WO2018024188A1 - Polycyclic compound, and manufacturing method, pharmaceutical composition, and application thereof - Google Patents

Polycyclic compound, and manufacturing method, pharmaceutical composition, and application thereof Download PDF

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Publication number
WO2018024188A1
WO2018024188A1 PCT/CN2017/095396 CN2017095396W WO2018024188A1 WO 2018024188 A1 WO2018024188 A1 WO 2018024188A1 CN 2017095396 W CN2017095396 W CN 2017095396W WO 2018024188 A1 WO2018024188 A1 WO 2018024188A1
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compound
substituted
group
unsubstituted
synthesis
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PCT/CN2017/095396
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French (fr)
Chinese (zh)
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陈寿军
利群
刘胜洋
郭洪利
刘凤涛
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上海迪诺医药科技有限公司
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Publication of WO2018024188A1 publication Critical patent/WO2018024188A1/en

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to a polycyclic compound, a process for its preparation, a pharmaceutical composition and use.
  • Indoleamine 2,3-dioxygenase is an immunomodulatory enzyme produced by some alternative activated macrophages and other immunoregulatory cells (also used by many tumors as a strategy to destroy immunity) in humans.
  • the middle is encoded by the IDO gene. Its role is to break down the essential L-tryptophan to kynurenine. The depletion of tryptophan and its metabolites lead to a strong inhibition of the immune response, causing the cessation of T cell growth, blocking the activation of T cells, inducing T cell apoptosis and increasing the production of regulatory T cells.
  • the metabolic pathway from tryptophan to kynurenine has now been established as a key regulatory pathway for innate and adaptive immunity.
  • IDO inhibitors can activate T cells to enhance the body's immune function
  • IDO inhibitors have therapeutic effects on many diseases, including tumor resistance and rejection, chronic infections, HIV infection and AIDS, autoimmune diseases or conditions, such as Rheumatoid arthritis, immune tolerance and prevention of fetal rejection in the uterus.
  • Inhibitors of IDO can also be used to treat neurological or neuropsychiatric diseases or disorders, such as depression (Protula et al, 2005, Blood, 106: 238290; Munn et al, 1998, Science 281:11913).
  • IDO inhibition can enhance the body's immunity and significantly improve the anti-tumor efficacy of various chemotherapeutic drugs and the efficacy of other immunosuppressive diseases (CJDAustin and LMRendina, Drug Discovery Today 2014, 1-9).
  • IDO-/- mouse knockout is feasible and the mice are healthy, which means that IDO inhibition may not cause serious toxicity by the mechanism of action.
  • IDO small molecule inhibitors currently under development to treat and prevent the above-mentioned IDO-related diseases
  • PCT Patent Application WO 99/29310 discloses a method of altering T cell-mediated immunity, including by administering a certain amount of 1-methyl DL. Tryptophan or p-(3 benzofuranyl)-DL-alanine alters the extracellular concentration of local tryptophan and tryptophan metabolites (Munn, 1999).
  • Compounds capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) are disclosed in WO2004/0234623; U.S. Patent Application No. 2004/0234623 discloses the treatment of cancer by administering an IDO inhibitor in combination with other treatments or The method of infecting patients.
  • IDO inhibitors have good treatment and prevention for immunosuppression, tumor suppression, chronic infection, viral infection including HIV infection, autoimmune diseases or disorders and intrauterine fetal rejection
  • a method of inhibiting IDO activity to inhibit inhibition of tryptophan.
  • an IDO inhibitor can be used to enhance the activity of T cells.
  • IDO chemistry has been well studied and its x-ray crystal structure has also been resolved, which has helped to better use structure-based drug design and structural optimization of drugs. IDO is currently a very attractive target for therapeutic intervention.
  • the technical problem to be solved by the present invention is to provide a novel polycyclic compound, a preparation method thereof, a pharmaceutical composition and use thereof.
  • the polycyclic compound of the present invention has a good IDO inhibitory action, and can effectively treat, alleviate and/or prevent various related diseases caused by immunosuppression, such as tumors, infectious diseases, and autoimmune diseases.
  • IDO inhibitors in the present invention may include the following meanings: IDO inhibitors, TDO inhibitors, or dual inhibitors of IDO and TDO.
  • the present invention provides a polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • ring A is a benzene ring or a 5-6 membered heteroaryl ring
  • the B ring is a 5-membered heteroaryl ring, and A 1 , A 2 , A 3 and A 4 are any combination of the following:
  • a 1 is C
  • a 2 is NR 4 , O or S
  • a 3 is CR 5
  • a 4 is CH or N;
  • a 1 is C
  • a 2 is CR 5 or N
  • a 3 is NR 4 , O or S
  • a 4 is CR 5a or N
  • a 1 is C
  • a 2 is CH or N
  • a 3 is CR 5
  • a 4 is NR 4 , O or S;
  • a 1 is N
  • a 2 is CR 5 or N
  • a 3 is CR 5a or N
  • a 4 is N or CR 5b ;
  • a 1 is CR 5
  • a 2 is C
  • a 3 is NR 4 , O or S
  • a 4 is NR 4 or CR 5a ;
  • a 1 is CR 5
  • a 2 is C
  • a 3 is CR 5a
  • a 4 is NR 4 , O or S;
  • X 1 is a linkage, -O-, -NR 4 - or -CR 6 R 6a -;
  • X 2 is -C(O)- or -S(O) 1-2 -;
  • X 3 is a linkage, -NR 4 - or -CR 6 R 6a -; and, when X 1 is -NR 4 -, X 2 is -C(O)-, X 3 is -NR 4 -;
  • Y is a bond or -(CR 6 R 6a ) p -;
  • U and V are each independently selected from N or CR 3 ;
  • Z and W are each independently selected from CHR 3 , NR 3 , O, C(O) or S(O) 2 ;
  • L is a linkage, C 2-6 alkenylene, C 2-6 alkynylene or -(CR 6 R 6a ) m -;
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl, -SH, -CN, -NO 2 , -OR b , -OC(O)R a , -OC(O)OR b , -OC(O)N(R b ) 2 , -C(O)OR b , -C(O)R a , -C(O)N(R b ) 2 , -NR b C(O)R a , -N(R b )C(O)OR b , -N(R b )C(O)N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 0-2 R a , -S(O) 2 N(
  • R 2 or R 3 are each independently selected from the group consisting of hydrogen, -NO 2 , -CN, -OH, -NH 2 , -SH, -OR 8 , -OC(O)R 8 , -OC(O)NR 7 R 8 , -OC(O)OR 8 , -OP(O)(OR 7 ) 2 , -OS(O) 2 (OH), -OS(O) 1-2 R 8 , -S(O) 1-2 OR 8 , -S(O) 2 NR 7 R 8 , -S(O) 0-2 R 8 , -S(O) 2 N(R 7 )C(O)NR 7 R 8 , -C(O)OR 8, -C (O) R 8 , -C (O) N (OH) R 8, -C (O) NR 7 R 8, -NR 7 R 8, -N (R 7) C (O) OR 8 , -N(R 7 )C(O)N(R
  • R 4 is H, C 1-6 alkyl or C 3-8 cycloalkyl
  • R 5 , R 5a and R 5b are each independently selected from H or C 1-6 alkyl;
  • R 6 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted alkoxy; substituted An alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, or a substituted alkoxy group is substituted at any position by one or more of the following groups: halogen, hydroxy, alkyl, heterocycloalkyl, cycloalkyl , alkoxy, amino, aryl, heteroaryl, -SR a , -N(R b ) 2 , -S(O) 2 N(R b ) 2 , -NR b C(O)N(R b 2 , -NR b C(O)R a , -C(O)R a , -S(O) 0
  • R 6a is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, -SR a , -OR b , -N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 2 N (R b ) 2 , -(CH 2 ) m S(O) 0-2 CH 3 , -OS(O) 3 H, -OP(O)(OR b ) 2 , -OC(O)R a ,- OC(O)N(R b ) 2 , -C(O)N(R b ) 2 , -(CH 2 ) m C(O)OH, -(CH 2 ) m OH, -(CH 2 ) m N (R b ) 2 or -(CH 2 ) m C(O)N(R b ) 2 ;
  • R 6 and R 6a together with the C atom to which they are attached form a 3-8 membered monocyclic cycloalkyl group
  • R 7 or R 8 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl When the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl group is substituted, It may be further substituted at any position by 1 to 3 substituents selected from a halogen, a hydroxyl group, an amino group,
  • R a and R b are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkylalkyl, cycloalkylalkyl, arylalkane Or a heteroarylalkyl group, or two R b together with the N atom to which they are attached together form a 3-8 membered monocyclic heterocycloalkyl group;
  • n, m and p are independently 1, 2 or 3;
  • q and t are independently 0, 1, or 2, respectively.
