes in gout medication:
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 is without anti-inflammatory and analgesic effect, and one is 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, Kai-match two Cotards, 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 sulfur heterocyclic ring carboxylic acid derivative representated by Formulas I, and pharmacy
Upper acceptable salt, solvate, hydrate and pharmaceutically acceptable prodrug, its planar structure is as follows:
Wherein:
X is CH or N；
R1Selected from hydrogen atom or C1-3Alkyl；
R2, R3Independently selected from H, cyano group, halogen, C1-6Alkyl or cycloalkyl, CF3, methoxyl group, ethyoxyl, carboxyl, acyl
Amine, sulfonamide；
A is-N=,-CH=,-CH2-or-CH2-CH2-；
M is H, C1-3Alkyl, carbonic ester, En Naka are than ester or pharmaceutically acceptable cation.
Wherein, when A is-N=or-CH=, without R1Substituent group.
Wherein, it is-CH as A2-or-CH2-CH2In-time, there are 4 chiral isomers, and can be by using chiral chromatogram
Method separation raceme obtains optically pure compound, then carries out into salt or synthesize its pharmaceutically acceptable prodrug.
Preferably, the compounds of this invention is:
8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 1)；
8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 2)；
8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
3)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group naphthalene-1-base)-2-methyl-3,
4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 4)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids ester (I 5)；
8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 6)；
8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 7)；
8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 8)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-
2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 9)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-
Carboxylate (I 10)；
7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 11)；
7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 12)；
7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 13)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base)-2-methyl-2,
3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 14)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-
2-carboxylic acid (I 15)；
7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 16)；
7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 17)；
7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 18)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base)-2,3-dihydro thiophene
Fen [3,2-c] pyridine-2-carboxylic acids (I 19)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
(I 20)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 21)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 22)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 23)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c]
And pyridine-2-carboxylic acids (I 24)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 25)；
7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 26)；
7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 27)；
7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 28)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c]
And pyridine-2-carboxylic acids (I 29)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 30)；
7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 31)；
7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 32)；
7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 33)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene
Fen-2-carboxylic acid (I 34)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 35)；
7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 36)；
7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 37)；
7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 38)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) benzo [d] thiophene
Azoles-2-carboxylic acid (I 39)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 40)；
8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 41)；
8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 42)；
8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
43)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-
Dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 44)；
1-(isobutyryl epoxide) ethyl 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylate (I 45)；
8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 46)；
8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 47)；
8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 48)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-
Thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 49)；
1-(isobutyryl epoxide) ethyl 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acid esters (I 50)；
7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 51)；
7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 52)；
7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 53)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-
Dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 54)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylic acid (I 55)；
7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 56)；
7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 57)；
7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 58)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene
[3,2-c] pyridine-2-carboxylic acids (I 59)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I
60)；
7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 61)；
7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 62)；
7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 63)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] and
Pyridine-2-carboxylic acids (I 64)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 65)；
7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 66)；
7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 67)；
7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 68)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] and
Pyridine-2-carboxylic acids (I 69)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 70)；
7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 71)；
7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 72)；
7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 73)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-
2-carboxylic acid (I 74)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 75)；
7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 76)；
7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 77)；
7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 78)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-
2-carboxylic acid (I 79)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 80)；
8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I
81)；
8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I
82)；
8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
83)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-
3,4-dihydros-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 84)；
1-(isobutyryl epoxide) ethyl 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c]
And pyridine-2-carboxylic acids ester (I 85)；
8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 86)；
8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 87)；
8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 88)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyclopropyl naphthalene-1-base)-3,4-bis-
Hydrogen-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 89)；
1-(isobutyryl epoxide) ethyl 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylate (I 90)；
7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 91)；
7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 92)；
7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I
93)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-
2,3-dihydro-thiophenes [3,2-c] pyridine-2-carboxylic acids (I 94)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole
Pyridine-2-carboxylic acid (I 95)；
7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 96)；
7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 97)；
7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 98)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro
Thiophene [3,2-c] pyridine-2-carboxylic acids (I 99)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic
Acid (I 100)；
7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 101)；
7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 102)；
7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 103)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-
C] and pyridine-2-carboxylic acids (I 104)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 105)；
7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 106)；
7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 107)；
7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 108)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-
C] and pyridine-2-carboxylic acids (I 109)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 110)；
7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 111)；
7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 112)；
7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 113)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene
Fen-2-carboxylic acid (I 114)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 115)；
7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 116)；
7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 117)；
7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 118)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiophene
Azoles-2-carboxylic acid (I 119)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 120)；
8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 121)；
8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I
122)；
8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
123)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,
4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 124)；
1-(isobutyryl epoxide) ethyl 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids ester (I 125)；
8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 126)；
8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 127)；
8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 128)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-
2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 129)；
1-(isobutyryl epoxide) ethyl 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-
Carboxylate (I 130)；
7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 131)；
7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 132)；
7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 133)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,
3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 134)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-
2-carboxylic acid (I 135)；
7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 136)；
7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 137)；
7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 138)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro thiophene
Fen [3,2-c] pyridine-2-carboxylic acids (I 139)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
(I 140)；
7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 141)；
7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 142)；
7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 143)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c]
And pyridine-2-carboxylic acids (I 144)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 145)；
7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 146)；
7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 147)；
7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 148)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c]
And pyridine-2-carboxylic acids (I 149)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 150)；
7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 151)；
7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 152)；
7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 153)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene
Fen-2-carboxylic acid (I 154)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 155)；
7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 156)；
7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 157)；
7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 158)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) benzo [d] thiophene
Azoles-2-carboxylic acid (I 159)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 160)；
8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I
161)；
8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium
(I 162)；
8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids second
Ester (I 163)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carbamoyl naphthalene-1-base)-2-first
Base-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 164)；
1-(isobutyryl epoxide) ethyl 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,
2-c] and pyridine-2-carboxylic acids ester (I 165)；
8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 166)；
8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I
167)；
8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
168)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carbamoyl naphthalene-1-base)-3,4-
Dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 169)；
1-(isobutyryl epoxide) ethyl 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylate (I 170)；
7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I
171)；
7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I
172)；
7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I
173)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base)-2-first
Base-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 174)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c]
And pyridine-2-carboxylic acids (I 175)；
7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 176)；
7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 177)；
7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 178)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base)-2,3-
Dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 179)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-
2-carboxylic acid (I 180)；
7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 181)；
7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 182)；
7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 183)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) thiophene
[3,2-c] pyridine-2-carboxylic acids (I 184)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I
185)；
7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 186)；
7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 187)；
7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 188)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) thiazole
[4,5-c] pyridine-2-carboxylic acids (I 189)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I
190)；
7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 191)；
7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 192)；
7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 193)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) benzo
[b] thiophene-2-carboxylic acid (I 194)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 195)；
7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 196)；
7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 197)；
7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 198)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) benzo
[d] thiazole-2-carboxylic acid (I 199)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 200)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I
201)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium
(I 202)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids second
Ester (I 203)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-first
Base-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 204)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-
C] and pyridine-2-carboxylic acids ester (I 205)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 206)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 207)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
208)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-
Dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 209)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylate (I 210)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I
211)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I
212)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I
213)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-first
Base-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 214)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] and
Pyridine-2-carboxylic acids ester (I 215)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 216)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 217)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 218)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-
Dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 219)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylate (I 220)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 221)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 222)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 223)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene
[3,2-c] pyridine-2-carboxylic acids ester (I 224)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I
225)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 226)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 227)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 228)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole
[4,5-c] pyridine-2-carboxylic acids ester (I 229)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I
230)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 231)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 232)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 233)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo
[b] thiophene-2-carboxylic acid ester (I 234)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 235)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 236)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 237)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 238)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo
[d] thiazole-2-carboxylate (I 239)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 240)；
Above-claimed cpd of the present invention, the structural formula of its correspondence is as follows:
Preferably, compound of the present invention is selected from:
8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I1)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group naphthalene-1-base)-2-methyl-3,
4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I4)；
7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I11)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I21)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I22)；
7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I26)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(I201)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I211)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I221)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I226)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I231)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I236)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I237)；
Series compound of the present invention, part is containing a chiral carbon, and due to its sterically hindered problem, exists
One chiral axis so that this compound comprises 2～4 optical isomers.
The optical isomer of compound of the present invention, the method that can be separated by chiral column, obtain single optically-active
Pure compound.
The invention still further relates to the one-tenth salt research of compound by above-mentioned Formulas I, include but not limited to Na, K, Li, Mg, Ca,
Zn salt, preferably Na, K, Li salt.
The invention still further relates to the pharmaceutically acceptable prodrug of this compound, include but not limited to ester, carbonic ester, sulfur generation
Carbonic ester, N-acyl derivative, N-acyloxy derivative, amino acid conjugates etc..
Second object of the present invention is to provide the sulfur heterocyclic ring carboxylic acid derivative representated by Formulas I or its officinal salt
Preparation method with prodrug.
The building-up process of formula I of the present invention please be provided:
(1) compound shown in Formula II and oxirane is made to generate compound shown in formula III under the effect of highly basic:
(2) compound compound shown in production V under alkali effect shown in compound shown in formula III and formula IV is made:
(3) make compound shown in Formula V and thionyl chloride react and generate compound shown in Formula IV:
(4) make compound shown in Formula IV react in the basic conditions and generate compound shown in Formula VII:
(5) make compound shown in Formula II under strongly alkaline conditions with compound shown in DMF production VIII:
(6) compound shown in compound shown in Formula VIII and formula IV is made to generate compound shown in Formula IX under alkali effect:
(7) make compound shown in Formula IX and thionyl chloride react and generate compound shown in X:
(8) compound shown in Formula X and zinc powder is made to react compound shown in production XI in acid condition:
(9) compound shown in Formula VIII and 2-ethyl thioglycolate reacting by heating production XII institute in the basic conditions are made
Show compound:
(10) compound shown in Formula X III and zinc powder is made to react compound shown in production XIV in acid condition:
(11) compound shown in Formula X IV and zinc powder is made to react compound shown in production XV in acid condition:
(12) compound shown in Formula X V and lawesson reagent is made to react compound shown in production XVI:
(13) compound shown in Formula VII, Formula X I, Formula X II and Formula X VI can be collectively expressed as compound shown in Formula X VII,
This compound reacts compound shown in production XIX, wherein M with compound shown in Formula X VIII1Represent H or ethyl:
(14) make compound shown in Formula X IX hydrolyze in the basic conditions and be acidified compound shown in production XX again:
(15) compound shown in Formula X X is made to react compound shown in production XXI, wherein M with corresponding aqueous slkali2Represent
Pharmaceutically useful cation:
(16) make compound shown in Formula X X and oxalyl chloride react acylated, then react production XXII with corresponding alcohol or ammonia
Shown compound, M2Represent C1-3Alkyl, amino, carbonic ester, En Naka compare ester
Concrete, the preparation method of sulfur heterocyclic ring carboxylic acid derivative of the present invention or its officinal salt and prodrug sees enforcement
Example.
Third object of the present invention is to provide a kind of pharmaceutical composition, containing representated by least one Formulas I
Sulfur heterocyclic ring carboxylic acid derivative and officinal salt, hydrate 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, sulfur heterocyclic ring carboxylic acid derivative representated by Formulas I or its officinal salt
Amount 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.
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.
In the pharmaceutical composition of the present invention, it is also possible to add the medicine of other gouts.
The medicine of other gouts is URAT1 inhibitor, xanthine oxidase inhibitor, xanthine dehydrogenase, xanthine
Oxidoreductase inhibitors, purine nucleoside phosphorylase inhibitor, uric acid transporter body inhibitor, glucose transporter inhibitor,
Organic anion transporter (OAT) inhibitor, OAT-4 inhibitor or combination.Preferably the medicine of gout is allopurinol, non-cloth
SU11248, Topiroxostat or a combination thereof.
Fourth object of the present invention is to provide sulfur heterocyclic ring carboxylic acid derivative and officinal salt thereof or prodrug in system
The application that standby gout, regulation blood uric acid levels are correlated with in the medicine of disease.
5th purpose of the present invention is to provide and makees with sulfur heterocyclic ring carboxylic acid derivative and officinal salt thereof or prodrug
Pharmaceutical composition for active component is being prepared gout, is being regulated the application that blood uric acid levels is correlated with in the medicine of disease.
Its relevant disease includes: 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 1,8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(I1)
Step 1:3-(2-ethoxy)-5-bromo-4-chloropyridine
Bromo-for 3-4-chloropyridine (25g, 130mmol) is dissolved in the oxolane that 200mL is dried, displacement nitrogen protection, will
System is cooled to-70 DEG C, adds lithium diisopropylamine (2M, 71.5mL), reacts 1 hour, drips oxirane in system
(5.72g, 130mmol), reacts 30 minutes, system is warming up to 0 DEG C, continues reaction 6.5 hours, system is poured in frozen water,
Stirring 30 minutes, be extracted with ethyl acetate (300ml*3 time), merge organic facies, concentrating under reduced pressure, residue separates pure through silicagel column
(eluant, petroleum ether: ethyl acetate=10: 1, v: v), obtain 4.6g yellow oily liquid, and yield is 15% in change.
Step 2:2-[[3-(2-ethoxy)-5-bromopyridine-4 base] sulfydryl] ethyl propionate
By 3-(2-ethoxy)-5-bromo-4-chloropyridine (4.5g, 19mmol) and ethyl 2-mercaptopropionate (3.83g,
28.6mmol) add in 50mL DMF, add potassium carbonate (6.05g, 57.1mmol), be stirred at room temperature 16 hours.By reaction system
Pouring in 200mL frozen water, add ethyl acetate extraction (100ml*3 time), organic facies concentrates, and residue is isolated and purified through silicagel column
(eluant, petroleum ether: ethyl acetate=5: 1, v: v) obtain 4.5g yellow solid, yield 70.7%
Step 3:2-[[3-(2-chloroethyl)-5-bromopyridine-4 base] sulfydryl] ethyl propionate
2-[[3-(2-ethoxy)-5-bromopyridine-4 base] sulfydryl] ethyl propionate (4.5g, 13.4mmol) is joined
In 40mL thionyl chloride, it is stirred at room temperature 16 hours.By system concentrating under reduced pressure, residue is through silicagel column isolated and purified (eluant, stone
Oil ether: ethyl acetate=5: 1, v: v), obtains 4.0g yellow solid, yield 84.3%.
Step 4:8-bromo-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
2-[[3-(2-chloroethyl)-5-bromopyridine-4 base] sulfydryl] ethyl propionate (3.0g, 8.51mmol) is dissolved in
In 30mLDMF, add sodium hydride (0.68g, 17.0mmol), displacement nitrogen protection, room temperature reaction 4 hours.System is poured into
In 20mL frozen water, stir 30 minutes, regulate pH to 3 with the dilute hydrochloric acid of 1M, be extracted with ethyl acetate (30mL*3 time), merge organic
Phase, concentrating under reduced pressure, through silicagel column, isolated and purified (eluant, petroleum ether: ethyl acetate=5: 1, v: v) obtain 1.2g yellow to residue
Color solid, yield is 49%.
