WO2018165822A1 - 磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 - Google Patents

磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 Download PDF

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WO2018165822A1
WO2018165822A1 PCT/CN2017/076445 CN2017076445W WO2018165822A1 WO 2018165822 A1 WO2018165822 A1 WO 2018165822A1 CN 2017076445 W CN2017076445 W CN 2017076445W WO 2018165822 A1 WO2018165822 A1 WO 2018165822A1
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group
formula
compound
cycloalkyl
alkyl
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French (fr)
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樊磊
杜武
李兴海
陈元伟
胥珂馨
陈锞
张少华
罗潼川
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成都海创药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached

Definitions

  • the present invention relates to sulfonamide compounds, processes for their preparation and use as urate transporter inhibitors.
  • Uracate transporter (URAT1) inhibitors can be used to treat diseases such as hyperuricemia and gout.
  • the present invention provides a class of sulfonamide compounds and their use as urate transporter inhibitors.
  • the present invention provides a compound represented by the formula (A), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,
  • X 1 is selected from N, CH or CR a ;
  • X 2 is selected from N, CH or CR a1 ;
  • X 3 is selected from N, CH or CR b ;
  • X 4 is selected from N, CH or CR b1;
  • R a , R a1 , R b , and R b1 are each independently selected from halogen or a C 1 -C 4 alkyl group and a cycloalkyl group, and the alkyl group or the cycloalkyl group is independently independently further optionally one or a plurality selected from halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylic acid esters Substituted by a substituent; and at least one of X 1 , X 2 , X 3 , X 4 is N;
  • R 1 is selected from Or a cycloalkyl group; the cycloalkyl group optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, Substituted by a substituent of a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
  • R 2 is selected from -SO 2 R r or -C(O)(CH 2 ) y COOH; y is 1, 2 or 3;
  • W 1 is selected from N or CR c ;
  • W 2 is selected from N or CR d ;
  • W 3 is selected from N or CR e ;
  • W 4 is selected from N or CR f ;
  • W 5 is selected from N or CR g ;
  • W 6 is selected from N Or CR h ;
  • W 7 is selected from N or CR i ;
  • W 8 is selected from N or CR j ;
  • W 9 is selected from N or CR k ;
  • W 10 is selected from N or CR l ;
  • W 11 is selected from N or CR m ;
  • 12 is selected from N or CR n ;
  • R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , R m , R n , R r are each independently selected from the group consisting of hydrogen, halogen, cyano, Nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR o , -S(O) z R o , -C(O)R o , C( O) OR o , -C(O)NR p R q , -NR p R q or NR p C(O)R q , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group Or an aryl or heteroaryl group, respectively, optionally further optionally one or more selected from the group consisting of
  • R o is selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted with a substituent of an aryl group, a carboxyl group, a carboxylate group, -C(O)NR p R q , -NR p R q or NR p C(O)R q ;
  • R p , R q are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl
  • said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally, independently, further selected from one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxyl group or a carboxylate group; and z is 0, 1 or 2.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (I):
  • R 1 and R 2 are as defined above.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (Ia):
  • R 1 and R r are as defined above.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (Iaa):
  • R c , R d , R e , R f , R g , R h , R i , R are as defined above.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R c , R d , R e , R f , At least one of R g , R h , R i is selected from a cyano group.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R c , R d , R e , R f , R g , R h , R i are each independently selected from hydrogen or cyano, and at least one of R c , R d , R e , R f , R g , R h , R i is selected from a cyano group.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (Iaaa):
  • R r is as defined above.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (Iab):
  • R j , R k , R l , R m , R n , R r are as defined above.
  • R j , R k , R l , R m , R n are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl or alkoxy; preferred halo is fluoro, preferred haloalkyl is trifluoromethyl, and preferred alkoxy is ⁇ Oxygen.
  • R j , R k , R l , R m , R n are each independently selected from the group consisting of hydrogen, cyano, fluorine, trifluoromethyl, methoxy;
  • R j , R k , R l , R m , R n is selected from the group consisting of a cyano group, a fluorine, a trifluoromethyl group or a methoxy group.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R j , R k , R l , R m , Any one of R n is selected from a cyano group, a fluorine, a trifluoromethyl group or a methoxy group, and the other four are selected from hydrogen.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof which has a formula represented by any one of the following formulae structure:
  • R r is as defined above.
  • W 8 to W 12 and R r are as defined above, and at least one of W 8 to W 12 is N.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof having the formula (Iaca), formula (Iacb) Or a structure represented by the formula (Iacc), preferably a structure of the formula (Iaca) or the formula (Iacc):
  • R r is as defined above.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (Iad):
  • R r is as defined above.
  • R r is selected from R 1 is selected from halogen, substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or not A substituted pyrrolyl group, a substituted or unsubstituted imidazolyl group, or a C 3 -C 6 cycloalkyl group.
  • R r is selected from the group consisting of F, Br, Cl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein the phenyl group is optionally further one or more Substituted by a substituent selected from methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.
  • R r is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl or phenyl.
  • the invention also provides a method of the aforementioned compound, characterized in that it comprises the steps of:
  • R 1 and R r are as defined above;
  • a compound of the formula (M2) is obtained by reacting a sulfonic acid chloride represented by the formula (S2) or a sulfonic acid anhydride represented by the formula (S3).
  • the present invention also provides the use of the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for the preparation of a URAT1 inhibitor.
  • the medicament is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kai- ⁇ Second syndrome, kidney disease, kidney stones, renal failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase
  • a drug that is deficient preferably a drug that prevents and/or treats gout or hyperuricemia.
  • the present invention also provides a pharmaceutical composition which comprises the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.
  • a pharmaceutical composition which comprises the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.
  • Formulations prepared with pharmaceutically acceptable excipients are prepared with pharmaceutically acceptable excipients.
  • the invention also provides the use of the pharmaceutical composition for the preparation of a URAT1 inhibitor.