  • the 5-6 membered heteroaryl group is preferably a thienyl group, a pyridyl group or a pyrimidinyl group.
  • the R 1 is preferably hydrogen, halogen, hydroxy, decyl, cyano, C 1-3 alkoxy, C 1-3 alkylthio, C 1-4 alkyl (eg, methyl, ethyl, n-propyl) Or isopropyl), halo C 1-3 alkyl (eg, trifluoromethyl, difluoromethyl) and halo C 1-3 alkoxy (eg, trifluoromethoxy, difluoromethyl) One or more of oxy), -C(O)OH, -C(O)NH 2 , -S(O) 2 CH 3 .
  • R 1 is one of H, F, Cl, Br, -CH 3 , -CN, -OH, -OCH 3 , -OCF 3 , -OCHF 2 and -C(O)NH 2 or A variety.
  • the R 4 is preferably H, methyl, ethyl, isopropyl or cyclopropyl.
  • the R 5 is preferably H, methyl, ethyl, n-propyl or isopropyl
  • the R 5a is preferably H, methyl, ethyl, n-propyl or isopropyl.
  • the R 5b is preferably H.
  • the R 6 is preferably hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, A substituted or unsubstituted 3-8 membered heterocycloalkyl group, or a substituted or unsubstituted C 1-4 alkoxy group.
  • the substituted alkyl group, substituted cycloalkyl group, substituted heterocycloalkyl group, or substituted alkoxy group is substituted at any position by one or more of the following groups: halogen, hydroxy, alkyl, Heterocycloalkyl, cycloalkyl, alkoxy, amino, aryl, heteroaryl, -SR a , -N(R b ) 2 , -S(O) 2 N(R b ) 2 , -NR b C (O) N (R b ) 2, -NR b C (O) R a, -C (O) R a, -S (O) 0-2 R a, -C (O) OR b, - ( CH 2 ) m OH or -(CH 2 ) m N(R b ) 2 .
  • the R 6a is preferably hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, -SR a , -OR b , -N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 2 N(R b ) 2 , -(CH 2 ) m S(O) 0-2 CH 3 , -OS(O) 3 H,- OP(O)(OR b ) 2 , -OC(O)R a , -OC(O)N(R b ) 2 , -C(O)N(R b ) 2 , -(CH 2 ) m C( O) OH, -(CH 2 ) m OH, -(CH 2 ) m N(R b ) 2 or -(CH 2 ) m C(O)N(R
  • R 6 or R 6a is H, -CH 3 , -CF 3 , -CH 2 CH 3 or F.
  • X 1 is preferably a linkage.
  • the X 2 is preferably -C(O)-, or -S(O) 1-2 -.
  • the X 3 is preferably a linkage, or -NH-.
  • the X 1 , X 2 and X 3 are preferably any combination of the following:
  • X 1 is a linkage, X 2 is -C(O)-, and X 3 is -NH-;
  • X 1 is a linkage
  • X 2 is -S(O) 2 -
  • X 3 is -NH-;
  • X 1 is -NH-
  • X 2 is -S(O) 2 -
  • X 3 is -NH-
  • X 1 is -NH-
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • X 1 , X 2 and X 3 are more preferably any combination of the following: X 1 is a linking bond, X 2 is -C(O)-, and X 3 is -NH-.
  • the Y is preferably a linkage, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -CHF- Or -CF 2 -.
  • the L is preferably a linkage, -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -CHF- or -CF 2 -.
  • L is a linkage or -O-.
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group, more preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, or a substituted group. Or unsubstituted propyl, substituted or unsubstituted isopropyl;
  • the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted C 6-10 aryl group, more preferably a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group;
  • the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-10 membered heteroaryl group, more preferably a substituted or unsubstituted pyridyl group, a substituted or unsubstituted N- group.
  • the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group, more preferably a substituted or unsubstituted C 3-8 monocyclic cycloalkyl group;
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 5-8 membered heterocycloalkyl group, more preferably a substituted or unsubstituted 5-8 membered monoheterocycloalkane. base;
  • R 2 or R 3 is a substituted alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group or a substituted heteroaryl group, the following 1 to 3 R A groups may be used.
  • the halogen is preferably F, Cl, Br, I; more preferably F or Cl;
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group; more preferably a methyl group, an ethyl group, a n-propyl group or a different group.
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group; more preferably a methyl group, an ethyl group, a n-propyl group or a different group.
  • the substituted or unsubstituted alkoxy group is preferably a substituted or unsubstituted C 1-4 alkoxy group; more preferably a methoxy group or an ethoxy group.
  • the substituted or unsubstituted alkylthio group is preferably a substituted or unsubstituted C 1-4 alkylthio group; more preferably a methylthio group or an ethylthio group.
  • the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted phenyl group.
  • the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-6 membered heteroaryl group.
  • the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group.
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 5-8 membered heterocycloalkyl group.
  • R 2 or R 3 in the R A , when the alkyl group, the alkoxy group, the aryl group, the heteroaryl group, the cycloalkyl group or the heterocycloalkyl group is substituted, it may be further selected from 1 to 3 Substituents from a halogen, a hydroxyl group, an amino group, a C 1-3 alkyl group, or a halogenated C 1-3 alkoxy group are substituted at any position.
  • R 7 or R 8 are each independently preferably hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted a 3-8 membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted C 3-8 cycloalkyl C 1-3 alkyl group, Substituted or unsubstituted 3-8 membered heterocycloalkyl C 1-3 alkyl, substituted or unsubstituted phenyl C 1-3 alkyl, or substituted or unsubstituted 5-6 membered heteroaryl C 1- 3 alkyl; or, R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered monoheterocycloalkyl
  • the alkylalkyl group when the alkyl group, the aryl group, the heteroaryl group, the cycloalkyl group, the heterocycloalkyl group, the arylalkyl group, the heteroarylalkyl group, the cycloalkylalkyl group or the heterocyclic ring
  • the alkylalkyl group when substituted, it may be further substituted at any position by 1 to 3 substituents selected from a halogen, a hydroxyl group, an amino group, a C 1-4 alkyl group, or a halogenated C 1-3 alkoxy group.
  • R 3 is hydrogen, fluorine, hydroxy, cyano, C 1-4 alkyl, or C 1-3 alkoxy.
  • R 2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-10 membered heteroaryl group.