Step 5:8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(I1)
By bromo-for 8-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (1.10g, 3.82mmol), 4-
Cyano group-1-naphthalene boronic acids pinacol ester (1.07g, 3.82mmol), sodium carbonate (1.21g, 11.46mmol) and [1,1 '-bis-(hexichol
Base phosphine) ferrocene] palladium chloride (139mg, 191mmol) is mixed to join water (2.0mL) and the mixed system of acetonitrile (5.0mL)
In, displacement nitrogen protection, system is placed in microwave tube 130 DEG C of reacting by heating 4 hours.System is poured in 20mL water, use 2M
Dilute hydrochloric acid regulation pH value to 2, be extracted with ethyl acetate (30mL*3 time) merge organic facies, with 30mL saturated aqueous common salt washing,
Anhydrous sodium sulfate is dried, concentrating under reduced pressure, and residue, with preparing liquid phase separation, obtains white solid 1.19g, yield 65.5%, LC-
MS:m/z361.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.88 (s, 1H), 8.60 (d, J=3.2Hz, 1H), 8.38 (d, J=
3.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t,
J=6.8Hz, 1H), 7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 3.01-3.14 (m, 2H), 2.27-2.36 (m, 1H),
1.95-2.01 (m, 1H), 1.46 (d, J=12Hz, 3H).
Prepare liquid-phase condition:
Column:Phenomenex luna (2) C18250*5010u；
Condition:0.1%TFA-CAN；
Begin B:20；End B:45；
Gradient Time (min): 25；
100%B Hold Time (min): 5；
FlowRate (ml/min): 80
Embodiment 2 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Sodium (I2)
By 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(100mg, 0.277mmol) is dissolved in 5mL methanol, adds sodium hydroxide solution (1M, 0.277mL), is stirred at room temperature 30 minutes, subtracts
Pressure is concentrated to dryness, and obtains white solid 106mg, yield 100%, LC-MS:m/z 361.1 [M+H]+。
Embodiment 3 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Ethyl ester (I3)
By 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(200mg, 0.554mmol) 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 dehydrated alcohol 5mL, be stirred at room temperature 30 points
Clock, is evaporated to do, and obtains white solid 215mg, yield 100%, LC-MS:m/z 389.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (d, J=5.2Hz, 1H), 8.39 (d, J=7.2Hz, 1H), 8.28
(d, J=7.2Hz, 1H), 8.21 (d, J=8.4Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d, J=6.8Hz, 1H),
7.60-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.73-3.90 (m, 2H) 3.11-3.17 (m, 2H), 2.25-2.37 (m,
1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.06 (t, J=6.8Hz, 3H).
Embodiment 4 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group naphthalene-1-base)-2-
Methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 4)
By 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(100mg, 0.277mmol) 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=10: 1, v: v) obtain 85mg white solid, and yield is 67%, LC-MS:m/
z 473.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.65 (d, J=7.2Hz, 1H), 8.40 (d, J=8.0Hz, 1H), 8.29
(d, J=7.2Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 7.88 (d, J=7.2Hz, 1H), 7.69 (d, J=6.4Hz, 1H),
7.59-7.63 (m, 1H), 7.51-7.55 (m, 1H), 4.55 (s, 2H), 3.13-3.19 (m, 2H), 2.65 (s, 3H), 2.26-
2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.46 (d, J=12Hz, 3H).
Embodiment 5 1-(isobutyryl epoxide) ethyl 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids ester (I5)
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
Add 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (100mg,
0.277mmol), 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 80mg white solid to excess, and yield is
61%, LC-MS:m/z 475.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.61 (d, J=3.2Hz, 1H), 8.37 (d, J=3.2Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H),
7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.02-3.14 (m, 2H), 2.76-2.80 (m,
1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.47 (d, J=12Hz, 3H),
1.02 (d, J=9.6Hz, 6H).
Embodiment 6 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I6)
With ethyl thioglycolate for raw material substitution ethyl 2-mercaptopropionate, synthetic method is with compound described in embodiment 1
Preparation method, LC-MS:m/z 347.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.78 (s, 1H), 8.78 (d, J=8.0Hz, 1H), 8.48 (d, J=
7.2Hz, 1H), 8.40 (d, J=7.6Hz, 1H), 8.33 (d, J=8.4Hz, 1H), 7.96 (t, J=7.2Hz, 1H), 7.78 (t,
J=6.8Hz, 1H), 7.72-7.78 (m, 1H), 7.44-7.47 (m, 1H), 3.40-3.45 (m, 1H), 3.11-3.24 (m, 2H),
2.37-2.46 (m, 1H), 1.99-2.11 (m, 1H).
Embodiment 78-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 7)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 347.1 [M+H]+。
Embodiment 8 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester
(I8)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 375.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.77 (d, J=8.4Hz, 1H), 8.49 (d, J=7.6Hz, 1H), 8.42
(d, J=7.6Hz, 1H), 8.35 (d, J=8.0Hz, 1H), 7.97 (t, J=7.2Hz, 1H), 7.76 (t, J=6.0Hz, 1H),
7.75-7.78 (m, 1H), 7.43-7.48 (m, 1H), 3.40-3.45 (m, 1H), 3.76-3.80 (m, 2H) 3.11-3.24 (m,
2H), 2.37-2.46 (m, 1H), 1.99-2.11 (m, 1H), 1.09 (t, J=6.4Hz, 3H).
Embodiment 9 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group naphthalene-1-base)-3,
4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 9)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 70%, LC-MS:m/z 459.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.75 (d, J=7.6Hz, 1H), 8.46 (d, J=7.2Hz, 1H), 8.41
(d, J=7.2Hz, 1H), 8.35 (d, J=8.4Hz, 1H), 7.95 (t, J=7.2Hz, 1H), 7.77 (t, J=6.4Hz, 1H),
7.70-7.78 (m, 1H), 7.41-7.46 (m, 1H), 4.60 (s, 2H), 3.41-3.46 (m, 1H), 3.10-3.23 (m, 2H),
2.59 (s, 3H), 2.37-2.45 (m, 1H), 1.90-2.01 (m, 1H).
Embodiment 10 1-(isobutyryl epoxide) ethyl 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c]
And pyridine-2-carboxylic acids ester (I10)；
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 62%, LC-MS:m/z 461.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.60 (d, J=3.2Hz, 1H), 8.37 (d, J=3.2Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H),
7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.40-3.46 (m, 1H), 3.01-3.14 (m,
2H), 2.76-2.80 (m, 1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.05
(d, J=9.6Hz, 6H).
Embodiment 11 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
(I11)
Step 1:5-bromo-4-chlorine cigarette aldehyde
By in bromo-for 3-4-chloropyridine (10.0g, 52.0mmol) the addition oxolane that is dried of 200ml, by this solution-
65 DEG C, under the protective condition of nitrogen, join in oxolane (200ml) solution of lithium diisopropylamine (2M, 23.4ml),
Keep-65 DEG C to react 2 hours, in system, add DMF (3.8g, 52.0mmol), be naturally warmed to room temperature.Add in system
50ml saturated ammonium chloride solution, is extracted with ethyl acetate (100ml*3 time), organic facies concentrating under reduced pressure, and residue divides through silicagel column
From purification, (eluant, petroleum ether: ethyl acetate=20: 1, v: v) obtain 6g yellow solid, and yield is 58%.
Step 2:7-bromo-3-hydroxy-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester
Bromo-for 5-4-chlorine cigarette aldehyde (6g, 27.2mmol) is dissolved in 60ml acetonitrile, addition ethyl 2-mercaptopropionate (4.0g,
30mmol), add triethylamine (5.5g, 54.4mmol), displacement nitrogen protection, be heated to 40 DEG C, react 12 hours.System is subtracted
Pressure concentrates, and through silicagel column, isolated and purified (eluant, petroleum ether: ethyl acetate=2: 1, v: v) obtain 3.5g yellow solid to residue
Body, yield is 40%.
Step 3:7-bromo-3-chloro-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester
By bromo-for 7-3-hydroxy-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester (2.2g,
6.9mmol) it is dissolved in 10ml dichloromethane, adds thionyl chloride (8.2g, 69mmol), be stirred at room temperature 3 hours.System is reduced pressure
Concentrating, obtain 2.2g oily liquids, yield is 100%.
Step 4:7-bromo-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester
By bromo-for 7-3-chloro-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester (2.2g, 6.5mmol)
It is dissolved in 20ml glacial acetic acid, adds zinc powder (4.28g, 65.4mmol), displacement nitrogen protection, room temperature reaction 3 hours.By reactant
System pours in 200ml saturated sodium bicarbonate solution, is extracted with ethyl acetate (100ml*2 time), organic facies concentrating under reduced pressure, residue
Through silicagel column, isolated and purified (eluant, petroleum ether: ethyl acetate=2: 1, v: v), obtain 1.4g yellow oily liquid, and yield is
66%.
Step 5:7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester
By bromo-for 7-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester (302mg, 1.0mmol), 4-
Cyano group-1-naphthalene boronic acids pinacol ester (305mg, 1.1mmol), sodium carbonate (210mg, 2.0mmol) and [1,1 '-bis-(diphenyl
Phosphine) ferrocene] palladium chloride (36.3mg, 0.05mmol) is mixed to join water (3.0mL), oxolane (3.0mL) and acetonitrile
(3.0mL) in mixed system, displacement nitrogen protection, system is placed in microwave tube 120 DEG C of reacting by heating 4 hours.Will reaction
Liquid is poured in 200mL water, is extracted with ethyl acetate (200mL*3 time), organic facies concentrating under reduced pressure, and residue separates pure through silicagel column
(eluant, petroleum ether: ethyl acetate=1: 1, v: v), obtain 206mg yellow oily liquid, and yield is 54.6% in change.
Step 6:7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
By 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester are dissolved in first
In the mixed solution of alcohol (8mL) and oxolane (8mL), add sodium hydroxide solution (8mL, 1.5mol/L), be stirred at room temperature
12h, concentrating under reduced pressure removes methanol and oxolane, and the salt acid for adjusting pH value of remaining aqueous solution 1N is 6～7, adds acetic acid
Ethyl ester extraction (100mL*2 time), organic facies saturated aqueous common salt washs (10mL), and anhydrous sodium sulfate is dried, and concentrates, through preparing liquid
Phase purification obtains 290mg sterling, and yield is 29%, LC-MS:m/z 347.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.67 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 8.31 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 3.98 (d, J=
16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 1.68 (d, J=10.8Hz, 3H).
Prepare liquid-phase condition:
Instrument:Gilson 281semi-preparative HPLC system
Mobile phase:A:TFA/H2O=0.075%v/v；B:ACN
Column:Luna C18 100*30 5u
Flow rate:25mL/min
Monitor wavelength:220&254nm
Embodiment 12 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium
(I 12)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 100%, LC-MS:m/z 347.1 [M+H]+。
Embodiment 13 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids first
Ester (I 13)
By 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (200mg,
0.577mmol) it is dissolved in the dichloromethane that 10mL is dried, adds oxalyl chloride (95mg, 0.750mmol) and 1 DMF catalysis, room
Temperature stirring 1h, TLC detect without starting material left, are evaporated to do.Add absolute methanol 5mL, be stirred at room temperature 30 minutes, reduce pressure dense
It is reduced to do, obtains white solid 207mg, yield 100%, LC-MS:m/z 361.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.45 (s, 1H), 8.36 (br.s, 1H), 8.35 (s, 1H), 7.98
(dd, J=7.6,1.6Hz, 1H), 7.67-7.74 (m, 3H), 7.51 (t, J=7.6Hz, 1H), 4.05 (d, J=16.0Hz,
1H), 3.92 (s, 3H), 3.34 (d, J=16.0Hz, 1H), 1.75 (s, 3H).
Embodiment 14 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base)-
2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 14)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 72%, LC-MS:m/z 459.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.50 (s, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 7.95 (d, J=
7.2Hz, 1H), 7.65-7.75 (m, 3H), 7.53 (t, J=8.0Hz, 1H), 4.80 (s, 2H), 4.10 (d, J=16.0Hz,
1H), 3.34 (d, J=16.4Hz, 1H), 2.62 (s, 3H), 1.75 (s, 3H).
Embodiment 15 1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-
C] and pyridine-2-carboxylic acids ester (I 15)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 69%, LC-MS:m/z 461.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.64 (s, 1H), 8.54 (s, 1H), 8.31 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50 (m, 1H), 3.98
(d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H), 1.68 (d, J=10.8Hz,
3H), 1.59 (d, J=9.6Hz, 3H), 1.03 (d, J=9.6Hz, 6H).
Embodiment 16 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 16)
With ethyl thioglycolate for raw material substitution ethyl 2-mercaptopropionate, synthetic method is with compound described in embodiment 11
Preparation method, LC-MS:m/z 333.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.75 (s, 1H), 8.87 (s, 1H), 8.74 (s, 1H), 8.53 (t, J=
6.0Hz, 1H), 8.31 (d, J=8.0Hz, 1H), 7.98 (t, J=8.4Hz, 1H), 7.69-7.75 (m, 3H), 3.90-3.95
(m, 1H), 3.76-3.78 (m, 1H), 3.43-3.45 (m, 1H).
Embodiment 17 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 17)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids into, receive
Rate 100%, LC-MS:m/z 333.0 [M+H]+。
Embodiment 18 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 18)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 347.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.76 (s, 1H), 8.65 (s, 1H), 8.41 (t, J=6.8Hz, 1H),
8.29 (d, J=7.6Hz, 1H), 7.88 (t, J=8.0Hz, 1H), 7.58-7.66 (m, 3H), 4.07-4.10 (m, 1H), 3.92
(s, 3H), 3.89-3.90 (m, 1H), 3.35-3.37 (m, 1H).
Embodiment 19 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base)-
2,3-dihydro-thiophenes [3,2-c] pyridine-2-carboxylic acids ester (I 19)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids into, receive
Rate 65%, LC-MS:m/z 445.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.86 (s, 1H), 8.71 (s, 1H), 8.53 (t, J=7.2Hz, 1H),
8.35 (d, J=7.2Hz, 1H), 7.95 (t, J=8.0Hz, 1H), 7.68-7.79 (m, 3H), 4.70 (s, 2H), 3.97-4.01
(m, 1H), 3.78-3.81 (m, 1H), 3.31-3.33 (m, 1H), 2.69 (s, 3H).
Embodiment 20 1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyrrole
Pyridine-2-carboxylate (I 20)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids into, receive
Rate 66%, LC-MS:m/z 447.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (s, 1H), 8.52 (s, 1H), 8.31 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50 (m, 1H), 4.10-
4.14 (m, 1H), 3.98 (d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H),
1.59 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 21 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 21)
Step 1: identical with embodiment 11 step 1
Step 2:7-bromothiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester
According to the method described in embodiment 11 step 2, simply change ethyl 2-mercaptopropionate into 2-ethyl thioglycolate, receive
Rate 90%.
Step 3:7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester
According to the method described in embodiment 11 step 5, simply by bromo-for 7-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole
Pyridine-2-carboxylic acid, ethyl ester changes 7-bromothiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester, yield 60.5% into.
Step 4:7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids
According to the method described in embodiment 11 step 6, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro thiophene
Fen [3,2-c] pyridine-2-carboxylic acids ethyl ester change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ethyl ester into,
Yield 43.5%, LC-MS:m/z 331.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.89 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.40 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H)。
Embodiment 22 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 22)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 100%,
LC-MS:m/z 331.0 [M+H]+。
Embodiment 23 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 23)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield 100%, LC-into
MS:m/z 345.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.65 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 3.80 (s, 3H).