  • the medicament is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kai- ⁇ Second syndrome, kidney disease, kidney stones, renal failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase
  • a drug that is deficient preferably a drug that prevents and/or treats gout or hyperuricemia.
  • the various compounds and their salts, hydrates or solvates provided by the present invention are selective uric acid reuptake inhibitors which can treat hyperuricemia and gout by promoting excretion of uric acid from the body and reducing serum uric acid.
  • the C 1 -C 4 alkyl group means a C 1 , C 2 , C 3 , C 4 alkyl group, that is, a linear or branched alkyl group having 1 to 4 carbon atoms, for example.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which comprise a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
  • the "salt" is an acid form and/or a base salt which forms a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitter ion salt (internal salt), and also includes a season.
  • An ammonium salt such as an alkylammonium salt.
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • Test Example Determination of the inhibitory activity of the compound of the present invention on URAT1
  • Penicillin-Streptomycin (Invitrogen, Cat. No. 15070-063)
  • Isoplate-96Microplate (PERKIN ELMER, Cat. No. 6005040)
  • HEK-293T cells stably expressing hURAT1 were cultured in 10% FBS and 1% P/S DMEM medium, and cultured overnight in a 37-degree incubator with 5% carbon dioxide.
  • the medium was removed, washed once with PBS, and then trypsinized for 2 minutes. After the cells were separated in a Petri dish, 10 ml of the medium was added to terminate the digestion.
  • the IC50 (nM) of the inhibition of hURAT1 activity by the compound of the present invention is shown in Table 1.
  • Compound number IC50(nM) Compound number IC50(nM) 3 4 53 9107 4 146 54 8099 5 713 56 214 6 1100 57 2139 7 597 58 4155 8 127 59 3937 9 320 60 2089 10 1400 62 498 11 2000 63 809 13 2 64 1098 14 203 65 709 15 610 66 720 16 451 39 4059 17 143 40 5032 20 12 41 4098 twenty one 240 42 2188 twenty two 509 44 215 twenty three 330 45 455 twenty four 110 46 674 26 twenty three 47 549 27 310 48 438 28 620 50 4054 29 440 51 9836 30 205 52 12457 32 65 35 280 33 280 36 240 34 540 38 717
  • the various compounds and their salts, hydrates or solvates provided by the present invention are selective uric acid reuptake inhibitors, which can treat hyperuricemia by promoting excretion of uric acid from the body and reducing serum uric acid. Symptoms and gout.

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Abstract

本发明公开了一类式(A)所示的磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途。本发明提供的各种化合物及其盐类、水合物或溶剂合物，是一种选择性尿酸再吸收抑制剂，可以通过促进尿酸从体内排泄并减少血清尿酸来治疗高尿酸血症和痛风。

Description

磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 技术领域
本发明涉及磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途。
背景技术
尿酸盐转运体(URAT1)抑制剂类药物可以用于治疗高尿酸血症、痛风等疾病。
发明内容
本发明提供了一类磺酰胺类化合物，以及它们作为尿酸盐转运体抑制剂类药物的用途。
本发明提供了式(A)所示的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，
Figure PCTCN2017076445-appb-000001
其中：
X1选自N、CH或C-Ra；
X2选自N、CH或C-Ra1；
X3选自N、CH或C-Rb；
X4选自N、CH或C-Rb1；
其中，Ra、Ra1、Rb、Rb1分别独立地选自卤素或C1～C4的烷基以及环烷基，所述烷基或环烷基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；且X1、X2、X3、X4中至少一个为N；
R1选自
Figure PCTCN2017076445-appb-000002
或环烷基；所述环烷基任选进一步被一个或多个 选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；
R2选自-SO2Rr或-C(O)(CH2)yCOOH；y为1、2或3；
W1选自N或CRc；W2选自N或CRd；W3选自N或CRe；W4选自N或CRf；W5选自N或CRg；W6选自N或CRh；W7选自N或CRi；W8选自N或CRj；W9选自N或CRk；W10选自N或CRl；W11选自N或CRm；W12选自N或CRn；
Rc、Rd、Re、Rf、Rg、Rh、Ri、Rj、Rk、Rl、Rm、Rn、Rr分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORo、-S(O)zRo、-C(O)Ro、C(O)ORo、-C(O)NRpRq、-NRpRq或NRpC(O)Rq，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORo、-S(O)mRo、-C(O)Ro、C(O)ORo、-C(O)NRpRq、-NRpRq或NRpC(O)Rq的取代基所取代；
Ro选自氢、卤素、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基、羧酸酯基、-C(O)NRpRq、-NRpRq或NRpC(O)Rq的取代基所取代；