  • the R a and R b are each independently preferably from hydrogen, C 1-4 alkyl, halo C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl C 1-3 alkyl, C 3-8 cycloalkyl C 1-3 alkyl, phenylalkyl, or 5-6 membered heteroaryl C 1-3 alkyl, or two R b together with the N atom to which they are attached form a 3-8 membered monocyclic heterocycloalkyl group.
  • R a is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • R b is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • the definitions of the A ring, the B ring, R 1 , R 2 , A 1 to A 4 , X 1 to X 3 , L, Y, U, W, Z, V, q, t and n are as described above.
  • the A 1 -A 4 are any combination of the following:
  • a 1 is C
  • a 2 is NR 4 , O or S
  • a 3 is CR 5
  • a 4 is CH or N;
  • a 1 is C
  • a 2 is CR 5 or N
  • a 3 is NR 4 , O or S
  • a 4 is CR 5a or N
  • a 1 is C
  • a 2 is CH or N
  • a 3 is CR 5
  • a 4 is NR 4 , O or S.
  • the A 1 -A 4 are in any combination of the following:
  • a 1 is C
  • a 2 is NR 4
  • a 3 is CR 5
  • a 4 is CH or N;
  • a 1 is C
  • a 2 is CR 5 or N
  • a 3 is NR 4
  • a 4 is CR 5a or N;
  • a 1 is C
  • a 2 is CH or N
  • a 3 is CR 5
  • a 4 is NR 4 .
  • the B ring Is any of the following structures:
  • the B ring Is any of the following structures
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • t is 1 and q is 1.
  • U is CR 3 and V is CH.
  • Z is CH 2 and W is CH 2 .
  • L is a linkage
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of: methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a ring the B ring
  • the B ring Preferably, it is any of the following structures;
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • t is 1 and q is 1.
  • U is CH and V is CH.
  • Z is CH 2 and W is CH 2 .
  • L is a linkage
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • W is N or CH
  • a 2 , A 3 and A 4 are the following combinations:
  • a 2 is CR 5 , A 3 is NR 4 , and A 4 is N;
  • a 2 is N
  • a 3 is NR 4
  • a 4 is CR 5a ;
  • a 2 is CR 5
  • a 3 is NR 4
  • a 4 is CR 5a ;
  • a 2 is N
  • a 3 is NR 4
  • a 4 is N
  • a 2 is N, A 3 is O or S, and A 4 is CH;
  • R 1 , R 2 , R 4 , R 5 , R 5a , L, X 1 to X 3 , Y, U, V, q and n are as described above.
  • a 2 is CR 5
  • a 3 is NR 4
  • a 4 is CR 5a .
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • q is one.
  • U is CR 3 and V is CH.
  • L is a linkage
  • R 3 is H or hydroxy
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • W is N or CH;
  • R 4 is H or -CH 3 ;
  • R 5 is H, methyl, ethyl or isopropyl;
  • R 5a is H, methyl, ethyl or isopropyl;
  • R 1 , R 2 , R 3 , L, Y and n are as described above.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • L is a linkage
  • R 3 is H or hydroxy
  • R 5 is H or methyl.
  • R 5a is H or methyl.
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a 2 , A 3 and A 4 are the following combinations:
  • a 2 is NR 4 , A 3 is CR 5 , and A 4 is CH;
  • a 2 is NR 4 , A 3 is N, and A 4 is CH;
  • a 2 is S, A 3 is CH, and A 4 is N;
  • a 2 is O, A 3 is CH, and A 4 is N;
  • R 1 , R 2 , R 4 , R 5 , L, X 1 , X 2 , X 3 , Y, U, V, W, n and q are as described above.
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • q is one.
  • U is CR 3
  • V is CH
  • R 3 is H or hydroxy
  • L is a linkage
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • W is N or CH
  • R 1 , R 2 , R 3 , R 5 , L, Y and n are as described above.
  • Y is -CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • L is a linkage
  • R 3 is H or hydroxy
  • R 5 is H, methyl, ethyl, or isopropyl.
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a 2 , A 3 and A 4 are the following combinations:
  • a 2 is CH
  • a 3 is CH
  • a 4 is NR 4 ;
  • a 2 is CH, A 3 is N, and A 4 is CH;
  • a 2 is N, A 3 is CH, and A 4 is CH;
  • a 2 is N, A 3 is N, and A 4 is CH;
  • a 2 is N
  • a 3 is N
  • a 4 is NR 4 ;
  • R 1 , R 2 , L, X, Y, U, V and W are as described above.
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a ring R 1 , R 2 , L, X 1 , X 2 , X 3 , Y, A 1 , A 2 , A 3 , A 4 and n are as described above.
  • the polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the present invention also provides a process for the preparation of the polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, which is any of the following methods:
  • the compound of the formula Ia can be obtained by the reaction formula 1 shown in the method 1, wherein the ring A, the ring B, the R 1 , the R 2 , the L, the X 1 , the A 1 , the A 2 , the A 3 , the A 4 , the U, V and n are defined as described above.
  • the method 1 comprises the steps of: subjecting the compound represented by 1a and 1b to a compound represented by Ia under a basic condition, and the conditions and steps of the condensation reaction may be the conditions and steps of a conventional condensation reaction in the art, and the present invention is particularly preferred.
  • the solvent is preferably dichloromethane
  • the condensing agent is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
  • the base is preferably N, N-diisopropylethylamine (DIPEA) or triethylamine (TEA)
  • the reaction temperature is preferably 0 ° C to room temperature, in order to accelerate the reaction rate, a catalytic amount of 4-dimethylaminopyridine can also be added to the reaction system.
  • the compound of the formula Ib can be obtained by the reaction formula 2 shown in the method 2, wherein the ring A, the ring B, the R 1 , the R 2 , the L, the X 1 , the A 1 , the A 2 , the A 3 , the A 4 , the U, V and n are defined as described above.
  • the method 2 comprises the steps of: obtaining a compound represented by Ib by nucleophilic substitution reaction under basic conditions, and the conditions and steps of the reaction may be conventional conditions and steps in the art, and the following reactions are particularly preferred in the present invention.
  • the solvent is preferably dichloromethane (DCM);
  • the base is preferably N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA), in general, in order to catalyze the progress of the reaction, in the reaction system
  • DIPEA N,N-diisopropylethylamine
  • TEA triethylamine
  • a catalytic amount of 4-dimethylaminopyridine is added, and the reaction temperature is preferably from 0 ° C to room temperature.
  • Boc is used as a protecting group
  • subsequent deprotection reactions can be carried out under standard conditions, for example, p-toluenesulfonic acid/methanol system, dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonate
  • the pharmaceutically acceptable salt of the polycyclic compound (I) can be synthesized by a general chemical method.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprising a polycyclic compound (I), an isomer thereof, a prodrug, a solvent
  • the active ingredient comprising a polycyclic compound (I), an isomer thereof, a prodrug, a solvent
  • a compound, a hydrate, a stable isotope derivative, and a pharmaceutically acceptable salt One or more of a compound, a hydrate, a stable isotope derivative, and a pharmaceutically acceptable salt.
  • the active ingredient may also include other therapeutic agents for cancer, viral infection or autoimmune diseases.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment.
  • dosage unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quatern
  • any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass. %.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
  • injectable solutions eg, glucose solutions and amino acid solutions
  • suppositories are given Drug to the rectum.
  • the present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is used in the preparation of hydrazine Use in indoleamine 2,3-dioxygenase inhibitors.
  • the indoleamine 2,3-dioxygenase inhibitor (IDO inhibitor) refers to inhibiting IDO activity or expression (including abnormal activity or overexpression of IDO) and reversing IDO-mediated immunosuppression. Compound.