Embodiment 24 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) thiophene
Fen [3,2-c] pyridine-2-carboxylic acids ester (I 24)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 69%,
LC-MS:m/z 443.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.95 (s, 2H),
2.60 (s, 3H).
Embodiment 25 1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids
Ester (I 25)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 66%,
LC-MS:m/z 445.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 6.46-6.51
(m, 1H), 2.75-2.80 (m, 1H), 1.61 (d, J=9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 26 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 26)
Step 1:5-bromo-4-chlorine-3-aminopyridine
By bromo-for 5-4-chloro-3-nitropyridine (5.0g, 0.021mol), it is dissolved in 50mL oxolane, adds 150mL and satisfy
With ammonium chloride solution and zinc powder (13g, 0.21mol), heat 40 DEG C and stir 1 hour, be cooled to room temperature, separatory, aqueous phase 100mL second
Acetoacetic ester washs, and merges organic facies, and respectively with water (100mL*2 time) and saturated aqueous common salt washing (50mL*2 time), organic facies is dense
Contracting, obtains 4.1g crude oil, yield 92%.
Step 2:2-[(5-bromo-4-chloropyridine-3-base)-amino]-2-glyoxylic acid ethyl ester
Bromo-for 5-4-chlorine-3-aminopyridine (4.1g, 0.020mol) is dissolved in 100mL oxolane, adds triethylamine
(2.4g, 0.024mol), is placed in system in 0 DEG C of ice bath, the oxolane of dropping ethyl oxalyl chloride (3.0g, 0.022mol)
Solution, reacts 1 hour under room temperature, concentrating under reduced pressure, adds ethyl acetate (100mL) dilution, washs with saturated sodium bicarbonate solution
(50mL*2 time), separatory, organic facies anhydrous sodium sulfate is dried, and is evaporated to do, and obtains solid 5.5g crude product, yield
90.0%.
Step 3:7-bromo thiazole [4,5-c] pyridine-2-carboxylic acids ethyl ester
2-[(5-bromo-4-chloropyridine-3-base)-amino]-2-glyoxylic acid ethyl ester (5.5g, 0.018mol) is dissolved in 100mL
In toluene, add lawesson reagent (4.9g, 0.012mol), be heated to reflux 2 hours, be cooled to room temperature, concentrating under reduced pressure, residue silicon
Glue post separates (PE: EA=2: 1), can obtain yellow solid 2.0g, yield 35%.
Step 4:7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ethyl ester
According to the method described in embodiment 11 step 5, simply by bromo-for 7-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole
Pyridine-2-carboxylic acid, ethyl ester changes 7-bromo thiazole [4,5-c] pyridine-2-carboxylic acids ethyl ester, yield 57.5% into.
Step 5:7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids
According to the method described in embodiment 11 step 6, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro thiophene
Fen [3,2-c] pyridine-2-carboxylic acids ethyl ester change 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ethyl ester into,
Yield 43.5%, LC-MS:m/z 332.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.97 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H).
Embodiment 27 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 27)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 100%,
LC-MS:m/z 332.0 [M+H]+。
Embodiment 28 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 28)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield 100%, LC-into
MS:m/z 346.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.64 (s, 1H), 8.51 (s, 1H), 8.30 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 3.83 (s, 3H).
Embodiment 29 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) thiophene
Azoles [4,5-c] pyridine-2-carboxylic acids ester (I 29)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 68%,
LC-MS:m/z 444.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (s, 1H), 8.54 (s, 1H), 8.33 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.96 (s, 2H), 2.61 (s,
3H)。
Embodiment 30 1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids
Ester (I 30)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 60%,
LC-MS:m/z 446.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 6.44-6.50 (m, 1H), 2.75-
2.81 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.06 (d, J=9.6Hz, 6H).
Embodiment 31 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 31)
With 3-bromo-2-fluorobenzaldehyde for raw material substitution 5-bromo-4-chlorine cigarette aldehyde, synthetic method is with compound described in embodiment 21
Preparation method, LC-MS:m/z 330.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.02 (s, 1H), 8.72 (d, J=8.0Hz, 1H), 8.68 (d, J=
8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=7.6Hz,
1H), 7.64-7.75 (m, 3H), 7.45-749 (m, 1H).
Embodiment 32 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 32)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 100%, LC-MS:
m/z 330.0[M+H]+。
Embodiment 33 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 33)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-MS:m/z into
344.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.70 (d, J=8.0Hz, 1H), 8.67 (d, J=8.0Hz, 1H), 8.42
(s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.94 (t, J=7.6Hz, 1H), 7.64-7.75
(m, 3H), 7.44-749 (m, 1H), 3.81 (s, 3H).
Embodiment 34 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) benzene
And [b] thiophene-2-carboxylic acid ester (I 34)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 64%, LC-MS:m/ into
z 442.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.44-749 (m,
1H), 4.96 (s, 2H), 2.60 (s, 3H).
Embodiment 35 1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I35)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 61%, LC-MS:m/ into
z 444.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.34 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-749 (m,
1H), 6.46-6.51 (m, 1H), 2.75-2.80 (m, 1H), 1.62 (d, J=9.6Hz, 3H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 36 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 36)
With 3-bromo-2-fluoronitrobenzene for the bromo-4-of raw material substitution 5-chloro-3-nitropyridine, synthetic method is with embodiment 26 institute
State the preparation method of compound, LC-MS:m/z 331.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.10 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H), 7.40-745 (m,
1H)。
Embodiment 37 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 37)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium, yield 100%, LC-into
MS:m/z 331.1 [M+H]+。
Embodiment 38 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 38)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-MS:m/z into
345.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.55 (s, 1H), 8.30 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 7.40-745 (m, 1H), 3.83
(s, 3H).
Embodiment 39 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) benzene
And [d] thiazole-2-carboxylate (I 39)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 69%, LC-MS:m/ into
z 443.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (s, 1H), 8.52 (s, 1H), 8.33 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-745 (m, 1H), 4.93
(s, 2H), 2.60 (s, 3H).
Embodiment 40 1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylate (I
40)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 63%, LC-MS:m/ into
z 445.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.70 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 7.40-745 (m, 1H), 6.45-
6.50 (m, 1H), 2.74-2.81 (m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 41 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(I 41)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 1, LC-MS:m/z 414.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.01 (s, 1H), 8.59 (d, J=3.2Hz, 1H), 8.39 (d, J=
3.2Hz, 1H), 8.31 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t,
J=6.8Hz, 1H), 7.61-7.70 (m, 1H), 7.54-7.57 (m, 1H), 3.00-3.14 (m, 2H), 2.28-2.36 (m, 1H),
1.95-2.01 (m, 1H), 1.47 (d, J=12Hz, 3H).
Embodiment 42 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Sodium (I 42)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-2-methyl-3 into, and 4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylic acid, yield 100%, LC-MS:m/z 414.0 [M+H]+。
Embodiment 43 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Ethyl ester (I 43)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-2-methyl-3 into, and 4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylic acid, yield 100%, LC-MS:m/z 442.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (d, J=5.2Hz, 1H), 8.40 (d, J=7.2Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d, J=6.8Hz, 1H),
7.59-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.74-3.90 (m, 2H) 3.11-3.17 (m, 2H), 2.25-2.37 (m,
1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.07 (t, J=6.8Hz, 3H).
Embodiment 44 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-bromonaphthalene-1-base)-2-first
Base-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 44)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-2-methyl-3 into, and 4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylic acid, yield 70%, LC-MS:m/z 526.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (d, J=7.2Hz, 1H), 8.42 (d, J=8.0Hz, 1H), 8.31
(d, J=7.2Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 7.90 (d, J=7.2Hz, 1H), 7.69 (d, J=6.4Hz, 1H),
7.59-7.63 (m, 1H), 7.50-7.55 (m, 1H), 4.55 (s, 2H), 3.13-3.19 (m, 2H), 2.65 (s, 3H), 2.26-
2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.47 (d, J=12Hz, 3H).
Embodiment 45 1-(isobutyryl epoxide) ethyl 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,
2-c] and pyridine-2-carboxylic acids ester (I 45)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-2-methyl-3 into, and 4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylic acid, yield 67%, LC-MS:m/z 528.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.60 (d, J=3.2Hz, 1H), 8.47 (d, J=3.2Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H),
7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.02-3.14 (m, 2H), 2.76-2.80 (m,
1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.47 (d, J=12Hz, 3H),
1.03 (d, J=9.6Hz, 6H).
Embodiment 46 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 46)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 6, LC-MS:m/z 400.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.89 (s, 1H), 8.78 (d, J=8.0Hz, 1H), 8.49 (d, J=
7.8Hz, 1H), 8.41 (d, J=7.6Hz, 1H), 8.34 (d, J=8.4Hz, 1H), 7.96 (t, J=7.2Hz, 1H), 7.78 (t,
J=6.8Hz, 1H), 7.73-7.78 (m, 1H), 7.45-7.48 (m, 1H), 3.40-3.45 (m, 1H), 3.12-3.26 (m, 2H),
2.37-2.46 (m, 1H), 1.99-2.11 (m, 1H).
Embodiment 47 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 47)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-3 into, 4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids,
Yield 100%, LC-MS:m/z 400.0 [M+H]+。
Embodiment 48 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
48)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-3 into, 4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids,
Yield 100%, LC-MS:m/z 428.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (d, J=5.2Hz, 1H), 8.41 (d, J=7.2Hz, 1H), 8.33
(d, J=7.2Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d, J=6.8Hz, 1H),
7.59-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.74-3.91 (m, 2H) 3.10-3.17 (m, 2H), 2.24-2.37 (m,
1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.08 (t, J=6.8Hz, 3H).
Embodiment 49 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-bromonaphthalene-1-base)-3,4-
Dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 49)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-3 into, 4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids,
Yield 70%, LC-MS:m/z 512.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (d, J=7.2Hz, 1H), 8.41 (d, J=8.0Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.91 (d, J=7.2Hz, 1H), 7.69 (d, J=6.4Hz, 1H),
7.59-7.63 (m, 1H), 7.50-7.57 (m, 1H), 4.55 (s, 2H), 3.14-3.19 (m, 2H), 2.65 (s, 3H), 2.26-
2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.48 (d, J=12Hz, 3H).
Embodiment 50 1-(isobutyryl epoxide) ethyl 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids ester (I 50)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-bromonaphthalene-1-base)-3 into, 4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids,
Yield 69%, LC-MS:m/z 514.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.60 (d, J=3.2Hz, 1H), 8.37 (d, J=3.2Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H),
7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.40-3.46 (m, 1H), 3.01-3.14 (m,
2H), 2.76-2.80 (m, 1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.05
(d, J=9.6Hz, 6H).
Embodiment 51 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I
51)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 11, LC-MS:m/z 400.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.78 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.31 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.67-7.73 (m, 3H), 3.98 (d, J=
16.4Hz, 1H), 3.51 (dd, J=16.0,5.2Hz, 1H), 1.65 (d, J=10.8Hz, 3H).
Embodiment 52 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I
52)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 400.0 [M+H]+。
Embodiment 53 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester
(I 53)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2-methyl-2 into, 3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids,
Yield 100%, LC-MS:m/z 414.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.47 (s, 1H), 8.38 (br.s, 1H), 8.36 (s, 1H), 7.98
(dd, J=7.6,1.6Hz, 1H), 7.69-7.74 (m, 3H), 7.53 (t, J=7.6Hz, 1H), 4.05 (d, J=16.0Hz,
1H), 3.95 (s, 3H), 3.34 (d, J=16.0Hz, 1H), 1.76 (s, 3H).
Embodiment 54 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base)-2-first
Base-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 54)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 72%, LC-MS:m/z 512.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.52 (s, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 7.96 (d, J=
7.2Hz, 1H), 7.64-7.75 (m, 3H), 7.53 (t, J=8.0Hz, 1H), 4.80 (s, 2H), 4.11 (d, J=16.0Hz,
1H), 3.33 (d, J=16.4Hz, 1H), 2.61 (s, 3H), 1.74 (s, 3H).
Embodiment 55 1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c]
And pyridine-2-carboxylic acids ester (I 55)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 69%, LC-MS:m/z 514.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.65 (s, 1H), 8.54 (s, 1H), 8.31 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50 (m, 1H), 3.98
(d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H), 1.68 (d, J=10.8Hz,
3H), 1.59 (d, J=9.6Hz, 3H), 1.03 (d, J=9.6Hz, 6H).
Embodiment 56 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 56)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 16, LC-MS:m/z 386.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.74 (s, 1H), 8.85 (s, 1H), 8.73 (s, 1H), 8.56 (t, J=
6.0Hz, 1H), 8.30 (d, J=8.0Hz, 1H), 7.98 (t, J=8.4Hz, 1H), 7.71-7.75 (m, 3H), 3.91-3.97
(m, 1H), 3.75-3.78 (m, 1H), 3.43-3.46 (m, 1H).
Embodiment 57 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 57)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 386.0 [M+H]+。
Embodiment 58 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 58)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 400.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.77 (s, 1H), 8.67 (s, 1H), 8.41 (t, J=6.8Hz, 1H),
8.28 (d, J=7.2Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.58-7.66 (m, 3H), 4.05-4.10 (m, 1H), 3.92
(s, 3H), 3.89-3.91 (m, 1H), 3.34-3.37 (m, 1H).
Embodiment 59 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base)-2,3-
Dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 59)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
67%, LC-MS:m/z 498.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.86 (s, 1H), 8.70 (s, 1H), 8.51 (t, J=7.2Hz, 1H),
8.35 (d, J=7.2Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.66-7.79 (m, 3H), 4.70 (s, 2H), 3.97-4.02
(m, 1H), 3.77-3.81 (m, 1H), 3.31-3.36 (m, 1H), 2.69 (s, 3H).
Embodiment 60 1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-
2-carboxylate (I 60)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
69%, LC-MS:m/z 500.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (s, 1H), 8.52 (s, 1H), 8.31 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50 (m, 1H), 4.10-
4.14 (m, 1H), 3.98 (d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H),
1.59 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 61 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 61)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 21, LC-MS:m/z 384.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.91 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.40 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.75 (m,
3H)。
Embodiment 62 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 62)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield 100%, LC-into
MS:m/z 384.0 [M+H]+。
Embodiment 63 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 63)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 100%, LC-MS:
m/z 398.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (s, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 3.81 (s, 3H).
Embodiment 64 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) thiophene
[3,2-c] pyridine-2-carboxylic acids ester (I 64)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield 68%, LC-into
MS:m/z 496.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.72 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.28 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.74 (m, 3H), 4.97 (s, 2H),
2.61 (s, 3H).
Embodiment 65 1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester
(I 65)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield 67%, LC-into
MS:m/z 498.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 6.46-6.51
(m, 1H), 2.75-2.80 (m, 1H), 1.61 (d, J=9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 66 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 66)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 26, LC-MS:m/z 385.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.92 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 7.65-7.73 (m, 3H).
Embodiment 67 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 67)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield 100%, LC-into
MS:m/z 385.0 [M+H]+。
Embodiment 68 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 68)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 100%, LC-MS:
m/z 399.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.65 (s, 1H), 8.50 (s, 1H), 8.32 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 3.82 (s, 3H).