Rp、Rq分别独立选自氢、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；且z为0、1或2。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰ)所示的结构：
Figure PCTCN2017076445-appb-000003
R1和R2如前述所定义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰa)所示的结构：
Figure PCTCN2017076445-appb-000004
R1和Rr如前述所定义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰaa)所示的结构：
Figure PCTCN2017076445-appb-000005
Rc、Rd、Re、Rf、Rg、Rh、Ri、R如前述所定义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，Rc、Rd、Re、Rf、Rg、Rh、Ri中至少一个选自氰基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，Rc、Rd、Re、Rf、Rg、Rh、Ri分别独立地选自氢或氰基，且Rc、Rd、Re、Rf、Rg、Rh、Ri中至少一个选自氰基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰaaa)所示的结构：
Figure PCTCN2017076445-appb-000006
Rr如前述所定义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰab)所示的结构：
Figure PCTCN2017076445-appb-000007
Rj、Rk、Rl、Rm、Rn、Rr如前述所定义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，Rj、Rk、Rl、Rm、Rn分别独立地选自氢、卤素、氰基、硝基、烷基、卤代烷基或烷氧基；优选的卤素为氟，优选的卤代烷基为三氟甲基，优选的烷氧基为甲氧基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中：
Rj、Rk、Rl、Rm、Rn分别独立地选自氢、氰基、氟、三氟甲基、甲氧基；
且Rj、Rk、Rl、Rm、Rn中至少一个选自氰基、氟、三氟甲基或甲氧基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，Rj、Rk、Rl、Rm、Rn任一个选自氰基、氟、三氟甲基或甲氧基，其他四个选自氢。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如下述任一项通式所示的结构：
Figure PCTCN2017076445-appb-000008
Rr如前述所定义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的 盐、或其前体药物，所述化合物具有如式(Ⅰac)所示的结构：
Figure PCTCN2017076445-appb-000009
W8～W12、Rr如前述所定义，且W8～W12中至少一个为N。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰaca)、式(Ⅰacb)或式(Ⅰacc)所示的结构，优选式(Ⅰaca)或式(Ⅰacc)的结构：
Figure PCTCN2017076445-appb-000010
Rr如前述所定义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰad)所示的结构：
Figure PCTCN2017076445-appb-000011
Rr如前述所定义。
进一步地，所述的化合物，其中，Rr选自R1选自卤素、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、或C3～C6的环烷基。
进一步地，所述的化合物，Rr选自F、Br、Cl、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代。
进一步地，所述的化合物，Rr选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基或苯基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，所述化合物为如下化合物之一：
Figure PCTCN2017076445-appb-000012
Figure PCTCN2017076445-appb-000013
本发明还提供了前述的化合物的方法，其特征在于：包括下述步骤：
Figure PCTCN2017076445-appb-000014
R1和Rr如前述所定义；
(1)将化合物1与式(B1)所示的取代硼酸酯或式(B2)所示的取代硼酸在碱性条件下反应，制备得到式(M1)所示化合物；
(2)将式(M2)化合物与式(S2)所示的磺酸氯或式(S3)所示的磺酸酐反应制备得到。
本发明还提供了所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物在制备URAT1抑制剂类药物中的用途。
进一步地，所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
本发明还提供了一种药物组合物，它是以所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明还提供了所述的药物组合物在制备URAT1抑制剂类药物中的用途。
进一步地，所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
本发明提供的各种化合物及其盐类、水合物或溶剂合物，是一种选择性尿酸再吸收抑制剂，可以通过促进尿酸从体内排泄并减少血清尿酸来治疗高尿酸血症和痛风。
此外，对于本发明的化合物而言，其同位素取代物，如氘代、氚代、14C代以及15N代也具有相同的活性和用途。上述同位素取代物均属于本发明的范围。
本发明中，所述C1～C4的烷基是指C1、C2、C3、C4的烷基，即具有1～4个碳原子的 直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基等等。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明中，“盐”是将化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
实施例1 4-(4-胺基吡啶-3-基)-1-萘甲腈(中间体2)的合成
Figure PCTCN2017076445-appb-000015
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1-萘甲腈(3.35g,12mmol),无水碳酸钠(1.59g,15mmol),二氧六环(20mL), 和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg,0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并,无水硫酸钠干燥,过滤,旋蒸后过柱得化合物2(2g)，收率82％。MS(M+1):246.2。
实施例2 N-(3-(4-氰基萘-1-基)吡啶-4-基)-1,1,1-三氟甲磺酰胺(3)的合成
Figure PCTCN2017076445-appb-000016
向50mL的反应瓶中加入化合物2(100mg，0.41mmol)，三乙胺(207mg,2.1mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(231mg,0.82mmol)反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物3(21mg)，收率14％。
1H NMR(DMSO，400MHz)：δ(ppm)8.44(dd,J＝7.0,1.1Hz,1H),8.42(s,1H),8.26(d,J＝7.4Hz,1H),8.19(d,J＝8.3Hz,1H),7.86–7.80(m,2H),7.68–7.63(m,1H),7.59(d,J＝8.2Hz,1H),7.56(d,J＝7.4Hz,1H).MS(M+1):378.3。
使用相同的合成方式，化合物4，5，6，7，8，9，10，11使用中间体2和相应的磺酰氯或磺酰胺制得。
N-(3-(4-氰基萘-1-基)吡啶-4-基)-甲烷磺酰胺(4)的合成
Figure PCTCN2017076445-appb-000017
1H NMR(DMSO，400MHz)：δ(ppm)12.75(1H,s),8.23(1H,d,J＝7.6Hz)，8.17(1H，d,J＝8.4Hz)，8.13(1H,d,J＝6.8Hz),8.09(1H,s),7.81(1H,dt,J1＝7.2Hz,J2＝1.2Hz,),7.66-7.71(2H,m),7.56(1H,d,J＝7.6Hz)。7.48(1H,d,J＝7.2Hz),2.60(3H,s).MS(M+1):324.0。