  • the IDO inhibitor can inhibit IDO.
  • the present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for stimulation Application in T cell proliferation drugs.
  • the present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for treatment
  • a medicament for alleviating and/or preventing a disease associated with guanamine 2,3-dioxygenase.
  • the N-hydroxy steroid compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition may also be a Or a variety of other types of therapeutic agents and/or therapeutic methods for treating cancer in combination for treating, ameliorating and/or preventing a disease associated with guanamine 2,3-dioxygenase.
  • the 2,3-dioxygenase-mediated related disease refers to a disease caused by 2,3-dioxygenase-mediated immunosuppression, which may include: a virus or other infection (eg, : skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.), cancer, or autoimmune diseases (eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).
  • a virus or other infection eg, : skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.
  • cancer eg. rheumatoid arthritis, lupus erythematosus, psoriasis, etc.
  • autoimmune diseases eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.
  • the other kind of therapeutic agent for treating cancer may be a therapeutic form for single administration with the polycyclic compound (I), or a therapeutic dosage form for sequential administration.
  • the other types of therapeutic agents and/or therapeutic methods for treating cancer may include, but are not limited to, tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum compounds, antimetabolites, Hormone and hormone analogs, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies (eg, specific kinase inhibitors), immunotherapeutics, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiotherapy One or more.
  • the tubulin inhibitor may be selected from, but not limited to, a vinblastine series (eg, vinblastine, vincristine, vinorelbine, vindesine), a taxane (docetaxel, paclitaxel), and a One or more of eribulin sulfonate.
  • a vinblastine series eg, vinblastine, vincristine, vinorelbine, vindesine
  • a taxane docetaxel, paclitaxel
  • eribulin sulfonate eribulin sulfonate
  • the alkylating agent may be selected from one or more of the group consisting of nitrogen mustard, ethyleneimine derivative, methanesulfonate, nitrosourea, and triazene.
  • the topozyme I/II inhibitor may be selected from, but not limited to, one or more of irinotecan, topotecan, doxorubicin, and dexrazoxane.
  • the platinum compound may be selected from, but not limited to, cisplatin and/or carboplatin.
  • the anti-metabolites may be selected from, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, for example: methotrexate, 5-fluorouracil, fluorouridine, arabinose One or more of cytidine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin, and gemcitabine.
  • the immunotherapeutic agent can be selected from, but not limited to, anti-tumor vaccines (eg, synthetic peptides, DNA vaccines, and recombinant viruses), oncolytic viruses, immunostimulatory antibodies, novel adjuvants, cytokine treatments (eg, IL2 and GM- One or more of CSF), chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulator, tumor microenvironmental modulator, and anti-angiogenic factor.
  • anti-tumor vaccines eg, synthetic peptides, DNA vaccines, and recombinant viruses
  • oncolytic viruses immunostimulatory antibodies
  • novel adjuvants eg, IL2 and GM- One or more of CSF
  • CAR-T chimeric antigen receptor T cell therapy
  • small molecule immunomodulator eg, tumor microenvironmental modulator, and anti-angiogenic factor.
  • the immunostimulatory antibodies can include, but are not limited to, 1) protein antagonists that inhibit T cell activity (eg, immunological checkpoint inhibitors): CTLA4 (eg, ipilimumab and tremelimumab), PD-1 (eg, pembrolizumab and nivolumab) ), PD-L1 (eg durvalumab, avelumab and atezolizumab), LAG3 And one or more of TIM3; 1) a protein agonist that stimulates T cell activity: one or more of GITR, OX40, OX40L, 4-1BB (CD137), CD27, and CD40.
  • CTLA4 eg, ipilimumab and tremelimumab
  • PD-1 eg, pembrolizumab and nivolumab
  • PD-L1 eg durvalumab, avelumab and atezolizumab
  • the signal transduction pathway inhibitor may be selected from, but not limited to, a BCR/ABL kinase inhibitor, an epidermal growth factor receptor inhibitor, a her-2/neu receptor inhibitor, an AKT family kinase inhibitor, PI3K Signal pathway inhibitors, and cell cycle checkpoint inhibitors.
  • the angiogenesis inhibitor can be selected from, but not limited to, one or more of a VEGF/VEGFR signaling pathway inhibitor, a Src family kinase inhibitor, a Src signaling pathway inhibitor, and a c-Fes kinase inhibitor.
  • the viral infection may include: from influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, chickenpox - Infections caused by viruses such as herpes zoster virus, Coxsackie virus, or human immunodeficiency virus (HIV).
  • HCV hepatitis C virus
  • HPV human papillomavirus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • poliovirus chickenpox - Infections caused by viruses such as herpes zoster virus, Coxsackie virus, or human immunodeficiency virus (HIV).
  • the cancer may include, but is not limited to, bone cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, One or more of head and neck cancer, lymphoma, leukemia and skin cancer.
  • the autoimmune diseases may include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (MCTD), systemic scleroderma (including: CREST syndrome), dermatomyositis, knot Segmental vasculitis, nephropathy (including: pulmonary hemorrhagic nephritis syndrome, acute glomerulonephritis, primary membrane proliferative glomerulonephritis, etc.), endocrine-related diseases (including: type I diabetes, gonadal insufficiency, malignancy) Anemia (including anemia, hyperthyroidism, etc.), liver disease (including: primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.) and autoimmune reactions due to infection (eg One or more of AIDS, malaria, etc.
  • MCTD mixed connective tissue disease
  • the present invention also provides a polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition
  • a method of inhibiting tryptophan degradation in a system comprising the steps of inhibiting degradation of tryptophan in a mammal by administering to a mammal a therapeutically effective amount of a compound of formula (I); said system being IDO-expressing Tissue, mammal or cell tissue.
  • Said mammal preferably a human.
  • substituent name is not preceded by the definition of "substituted or unsubstituted”, and is meant to mean unsubstituted, for example, "alkyl” means unsubstituted alkyl, “cycloalkyl” "" means an unsubstituted cycloalkyl group.
  • substituted at one position by one or more groups means that any one or more of the hydrogen atoms of one or more atoms specified on the group are represented by the specified group. Substituted, provided that the normal valence of the specified atom is not exceeded, the substitutions are all reasonable substitutions that are common in the art. For example, substitution of 1 to 3 groups at any position means that one, two or three identical or different substituents may be reasonably substituted at any position.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, and representative examples of alkyl groups include, but are not limited to, : methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, 4, 4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof.
  • cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) containing from 3 to 20 carbon atoms. Monocyclic or polycyclic groups. "monocyclic cycloalkyl” is preferably a 3-10 membered monocycloalkyl group, more preferably a 5-8 membered monocycloalkyl group, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring Octyl, cyclodecyl, cyclododecyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “fused cycloalkyl” and “spirocycloalkyl", and “fused cycloalkyl” includes a monocyclic ring fused to an aryl, cycloalkyl, or heteroaryl group.
  • Alkyl rings, fused bicyclic cycloalkyl groups include, but are not limited to, benzocyclobutene, 2,3-dihydro-1-H-indole, 2,3-cyclopentenopyridine, 5,6-dihydro -4H-cyclopentyl [B] thiophene, decalin, and the like.
  • “Spirocycloalkyl” refers to a bicyclic group formed by the sharing of one carbon atom by two cycloalkyl groups, including but not limited to: spiro[2.4]heptyl, spiro[4.5]decane, and the like.
  • a monocyclic cycloalkyl or bicyclic cycloalkyl group can be attached to the parent molecule through any carbon atom on the ring.