Embodiment 69 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) thiazole
[4,5-c] pyridine-2-carboxylic acids ester (I 69)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield 69%, LC-into
MS:m/z 497.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.77 (s, 1H), 8.56 (s, 1H), 8.36 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.98 (s, 2H), 2.65 (s,
3H)。
Embodiment 70 1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester
(I 70)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 62%,
LC-MS:m/z 499.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 6.44-6.50 (m, 1H), 2.75-
2.81 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.06 (d, J=9.6Hz, 6H).
Embodiment 71 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 71)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 31, LC-MS:m/z 383.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.02 (s, 1H), 8.72 (d, J=8.0Hz, 1H), 8.68 (d, J=
8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=7.6Hz,
1H), 7.64-7.75 (m, 3H), 7.45-749 (m, 1H).
Embodiment 72 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 72)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-MS:m/z into
383.0[M+H]+。
Embodiment 73 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 73)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-MS:m/z into
397.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.70 (d, J=8.0Hz, 1H), 8.67 (d, J=8.0Hz, 1H), 8.42
(s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.94 (t, J=7.6Hz, 1H), 7.64-7.75
(m, 3H), 7.44-749 (m, 1H), 3.81 (s, 3H).
Embodiment 74 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) benzo
[b] thiophene-2-carboxylic acid ester (I 74)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 65%, LC-MS:m/z into
495.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.44-749 (m,
1H), 4.96 (s, 2H), 2.60 (s, 3H).
Embodiment 75 1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 75)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 61%, LC-MS:m/z into
497.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.34 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-749 (m,
1H), 6.46-6.51 (m, 1H), 2.75-2.80 (m, 1H), 1.62 (d, J=9.6Hz, 3H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 76 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 76)
With 4-bromo-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is with real
Execute the preparation method of compound described in example 36, LC-MS:m/z 384.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.10 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H), 7.40-745 (m,
1H)。
Embodiment 77 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 77)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-MS:m/z into
384.0[M+H]+。
Embodiment 78 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 78)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-MS:m/z into
398.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.55 (s, 1H), 8.30 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 7.40-745 (m, 1H), 3.83
(s, 3H).
Embodiment 79 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) benzo
[d] thiazole-2-carboxylate (I 79)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 64%, LC-MS:m/z into
496.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (s, 1H), 8.52 (s, 1H), 8.33 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-745 (m, 1H), 4.93
(s, 2H), 2.60 (s, 3H).
Embodiment 80 1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 80)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 61%, LC-MS:m/z into
498.0[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.70 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 7.40-745 (m, 1H), 6.45-
6.50 (m, 1H), 2.74-2.81 (m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 81 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-
Carboxylic acid (I 81)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 1, LC-MS:m/z 376.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.05 (s, 1H), 8.69 (d, J=3.2Hz, 1H), 8.48 (d, J=
3.2Hz, 1H), 8.33 (d, J=7.2Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t,
J=6.8Hz, 1H), 7.61-7.70 (m, 1H), 7.54-7.57 (m, 1H), 3.00-3.14 (m, 2H), 2.52-2.56 (m, 1H),
2.28-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.47 (d, J=12Hz, 3H), 1.17-1.19 (m, 2H), 0.88-0.89
(m, 2H).
Embodiment 82 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-
Carboxylic acid sodium (I 82)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3 into, 4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids, yield 100%, LC-MS:m/z 376.1 [M+H]+。
Embodiment 83 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-
Carboxylic acid, ethyl ester (I 83)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3 into, 4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids, yield 100%, LC-MS:m/z 404.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.64 (d, J=5.2Hz, 1H), 8.41 (d, J=7.2Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d, J=6.8Hz, 1H),
7.59-7.65 (m, 1H), 7.55-7.57 (m, 1H), 3.74-3.90 (m, 2H) 3.11-3.17 (m, 2H), 2.52-2.55 (m,
1H), 2.25-2.37 (m, 1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.17-1.18 (m, 2H), 1.07
(t, J=6.8Hz, 3H), 0.87-0.89 (m, 2H).
Embodiment 84 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyclopropyl naphthalene-1-base)-
2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 84)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3 into, 4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids, yield 70%, LC-MS:m/z 488.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.65 (d, J=7.2Hz, 1H), 8.41 (d, J=8.0Hz, 1H), 8.32
(d, J=7.2Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 7.90 (d, J=7.2Hz, 1H), 7.69 (d, J=6.4Hz, 1H),
7.59-7.63 (m, 1H), 7.51-7.55 (m, 1H), 4.55 (s, 2H), 3.13-3.19 (m, 2H), 2.65 (s, 3H), 2.53-
2.55 (m, 1H), 2.26-2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.47 (d, J=12Hz, 3H), 1.16-1.18 (m,
2H), 0.88-0.89 (m, 2H).
Embodiment 85 1-(isobutyryl epoxide) ethyl 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiophene
Mutter [3,2-c] pyridine-2-carboxylic acids ester (I 85)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3 into, 4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids, yield 63%, LC-MS:m/z 490.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (d, J=3.2Hz, 1H), 8.48 (d, J=3.2Hz, 1H), 8.33
(d, J=7.2Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H),
7.61-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.00-3.14 (m, 2H), 2.74-2.81 (m,
1H), 2.52-2.56 (m, 1H), 2.28-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.47
(d, J=12Hz, 3H), 1.17-1.19 (m, 2H), 1.01 (d, J=9.6Hz, 6H), 0.88-0.89 (m, 2H).
Embodiment 86 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(I86)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 6, LC-MS:m/z 362.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.86 (s, 1H), 8.78 (d, J=8.0Hz, 1H), 8.49 (d, J=
7.8Hz, 1H), 8.43 (d, J=7.6Hz, 1H), 8.34 (d, J=8.4Hz, 1H), 7.96 (t, J=7.2Hz, 1H), 7.78 (t,
J=6.8Hz, 1H), 7.74-7.78 (m, 1H), 7.45-7.48 (m, 1H), 3.40-3.45 (m, 1H), 3.12-3.26 (m, 2H),
2.53-2.54 (m, 1H), 2.37-2.46 (m, 1H), 1.99-2.11 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89 (m,
2H).
Embodiment 87 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I
87)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-into
Carboxylic acid, yield 100%, LC-MS:m/z 362.1 [M+H]+。
Embodiment 88 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester
(I 88)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-into
Carboxylic acid, yield 100%, LC-MS:m/z 390.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (d, J=5.2Hz, 1H), 8.41 (d, J=7.2Hz, 1H), 8.33
(d, J=7.2Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d, J=6.8Hz, 1H),
7.59-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.74-3.91 (m, 2H) 3.10-3.17 (m, 2H), 2.52-2.54 (m,
1H), 2.24-2.37 (m, 1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.17-1.19 (m, 2H), 1.08
(t, J=6.8Hz, 3H), 0.87-0.88 (m, 2H).
Embodiment 89 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyclopropyl naphthalene-1-base)-
3,4-dihydros-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 89)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-into
Carboxylic acid, yield 70%, LC-MS:m/z 474.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (d, J=7.2Hz, 1H), 8.42 (d, J=8.0Hz, 1H), 8.30
(d, J=7.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.91 (d, J=7.2Hz, 1H), 7.69 (d, J=6.4Hz, 1H),
7.59-7.63 (m, 1H), 7.50-7.57 (m, 1H), 4.55 (s, 2H), 3.14-3.19 (m, 2H), 2.65 (s, 3H), 2.52-
2.55 (m, 1H), 2.26-2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.48 (d, J=12Hz, 3H), 1.16-1.18 (m,
2H), 0.88-0.89 (m, 2H).
Embodiment 90 1-(isobutyryl epoxide) ethyl 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-
C] and pyridine-2-carboxylic acids ester
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-into
Carboxylic acid, yield 65%, LC-MS:m/z 476.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.78 (d, J=8.0Hz, 1H), 8.49 (d, J=7.8Hz, 1H), 8.43
(d, J=7.6Hz, 1H), 8.34 (d, J=8.4Hz, 1H), 7.96 (t, J=7.2Hz, 1H), 7.78 (t, J=6.8Hz, 1H),
7.74-7.78 (m, 1H), 7.45-7.48 (m, 1H), 6.45-6.50 (m, 1H), 3.40-3.45 (m, 1H), 3.12-3.26 (m,
2H), 2.74-2.81 (m, 1H), 2.53-2.54 (m, 1H), 2.37-2.46 (m, 1H), 1.99-2.11 (m, 1H), 1.63 (d, J
=9.6Hz, 3H), 1.17-1.18 (m, 2H), 1.01 (d, J=9.6Hz, 6H), 0.87-0.89 (m, 2H).
Embodiment 91 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
(I 91)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 11, LC-MS:m/z 362.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.79 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.67-7.73 (m, 3H), 3.98 (d, J=
16.4Hz, 1H), 3.51 (dd, J=16.0,5.2Hz, 1H), 2.53-2.55 (m, 1H), 1.65 (d, J=10.8Hz, 3H),
1.17-1.18 (m, 2H), 0.86-0.89 (m, 2H).
Embodiment 92 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
Sodium (I 92)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2 into, and 3-dihydro-thiophene [3,2-c] pyridine-
2-carboxylic acid, yield 100%, LC-MS:m/z 362.1 [M+H]+。
Embodiment 93 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
Methyl ester (I 93)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 100%, LC-MS:m/z 376.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.57 (s, 1H), 8.45 (br.s, 1H), 8.36 (s, 1H), 7.98
(dd, J=7.6,1.6Hz, 1H), 7.69-7.74 (m, 3H), 7.53 (t, J=7.6Hz, 1H), 4.05 (d, J=16.0Hz,
1H), 3.95 (s, 3H), 3.34 (d, J=16.0Hz, 1H), 2.52-2.54 (m, 1H), 1.76 (s, 3H), 1.16-1.17 (m,
2H), 0.86-0.88 (m, 2H).
Embodiment 94 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)-
2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 94)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 72%, LC-MS:m/z 474.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.54 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 7.96 (d, J=
7.2Hz, 1H), 7.64-7.75 (m, 3H), 7.53 (t, J=8.0Hz, 1H), 4.80 (s, 2H), 4.11 (d, J=16.0Hz,
1H), 3.33 (d, J=16.4Hz, 1H), 2.61 (s, 3H), 2.52-2.53 (m, 1H), 1.74 (s, 3H), 1.17-1.19 (m,
2H), 0.87-0.88 (m, 2H).
Embodiment 95 1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids ester (I 95)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2 into, and 3-dihydro-thiophene [3,2-c] pyridine-
2-carboxylic acid, yield 67%, LC-MS:m/z 476.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (s, 1H), 8.54 (s, 1H), 8.32 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.67-7.73 (m, 3H), 6.45-6.50 (m, 1H), 3.98
(d, J=16.4Hz, 1H), 3.51 (dd, J=16.0,5.2Hz, 1H), 2.74-2.81 (m, 1H), 2.53-2.55 (m, 1H),
1.65 (d, J=10.8Hz, 3H), 1.60 (d, J=9.6Hz, 3H), 1.17-1.18 (m, 2H), 1.01 (d, J=9.6Hz, 6H),
0.86-0.89 (m, 2H).
Embodiment 96 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 96)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 16, LC-MS:m/z 348.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.54 (s, 1H), 8.87 (s, 1H), 8.75 (s, 1H), 8.56 (t, J=
6.0Hz, 1H), 8.30 (d, J=8.0Hz, 1H), 7.98 (t, J=8.4Hz, 1H), 7.71-7.75 (m, 3H), 3.91-3.97
(m, 1H), 3.75-3.78 (m, 1H), 3.43-3.46 (m, 1H), 2.53-2.54 (m, 1H), 1.18-1.19 (m, 2H), 0.87-
0.89 (m, 2H).
Embodiment 97 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 97)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base)-2 into, 3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids,
Yield 100%, LC-MS:m/z 348.1 [M+H]+。
Embodiment 98 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I
98)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base)-2 into, 3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, receive
Rate 100%, LC-MS:m/z 362.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.74 (s, 1H), 8.63 (s, 1H), 8.40 (t, J=6.8Hz, 1H),
8.28 (d, J=7.2Hz, 1H), 7.86 (t, J=8.0Hz, 1H), 7.58-7.66 (m, 3H), 4.05-4.10 (m, 1H), 3.92
(s, 3H), 3.89-3.91 (m, 1H), 3.34-3.37 (m, 1H), 2.52-2.54 (m, 1H), 1.17-1.19 (m, 2H), 0.88-
0.89 (m, 2H).
Embodiment 99 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)-
2,3-dihydro-thiophenes [3,2-c] pyridine-2-carboxylic acids ester (I 99)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
67%, LC-MS:m/z 460.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.87 (s, 1H), 8.72 (s, 1H), 8.52 (t, J=7.2Hz, 1H),
8.35 (d, J=7.2Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.66-7.79 (m, 3H), 4.70 (s, 2H), 3.97-4.02
(m, 1H), 3.77-3.81 (m, 1H), 3.31-3.36 (m, 1H), 2.69 (s, 3H), 2.52-2.53 (m, 1H), 1.18-1.19
(m, 2H), 0.87-0.89 (m, 2H).
Embodiment 1001-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] and
Pyridine-2-carboxylic acids ester (I 100)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base)-2 into, 3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids,
Yield 68%, LC-MS:m/z 462.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.87 (s, 1H), 8.75 (s, 1H), 8.56 (t, J=6.0Hz, 1H),
8.30 (d, J=8.0Hz, 1H), 7.98 (t, J=8.4Hz, 1H), 7.71-7.75 (m, 3H), 6.45-6.50 (m, 1H), 3.91-
3.97 (m, 1H), 3.75-3.78 (m, 1H), 3.43-3.46 (m, 1H), 2.74-2.81 (m, 1H), 2.53-2.54 (m, 1H),
1.63 (d, J=9.6Hz, 3H), 1.18-1.19 (m, 2H), 1.01 (d, J=9.6Hz, 6H), 0.87-0.89 (m, 2H).
Embodiment 101 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 101)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 21, LC-MS:m/z 346.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.88 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.40 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 2.53-2.55 (m, 1H), 1.17-1.18 (m, 2H), 0.86-0.89 (m, 2H).
Embodiment 102 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 102)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 346.1 [M+H]+。
Embodiment 103 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 103)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 100%,
LC-MS:m/z 360.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 3.80 (s, 3H),
2.52-2.53 (m, 1H), 1.16-1.18 (m, 2H), 0.88-0.89 (m, 2H).
Embodiment 104 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)
Thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 104)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 71%,
LC-MS:m/z 458.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.95 (s, 2H),
2.60 (s, 3H), 2.52-2.54 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89 (m, 2H).
Embodiment 105 1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic
Acid esters (I 105)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 64%,
LC-MS:m/z 460.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 6.45-6.50
(m, 1H), 2.74-2.81 (m, 1H), 2.53-2.55 (m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.17-1.18 (m, 2H),
1.01 (d, J=9.6Hz, 6H), 0.86-0.89 (m, 2H).
Embodiment 106 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 106)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 26, LC-MS:m/z 347.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.84 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H), 2.52-2.54
(m, 1H), 1.18-1.19 (m, 2H), 0.88-0.89 (m, 2H).