N-(3-(4-氰基萘-1-基)吡啶-4-基)–乙烷磺酰胺(5)的合成
Figure PCTCN2017076445-appb-000018
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝7.2Hz,1H),8.17(d,J＝8.0Hz,1H),8.08(s,2H),7.80(t,J＝7.3Hz,1H),7.74–7.62(m,2H),7.55(d,J＝7.4Hz,1H),7.45(d,J＝6.4Hz,1H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):338.2。
N-(3-(4-氰基萘-1-基)吡啶-4-基)–丙烷磺酰胺(6)的合成
Figure PCTCN2017076445-appb-000019
1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝7.4Hz,1H),8.16(d,J＝8.3Hz,1H),8.08(d,J＝8.3Hz,2H),7.83–7.77(m,1H),7.72–7.61(m,2H),7.54(d,J＝7.4Hz,1H),7.45(d,J＝7.1Hz,1H),1.40–0.84(m,4H),0.66(t,J＝7.5Hz,3H).MS(M+1):352.2。
N-(3-(4-氰基萘-1-基)吡啶-4-基)–2-甲基丙烷-1-磺酰胺(7)的合成
Figure PCTCN2017076445-appb-000020
1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝7.4Hz,1H),8.16(d,J＝8.3Hz,1H),8.08(s,2H),7.80(ddd,J＝8.3,6.2,1.9Hz,1H),7.66(tt,J＝8.5,4.1Hz,2H),7.53(d,J＝7.4Hz,1H),7.42(d,J＝7.5Hz,1H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):366.3。
N-(3-(4-氰基萘-1-基)吡啶-4-基)–苯磺酰胺(8)的合成
Figure PCTCN2017076445-appb-000021
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝7.3Hz,1H),8.18(d,J＝8.3Hz,1H),8.09(d,J＝6.5Hz,2H),7.82(t,J＝7.5Hz,1H),7.66–7.58(m,1H),7.54(dt,J＝12.2,6.3Hz,4H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,2H),7.38(d,J＝7.2Hz,1H).MS(M+1):386.2。
4-(3-(4-氰基萘-1-基)吡啶-4-基胺基)-4-氧代丁酸(9)的合成
Figure PCTCN2017076445-appb-000022
1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝7.4Hz,1H),8.16(d,J＝8.3Hz,1H),8.08(s,2H),7.80(ddd,J＝8.3,6.2,1.9Hz,1H),7.66(tt,J＝8.5,4.1Hz,2H),7.53(d,J＝7.4Hz,1H),7.42(d,J＝7.5Hz,1H),2.74(t,J＝7.1Hz,2H),2.49(t,J＝7.1Hz,2H).MS(M+1):346.2。
N-(3-(4-氰基萘-1-基)吡啶-4-基)–对氟苯磺酰胺(10)的合成
Figure PCTCN2017076445-appb-000023
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝7.3Hz,1H),8.18(d,J＝8.3Hz,1H),8.09(d,J＝6.5Hz,2H),7.82(t,J＝7.5Hz,1H),7.66–7.58(m,1H),7.54(dt,J＝12.2,6.3Hz,4H),7.45–7.40(m,2H),7.38(d,J＝7.2Hz,1H).MS(M+1):404.2。
N-(3-(4-氰基萘-1-基)吡啶-4-基)–对氰基苯磺酰胺(11)的合成
Figure PCTCN2017076445-appb-000024
1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝7.3Hz,1H),8.18(d,J＝8.3Hz,1H),8.09(d,J＝6.5Hz,2H),7.82(t,J＝7.5Hz,1H),7.66–7.58(m,1H),7.54(dt,J＝12.2,6.3Hz,4H),7.45–7.40(m,2H),7.38(d,J＝7.2Hz,1H).MS(M+1):411.2。
实施例3 4-(4-胺基吡啶-3-基)苯甲腈(中间体12)的合成
Figure PCTCN2017076445-appb-000025
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，对氰基苯硼酸(1.76g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物12(1.76g)，收率90％。MS(M+1):196.2。
实施例4 N-(3-(4-氰基苯-1-基)吡啶-4-基)-1,1,1-三氟甲磺酰胺(13)的合成
Figure PCTCN2017076445-appb-000026
向50mL的反应瓶中加入化合物12(100mg，0.51mmol)，三乙胺(258mg，2.6mmol) 和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(282mg，1mmol).反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物13(27mg)，收率16％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H).MS(M+1):328.2。
使用相同的合成方式，化合物14，15，16，17，18使用中间体12和相应的磺酰氯或磺酰胺制得。
N-(3-(4-氰基苯-1-基)吡啶-4-基)-甲烷磺酰胺(14)的合成
Figure PCTCN2017076445-appb-000027
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),2.81(s,3H).MS(M+1):274.3。
N-(3-(4-氰基苯-1-基)吡啶-4-基)–乙烷磺酰胺(15)的合成
Figure PCTCN2017076445-appb-000028
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):288.3。
N-(3-(4-氰基苯-1-基)吡啶-4-基)–2-甲基丙烷-1-磺酰胺(16)的合成
Figure PCTCN2017076445-appb-000029
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):316.2。
N-(3-(4-氰基苯-1-基)吡啶-4-基)–苯磺酰胺(17)的合成
Figure PCTCN2017076445-appb-000030
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H).MS(M+1):336.3。
N-(3-(4-氰基苯-1-基)吡啶-4-基)–苯磺酰胺(18)的合成
Figure PCTCN2017076445-appb-000031
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,2H),7.38(d,J＝7.2Hz,1H).MS(M+1):354.3。
实施例5 3,4'-联吡啶-4-胺(中间体19)的合成
Figure PCTCN2017076445-appb-000032
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，吡啶-4-硼酸(1.48g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物19(1.45g)，收率85％。MS(M+1):172.2。
实施例6 N-(3,4'-联吡啶-4-基)-1,1,1-三氟甲磺酰胺(20)的合成
Figure PCTCN2017076445-appb-000033
向50mL的反应瓶中加入化合物19(100mg，0.58mmol)，三乙胺(295mg，2.9mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(327mg，1.2mmol).反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物20(15mg)，收率9％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H).MS(M+1):304.2。