  • heterocycloalkyl refers to a 3-20 membered non-aromatic cyclic group consisting of a carbon atom and a saturated or partially unsaturated (containing 1 or 2 double bonds) consisting of a hetero atom selected from nitrogen, oxygen or sulfur.
  • the cyclic group may be a monocyclic or bicyclic group.
  • the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and a nitrogen, carbon or sulfur atom in the heterocycloalkyl group. It can optionally be oxidized.
  • the nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl group” is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 5-8 membered monocyclic heterocycloalkyl group.
  • monocyclic heterocycloalkyl group is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 5-8 membered monocyclic heterocycloalkyl group.
  • aziridine tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholine-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl and the like.
  • Polycycloheterocycloalkyl includes “fused heterocycloalkyl” and “spiroheterocyclyl”.
  • “Fused heterocycloalkyl” includes a monocyclic heterocycloalkyl ring fused to a phenyl, heterocycloalkyl, cycloalkyl or heteroaryl group, including but not limited to: 2,3 - dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indanyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolinyl, Wait.
  • Spiroheterocyclyl means a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing one carbon atom, and spiroheterocyclyl groups include, but are not limited to: Wait.
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be attached to the parent molecule through any ring atom on the ring.
  • the above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group.
  • cycloalkylalkyl embraces the definitions of alkyl and cycloalkyl as described above.
  • heterocycloalkylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heterocycloalkylalkyl embraces the definitions of alkyl and heterocycloalkyl as described above.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group.
  • alkoxy includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • alkylthio means that a cyclic or acyclic alkyl group is bonded to each other through a sulfur atom and a parent molecule, and includes an alkyl fluorenyl group, a cycloalkyl fluorenyl group, and a heterocycloalkyl fluorenyl group.
  • alkylthio embraces the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • hydroxyalkyl refers to an alkyl arbitrary one hydrogen atom is substituted with a hydroxyl group, including but not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C (CH 3) 2 OH.
  • alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C 2-4 alkenyl means having 2-4 carbon atoms, an alkenyl group
  • C 2-6 alkenyl means an alkenyl radical having 2-6 carbon atoms, include ethenyl, propenyl , butenyl, 2-methylbutenyl and cyclohexenyl.
  • the alkenyl group may be substituted.
  • alkynyl refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, and includes ethynyl, propynyl, butynyl and 3-methylbutynyl.
  • aryl refers to any stable 6-10 membered monocyclic or bicyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl.
  • heteroaryl refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-12 A bicyclic structure, preferably a 5-6 membered heteroaryl group.
  • the number of heteroatoms is preferably 1, 2 or 3, including but not limited to: pyridyl, pyrimidinyl, pyridazine-3(2H)-one, furyl, thienyl, thiazolyl, pyrrolyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1 , 2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolyl, isodecyl, benzofuranyl, benzothienyl, benzo[d][1 , 3] dioxolane, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolinyl and the like.
  • cyclo-heteroaryl refers to a group formed by a monocyclic heteroaryl group and a group selected from a monocyclic heteroaryl group or a monocyclic aryl group sharing two adjacent ring atoms, said "co-ring"
  • a heteroaryl group is a bicyclic group.
  • the cycloheteroaryl group is preferably a 8-12 membered bicyclic group including, but not limited to, carbazolyl, isoxazolyl, indolyl, isodecyl, benzofuranyl, benzothienyl, Benzothiazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 4-aza Sulfhydryl, 5-azaindolyl, 2-azaindolyl, 6-azaindolyl, 7-azaindolyl, 1H-pyrrolo[2,3-B]pyridinyl, 4-Azacarbazolyl, 7-azacarbazolyl, 6-azacarbazolyl, 1H-pyrazolo[3,4-C]pyridine, and the like.
  • arylalkyl refers to an alkyl linkage between the aryl group and the parent core structure.
  • arylalkyl embraces the definition of alkyl and aryl as defined above.
  • heteroarylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heteroarylalkyl embraces the definitions of alkyl and heteroaryl as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group optionally substituted by halogen.
  • haloalkyl embraces the definitions of the above halo and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted by halogen.
  • haloalkoxy includes the definitions of the above halo and alkoxy.
  • amino means -NH 2
  • alkylamino refers to at least one amino hydrogen atoms are substituted by alkyl groups, including but not limited to: -NHCH 2, -NHCH 2 CH 3 .
  • aminoalkyl means that any one of the hydrogen atoms on the alkyl group is replaced by an amino group, including but not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 .
  • alkylamino and aminoalkyl embrace the definitions of alkyl and amino groups described above.
  • alkylene refers to an alkyl, alkenyl or alkynyl group which may serve as a linking bond to the other two groups, which may be straight chain as well. It may be a branched structure such as -(CH 2 ) q -; the alkenylene or alkynylene group may be a branched, straight chain or cyclic structure.
  • Root temperature as used herein means 15-30 °C.
  • the isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms.
  • prodrug is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.
  • “Pharmaceutically acceptable salts” as described herein are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.
  • the compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,
  • the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • “isomer” means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention.
  • a compound of the formula I or a salt thereof, in stereoisomeric form is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention.
  • the invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted.
  • the scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures.
  • the invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers.
  • the invention includes all combinations and subsets of stereoisomers of all the specific groups defined above.
  • the invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.
  • the reagents and starting materials used in the present invention are commercially available.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • All of the compounds of the present invention can be separated by high performance liquid chromatography, silica gel column chromatography, thin layer silica gel plates, flash separators or by supercritical fluid chromatography (SFC).
  • SFC supercritical fluid chromatography
  • Flash column chromatography Flash system / Cheetah TM
  • Agela Technologies MP200 supporting the use of a separation column for Flash columm Silica-CS (80g) , Cat No.CS140080-0.
  • High performance liquid chromatography was carried out using Shimadzu LC-20 preparative liquid chromatography at a detection wavelength of 214 nm & 254 nm; flow rate: 9.0 mL / min.
  • the column is: waters xbridge Pre C18, 10um, 19mm x 260mm.
  • Elution conditions (acidic conditions): Condition 1: 30 to 65% mobile phase A and 70 to 35% mobile phase B; Condition 2: 40 to 60% mobile phase A and 60 to 40% mobile phase B; Condition 10: 80 ⁇ 40% mobile phase A and 20-60% mobile phase B; Condition 11: 15-30% mobile phase A and 85-70% mobile phase B; mobile phase A: 0.05% aqueous trifluoroacetic acid solution (percentage percent by volume) , mobile phase B: acetonitrile.
  • Elution conditions (basic conditions): Condition 3: 65 to 70% mobile phase A and 35 to 30% mobile phase B; Condition 4: 30 to 55% mobile phase A and 70 to 45% mobile phase B; Condition 5: 30-65% mobile phase A and 70-35% mobile phase B; Condition 6: 40-70% mobile phase A and 60-30% mobile phase B; Condition 7: 45-75% mobile phase A and 55-25% Mobile phase B; Condition 8: 70 to 25% mobile phase A and 30 to 75% mobile phase B; Condition 9: 70 to 30% mobile phase A and 30 to 70% mobile phase B; Condition 12: 30 to 45% flow Phase A and 70-55% mobile phase B; Condition 13: 20-40% mobile phase A and 80-60% mobile phase B; Condition 14: 20-35% mobile phase A and 80-65% mobile phase B; conditions 15:25-40% mobile phase A and 75-60% mobile phase B; Condition 16: 65-35% mobile phase A and 35-65% mobile phase B; Condition 17: 25-65% mobile phase A and 75 ⁇ 35% mobile phase B; Condition 18: 15 to 35% mobile phase A and 85 to 65% mobile phase B; Condition
  • Supercritical fluid chromatography used SFC-80 (Thar, Waters) at a flow rate of 80 g/min and a column temperature of 35 °C.