Embodiment 107 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 107)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 347.1 [M+H]+。
Embodiment 108 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 108)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 100%,
LC-MS:m/z 361.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.64 (s, 1H), 8.51 (s, 1H), 8.30 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 3.80 (s, 3H), 2.53-2.54
(m, 1H), 1.17-1.19 (m, 2H), 0.87-0.88 (m, 2H).
Embodiment 109 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)
Thiazole [4,5-c] pyridine-2-carboxylic acids (I 109)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 104) into, receive
Rate 70%, LC-MS:m/z 359.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.65 (s, 1H), 8.54 (s, 1H), 8.34 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.96 (s, 2H), 2.61 (s,
3H), 2.53-2.54 (m, 1H), 1.17-1.19 (m, 2H), 0.87-0.88 (m, 2H).
Embodiment 110 1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic
Acid esters (I 110)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 61%,
LC-MS:m/z 461.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.56 (s, 1H), 8.33 (t, J=5.2Hz, 1H),
8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H), 6.45-6.50 (m, 1H), 2.74-
2.81 (m, 1H), 2.53-2.55 (m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.17-1.18 (m, 2H), 1.02 (d, J=
9.6Hz, 6H), 0.87-0.89 (m, 2H).
Embodiment 111 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 111)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 31, LC-MS:m/z 345.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.02 (s, 1H), 8.72 (d, J=8.0Hz, 1H), 8.68 (d, J=
8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=7.6Hz,
1H), 7.64-7.75 (m, 3H), 7.45-749 (m, 1H), 2.53-2.55 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89
(m, 2H).
Embodiment 112 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 112)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-into
MS:m/z 345.1 [M+H]+。
Embodiment 113 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 113)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-MS:m/ into
z 359.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.70 (d, J=8.0Hz, 1H), 8.67 (d, J=8.0Hz, 1H), 8.42
(s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.94 (t, J=7.6Hz, 1H), 7.64-7.75
(m, 3H), 7.44-749 (m, 1H), 3.81 (s, 3H), 2.53-2.55 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89 (m,
2H)。
Embodiment 114 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)
Benzo [b] thiophene-2-carboxylic acid ester (I 114)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 66%, LC-MS:
m/z 457.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.44-749 (m,
1H), 4.96 (s, 2H), 2.60 (s, 3H), 2.53-2.55 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89 (m, 2H).
Embodiment 115 1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I
115)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 60%, LC-MS:
m/z 459.2[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.72 (d, J=8.0Hz, 1H), 8.68 (d, J=8.0Hz, 1H), 8.42
(s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=7.6Hz, 1H), 7.64-7.75
(m, 3H), 7.45-749 (m, 1H), 6.45-6.50 (m, 1H), 2.74-2.81 (m, 1H), 2.53-2.55 (m, 1H), 1.63 (d,
J=9.6Hz, 3H), 1.17-1.18 (m, 2H), 1.02 (d, J=9.6Hz, 6H), 0.87-0.89 (m, 2H).
Embodiment 116 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 116)
With 4-cyclopropyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method
With the preparation method of compound described in embodiment 36, LC-MS:m/z 346.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.10 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H), 7.40-745 (m,
1H), 2.53-2.55 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89 (m, 2H).
Embodiment 117 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 117)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-into
MS:m/z 346.1 [M+H]+。
Embodiment 118 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 118)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-C] and pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-MS:m/ into
z 360.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.70 (d, J=8.0Hz, 1H), 8.67 (d, J=8.0Hz, 1H), 8.33
(t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.94 (t, J=7.6Hz, 1H), 7.64-7.75 (m, 3H), 7.44-
749 (m, 1H), 3.81 (s, 3H), 2.53-2.55 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89 (m, 2H).
Embodiment 119 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-
Base) benzo [d] thiazole-2-carboxylate (I 119)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid into, yield 66%, LC-MS:
m/z 458.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.55 (s, 1H), 8.33 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.44-749 (m, 1H), 4.96
(s, 2H), 2.60 (s, 3H), 2.53-2.55 (m, 1H), 1.17-1.18 (m, 2H), 0.87-0.89 (m, 2H).
Embodiment 120 1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate (I
120)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid into, yield 60%, LC-MS:
m/z 460.2[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.72 (d, J=8.0Hz, 1H), 8.68 (d, J=8.0Hz, 1H), 8.33
(t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=7.6Hz, 1H), 7.64-7.75 (m, 3H), 7.45-
749 (m, 1H), 6.45-6.50 (m, 1H), 2.74-2.81 (m, 1H), 2.53-2.55 (m, 1H), 1.63 (d, J=9.6Hz,
3H), 1.17-1.18 (m, 2H), 1.02 (d, J=9.6Hz, 6H), 0.87-0.89 (m, 2H).
Embodiment 121 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acid (I 121)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 1, LC-MS:m/z 380.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.01 (s, 1H), 10.89 (s, 1H), 8.59 (d, J=3.2Hz, 1H),
8.39 (d, J=3.2Hz, 1H), 8.33 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz,
1H), 7.68 (t, J=6.8Hz, 1H), 7.61-7.70 (m, 1H), 7.54-7.57 (m, 1H), 3.00-3.14 (m, 2H), 2.28-
2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.48 (d, J=12Hz, 3H).
Embodiment 122 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acid sodium (I 122)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 100%, LC-MS:m/z 380.1 [M+H]+。
Embodiment 123 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acetoacetic ester (I 123)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 100%, LC-MS:m/z 408.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.12 (s, 1H), 8.67 (d, J=5.2Hz, 1H), 8.40 (d, J=
7.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.8Hz, 1H), 7.59-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.74-3.90 (m, 2H) 3.11-3.17 (m, 2H),
2.25-2.37 (m, 1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.07 (t, J=6.8Hz, 3H).
Embodiment 124 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carboxyl naphthalene-1-base)-
2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 124)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 70%, LC-MS:m/z 492.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.10 (s, 1H), 8.77 (d, J=7.2Hz, 1H), 8.42 (d, J=
8.0Hz, 1H), 8.31 (d, J=7.2Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 7.90 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.4Hz, 1H), 7.59-7.63 (m, 1H), 7.50-7.55 (m, 1H), 4.55 (s, 2H), 3.13-3.19 (m, 2H), 2.65
(s, 3H), 2.26-2.35 (m, 1H), 1.97-2.05 (m, 1H), 1.47 (d, J=12Hz, 3H).
Embodiment 125 1-(isobutyryl epoxide) ethyl 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids ester (I 125)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 62%, LC-MS:m/z 494.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.01 (s, 1H), 8.59 (d, J=3.2Hz, 1H), 8.39 (d, J=
3.2Hz, 1H), 8.33 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t,
J=6.8Hz, 1H), 7.61-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.02-3.14 (m, 2H),
2.76-2.80 (m, 1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.47 (d, J
=12Hz, 3H), 1.03 (d, J=9.6Hz, 6H).
Embodiment 126 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(I126)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 6, LC-MS:m/z 366.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.09 (s, 1H), 10.88 (s, 1H), 8.75 (d, J=8.0Hz, 1H),
8.49 (d, J=7.8Hz, 1H), 8.41 (d, J=7.6Hz, 1H), 8.34 (d, J=8.4Hz, 1H), 7.96 (t, J=7.2Hz,
1H), 7.78 (t, J=6.8Hz, 1H), 7.73-7.78 (m, 1H), 7.45-7.48 (m, 1H), 3.40-3.45 (m, 1H), 3.12-
3.26 (m, 2H), 2.37-2.46 (m, 1H), 1.99-2.11 (m, 1H).
Embodiment 127 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium
(I127)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 366.1 [M+H]+。
Embodiment 128 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester
(I 128)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 394.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.03 (s, 1H), 8.68 (d, J=5.2Hz, 1H), 8.41 (d, J=
7.2Hz, 1H), 8.33 (d, J=7.2Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.8Hz, 1H), 7.59-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.74-3.91 (m, 2H) 3.10-3.17 (m, 2H),
2.24-2.37 (m, 1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.08 (t, J=6.8Hz, 3H).
Embodiment 129 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carboxyl naphthalene-1-base)-
3,4-dihydros-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 129)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 70%, LC-MS:m/z 478.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.01 (s, 1H), 8.66 (d, J=7.2Hz, 1H), 8.41 (d, J=
8.0Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.91 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.4Hz, 1H), 7.59-7.63 (m, 1H), 7.50-7.57 (m, 1H), 4.55 (s, 2H), 3.14-3.19 (m, 2H), 2.65
(s, 3H), 2.26-2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.48 (d, J=12Hz, 3H).
Embodiment 130 1-(isobutyryl epoxide) ethyl 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c]
And pyridine-2-carboxylic acids ester (I 130)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic into
Acid, yield 67%, LC-MS:m/z 480.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.09 (s, 1H), 8.60 (d, J=3.2Hz, 1H), 8.37 (d, J=
3.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t,
J=6.8Hz, 1H), 7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.40-3.46 (m, 1H),
3.01-3.14 (m, 2H), 2.76-2.80 (m, 1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=
9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 131 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
(I131)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 11, LC-MS:m/z 366.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.07 (s, 1H), 10.78 (s, 1H), 8.65 (s, 1H), 8.56 (s,
1H), 8.31 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.67-7.73 (m,
3H), 3.98 (d, J=16.4Hz, 1H), 3.51 (dd, J=16.0,5.2Hz, 1H), 1.65 (d, J=10.8Hz, 3H).
Embodiment 132 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium
(I 132)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 100%, LC-MS:m/z 366.0 [M+H]+。
Embodiment 133 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids first
Ester (I 133)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 380.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.05 (s, 1H), 8.45 (s, 1H), 8.38 (br.s, 1H), 8.36
(s, 1H), 7.98 (dd, J=7.6,1.6Hz, 1H), 7.69-7.74 (m, 3H), 7.53 (t, J=7.6Hz, 1H), 4.05 (d, J
=16.0Hz, 1H), 3.95 (s, 3H), 3.34 (d, J=16.0Hz, 1H), 1.77 (s, 3H).
Embodiment 134 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)-
2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 134)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 72%, LC-MS:m/z 478.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.01 (s, 1H), 8.52 (s, 1H), 8.37 (s, 1H), 8.34 (s,
1H), 7.96 (d, J=7.2Hz, 1H), 7.64-7.75 (m, 3H), 7.53 (t, J=8.0Hz, 1H), 4.80 (s, 2H), 4.11
(d, J=16.0Hz, 1H), 3.33 (d, J=16.4Hz, 1H), 2.61 (s, 3H), 1.74 (s, 3H).
Embodiment 135 1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids ester (I 135)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 66%, LC-MS:m/z 480.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.09 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 8.31 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50
(m, 1H), 3.98 (d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H), 1.68 (d,
J=10.8Hz, 3H), 1.59 (d, J=9.6Hz, 3H), 1.03 (d, J=9.6Hz, 6H).
Embodiment 136 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 136)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 16, LC-MS:m/z 352.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.02 (s, 1H), 10.74 (s, 1H), 8.85 (s, 1H), 8.73 (s,
1H), 8.56 (t, J=6.0Hz, 1H), 8.30 (d, J=8.0Hz, 1H), 7.98 (t, J=8.4Hz, 1H), 7.71-7.75 (m,
3H), 3.91-3.97 (m, 1H), 3.75-3.78 (m, 1H), 3.43-3.46 (m, 1H).
Embodiment 137 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 137)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids into, receive
Rate 100%, LC-MS:m/z 352.1 [M+H]+。
Embodiment 138 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester
(I138)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 366.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.07 (s, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.41 (t, J=
6.8Hz, 1H), 8.28 (d, J=7.2Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.58-7.66 (m, 3H), 4.05-4.10
(m, 1H), 3.92 (s, 3H), 3.89-3.91 (m, 1H), 3.34-3.37 (m, 1H).
Embodiment 139 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)-
2,3-dihydro-thiophenes [3,2-c] pyridine-2-carboxylic acids ester (I 139)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids into, receive
Rate 67%, LC-MS:m/z 464.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.10 (s, 1H), 8.86 (s, 1H), 8.70 (s, 1H), 8.51 (t, J=
7.2Hz, 1H), 8.35 (d, J=7.2Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.66-7.79 (m, 3H), 4.70 (s, 2H),
3.97-4.02 (m, 1H), 3.77-3.81 (m, 1H), 3.31-3.36 (m, 1H), 2.69 (s, 3H).
Embodiment 140 1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyrrole
Pyridine-2-carboxylate (I 140)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids into, receive
Rate 63%, LC-MS:m/z 466.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.15 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.31 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50
(m, 1H), 4.10-4.14 (m, 1H), 3.98 (d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-
2.80 (m, 1H), 1.59 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 141 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 141)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 21, LC-MS:m/z 350.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.97 (s, 1H), 10.79 (s, 1H), 8.67 (s, 1H), 8.54 (s,
1H), 8.40 (s, 1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H),
7.65-7.74 (m, 3H).
Embodiment 142 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 142)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 100%,
LC-MS:m/z 350.0 [M+H]+。
Embodiment 143 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 143)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield 100%, LC-into
MS:m/z 364.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.68 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.40 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 3.81 (s, 3H).
Embodiment 144 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)
Thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 144)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 59%,
LC-MS:m/z 462.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.68 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s,
1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 4.95 (s, 2H), 2.60 (s, 3H).
Embodiment 145 1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids
Ester (I 145)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 63%,
LC-MS:m/z 464.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.38 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.40 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 6.46-6.51 (m, 1H), 2.75-2.80 (m, 1H), 1.61 (d, J=9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 146 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 146)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 26, LC-MS:m/z 351.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.93 (s, 1H), 10.97 (s, 1H), 8.69 (s, 1H), 8.56 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m,
3H)。
Embodiment 147 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 147)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 100%,
LC-MS:m/z 351.0 [M+H]+。
Embodiment 148 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 148)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield 100%, LC-into
MS:m/z 365.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.68 (s, 1H), 8.64 (s, 1H), 8.51 (s, 1H), 8.30 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 3.82 (s, 3H).
Embodiment 149 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)
Thiazole [4,5-c] pyridine-2-carboxylic acids ester (I 149)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 69%,
LC-MS:m/z 443.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.79 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.96 (s, 2H),
2.61 (s, 3H).
Embodiment 150 1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids
Ester (I 150)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids into, yield 68%,
LC-MS:m/z 465.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.80 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s,
1H), 8.34 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 7.40-749 (m, 1H), 6.46-6.51 (m, 1H), 2.75-2.80 (m, 1H), 1.62 (d, J=9.6Hz, 3H), 1.02
(d, J=9.6Hz, 6H).
Embodiment 151 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 151)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 31, LC-MS:m/z 349.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.87 (s, 1H), 11.02 (s, 1H), 8.72 (d, J=8.0Hz, 1H),
8.68 (d, J=8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93
(t, J=7.6Hz, 1H), 7.64-7.75 (m, 3H), 7.45-749 (m, 1H).
Embodiment 152 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 152)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 100%, LC-MS:
m/z 349.0[M+H]+。
Embodiment 153 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 153)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-MS:m/z into
363.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.57 (s, 1H), 8.70 (d, J=8.0Hz, 1H), 8.67 (d, J=
8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.94 (t, J=7.6Hz,
1H), 7.64-7.75 (m, 3H), 7.44-749 (m, 1H), 3.80 (s, 3H).