使用相同的合成方式，化合物21，22，23，24使用中间体19和相应的磺酰氯或磺酰胺制得。
N-(3,4'-联吡啶-4-基)-甲烷磺酰胺(21)的合成
Figure PCTCN2017076445-appb-000034
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),2.81(s,3H).MS(M+1):250.3。
N-(3,4'-联吡啶-4-基)–乙烷磺酰胺(22)的合成
Figure PCTCN2017076445-appb-000035
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):264.3。
N-(3,4'-联吡啶-4-基)–2-甲基丙烷-1-磺酰胺(23)的合成
Figure PCTCN2017076445-appb-000036
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):292.3。
N-(3,4'-联吡啶-4-基)–苯磺酰胺(24)的合成
Figure PCTCN2017076445-appb-000037
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H).MS(M+1):312.3。
实施例7 3,3'-联吡啶-4-胺(中间体25)的合成
Figure PCTCN2017076445-appb-000038
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，吡啶-3-硼酸(1.48g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物25(1.42g)，收率83％。MS(M+1):172.2。
实施例8 N-(3,3'-联吡啶-4-基)-1,1,1-三氟甲磺酰胺(26)的合成
Figure PCTCN2017076445-appb-000039
向50mL的反应瓶中加入化合物25(100mg，0.58mmol)，三乙胺(295mg，2.9mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(327mg，1.2mmol).反应液搅拌4个 小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物26(29mg)，收率18％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H).MS(M+1):304.2。
使用相同的合成方式，化合物27，28，29，30使用中间体25和相应的磺酰氯或磺酰胺制得。
N-(3,3'-联吡啶-4-基)-甲烷磺酰胺(27)的合成
Figure PCTCN2017076445-appb-000040
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),2.81(s,3H).MS(M+1):250.2。
N-(3,3'-联吡啶-4-基)–乙烷磺酰胺(28)的合成
Figure PCTCN2017076445-appb-000041
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):264.3。
N-(3,3'-联吡啶-4-基)–2-甲基丙烷-1-磺酰胺(29)的合成
Figure PCTCN2017076445-appb-000042
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):292.3。
N-(3,3'-联吡啶-4-基)–苯磺酰胺(30)的合成
Figure PCTCN2017076445-appb-000043
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H).MS(M+1):312.3。
实施例9 3-(4-氟苯基)-4-胺基吡啶(中间体31)的合成
Figure PCTCN2017076445-appb-000044
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，对氟苯硼酸(1.68g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物31(1.73g)，收率92％。MS(M+1):189.2。
实施例10 N-(3-(4-氟苯-1-基)吡啶-4-基)-1,1,1-三氟甲磺酰胺(32)的合成
Figure PCTCN2017076445-appb-000045
向50mL的反应瓶中加入化合物31(100mg，0.53mmol)，三乙胺(269mg，2.7mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(282mg，1mmol).反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物32(23mg)，收率14％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H).MS(M+1):321.2。
使用相同的合成方式，化合物33，34，35，36使用中间体31和相应的磺酰氯或磺酰胺制得。
N-(3-(4-氟苯-1-基)吡啶-4-基)-甲烷磺酰胺(33)的合成
Figure PCTCN2017076445-appb-000046
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),2.81(s,3H).MS(M+1):267.2。
N-(3-(4-氟苯-1-基)吡啶-4-基)–乙烷磺酰胺(34)的合成
Figure PCTCN2017076445-appb-000047
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.19(dd,J＝19.5,12.2Hz, 2H),0.85–0.77(m,3H).MS(M+1):281.3。
N-(3-(4-氟苯-1-基)吡啶-4-基)–2-甲基丙烷-1-磺酰胺(35)的合成
Figure PCTCN2017076445-appb-000048
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):309.3。
N-(3-(4-氟基苯-1-基)吡啶-4-基)–苯磺酰胺(36)的合成
Figure PCTCN2017076445-appb-000049
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H).MS(M+1):329.3。
实施例11 3-(4-三氟甲基苯基)-4-胺基吡啶(中间体37)的合成
Figure PCTCN2017076445-appb-000050
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，对三氟甲基苯硼酸(2.28g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气 保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物37(2.14g)，收率90％。MS(M+1):239.2。
实施例12 N-(3-(4-三氟甲基苯-1-基)吡啶-4-基)-1,1,1-三氟甲磺酰胺(38)的合成
Figure PCTCN2017076445-appb-000051
向50mL的反应瓶中加入化合物37(100mg，0.42mmol)，三乙胺(212mg，2.1mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(237mg，0.84mmol).反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物38(29mg)，收率19％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H).MS(M+1):371.2。
使用相同的合成方式，化合物39，40，41，42使用中间体37和相应的磺酰氯或磺酰胺制得。
N-(3-(4-三氟甲基苯-1-基)吡啶-4-基)-甲烷磺酰胺(39)的合成
Figure PCTCN2017076445-appb-000052
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),2.81(s,3H).MS(M+1):317.3。
N-(3-(4-三氟甲基苯-1-基)吡啶-4-基)–乙烷磺酰胺(40)的合成
Figure PCTCN2017076445-appb-000053