  • the detection wavelength is 214.
  • the chiral analysis was performed using a supercritical fluid chromatography analyzer SFC Method Station (Thar, Waters) at a flow rate of 4.0 mL/min, a column temperature of 35 ° C, and a detection wavelength of 214.
  • the thin layer silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
  • Step 3 Synthesis of Compound 1.3
  • Step 1 Synthesis of Compounds 2.1a and 2.1b:
  • Step 2 Synthesis of compounds 2.2a and 2.2b
  • N-phenylbis(trifluoromethanesulfonimide) (8.2 g, 23.1 mmol) of methyl tert-butyl ether (75 mL)
  • a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran 2.0 M, 11.5 mL, 23.1 mmol
  • EtOAc EtOAc
  • Step 1 Synthesis of Compound 7.1
  • Methyl cinnamate (1.0 g, 6.1 mmol) and p-toluenesulfonylmethyl isocyanide (TosMIC) (1.31 g, 6.71 mmol) were dissolved in tetrahydrofuran and dimethyl sulfoxide (25 mL, 4: In a mixed solution of 1), a suspension of sodium hydrogen (60%, 370 mg, 9.15 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture. After the completion of the dropwise addition, the reaction system was heated to 80 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, and then the mixture was evaporated. The combined organic layers were washed with brine brine and evaporated The residue was purified by silica gel chromatography chromatography elut elut elut elut elut elut elut
  • the methyl cinnamate in step 2 is replaced by the corresponding substituted methyl cinnamate, the substituted ethyl cinnamate or the substituted tert-butyl cinnamate to obtain the compound 8.3 to 8.31:
  • compound 8.33 was synthesized using 3-hydroxycinnamic acid as a starting material:
  • Step 1 Synthesis of Compound 10.1
  • the compound 10.1 (850 mg, 3.9 mmol) was added to a mixed solvent of anhydrous tetrahydrofuran (15 mL), ethanol (2 mL) and water (2 mL), and the mixture was stirred at 80 ° C for 12 hours, concentrated under reduced pressure, with hydrochloric acid (1.0 M) The pH was adjusted to 5 to 6. The solid was filtered, and the filter cake was dried to give Compound 10.2 (520 mg, yield: 71%) as a white solid.
  • Acetyl chloride (1.3 g, 16.5 mmol) was added dropwise to a solution of aminoacetaldehyde diethyl acetal (2 g, 15.0 mmol) and triethylamine (2.13 g, 21.0 mmol) in ethyl acetate (30 mL). .
  • the reaction mixture was stirred at room temperature for 1 hour, then ethanol (0.3 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr. reaction.
  • Step 1 Synthesis of ethyl 3-(pyridin-3-yl)acrylate
  • the compound 200.3 is reacted with 1-bromo-3-methyl-2-butanone and ethyl benzoylacetate or ethyl 2-cyanobenzoylacetate to give the compound 20.17 to 20.18:
  • the compound 20.20 was obtained by the reaction of the compound 20.3 by the reaction of methyl 2-cyano-6-methoxybenzoylacetate.
  • Compound 20.20 160 mg, 0.59 mmol
  • sodium hydroxide 47 mg, 1.18 mmol
  • the reaction mixture was adjusted to pH 2-3 with hydrochloric acid (1.0M), ethyl acetate (20 mL ⁇ 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture of compound 20.21. (95 mg, yield: 59%) was obtained as a white solid.
  • Compound 4-1 (187 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 4-1a (20 mg, peak time: 18.5 to 20.0 minutes, single stereo configuration) and 4-1b ( 12 mg, peak time: 16.3 to 18.0 minutes, single stereo configuration), all white solids.
  • Compound 4-2 (187 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 4-2a (28 mg, peak time: 17.0 to 18.5 minutes, single stereo configuration) and 4-2b ( 16 mg, peak time: 18.7 to 19.0 minutes, single stereo configuration), all white solids.
  • the more polar compound 6-5b (2.6 mg, single stereo configuration) was a white solid.
  • the less polar compound 6-24b (26.5 mg, single stereo configuration) was a white solid.
  • the more polar compound, 6-32b (20.3 mg, single stereo configuration), was a white solid.
  • the less polar compound 6-44b (18.3 mg, single stereo configuration) was a white solid.
  • the configuration and the more polar compound 8-1b (40 mg, single stereo configuration) were both white solids.
  • the configuration and the more polar compound 8-2b (14 mg, single stereo configuration) were all white solids.
  • the compound 8-21a-8-23a was synthesized by the synthesis method of the compound 6-38a using the compound 8-13a, 8-12a or 8-16a as a starting material:
  • the more polar compound 9-1b (3.5 mg, single stereo configuration) was a white solid.
  • the configuration and the less polar compound 13-11b (23 mg, single stereo configuration) were both white solids.
  • Compound 14-12 (213 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 14-12a (30 mg, peak time: 15.5 to 16.0 min, single stereo configuration) and 14-12b (40 mg, peak time: 16.2 to 16.6 minutes, single stereo configuration), all white-like solids.

Abstract

Provided are a polycyclic compound and a manufacturing method, pharmaceutical composition, and application thereof. The structure of the polycyclic compound and an isomer, prodrug, solvate, hydrate, stable isotopic derivative, or pharmaceutically acceptable salt thereof are represented by formula (I). The polycyclic compound has an excellent inhibitory effect against ID01, and can effectively treat, mitigate and/or prevent various diseases caused by immunosuppression, including an autoimmune disease caused by a tumor or viral infection.

Description

多环化合物、其制备方法、药物组合物及应用Polycyclic compound, preparation method thereof, pharmaceutical composition and application thereof 技术领域Technical field
本发明涉及一种多环化合物、其制备方法、药物组合物及应用。The present invention relates to a polycyclic compound, a process for its preparation, a pharmaceutical composition and use.
背景技术Background technique
吲哚胺2,3-双加氧酶(IDO)是由一些替代性活化巨噬细胞和其它免疫调节细胞(也被许多肿瘤用来作为破坏免疫的策略)所产生的免疫调节酶，在人类中是由IDO基因编码。它的作用是分解必需L-色氨酸到犬尿氨酸(kynurenine)。色氨酸的耗竭以及其代谢产物会导致对免疫反应的强烈抑制作用，造成T细胞的生长的停止，阻断T细胞的活化，诱导T细胞凋亡和增加调节性T细胞的生成。由色氨酸到犬尿氨酸代谢途径现已确立为固有免疫和适应性免疫的关键调节通路。Indoleamine 2,3-dioxygenase (IDO) is an immunomodulatory enzyme produced by some alternative activated macrophages and other immunoregulatory cells (also used by many tumors as a strategy to destroy immunity) in humans. The middle is encoded by the IDO gene. Its role is to break down the essential L-tryptophan to kynurenine. The depletion of tryptophan and its metabolites lead to a strong inhibition of the immune response, causing the cessation of T cell growth, blocking the activation of T cells, inducing T cell apoptosis and increasing the production of regulatory T cells. The metabolic pathway from tryptophan to kynurenine has now been established as a key regulatory pathway for innate and adaptive immunity.