Embodiment 154 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)
Benzo [b] thiophene-2-carboxylic acid ester (I 154)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 51%, LC-MS:m/ into
z 461.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.67 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s,
1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 7.44-749 (m, 1H), 4.96 (s, 2H), 2.60 (s, 3H).
Embodiment 155 1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester
(I155)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 34%, LC-MS:m/ into
z 463.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.52 (s, 1H), 8.72 (d, J=8.0Hz, 1H), 8.68 (d, J=
8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=7.6Hz,
1H), 7.64-7.75 (m, 3H), 7.45-749 (m, 1H), 6.46-6.51 (m, 1H), 2.75-2.80 (m, 1H), 1.62 (d, J=
9.6Hz, 3H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 156 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 156)
With 4-carboxyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthetic method is same
The preparation method of compound described in embodiment 36, LC-MS:m/z 350.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.97 (s, 1H), 11.20 (s, 1H), 8.69 (s, 1H), 8.56 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m,
3H), 7.40-745 (m, 1H).
Embodiment 157 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 157)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid into, yield 100%, LC-MS:
m/z 350.0[M+H]+。
Embodiment 158 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 158)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-MS:m/z into
364.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.60 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 8.30 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 7.40-745 (m,
1H), 3.83 (s, 3H).
Embodiment 159 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) benzene
And [d] thiazole-2-carboxylate (I 159)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 46%, LC-MS:m/ into
z 462.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.65 (s, 1H), 8.66 (s, 1H), 8.52 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-745 (m,
1H), 4.93 (s, 2H), 2.60 (s, 3H).
Embodiment 160 1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate (I
160)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 36%, LC-MS:m/ into
z 464.1[M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.55 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 7.40-745 (m,
1H), 6.45-6.50 (m, 1H), 2.74-2.81 (m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 161 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylic acid (I 161)
With 4-carbamoyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 1, LC-MS:m/z 378.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.21 (s, 1H), 10.22 (s, 2H), 8.59 (d, J=3.2Hz, 1H),
8.39 (d, J=3.2Hz, 1H), 8.31 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz,
1H), 7.68 (t, J=6.8Hz, 1H), 7.61-7.70 (m, 1H), 7.54-7.57 (m, 1H), 3.00-3.14 (m, 2H), 2.28-
2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.47 (d, J=12Hz, 3H).
Embodiment 162 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylic acid sodium (I 162)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-into
C] and pyridine-2-carboxylic acids, yield 100%, LC-MS:m/z 378.1 [M+H]+。
Embodiment 163 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylic acid, ethyl ester (I 163)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-into
C] and pyridine-2-carboxylic acids, yield 100%, LC-MS:m/z 407.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.25 (s, 2H), 8.67 (d, J=5.2Hz, 1H), 8.40 (d, J=
7.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.8Hz, 1H), 7.59-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.74-3.90 (m, 2H) 3.11-3.17 (m, 2H),
2.25-2.37 (m, 1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.07 (t, J=6.8Hz, 3H).
Embodiment 164 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carbamoyl naphthalene-
1-yl)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 164)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-into
C] and pyridine-2-carboxylic acids, yield 70%, LC-MS:m/z 491.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.29 (s, 2H), 8.67 (d, J=7.2Hz, 1H), 8.42 (d, J=
8.0Hz, 1H), 8.31 (d, J=7.2Hz, 1H), 8.25 (d, J=8.4Hz, 1H), 7.90 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.4Hz, 1H), 7.59-7.63 (m, 1H), 7.50-7.55 (m, 1H), 4.55 (s, 2H), 3.13-3.19 (m, 2H), 2.65
(s, 3H), 2.26-2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.47 (d, J=12Hz, 3H).
Embodiment 165 1-(isobutyryl epoxide) ethyl 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-
2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 165)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-into
C] and pyridine-2-carboxylic acids, yield 66%, LC-MS:m/z 493.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.19 (s, 2H), 8.61 (d, J=3.2Hz, 1H), 8.37 (d, J=
3.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t,
J=6.8Hz, 1H), 7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.02-3.14 (m, 2H),
2.76-2.80 (m, 1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.47 (d, J
=12Hz, 3H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 166 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acid (I 166)
With 4-carbamoyl naphthalene-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, close
One-tenth method is with the preparation method of compound described in embodiment 6, LC-MS:m/z 365.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.29 (s, 1H), 10.16 (s, 2H), 8.78 (d, J=8.0Hz, 1H),
8.49 (d, J=7.8Hz, 1H), 8.41 (d, J=7.6Hz, 1H), 8.34 (d, J=8.4Hz, 1H), 7.96 (t, J=7.2Hz,
1H), 7.78 (t, J=6.8Hz, 1H), 7.73-7.78 (m, 1H), 7.45-7.48 (m, 1H), 3.40-3.45 (m, 1H), 3.12-
3.26 (m, 2H), 2.37-2.46 (m, 1H), 1.99-2.11 (m, 1H).
Embodiment 167 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acid sodium (I 167)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 100%, LC-MS:m/z 365.1 [M+H]+。
Embodiment 168 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acetoacetic ester (I 168)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 100%, LC-MS:m/z 393.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.15 (s, 2H), 8.68 (d, J=5.2Hz, 1H), 8.41 (d, J=
7.2Hz, 1H), 8.33 (d, J=7.2Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.8Hz, 1H), 7.59-7.65 (m, 1H), 7.54-7.57 (m, 1H), 3.74-3.91 (m, 2H) 3.10-3.17 (m, 2H),
2.24-2.37 (m, 1H), 1.94-2.02 (m, 1H), 1.45 (d, J=12Hz, 3H), 1.08 (t, J=6.8Hz, 3H).
Embodiment 169 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carbamoyl naphthalene-
1-yl)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 169)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 70%, LC-MS:m/z 477.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.21 (s, 2H), 8.66 (d, J=7.2Hz, 1H), 8.41 (d, J=
8.0Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.91 (d, J=7.2Hz, 1H), 7.69 (d,
J=6.4Hz, 1H), 7.59-7.63 (m, 1H), 7.50-7.57 (m, 1H), 4.55 (s, 2H), 3.14-3.19 (m, 2H), 2.65
(s, 3H), 2.26-2.35 (m, 1H), 1.96-2.05 (m, 1H), 1.48 (d, J=12Hz, 3H).
Embodiment 170 1-(isobutyryl epoxide) ethyl 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids ester (I 170)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 68%, LC-MS:m/z 479.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.29 (s, 2H), 8.60 (d, J=3.2Hz, 1H), 8.37 (d, J=
3.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t,
J=6.8Hz, 1H), 7.62-7.70 (m, 1H), 7.54-7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.40-3.46 (m, 1H),
3.01-3.14 (m, 2H), 2.76-2.80 (m, 1H), 2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=
9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 171 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylic acid (I 171)
With 4-carbamoyl naphthalene-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, close
One-tenth method is with the preparation method of compound described in embodiment 11, LC-MS:m/z 365.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.78 (s, 1H), 10.27 (s, 2H), 8.65 (s, 1H), 8.56 (s,
1H), 8.31 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.67-7.73 (m,
3H), 3.98 (d, J=16.4Hz, 1H), 3.51 (dd, J=16.0,5.2Hz, 1H), 1.65 (d, J=10.8Hz, 3H).
Embodiment 172 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylic acid sodium (I 172)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2 into, 3-dihydro-thiophene [3,2-c] and
Pyridine-2-carboxylic acids, yield 100%, LC-MS:m/z 365.1 [M+H]+。
Embodiment 173 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylate methyl ester (I 173)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 100%, LC-MS:m/z 379.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.29 (s, 2H), 8.47 (s, 1H), 8.38 (br.s, 1H), 8.36
(s, 1H), 7.98 (dd, J=7.6,1.6Hz, 1H), 7.69-7.74 (m, 3H), 7.53 (t, J=7.6Hz, 1H), 4.05 (d, J
=16.0Hz, 1H), 3.95 (s, 3H), 3.34 (d, J=16.0Hz, 1H), 1.76 (s, 3H).
Embodiment 174 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-
1-yl)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 174)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2 into, 3-dihydro-thiophene [3,2-c] and
Pyridine-2-carboxylic acids, yield 72%, LC-MS:m/z 477.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.22 (s, 2H), 8.52 (s, 1H), 8.37 (s, 1H), 8.34 (s,
1H), 7.96 (d, J=7.2Hz, 1H), 7.64-7.75 (m, 3H), 7.53 (t, J=8.0Hz, 1H), 4.80 (s, 2H), 4.11
(d, J=16.0Hz, 1H), 3.33 (d, J=16.4Hz, 1H), 2.61 (s, 3H), 1.74 (s, 3H).
Embodiment 175 1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro thiophene
Fen [3,2-c] pyridine-2-carboxylic acids ester (I 175)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2 into, 3-dihydro-thiophene [3,2-c] and
Pyridine-2-carboxylic acids, yield 62%, LC-MS:m/z 479.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.32 (s, 2H), 8.64 (s, 1H), 8.54 (s, 1H), 8.31 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50
(m, 1H), 3.98 (d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H), 1.68 (d,
J=10.8Hz, 3H), 1.59 (d, J=9.6Hz, 3H), 1.03 (d, J=9.6Hz, 6H).
Embodiment 176 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
(I176)
With 4-carbamoyl naphthalene-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, close
One-tenth method is with the preparation method of compound described in embodiment 16, LC-MS:m/z 351.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.74 (s, 1H), 10.12 (s, 2H), 8.85 (s, 1H), 8.73 (s,
1H), 8.56 (t, J=6.0Hz, 1H), 8.30 (d, J=8.0Hz, 1H), 7.98 (t, J=8.4Hz, 1H), 7.71-7.75 (m,
3H), 3.91-3.97 (m, 1H), 3.75-3.78 (m, 1H), 3.43-3.46 (m, 1H).
Embodiment 177 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium
(I 177)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 100%, LC-MS:m/z 351.1 [M+H]+。
Embodiment 178 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids first
Ester (I 178)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 365.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.22 (s, 2H), 8.77 (s, 1H), 8.67 (s, 1H), 8.41 (t, J=
6.8Hz, 1H), 8.28 (d, J=7.2Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.58-7.66 (m, 3H), 4.05-4.10
(m, 1H), 3.92 (s, 3H), 3.89-3.91 (m, 1H), 3.34-3.37 (m, 1H).
Embodiment 179 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-
1-yl)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 179)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
67%, LC-MS:m/z 463.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.20 (s, 2H), 8.86 (s, 1H), 8.70 (s, 1H), 8.51 (t, J=
7.2Hz, 1H), 8.35 (d, J=7.2Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.66-7.79 (m, 3H), 4.70 (s, 2H),
3.97-4.02 (m, 1H), 3.77-3.81 (m, 1H), 3.31-3.36 (m, 1H), 2.69 (s, 3H).
Embodiment 180 1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-
C] and pyridine-2-carboxylic acids ester (I 180)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-into
Carboxylic acid, yield 65%, LC-MS:m/z 465.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.30 (s, 2H), 8.67 (s, 1H), 8.52 (s, 1H), 8.31 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50
(m, 1H), 4.10-4.14 (m, 1H), 3.98 (d, J=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-
2.80 (m, 1H), 1.59 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 181 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 181)
With 4-carbamoyl naphthalene-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, close
One-tenth method is with the preparation method of compound described in embodiment 21, LC-MS:m/z 349.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.99 (s, 1H), 10.12 (s, 2H), 8.67 (s, 1H), 8.54 (s,
1H), 8.40 (s, 1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H),
7.65-7.74 (m, 3H).
Embodiment 182 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 182)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 349.1 [M+H]+。
Embodiment 183 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 183)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 363.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.10 (s, 2H), 8.65 (s, 1H), 8.52 (s, 1H), 8.40 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 3.80 (s, 3H).
Embodiment 184 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-
1-yl) thiophene [3,2-c] pyridine-2-carboxylic acids (I 184)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
58%, LC-MS:m/z 461.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.11 (s, 2H), 8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s,
1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 4.92 (s, 2H), 2.61 (s, 3H).
Embodiment 185 1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-
2-carboxylate (I 185)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
69%, LC-MS:m/z 463.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.31 (s, 2H), 8.67 (s, 1H), 8.54 (s, 1H), 8.40 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 6.46-6.51 (m, 1H), 2.75-2.80 (m, 1H), 1.61 (d, J=9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 186 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 186)
With 4-carbamoyl naphthalene-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, close
One-tenth method is with the preparation method of compound described in embodiment 26, LC-MS:m/z 350.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.91 (s, 1H), 10.09 (s, 2H), 8.68 (s, 1H), 8.55 (s,
1H), 8.31 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m,
3H)。
Embodiment 187 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 187)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 350.0 [M+H]+。
Embodiment 188 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 188)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 364.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.13 (s, 2H), 8.64 (s, 1H), 8.51 (s, 1H), 8.30 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 3.80 (s, 3H).
Embodiment 189 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-
1-yl) thiazole [4,5-c] pyridine-2-carboxylic acids (I 189)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
69%, LC-MS:m/z 462.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.15 (s, 2H), 8.66 (s, 1H), 8.51 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.96 (s, 2H),
2.62 (s, 3H).
Embodiment 190 1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-
2-carboxylate (I 190)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
60%, LC-MS:m/z 446.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.25 (s, 2H), 8.69 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 6.44-6.50
(m, 1H), 2.75-2.81 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.06 (d, J=9.6Hz, 6H).
Embodiment 191 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 191)
With 4-carbamoyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 31, LC-MS:m/z 348.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.67 (s, 1H), 10.12 (s, 2H), 8.72 (d, J=8.0Hz, 1H),
8.68 (d, J=8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93
(t, J=7.6Hz, 1H), 7.64-7.75 (m, 3H), 7.45-749 (m, 1H).
Embodiment 192 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 192)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 100%,
LC-MS:m/z 348.1 [M+H]+。
Embodiment 193 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 193)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-into
MS:m/z 362.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.22 (s, 2H), 8.70 (d, J=8.0Hz, 1H), 8.67 (d, J=
8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.94 (t, J=7.6Hz,
1H), 7.64-7.75 (m, 3H), 7.44-749 (m, 1H), 3.81 (s, 3H).
Embodiment 194 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-
1-yl) benzo [b] thiophene-2-carboxylic acid ester (I 194)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 65%,
LC-MS:m/z 460.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.16 (s, 2H), 8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s,
1H), 8.33 (t, J=5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 7.44-749 (m, 1H), 4.96 (s, 2H), 2.60 (s, 3H).
Embodiment 195 1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid
Ester (I 195)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 61%,
LC-MS:m/z 462.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.19 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s,
1H), 8.34 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m,
3H), 7.40-749 (m, 1H), 6.46-6.51 (m, 1H), 2.75-2.80 (m, 1H), 1.62 (d, J=9.6Hz, 3H), 1.02
(d, J=9.6Hz, 6H).
Embodiment 196 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 196)
With 4-carbamoyl-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 36, LC-MS:m/z 349.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.10 (s, 1H), 10.11 (s, 2H), 8.69 (s, 1H), 8.56 (s,
1H), 8.32 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m,
3H), 7.40-745 (m, 1H).