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):331.3。
N-(3-(4-三氟甲基苯-1-基)吡啶-4-基)–2-甲基丙烷-1-磺酰胺(41)的合成
Figure PCTCN2017076445-appb-000054
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):359.3。
N-(3-(4-三氟甲基苯-1-基)吡啶-4-基)–苯磺酰胺(42)的合成
Figure PCTCN2017076445-appb-000055
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H).MS(M+1):379.3。
实施例13 3-(4-甲氧基苯基)-4-胺基吡啶(中间体43)的合成
Figure PCTCN2017076445-appb-000056
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，对甲氧基苯硼酸(1.82g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物43(1.8g)，收率90％。MS(M+1):201.2。
实施例14 N-(3-(4-甲氧基苯-1-基)吡啶-4-基)-1,1,1-三氟甲磺酰胺(44)的合成
Figure PCTCN2017076445-appb-000057
向50mL的反应瓶中加入化合物43(100mg，0.5mmol)，三乙胺(253mg，2.5mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(282mg，1mmol).反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物44(20mg)，收率12％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H).MS(M+1):333.3。
使用相同的合成方式，化合物45，46，47，48使用中间体43和相应的磺酰氯或磺酰胺制得。
N-(3-(4-甲氧基苯-1-基)吡啶-4-基)-甲烷磺酰胺(45)的合成
Figure PCTCN2017076445-appb-000058
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),3.83(s,3H),2.81(s,3H).MS(M+1):279.3。
N-(3-(4-甲氧基苯-1-基)吡啶-4-基)–乙烷磺酰胺(46)的合成
Figure PCTCN2017076445-appb-000059
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):293.3。
-(3-(4-甲氧基苯-1-基)吡啶-4-基)–2-甲基丙烷-1-磺酰胺(47)的合成
Figure PCTCN2017076445-appb-000060
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):321.2。
N-(3-(4-甲氧基苯-1-基)吡啶-4-基)–苯磺酰胺(48)的合成
Figure PCTCN2017076445-appb-000061
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H),3.83(s,3H).MS(M+1):341.3。
实施例15 3-(3-甲氧基苯基)-4-胺基吡啶(中间体49)的合成
Figure PCTCN2017076445-appb-000062
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，3-甲氧基苯硼酸(1.82g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物49(1.7g)，收率85％。MS(M+1):201.2。
实施例16 N-(3-(3-甲氧基苯-1-基)吡啶-4-基)-1,1,1-三氟甲磺酰胺(50)的合成
Figure PCTCN2017076445-appb-000063
向50mL的反应瓶中加入化合物49(100mg，0.5mmol),三乙胺(253mg,2.5mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(282mg,1mmol).反应液搅拌4个小时， 加入水(5mL),分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物50(30mg)，收率18％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H).MS(M+1):333.3。
使用相同的合成方式，化合物51，52，53，54使用中间体49和相应的磺酰氯或磺酰胺制得。
N-(3-(3-甲氧基苯-1-基)吡啶-4-基)-甲烷磺酰胺(51)的合成
Figure PCTCN2017076445-appb-000064
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),3.83(s,3H),2.81(s,3H).MS(M+1):279.3。
N-(3-(3-甲氧基苯-1-基)吡啶-4-基)–乙烷磺酰胺(52)的合成
Figure PCTCN2017076445-appb-000065
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):293.3。
N-(3-(3-甲氧基苯-1-基)吡啶-4-基)–2-甲基丙烷-1-磺酰胺(53)的合成
Figure PCTCN2017076445-appb-000066
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):321.3。
N-(3-(3-甲氧基苯-1-基)吡啶-4-基)–苯磺酰胺(54)的合成
Figure PCTCN2017076445-appb-000067
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H),3.83(s,3H).MS(M+1):341.2。
实施例17 3-(2-甲氧基苯基)-4-胺基吡啶(中间体55)的合成
Figure PCTCN2017076445-appb-000068
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，3-甲氧基苯硼酸(1.82g，12mmol)，无水碳酸钠(1.59g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物55(1.8g)，收率90％。MS(M+1):201.2。
实施例18 N-(3-(2-甲氧基苯-1-基)吡啶-4-基)-1,1,1-三氟甲磺酰胺(56)的合成
Figure PCTCN2017076445-appb-000069
向50mL的反应瓶中加入化合物55(100mg，0.5mmol)，三乙胺(253mg，2.5mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(282mg，1mmol).反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物56(25mg)，收率15％。
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H).MS(M+1):333.3。
使用相同的合成方式，化合物57，58，59，60使用中间体55和相应的磺酰氯或磺酰胺制得。
N-(3-(2-甲氧基苯-1-基)吡啶-4-基)-甲烷磺酰胺(57)的合成
Figure PCTCN2017076445-appb-000070
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96(d,J＝7.0Hz,1H),7.87(d,J＝8.4Hz,2H),7.80(d,J＝8.4Hz,2H),7.37(d,J＝7.2Hz,1H),3.83(s,3H),2.81(s,3H).MS(M+1):279.3。
N-(3-(2-甲氧基苯-1-基)吡啶-4-基)–乙烷磺酰胺(58)的合成
Figure PCTCN2017076445-appb-000071
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,3H).MS(M+1):293.3。
N-(3-(2-甲氧基苯-1-基)吡啶-4-基)–2-甲基丙烷-1-磺酰胺(59)的合成
Figure PCTCN2017076445-appb-000072
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),3.83(s,3H),1.76–1.20(m,2H),1.19–0.80(m,1H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):321.3。