大量的临床前研究表明这个免疫耐受途径在肿瘤免疫，自身免疫，感染，移植排斥，和过敏中都是激活的。癌细胞IDO的活性的增高现在被认为是癌的增值和转移的一个重要的因素。研究表明，IDO使得肿瘤特异性细胞毒性T淋巴细胞功能失活或不再能攻击病人的癌细胞，事实上，许多人类癌症，如前列腺癌，结肠直肠癌，胰腺癌，子宫颈癌，胃癌，卵巢癌，脑癌，肺癌等，都过量表达人类IDO。IDO的抑制可以逆转肿瘤对人体免疫功能的抑制，从而产生一种有效的抗肿瘤免疫反应。由于IDO抑制剂可以激活T细胞从而增强人体的免疫功能，IDO抑制剂对许多疾病都有治疗作用，包括肿瘤耐药性和排斥，慢性感染，HIV感染和艾滋病，自身免疫性疾病或病症，如类风湿性关节炎，免疫耐受和预防子宫内胎儿排斥。IDO的抑制剂也可以用于治疗神经或神经精神疾病或障碍，如抑郁症(Protula等人，2005，血液，106:238290；Munn等，1998年，科学281:11913)。A large number of preclinical studies have shown that this immune tolerance pathway is activated in tumor immunity, autoimmunity, infection, transplant rejection, and allergies. The increased activity of cancer cell IDO is now considered to be an important factor in the proliferation and metastasis of cancer. Studies have shown that IDO inactivates tumor-specific cytotoxic T lymphocytes or can no longer attack cancer cells in patients. In fact, many human cancers, such as prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, and gastric cancer, Ovarian cancer, brain cancer, lung cancer, etc., all overexpress human IDO. Inhibition of IDO can reverse the inhibition of tumor immune function, resulting in an effective anti-tumor immune response. Because IDO inhibitors can activate T cells to enhance the body's immune function, IDO inhibitors have therapeutic effects on many diseases, including tumor resistance and rejection, chronic infections, HIV infection and AIDS, autoimmune diseases or conditions, such as Rheumatoid arthritis, immune tolerance and prevention of fetal rejection in the uterus. Inhibitors of IDO can also be used to treat neurological or neuropsychiatric diseases or disorders, such as depression (Protula et al, 2005, Blood, 106: 238290; Munn et al, 1998, Science 281:11913).
大量临床前和临床研究表明，抑制IDO能够增强机体的免疫能力，并显著提高各种化学治疗药物的抗肿瘤药效和对其它免疫抑制所引起的疾病的疗效(C.J.D.Austin and L.M.Rendina,Drug Discovery Today 2014，1-9)。IDO-/-小鼠基因敲除是可行的，而且小鼠是健康的，这意味着IDO抑制可能不会造成严重的由作用机理产生的毒性。A large number of preclinical and clinical studies have shown that inhibition of IDO can enhance the body's immunity and significantly improve the anti-tumor efficacy of various chemotherapeutic drugs and the efficacy of other immunosuppressive diseases (CJDAustin and LMRendina, Drug Discovery Today 2014, 1-9). IDO-/- mouse knockout is feasible and the mice are healthy, which means that IDO inhibition may not cause serious toxicity by the mechanism of action.
目前正在开发的IDO小分子抑制剂来治疗和预防上述与IDO相关的疾病，例如，PCT专利申请WO99/29310公开了改变T细胞介导免疫的方法，包括通过给予一定量的1-甲基DL色氨酸或p-(3苯并呋喃基)-DL-丙氨酸来改变局部色氨酸和色氨酸代谢物的胞外浓度(Munn，1999年)。WO2004/0234623中公开了能够抑制吲哚胺2,3-双加氧酶(IDO)活性的化合物；美国专利申请2004/0234623公开了一种通过服用IDO抑制剂并结合其它治疗方式来治疗癌症或感染患者的方法。IDO small molecule inhibitors currently under development to treat and prevent the above-mentioned IDO-related diseases, for example, PCT Patent Application WO 99/29310 discloses a method of altering T cell-mediated immunity, including by administering a certain amount of 1-methyl DL. Tryptophan or p-(3 benzofuranyl)-DL-alanine alters the extracellular concentration of local tryptophan and tryptophan metabolites (Munn, 1999). Compounds capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) are disclosed in WO2004/0234623; U.S. Patent Application No. 2004/0234623 discloses the treatment of cancer by administering an IDO inhibitor in combination with other treatments or The method of infecting patients.
鉴于大量实验数据表明IDO抑制剂对免疫抑制、肿瘤抑制、慢性感染、病毒感染包括HIV感染、自身免疫性疾病或紊乱及宫内胎儿排斥反应等有良好的治疗和预防，因此，最好采用通过抑制IDO活性达到抑制色氨酸降解的治疗方法。当恶性肿瘤或HIV等病毒抑制T细胞时，IDO抑制剂可以用于增强T细胞的活性。此外，IDO化学已经研究得比较清楚，并且其x-光晶体结构也得到解析，这有助于更好地用基于结构的药物设计和药物的结构优化。IDO是目前用于治疗性干预的一个很有吸引力的靶标。 In view of the large number of experimental data indicating that IDO inhibitors have good treatment and prevention for immunosuppression, tumor suppression, chronic infection, viral infection including HIV infection, autoimmune diseases or disorders and intrauterine fetal rejection, it is best to adopt A method of inhibiting IDO activity to inhibit inhibition of tryptophan. When a malignant tumor or a virus such as HIV inhibits T cells, an IDO inhibitor can be used to enhance the activity of T cells. In addition, IDO chemistry has been well studied and its x-ray crystal structure has also been resolved, which has helped to better use structure-based drug design and structural optimization of drugs. IDO is currently a very attractive target for therapeutic intervention.
发明内容Summary of the invention
本发明所要解决的技术问题在于，提供了一种新型多环化合物、其制备方法、药物组合物及应用。本发明的多环化合物具有良好的IDO抑制作用，可以有效治疗、缓解和/或预防由于免疫抑制所引起的各种相关疾病，例如肿瘤、传染性疾病及自身免疫类疾病等。The technical problem to be solved by the present invention is to provide a novel polycyclic compound, a preparation method thereof, a pharmaceutical composition and use thereof. The polycyclic compound of the present invention has a good IDO inhibitory action, and can effectively treat, alleviate and/or prevent various related diseases caused by immunosuppression, such as tumors, infectious diseases, and autoimmune diseases.
尽管本发明公开的如式(I)所示的化合物的活性是通过抑制IDO表现出来的，但是其抑制IDO活性的机制尚未研究透彻，并且也不排除其具有抑制TDO(色氨酸2,3-双加氧酶)活性的可能性。因此，本发明中所有涉及“IDO抑制剂”均可包括以下含义：IDO抑制剂、TDO抑制剂、或IDO和TDO双抑制剂。Although the activity of the compound represented by the formula (I) disclosed in the present invention is manifested by inhibition of IDO, its mechanism of inhibiting IDO activity has not been thoroughly studied, and it is not excluded that it has inhibition of TDO (tryptophan 2, 3 - the possibility of dioxygenase activity. Thus, all references to "IDO inhibitors" in the present invention may include the following meanings: IDO inhibitors, TDO inhibitors, or dual inhibitors of IDO and TDO.