Embodiment 197 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 197)
According to the method described in embodiment 2, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-into
MS:m/z 349.1 [M+H]+。
Embodiment 198 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 198)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-into
MS:m/z 363.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.13 (s, 2H), 8.68 (s, 1H), 8.55 (s, 1H), 8.30 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 7.40-745 (m,
1H), 3.83 (s, 3H).
Embodiment 199 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-
1-yl) benzo [d] thiazole-2-carboxylate (I 199)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid into, yield 64%,
LC-MS:m/z 461.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.23 (s, 2H), 8.66 (s, 1H), 8.52 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-745 (m,
1H), 4.93 (s, 2H), 2.60 (s, 3H).
Embodiment 200 1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid
Ester (I 200)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid into, yield 61%,
LC-MS:m/z 463.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.17 (s, 2H), 8.70 (s, 1H), 8.56 (s, 1H), 8.32 (t, J=
5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 7.40-745 (m,
1H), 6.45-6.50 (m, 1H), 2.74-2.81 (m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 201 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylic acid (I 201)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 1, LC-MS:m/z 379.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.01 (s, 1H), 8.39 (d, J=3.2Hz, 1H), 8.31 (d, J=
7.2Hz, 1H), 8.23 (d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H), 7.61-
7.70 (m, 1H), 7.54-7.57 (m, 1H), 3.00-3.14 (m, 2H), 2.28-2.36 (m, 1H), 1.95-2.01 (m, 1H),
1.47 (d, J=12Hz, 3H).
Embodiment 202 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylic acid sodium (I 202)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] into
And pyridine-2-carboxylic acids, yield 100%, LC-MS:m/z 379.1 [M+H]+。
Embodiment 203 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylic acid, ethyl ester (I 203)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] into
And pyridine-2-carboxylic acids, yield 100%, LC-MS:m/z 407.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.40 (d, J=7.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.22
(d, J=8.4Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d, J=6.8Hz, 1H), 7.59-7.65 (m, 1H), 7.54-
7.57 (m, 1H), 3.74-3.90 (m, 2H) 3.11-3.17 (m, 2H), 2.25-2.37 (m, 1H), 1.94-2.02 (m, 1H),
1.45 (d, J=12Hz, 3H), 1.07 (t, J=6.8Hz, 3H).
Embodiment 204 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group-5-fluoronaphthalene-1-
Base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 204)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] into
And pyridine-2-carboxylic acids, yield 70%, LC-MS:m/z 491.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.42 (d, J=8.0Hz, 1H), 8.31 (d, J=7.2Hz, 1H), 8.25
(d, J=8.4Hz, 1H), 7.90 (d, J=7.2Hz, 1H), 7.69 (d, J=6.4Hz, 1H), 7.59-7.63 (m, 1H), 7.50-
7.55 (m, 1H), 4.55 (s, 2H), 3.13-3.19 (m, 2H), 2.65 (s, 3H), 2.26-2.35 (m, 1H), 1.96-2.05 (m,
1H), 1.47 (d, J=12Hz, 3H).
Embodiment 205 1-(isobutyryl epoxide) ethyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-
2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 205)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] into
And pyridine-2-carboxylic acids, yield 67%, LC-MS:m/z 493.2 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.47 (d, J=3.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.23
(d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H), 7.62-7.70 (m, 1H), 7.54-
7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.02-3.14 (m, 2H), 2.76-2.80 (m, 1H), 2.27-2.36 (m, 1H),
1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.47 (d, J=12Hz, 3H), 1.03 (d, J=9.6Hz, 6H).
Embodiment 206 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
(I 206)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 6, LC-MS:m/z 365.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.89 (s, 1H), 8.78 (d, J=8.0Hz, 1H), 8.41 (d, J=
7.6Hz, 1H), 8.34 (d, J=8.4Hz, 1H), 7.96 (t, J=7.2Hz, 1H), 7.78 (t, J=6.8Hz, 1H), 7.73-
7.78 (m, 1H), 7.45-7.48 (m, 1H), 3.40-3.45 (m, 1H), 3.12-3.26 (m, 2H), 2.37-2.46 (m, 1H),
1.99-2.11 (m, 1H).
Embodiment 207 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Sodium (I 207)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change into 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylic acid, yield 100%, LC-MS:m/z 365.1 [M+H]+。
Embodiment 208 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Ethyl ester (I 208)
According to the method described in embodiment 3, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 8-(4--cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 100%, LC-MS:m/z 393.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.41 (d, J=7.2Hz, 1H), 8.33 (d, J=7.2Hz, 1H), 8.22
(d, J=8.0Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.69 (d, J=6.8Hz, 1H), 7.59-7.65 (m, 1H), 7.54-
7.57 (m, 1H), 3.74-3.91 (m, 2H) 3.10-3.17 (m, 2H), 2.24-2.37 (m, 1H), 1.94-2.02 (m, 1H),
1.45 (d, J=12Hz, 3H), 1.08 (t, J=6.8Hz, 3H).
Embodiment 209 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group-5-fluoronaphthalene-1-
Base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 209)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change into 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylic acid, yield 70%, LC-MS:m/z 477.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.41 (d, J=8.0Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.26
(d, J=8.4Hz, 1H), 7.91 (d, J=7.2Hz, 1H), 7.69 (d, J=6.4Hz, 1H), 7.59-7.63 (m, 1H), 7.50-
7.57 (m, 1H), 4.55 (s, 2H), 3.14-3.19 (m, 2H), 2.65 (s, 3H), 2.26-2.35 (m, 1H), 1.96-2.05 (m,
1H), 1.48 (d, J=12Hz, 3H).
Embodiment 210 1-(isobutyryl epoxide) ethyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids ester (I 210)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change into 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylic acid, yield 69%, LC-MS:m/z 479.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.37 (d, J=3.2Hz, 1H), 8.30 (d, J=7.2Hz, 1H), 8.23
(d, J=8.4Hz, 1H), 7.86 (t, J=7.2Hz, 1H), 7.68 (t, J=6.8Hz, 1H), 7.62-7.70 (m, 1H), 7.54-
7.57 (m, 1H), 6.45-6.50 (m, 1H), 3.40-3.46 (m, 1H), 3.01-3.14 (m, 2H), 2.76-2.80 (m, 1H),
2.27-2.36 (m, 1H), 1.95-2.01 (m, 1H), 1.60 (d, J=9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 211 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylic acid (I 211)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 11, LC-MS:m/z 365.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.78 (s, 1H), 8.56 (s, 1H), 8.31 (t, J=5.2Hz, 1H),
8.27 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.67-7.73 (m, 3H), 3.98 (d, J=16.4Hz, 1H),
3.51 (dd, J=16.0,5.2Hz, 1H), 1.65 (d, J=10.8Hz, 3H).
Embodiment 212 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylic acid sodium (I 212)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 100%, LC-MS:m/z 365.1 [M+H]+。
Embodiment 213 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylate methyl ester (I 213)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2 into, 3-dihydro-thiophene [3,2-c] pyridine-
2-carboxylic acid, yield 100%, LC-MS:m/z 379.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.47 (s, 1H), 8.36 (s, 1H), 7.98 (dd, J=7.6,1.6Hz,
1H), 7.69-7.74 (m, 3H), 7.53 (t, J=7.6Hz, 1H), 4.05 (d, J=16.0Hz, 1H), 3.95 (s, 3H), 3.34
(d, J=16.0Hz, 1H), 1.76 (s, 3H).
Embodiment 214 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-
Base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 214)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 72%, LC-MS:m/z 477.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.52 (s, 1H), 8.34 (s, 1H), 7.96 (d, J=7.2Hz, 1H),
7.64-7.75 (m, 3H), 7.53 (t, J=8.0Hz, 1H), 4.80 (s, 2H), 4.11 (d, J=16.0Hz, 1H), 3.33 (d, J
=16.4Hz, 1H), 2.61 (s, 3H), 1.74 (s, 3H).
Embodiment 215 1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro thiophene
Fen [3,2-c] pyridine-2-carboxylic acids ester (I 215)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole into
Pyridine-2-carboxylic acid, yield 69%, LC-MS:m/z 479.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.54 (s, 1H), 8.31 (s, 1H), 8.26 (d, J=8.4Hz, 1H),
7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50 (m, 1H), 3.98 (d, J=16.4Hz, 1H), 3.50
(dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H), 1.68 (d, J=10.8Hz, 3H), 1.59 (d, J=9.6Hz,
3H), 1.03 (d, J=9.6Hz, 6H).
Embodiment 216 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
(I216)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 16, LC-MS:m/z 351.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.74 (s, 1H), 8.85 (s, 1H), 8.73 (s, 1H), 8.30 (d, J=
8.0Hz, 1H), 7.98 (t, J=8.4Hz, 1H), 7.71-7.75 (m, 3H), 3.91-3.97 (m, 1H), 3.75-3.78 (m,
1H), 3.43-3.46 (m, 1H).
Embodiment 217 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium
(I217)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 100%, LC-MS:m/z 351.0 [M+H]+。
Embodiment 218 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester
(I 218)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2 into, 3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids,
Yield 100%, LC-MS:m/z 365.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.77 (s, 1H), 8.67 (s, 1H), 8.28 (d, J=7.2Hz, 1H),
7.87 (t, J=8.0Hz, 1H), 7.58-7.66 (m, 3H), 4.05-4.10 (m, 1H), 3.92 (s, 3H), 3.89-3.91 (m,
1H), 3.34-3.37 (m, 1H).
Embodiment 219 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-
Base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 219)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 67%, LC-MS:m/z 463.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.80 (s, 1H), 8.70 (s, 1H), 8.35 (d, J=7.2Hz, 1H),
7.94 (t, J=8.0Hz, 1H), 7.66-7.79 (m, 3H), 4.70 (s, 2H), 3.97-4.02 (m, 1H), 3.77-3.81 (m,
1H), 3.31-3.36 (m, 1H), 2.69 (s, 3H).
Embodiment 220 1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-
C] and pyridine-2-carboxylic acids ester (I 220)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic into
Acid, yield 69%, LC-MS:m/z 465.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (s, 1H), 8.52 (s, 1H), 8.26 (d, J=8.4Hz, 1H),
7.90 (t, J=8.0Hz, 1H), 7.66-7.73 (m, 3H), 6.45-6.50 (m, 1H), 4.10-4.14 (m, 1H), 3.98 (d, J
=16.4Hz, 1H), 3.50 (dd, J=16.0,5.2Hz, 1H), 2.75-2.80 (m, 1H), 1.59 (d, J=9.6Hz, 3H),
1.01 (d, J=9.6Hz, 6H).
Embodiment 221 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 221)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 21, LC-MS:m/z 349.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.81 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.40 (s,
1H), 8.26 (d, J=8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H).
Embodiment 222 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 222)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 349.0 [M+H]+。
Embodiment 223 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 223)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 363.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.64 (s, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=
8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 3.81 (s, 3H).
Embodiment 224 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-
Base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 224)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
68%, LC-MS:m/z 461.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.72 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.28 (d, J=
8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.64-7.74 (m, 3H), 4.97 (s, 2H), 2.61 (s, 3H).
Embodiment 225 1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-
2-carboxylate (I 225)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids, yield into
67%, LC-MS:m/z 463.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.26 (d, J=
8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 6.46-6.51 (m, 1H), 2.75-2.80 (m,
1H), 1.61 (d, J=9.6Hz, 3H), 1.05 (d, J=9.6Hz, 6H).
Embodiment 226 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 226)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 26, LC-MS:m/z 350.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=10.92 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=
8.4Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 7.65-7.73 (m, 3H).
Embodiment 227 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 227)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 350.0 [M+H]+。
Embodiment 228 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 228)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
100%, LC-MS:m/z 364.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.65 (s, 1H), 8.50 (s, 1H), 8.27 (d, J=8.4Hz, 1H),
7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 3.82 (s, 3H).
Embodiment 229 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-
Base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I 229)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids, yield into
59%, LC-MS:m/z 462.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.77 (s, 1H), 8.56 (s, 1H), 8.27 (d, J=8.4Hz, 1H),
7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 4.98 (s, 2H), 2.65 (s, 3H).
Embodiment 230 1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-
2-carboxylate (I 230)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids into, yield 61%,
LC-MS:m/z 464.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=8.4Hz, 1H),
7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 6.44-6.50 (m, 1H), 2.75-2.81 (m, 1H), 1.60 (d, J
=9.6Hz, 3H), 1.06 (d, J=9.6Hz, 6H).
Embodiment 231 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 231)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 31, LC-MS:m/z 348.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.02 (s, 1H), 8.68 (d, J=8.0Hz, 1H), 8.42 (s, 1H),
8.33 (t, J=5.2Hz, 1H), 8.26 (d, J=8.4Hz, 1H), 7.93 (t, J=7.6Hz, 1H), 7.64-7.75 (m, 3H),
(7.45-749 m, 1H).
Embodiment 232 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 232)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid into, yield 100%,
LC-MS:m/z 348.0 [M+H]+。
Embodiment 233 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 233)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 100%, LC-into
MS:m/z 362.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.67 (d, J=8.0Hz, 1H), 8.42 (s, 1H), 8.33 (t, J=
5.2Hz, 1H), 8.27 (d, J=8.4Hz, 1H), 7.94 (t, J=7.6Hz, 1H), 7.64-7.75 (m, 3H), 7.44-749 (m,
1H), 3.81 (s, 3H).
Embodiment 234 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-
Base) benzo [b] thiophene-2-carboxylic acid ester (I 234)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 65%, LC-into
MS:m/z 460.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.69 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=
8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.44-749 (m, 1H), 4.96 (s, 2H), 2.60
(s, 3H).
Embodiment 235 1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid
Ester (I 235)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid, yield 56%, LC-into
MS:m/z 462.1 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.26 (d, J=
8.4Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-749 (m, 1H), 6.46-6.51 (m, 1H),
2.75-2.80 (m, 1H), 1.62 (d, J=9.6Hz, 3H), 1.02 (d, J=9.6Hz, 6H).
Embodiment 236 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 236)
With 4-cyano group-5-fluoro-1-naphthalene boronic acids pinacol ester for raw material substitution 4-cyano group-1-naphthalene boronic acids pinacol ester, synthesis
Method is with the preparation method of compound described in embodiment 36, LC-MS:m/z 349.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=11.10 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=
8.4Hz, 1H), 7.93 (t, J=8.0Hz, 1H), 7.65-7.75 (m, 3H), 7.40-745 (m, 1H).
Embodiment 237 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 237)
According to the method described in embodiment 2, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid into, yield 100%,
LC-MS:m/z 349.0 [M+H]+。
Embodiment 238 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 238)
According to the method described in embodiment 13, simply by 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 100%, LC-into
MS:m/z 363.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.68 (s, 1H), 8.55 (s, 1H), 8.27 (d, J=8.4Hz, 1H),
7.90 (t, J=8.0Hz, 1H), 7.64-7.73 (m, 3H), 7.40-745 (m, 1H), 3.83 (s, 3H).