N-(3-(2-甲氧基苯-1-基)吡啶-4-基)–苯磺酰胺(60)的合成
Figure PCTCN2017076445-appb-000073
1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝0.9Hz,1H),8.33(dd,J＝7.0,1.1Hz,1H),7.94(d,J＝8.5Hz,2H),7.75(s,1H),7.73(dd,J＝4.4,2.5Hz,2H),7.47(d,J＝7.2Hz,1H),7.45–7.40(m,3H),7.38(d,J＝7.2Hz,1H),3.83(s,3H).MS(M+1):341.3。
实施例19 3-环丙基-4-胺基吡啶(中间体61)的合成
Figure PCTCN2017076445-appb-000074
向100mL的反应瓶中加入3-溴-4-氨基吡啶(1.73g，10mmol)，环丙基硼酸(1.82g，12mmol)，无水碳酸钠(1.29g，15mmol)，二氧六环(20mL)，和水(10mL).换成氮气保护，加入四(三苯基膦)钯(578mg，0.5mmol)，加热搅拌到80℃，反应大约3个小时，反应完毕后，加入水(20mL)，用乙酸乙酯萃取三次(3×20mL)，有机层合并，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物61(950mg)，收率70％。MS(M+1):135.2。
实施例20 N-(3-环丙基吡啶-4-基)-1,1,1-三氟甲磺酰胺(62)的合成
Figure PCTCN2017076445-appb-000075
向50mL的反应瓶中加入化合物61(100mg，0.7mmol)，三乙胺(374mg，3.7mmol)和二氯甲烷(8mL)，搅拌下慢慢滴加三氟甲磺酸酐(423mg，1.5mmol).反应液搅拌4个小时，加入水(5mL)，分层，用二氯甲烷萃取三次(3×3mL)将合并有机相，无水硫酸钠干燥，浓缩溶剂，残留物通过反相柱纯化得到化合物62(21mg)，收率8％。
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.33(d,J＝7.0,1H),7.94(d,J＝7.0Hz,1H),1.51(m,1H),1.24(m,2H),0.89(m,2H).MS(M+1):267.2。
使用相同的合成方式，化合物63，64，65，66使用中间体61和相应的磺酰氯或磺酰胺制得。
N-(3-环丙基吡啶-4-基)-甲烷磺酰胺(63)的合成
Figure PCTCN2017076445-appb-000076
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.33(d,J＝7.0,1H),7.94(d,J＝7.0Hz,1H),2.81(s,3H),1.51(m,1H),1.24(m,2H),0.89(m,2H).MS(M+1):213.2。
N-(3-环丙基吡啶-4-基)–乙烷磺酰胺(64)的合成
Figure PCTCN2017076445-appb-000077
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.33(d,J＝7.0,1H),7.94(d,J＝7.0Hz,1H),1.51(m,1H),1.24(m,2H),1.19(dd,J＝19.5,12.2Hz,2H),0.85–0.77(m,5H).MS(M+1):227.3。
N-(3-环丙基吡啶-4-基)–2-甲基丙烷-1-磺酰胺(65)的合成
Figure PCTCN2017076445-appb-000078
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.33(d,J＝7.0,1H),7.94(d,J＝7.0Hz,1H),1.76–1.20(m,5H),1.19–0.80(m,3H),0.68(d,J＝6.7Hz,3H),0.62(d,J＝6.6Hz,3H).MS(M+1):255.3。
N-(3-环丙基吡啶-4-基)–苯磺酰胺(66)的合成
Figure PCTCN2017076445-appb-000079
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.33(d,J＝7.0,1H),7.94(d,J＝7.0Hz,1H),7.73(m,5H),1.51(m,1H),1.24(m,2H),0.89(m,2H).MS(M+1):275.3。
实施例21本发明化合物的生物学测定
测试例：本发明化合物对URAT1抑制活性的测定
实验材料：
Figure PCTCN2017076445-appb-000080
FBS(Invitrogen,Cat.No.10099141)
Figure PCTCN2017076445-appb-000081
Trypsin(Invitrogen,Cat.No.25200056)
Figure PCTCN2017076445-appb-000082
DPBS(Invitrogen,Cat.No.14190250)
Figure PCTCN2017076445-appb-000083
DMEM(Invitrogen,Cat.No.10564)
Figure PCTCN2017076445-appb-000084
Penicillin-Streptomycin(Invitrogen,Cat.No.15070-063)
Figure PCTCN2017076445-appb-000085
TransIT-293Transfection Reagent(MIRUS BIO,Cat.No.MIR2706)
Figure PCTCN2017076445-appb-000086
Opti-
Figure PCTCN2017076445-appb-000087
I Reduced Serum Medium(Invitrogen,Cat.No.31985-070)
Figure PCTCN2017076445-appb-000088
URAT1plasmid(Genecopoeia,Cat.No.EX-T4563-M03)
Figure PCTCN2017076445-appb-000089
Uric acid[8-14C](ARC,Cat.No.ARC0513-250UCI)
Figure PCTCN2017076445-appb-000090
Ultima GoldTM XR(PerkinElmer,Cat.No.6013111)
Figure PCTCN2017076445-appb-000091
Benzbromarone(百灵威科技,Cat.No.3562-84-3)
Figure PCTCN2017076445-appb-000092
D-Gluconic acid sodium salt(阿拉丁,Cat.No.527-07-1)
Figure PCTCN2017076445-appb-000093
Potassium D-gluconate(阿拉丁,Cat.No.299-27-4)
Figure PCTCN2017076445-appb-000094
Calcium gluconate(阿拉丁,Cat.No.299-28-5)
Figure PCTCN2017076445-appb-000095
DMSO(Sigma,Cat.No.D2650)
Figure PCTCN2017076445-appb-000096
Tube,15mL(Greiner,Cat.No.07030115)
Figure PCTCN2017076445-appb-000097
Tube,50mL(BD Falcon,Cat.No.352098)
Figure PCTCN2017076445-appb-000098
Poly-D-lysine 96-well microplates(BD,Cat.No.356461)
Figure PCTCN2017076445-appb-000099
Isoplate-96Microplate(PERKIN ELMER,Cat.No.6005040)
实验方法：
缓冲液配制
Figure PCTCN2017076445-appb-000100
Figure PCTCN2017076445-appb-000101
细胞培养：
1.将稳定表达hURAT1的HEK-293T细胞培养于10％FBS和1％P/S的DMEM培养基中，在5％二氧化碳的37度培养箱中培养过夜。
2.将培养基去掉后用PBS清洗一次，然后加入胰酶消化2分钟，待细胞于培养皿分离后加入10毫升培养基终止消化。
3.把细胞放入离心机1000转离心2分钟，加入新的10毫升培养基来重悬细胞，并计算细胞个数。将细胞个数调整为4x105个细胞每毫升。
4.将上述计数好的细胞接种到96孔板中，每孔100微升。
5.将接种好细胞的96孔板放置于37度细胞培养箱中培养过夜。
同位素碳14标记的尿酸吸收实验：
1.在15毫升离心管中加入5毫升Cl-free HBSS缓冲液，然后加入碳14标记的尿酸，使尿酸的浓度达到2uCi/mL.
2.将之前培养过夜的96孔板中的培养基吸干净，加入100毫升预热过的Cl-free HBSS缓冲液清洗三次。
3.将清洗好后的96孔板中的所以缓冲液吸干净。
4.清洗好的96孔板上每孔中加入50微升含有碳14标记的尿酸的Cl-free HBSS缓冲液，然后加入需要测试的化合物。
5.把上述96孔板在室温下静置5分钟后，将里面所有的液体吸干。
6.加入100毫升预冷的Cl-free HBSS缓冲液清洗三次。
7.把板里残留的液体吸干净后，于每孔中加入50微升的细胞裂解液，在混匀器上以每分钟600转的速度振荡10分钟。
8.加入50微升Ultima GoldTM XR scitillation cocktail闪烁液后，继续振荡10分钟。
9.将振荡好的板用封板膜贴好后，于MicroBeta Trilux上读数。
10.将测试化合物溶解在DMSO中，然后将相同浓度的DMSO加入不包含测试化合物的 HEK293/hURAT1细胞孔中。将各测试浓度下的细胞的尿酸摄取表示为相对DMSO对照的平均百分比抑制率。将对包含DMSO的孔得到的放射性值视为细胞的100％摄取。化合物的IC50值可通过不同浓度下的抑制率计算得出。
本发明化合物对hURAT1的活性抑制的IC50(nM)如表1所示。
表1
化合物编号 IC50(nM) 化合物编号 IC50(nM)
3 4 53 9107
4 146 54 8099
5 713 56 214
6 1100 57 2139
7 597 58 4155
8 127 59 3937
9 320 60 2089
10 1400 62 498
11 2000 63 809
13 2 64 1098
14 203 65 709
15 610 66 720
16 451 39 4059
17 143 40 5032
20 12 41 4098
21 240 42 2188
22 509 44 215
23 330 45 455
24 110 46 674
26 23 47 549
27 310 48 438
28 620 50 4054
29 440 51 9836
30 205 52 12457
32 65 35 280
33 280 36 240
34 540 38 717
经试验验证，本发明提供的各种化合物及其盐类、水合物或溶剂合物，是一种选择性尿酸再吸收抑制剂，可以通过促进尿酸从体内排泄并减少血清尿酸来治疗高尿酸血症和痛风。

Claims (10)

  1. 式(A)所示的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，
    Figure PCTCN2017076445-appb-100001
    其中：
    X1选自N、CH或C-Ra；
    X2选自N、CH或C-Ra1；
    X3选自N、CH或C-Rb；
    X4选自N、CH或C-Rb1；
    其中，Ra、Ra1、Rb、Rb1分别独立地选自卤素或C1～C4的烷基以及环烷基，所述烷基或环烷基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；且X1、X2、X3、X4中至少一个为N；
    R1选自
    Figure PCTCN2017076445-appb-100002
    或环烷基；所述环烷基任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；
    R2选自-SO2Rr或-C(O)(CH2)yCOOH；y为1、2或3；
    W1选自N或CRc；W2选自N或CRd；W3选自N或CRe；W4选自N或CRf；W5选自N或CRg；W6选自N或CRh；W7选自N或CRi；W8选自N或CRj；W9选自N或CRk；W10选自N或CRl；W11选自N或CRm；W12选自N或CRn；
    Rc、Rd、Re、Rf、Rg、Rh、Ri、Rj、Rk、Rl、Rm、Rn、Rr分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORo、-S(O)zRo、-C(O)Ro、C(O)ORo、-C(O)NRpRq、-NRpRq或NRpC(O)Rq，其中所述的烷基、烯基、炔基、环烷基、 杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORo、-S(O)mRo、-C(O)Ro、C(O)ORo、-C(O)NRpRq、-NRpRq或NRpC(O)Rq的取代基所取代；
    Ro选自氢、卤素、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基、羧酸酯基、-C(O)NRpRq、-NRpRq或NRpC(O)Rq的取代基所取代；
    Rp、Rq分别独立选自氢、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；且z为0、1或2。
  2. 根据权利要求1所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰaaa)所示的结构：
    Figure PCTCN2017076445-appb-100003
    Rr具有权利要求1中所述的含义。
  3. 根据权利要求1所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰab)所示的结构：
    Figure PCTCN2017076445-appb-100004
    其中，Rj、Rk、Rl、Rm、Rn分别独立地选自氢、卤素、氰基、硝基、烷基、卤代烷基或烷氧基；优选的卤素为氟，优选的卤代烷基为三氟甲基，优选的烷氧基为甲氧基；
    更优选的，所述化合物具有如下述任一项通式所示的结构：
    Figure PCTCN2017076445-appb-100005
    Rr具有权利要求1中所述的含义。
  4. 根据权利要求1所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰac)所示的结构：
    Figure PCTCN2017076445-appb-100006
    W8～W12、Rr均具有权利要求1中所述的含义，且W8～W12中至少一个为N。
    优选的，所述化合物具有如式(Ⅰaca)、式(Ⅰacb)或式(Ⅰacc)所示的结构，优选式(Ⅰaca)或式(Ⅰacc)的结构：
    Figure PCTCN2017076445-appb-100007
    Rr具有权利要求1中所述的含义。
  5. 根据权利要1所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ⅰad)所示的结构：
    Figure PCTCN2017076445-appb-100008
    Rr具有权利要求1中所述的含义。
  6. 根据权利要求1-5任一项所述的化合物，其中，Rr选自R1选自卤素、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、或C3～C6的环烷基；
    优选的，Rr选自F、Br、Cl、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代；
    更优选的，Rr选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基或苯基。
  7. 根据权利要求1-6任一项所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，所述化合物为如下化合物之一：
    Figure PCTCN2017076445-appb-100009
    Figure PCTCN2017076445-appb-100010
  8. 制备权利要求2-7任一项所述的化合物的方法，其特征在于：包括下述步骤：
    Figure PCTCN2017076445-appb-100011
    R1和Rr均具有权利要求1中所述的含义；
    (1)将化合物1与式(B1)所示的取代硼酸酯或式(B2)所示的取代硼酸在碱性条件下反应，制备得到式(M1)所示化合物；
    (2)将式(M1)化合物与式(S2)所示的磺酸氯或式(S3)所示的磺酸酐反应制备得到式(Ⅰ)化合物。
  9. 权利要求1-7任一项所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物在制备URAT1抑制剂类药物中的用途。
  10. 根据权利要求9所述的用途，所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
PCT/CN2017/076445 2017-03-13 2017-03-13 磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 WO2018165822A1 (zh)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101217957A (zh) * 2005-04-21 2008-07-09 雪兰诺实验室有限公司 作为crth2抑制剂的2,3-取代的吡嗪磺酰胺
CN106831556A (zh) * 2015-12-07 2017-06-13 成都海创药业有限公司 磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101217957A (zh) * 2005-04-21 2008-07-09 雪兰诺实验室有限公司 作为crth2抑制剂的2,3-取代的吡嗪磺酰胺
CN106831556A (zh) * 2015-12-07 2017-06-13 成都海创药业有限公司 磺酰胺类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途

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