Embodiment 239 (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-
Base) benzo [d] thiazole-2-carboxylate (I 239)
According to the method described in embodiment 4, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 60%, LC-into
MS:m/z 461.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.66 (s, 1H), 8.52 (s, 1H), 8.27 (d, J=8.4Hz, 1H),
7.90 (t, J=8.0Hz, 1H), 7.65-7.74 (m, 3H), 7.40-745 (m, 1H), 4.93 (s, 2H), 2.60 (s, 3H).
Embodiment 240 1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid
Ester (I 240)
According to the method described in embodiment 5, simply by 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids change 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid, yield 61%, LC-into
MS:m/z 498.0 [M+H]+。
1H NMR (400MHz, DMSO-d6): δ=8.70 (s, 1H), 8.56 (s, 1H), 8.26 (d, J=8.4Hz, 1H),
7.93 (t, J=8.0Hz, 1H), 7.64-7.75 (m, 3H), 7.40-745 (m, 1H), 6.45-6.50 (m, 1H), 2.74-2.81
(m, 1H), 1.63 (d, J=9.6Hz, 3H), 1.01 (d, J=9.6Hz, 6H).
Embodiment 241
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 is in the range of ＞ is 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 during reception6-8 week old.Animal adapts to 5 days in the environment
After start experiment.Body weight during experimentIt 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.Electronics
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, I4, I21, I26 effect under 20mg/kg dosage is suitable with Lesinurad 40mg/kg effect, points out its internal fall urine
Acid effect may be 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 sulfur heterocyclic ring carboxylic acid derivative for general formula I, and pharmaceutically acceptable salt, solvate,
Hydrate and pharmaceutically acceptable prodrug, its planar structure is as follows:
Wherein:
X is CH or N；
R1Selected from H or C1-3Alkyl；
R2, R3Independently selected from H, cyano group, halogen, C1-6Alkyl or cycloalkyl, CF3, methoxyl group, ethyoxyl, carboxyl, amide, sulphur
Amide；
A is-N=,-CH=,-CH2-or-CH2-CH2-；
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 when A is-N=or-CH=, without R1Substituent group.
3. compound as claimed in claim 1, it is characterised in that when A is-CH2-or-CH2-CH2In-time, there are 4 chiral photo-isomerisation
Body, and optically pure compound can be obtained by using chiral chromatography separation raceme, then carry out into salt or synthesize its medicine
Acceptable prodrug on.
4. compound as claimed in claim 1, it is characterised in that the form of its salt is Na, K, Li, Ca, Mg, preferably Na, K,
Li salt.
5. compound as claimed in claim 1, its pharmaceutically acceptable prodrug, include but not limited to ester, carbonic ester, sulfur generation
Carbonic ester, 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:
8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 1)；
8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 2)；
8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 3)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-two
Hydrogen-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 4)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylate (I 5)；
8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 6)；
8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 7)；
8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 8)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiophene
Mutter [3,2-c] and pyridine-2-carboxylic acids ester (I 9)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Ester (I 10)；
7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 11)；
7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 12)；
7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 13)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-two
Hydrogen thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 14)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic
Acid esters (I 15)；
7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 16)；
7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 17)；
7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 18)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene
[3,2-c] pyridine-2-carboxylic acids ester (I 19)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I
20)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 21)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 22)；
7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 23)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyrrole
Pyridine-2-carboxylate (I 24)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 25)；
7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 26)；
7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 27)；
7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 28)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyrrole
Pyridine-2-carboxylate (I 29)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I 30)；
7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 31)；
7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 32)；
7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 33)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-
Carboxylate (I 34)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 35)；
7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 36)；
7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 37)；
7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 38)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-
Carboxylate (I 39)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group naphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 40)；
8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 41)；
8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 42)；
8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 43)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-
2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 44)；
1-(isobutyryl epoxide) ethyl 8-(4-bromonaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-
Carboxylate (I 45)；
8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 46)；
8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 47)；
8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 48)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran
[3,2-c] pyridine-2-carboxylic acids ester (I 49)；
1-(isobutyryl epoxide) ethyl 8-(4-bromonaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester
(Ⅰ50)；
7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 51)；
7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 52)；
7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 53)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro
Thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 54)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
Ester (I 55)；
7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 56)；
7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 57)；
7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 58)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,
2-c] and pyridine-2-carboxylic acids ester (I 59)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I
60)；
7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 61)；
7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 62)；
7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 63)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyrrole
Pyridine-2-carboxylate (I 64)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 65)；
7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 66)；
7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 67)；
7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 68)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyrrole
Pyridine-2-carboxylate (I 69)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I 70)；
7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 71)；
7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 72)；
7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 73)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic
Acid esters (I 74)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 75)；
7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 76)；
7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 77)；
7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 78)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylic
Acid esters (I 79)；
1-(isobutyryl epoxide) ethyl 7-(4-bromonaphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 80)；
8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 81)；
8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 82)；
8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 83)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-
Dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 84)；
1-(isobutyryl epoxide) ethyl 8-(4-cyclopropyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyrrole
Pyridine-2-carboxylate (I 85)；
8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 86)；
8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 87)；
8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 88)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-
Thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 89)；
1-(isobutyryl epoxide) ethyl 8-(4-cyclopropyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic
Acid esters (I 90)；
7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 91)；
7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 92)；
7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 93)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-
Dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 94)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-
Carboxylate (I 95)；
7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 96)；
7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 97)；
7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 98)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene
[3,2-c] pyridine-2-carboxylic acids ester (I 99)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester
(Ⅰ100)；
7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 101)；
7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 102)；
7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 103)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] and
Pyridine-2-carboxylic acids ester (I 104)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 105)；
7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 106)；
7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 107)；
7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 108)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] and
Pyridine-2-carboxylic acids ester (I 109)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I 110)；
7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 111)；
7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 112)；
7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 113)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-
2-carboxylate (I 114)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 115)；
7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 116)；
7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 117)；
7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 118)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-
2-carboxylate (I 119)；
1-(isobutyryl epoxide) ethyl 7-(4-cyclopropyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 120)；
8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 121)；
8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 122)；
8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 123)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-two
Hydrogen-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 124)；
1-(isobutyryl epoxide) ethyl 8-(4-carboxyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylate (I 125)；
8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 126)；
8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 127)；
8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 128)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiophene
Mutter [3,2-c] and pyridine-2-carboxylic acids ester (I 129)；
1-(isobutyryl epoxide) ethyl 8-(4-carboxyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids
Ester (I 130)；
7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 131)；
7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 132)；
7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 133)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-two
Hydrogen thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 134)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic
Acid esters (I 135)；
7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 136)；
7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 137)；
7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 138)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene
[3,2-c] pyridine-2-carboxylic acids ester (I 139)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I
140)；
7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 141)；
7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 142)；
7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 143)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyrrole
Pyridine-2-carboxylate (I 144)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 145)；
7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 146)；
7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 147)；
7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 148)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyrrole
Pyridine-2-carboxylate (I 149)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I 150)；
7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 151)；
7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 152)；
7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 153)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-
Carboxylate (I 154)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 155)；
7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 156)；
7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 157)；
7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 158)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-
Carboxylate (I 159)；
1-(isobutyryl epoxide) ethyl 7-(4-carboxyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 160)；
8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I
161)；
8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I
162)；
8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
163)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carbamoyl naphthalene-1-base)-2-methyl-
3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 164)；
1-(isobutyryl epoxide) ethyl 8-(4-carbamoyl naphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c]
And pyridine-2-carboxylic acids ester (I 165)；
8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 166)；
8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 167)；
8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 168)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-carbamoyl naphthalene-1-base)-3,4-two
Hydrogen-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 169)；
1-(isobutyryl epoxide) ethyl 8-(4-carbamoyl naphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-
2-carboxylate (I 170)；
7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 171)；
7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 172)；
7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I
173)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base)-2-methyl-
2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 174)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole
Pyridine-2-carboxylate (I 175)；
7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 176)；
7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 177)；
7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 178)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro
Thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 179)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic
Acid esters (I 180)；
7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 181)；
7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 182)；
7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 183)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-
C] and pyridine-2-carboxylic acids ester (I 184)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I
185)；
7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 186)；
7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 187)；
7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 188)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-
C] and pyridine-2-carboxylic acids ester (I 189)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I
190)；
7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 191)；
7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 192)；
7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 193)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene
Fen-2-carboxylate (I 194)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 195)；
7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 196)；
7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 197)；
7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 198)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiophene
Azoles-2-carboxylate (I 199)；
1-(isobutyryl epoxide) ethyl 7-(4-carbamoyl naphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 200)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 201)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I
202)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I
203)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,
4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 204)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-3,4-dihydro-2H-thiapyran [3,2-c] and
Pyridine-2-carboxylic acids ester (I 205)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids (I 206)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids sodium (I 207)；
8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ethyl ester (I 208)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-
2H-thiapyran [3,2-c] pyridine-2-carboxylic acids ester (I 209)；
1-(isobutyryl epoxide) ethyl 8-(4-cyano group-5-fluoronaphthalene-1-base)-3,4-dihydro-2H-thiapyran [3,2-c] pyridine-2-
Carboxylate (I 210)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 211)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 212)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 213)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,
3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 214)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2-methyl-2,3-dihydro-thiophene [3,2-c] pyrrole
Pyridine-2-carboxylate (I 215)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids (I 216)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 217)；
7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 218)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro
Thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 219)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base)-2,3-dihydro-thiophene [3,2-c] pyridine-2-carboxylic acids
Ester (I 220)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids (I 221)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids sodium (I 222)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids methyl ester (I 223)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-
C] and pyridine-2-carboxylic acids ester (I 224)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiophene [3,2-c] pyridine-2-carboxylic acids ester (I 225)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids (I 226)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids sodium (I 227)；
7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids methyl ester (I 228)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-
C] and pyridine-2-carboxylic acids ester (I 229)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) thiazole [4,5-c] pyridine-2-carboxylic acids ester (I 230)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid (I 231)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid sodium (I 232)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid methyl ester (I 233)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene
Fen-2-carboxylate (I 234)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [b] thiophene-2-carboxylic acid ester (I 235)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid (I 236)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylic acid sodium (I 237)；
7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylate methyl ester (I 238)；
(5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiophene
Azoles-2-carboxylate (I 239)；
1-(isobutyryl epoxide) ethyl 7-(4-cyano group-5-fluoronaphthalene-1-base) benzo [d] thiazole-2-carboxylate (I 240).
7. the preparation method of the compound described in claim 1, comprises the following steps:
(1) compound shown in formula II and oxirane is made to generate compound shown in formula III under the effect of highly basic:
(2) compound compound shown in production V under alkali effect shown in compound shown in formula III and formula IV is made:
(3) compound and thionyl chloride 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:
(5) make compound shown in formula II under strongly alkaline conditions with compound shown in DMF production VIII:
(6) compound compound shown in production Ⅸ under alkali effect shown in compound shown in formula VIII and formula IV is made:
(7) make compound and thionyl chloride shown in formula Ⅸ react and generate compound shown in Ⅹ:
(8) compound shown in formula Ⅹ and zinc powder is made to react compound shown in production Ⅺ in acid condition:
(9) compound shown in formula VIII and 2-ethyl thioglycolate chemical combination shown in reacting by heating production Ⅻ in the basic conditions are made
Thing:
(10) compound shown in Formula X III and zinc powder is made to react compound shown in production XIV in acid condition:
(11) compound shown in Formula X IV and zinc powder is made to react compound shown in production XV in acid condition:
(12) compound shown in Formula X V and lawesson reagent is made to react compound shown in production XVI:
(13) compound shown in formula VII, formula Ⅺ, formula Ⅻ and Formula X VI can be collectively expressed as compound shown in Formula X VII, this chemical combination
Thing reacts compound shown in production XIX, wherein M with compound shown in Formula X VIII1Represent H or ethyl:
(14) make compound shown in Formula X IX hydrolyze in the basic conditions and be acidified compound shown in production XX again:
(15) compound shown in Formula X X is made to react compound shown in production XXI, wherein M with corresponding aqueous slkali2Represent pharmaceutically acceptable
Cation:
(16) make compound shown in Formula X X and oxalyl chloride react acylated, then react shown in production XXII with corresponding alcohol or ammonia
Compound, M2Represent C1-3Alkyl, amino, carbonic ester, En Naka compare ester
8. the answering in the medicine preparing gout, regulation blood uric acid levels relevant disease of the compound described in claim 1
With, wherein, described relevant disease includes: hyperuricemia, gout, gouty arthritis, inflammatory arthritis, nephropathy, nephrolith
Disease, arthritis, urate crystal deposit in joint, urinary calculus, urate crystal deposit in excess of the kidney matter, gout is shown effect,
Chalky gout or a combination thereof.
9. a pharmaceutical composition, containing the sulfur heterocyclic ring carboxylic acid derivative representated by least one formula I and pharmaceutically acceptable
Salt, hydrate or pharmaceutically acceptable prodrug.
10. the pharmaceutical composition of claim 9, 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,
Preferably medicine is allopurinol, Febuxostat, Topiroxostat or a combination thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107955029A (en) * | 2017-12-07 | 2018-04-24 | 成都美域高制药有限公司 | A kind of preparation method of the western Nader of thunder |
| CN111592558A (en) * | 2019-02-20 | 2020-08-28 | 北京桦冠医药科技有限公司 | Heterocyclic compound having uric acid reabsorption inhibiting effect |
| CN111943957A (en) * | 2019-05-17 | 2020-11-17 | 中国医学科学院药物研究所 | Quinoline carboxamide compounds and preparation method and use thereof |
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| CN1615299A (en) * | 2001-11-16 | 2005-05-11 | 日本化学医药株式会社 | Xanthine oxidase inhibitors |
| EP2669270A1 (en) * | 2011-01-28 | 2013-12-04 | Sato Pharmaceutical Co., Ltd. | Ring-fused compound |
| CN106008340A (en) * | 2015-03-24 | 2016-10-12 | 上海璎黎药业有限公司 | Condensed ring derivative, preparation method, intermediate, pharmaceutical composition and application thereof |
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| CN1615299A (en) * | 2001-11-16 | 2005-05-11 | 日本化学医药株式会社 | Xanthine oxidase inhibitors |
| EP2669270A1 (en) * | 2011-01-28 | 2013-12-04 | Sato Pharmaceutical Co., Ltd. | Ring-fused compound |
| CN106008340A (en) * | 2015-03-24 | 2016-10-12 | 上海璎黎药业有限公司 | Condensed ring derivative, preparation method, intermediate, pharmaceutical composition and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107955029A (en) * | 2017-12-07 | 2018-04-24 | 成都美域高制药有限公司 | A kind of preparation method of the western Nader of thunder |
| CN107955029B (en) * | 2017-12-07 | 2020-08-11 | 成都美域高制药有限公司 | Preparation method of Raschindde |
| CN111592558A (en) * | 2019-02-20 | 2020-08-28 | 北京桦冠医药科技有限公司 | Heterocyclic compound having uric acid reabsorption inhibiting effect |
| CN111592558B (en) * | 2019-02-20 | 2021-09-07 | 北京桦冠医药科技有限公司 | Heterocyclic compound having uric acid reabsorption inhibiting effect |
| CN111943957A (en) * | 2019-05-17 | 2020-11-17 | 中国医学科学院药物研究所 | Quinoline carboxamide compounds and preparation method and use thereof |
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| CN106146533B (en) | 2018-04-03 |
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