本发明提供了一种多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；The present invention provides a polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
Figure PCTCN2017095396-appb-000001
Figure PCTCN2017095396-appb-000001
其中，A环为苯环、或5-6元杂芳环；Wherein the ring A is a benzene ring or a 5-6 membered heteroaryl ring;
B环为5元杂芳环，并且A1、A2、A3和A4为如下任一组合：The B ring is a 5-membered heteroaryl ring, and A 1 , A 2 , A 3 and A 4 are any combination of the following:
1)A1为C、A2为NR4、O或S、A3为CR5、A4为CH或N；1) A 1 is C, A 2 is NR 4 , O or S, A 3 is CR 5 , and A 4 is CH or N;
2)A1为C、A2为CR5或N、A3为NR4、O或S、A4为CR5a或N；2) A 1 is C, A 2 is CR 5 or N, A 3 is NR 4 , O or S, and A 4 is CR 5a or N;
3)A1为C、A2为CH或N、A3为CR5、A4为NR4、O或S；3) A 1 is C, A 2 is CH or N, A 3 is CR 5 , and A 4 is NR 4 , O or S;
4)A1为N、A2为CR5或N、A3为CR5a或N、A4为N或CR5b；4) A 1 is N, A 2 is CR 5 or N, A 3 is CR 5a or N, and A 4 is N or CR 5b ;
5)A1为CR5、A2为C、A3为NR4、O或S、A4为NR4或CR5a；5) A 1 is CR 5 , A 2 is C, A 3 is NR 4 , O or S, and A 4 is NR 4 or CR 5a ;
6)A1为CR5、A2为C、A3为CR5a、A4为NR4、O或S；6) A 1 is CR 5 , A 2 is C, A 3 is CR 5a , and A 4 is NR 4 , O or S;
X1为连接键、-O-、-NR4-或-CR6R6a-；X 1 is a linkage, -O-, -NR 4 - or -CR 6 R 6a -;
X2为-C(O)-或-S(O)1-2-；X 2 is -C(O)- or -S(O) 1-2 -;
X3为连接键、-NR4-或-CR6R6a-；并且，当X1为-NR4-，X2为-C(O)-时，X3为-NR4-；X 3 is a linkage, -NR 4 - or -CR 6 R 6a -; and, when X 1 is -NR 4 -, X 2 is -C(O)-, X 3 is -NR 4 -;
Y为连接键或-(CR6R6a)p-；Y is a bond or -(CR 6 R 6a ) p -;
U和V分别独立地选自N或CR3；U and V are each independently selected from N or CR 3 ;
Z和W分别独立地选自CHR3、NR3、O、C(O)或S(O)2；Z and W are each independently selected from CHR 3 , NR 3 , O, C(O) or S(O) 2 ;
L为连接键、C2-6亚烯基、C2-6亚炔基或-(CR6R6a)m-；L is a linkage, C 2-6 alkenylene, C 2-6 alkynylene or -(CR 6 R 6a ) m -;
R1选自氢、卤素、羟基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C2-6炔基、C2-6烯基、-SH、-CN、-NO2、-ORb、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-NRbC(O)Ra、-N(Rb)C(O)ORb、-N(Rb)C(O)N(Rb)2、-NRbS(O)2Ra、-S(O)0-2Ra、-S(O)2N(Rb)2、芳基、环烷基、杂环烷基和杂芳基中的一种或多种；R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl, -SH, -CN, -NO 2 , -OR b , -OC(O)R a , -OC(O)OR b , -OC(O)N(R b ) 2 , -C(O)OR b , -C(O)R a , -C(O)N(R b ) 2 , -NR b C(O)R a , -N(R b )C(O)OR b , -N(R b )C(O)N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 0-2 R a , -S(O) 2 N(R b ) 2 , aryl, cycloalkyl, heterocycloalkyl and hetero One or more of aryl groups;
R2或R3分别独立地选自氢、-NO2、-CN、-OH、-NH2、-SH、-OR8、-OC(O)R8、-OC(O)NR7R8、-OC(O)OR8、-OP(O)(O-R7)2、-OS(O)2(OH)、-OS(O)1-2R8、-S(O)1-2OR8、-S(O)2NR7R8、-S(O)0-2R8、-S(O)2N(R7)C(O)NR7R8、-C(O)OR8、-C(O)R8、-C(O)N(OH)R8、-C(O)NR7R8、-NR7R8、-N(R7)C(O)OR8、-N(R7)C(O)N(R7)S(O)2R8、-N(R7)C(O)NR7R8、-N(R7)S(O)1-2R8、-N(R7)C(O)R8、 -N(R7)S(O)1-2NR7R8、-N(R7)C(O)R8、-N(R7)OR8、-N(R7)C(O)NR7R8、取代或未取代的烷基、取代或未取代的杂芳基、取代或未取代的环烷基、取代或未取代的杂环烷基或取代或未取代的芳基；当所述的R2或R3为取代的烷基、取代的环烷基、取代的杂环烷基、取代的芳基或取代的杂芳基时可被如下1～3个RA基团取代在任意位置：-OH、-SH、-CN、-NO2、-NH2、卤素、烷硫基、-C(O)N(Rb)2、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-N(Rb)2、-NRbC(O)Ra、-NRbC(O)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC(O)N(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0-2Ra、-S(O)2N(Rb)2、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的杂环烷基或取代或未取代的杂芳基；RA中，所述烷基、烷氧基、芳基、杂芳基、环烷基或杂环烷基被取代时，可进一步被1～3个选自卤素、羟基、氨基、C1-4烷基或卤代C1-3烷氧基的取代基取代在任意位置；R 2 or R 3 are each independently selected from the group consisting of hydrogen, -NO 2 , -CN, -OH, -NH 2 , -SH, -OR 8 , -OC(O)R 8 , -OC(O)NR 7 R 8 , -OC(O)OR 8 , -OP(O)(OR 7 ) 2 , -OS(O) 2 (OH), -OS(O) 1-2 R 8 , -S(O) 1-2 OR 8 , -S(O) 2 NR 7 R 8 , -S(O) 0-2 R 8 , -S(O) 2 N(R 7 )C(O)NR 7 R 8 , -C(O)OR 8, -C (O) R 8 , -C (O) N (OH) R 8, -C (O) NR 7 R 8, -NR 7 R 8, -N (R 7) C (O) OR 8 , -N(R 7 )C(O)N(R 7 )S(O) 2 R 8 , -N(R 7 )C(O)NR 7 R 8 , -N(R 7 )S(O) 1 -2 R 8 , -N(R 7 )C(O)R 8 , -N(R 7 )S(O) 1-2 NR 7 R 8 , -N(R 7 )C(O)R 8 ,- N(R 7 )OR 8 , -N(R 7 )C(O)NR 7 R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted heterocycloalkyl group or a substituted or unsubstituted aryl group; when said R 2 or R 3 is a substituted alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group or The substituted heteroaryl group may be substituted at any position by the following 1 to 3 R A groups: -OH, -SH, -CN, -NO 2 , -NH 2 , halogen, alkylthio, -C(O) N(R b ) 2 , -OC(O)R a , -OC(O)OR b , -OC(O)N(R b 2 , -C(O)OR b , -C(O)R a , -C(O)N(R b ) 2 , -N(R b ) 2 , -NR b C(O)R a ,- NR b C(O)R a , -NR b C(O)OR a , -NR b C(O)N(R b ) 2 , -NR b C(O)N(R b ) 2 , -NR b S(O) 2 R a , -NR b S(O) 2 N(R b ) 2 , -S(O) 0-2 R a , -S(O) 2 N(R b ) 2 , substituted or not a substituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group or a substituted or unsubstituted heteroaryl group; R A, the said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted, may be further substituted with 1 to 3 substituents selected from halo, hydroxy, amino, C 1- a substituent of a 4- alkyl or halogenated C 1-3 alkoxy group at any position;
R4为H、C1-6烷基或C3-8环烷基；R 4 is H, C 1-6 alkyl or C 3-8 cycloalkyl;
R5、R5a和R5b分别独立地选自H或C1-6烷基；R 5 , R 5a and R 5b are each independently selected from H or C 1-6 alkyl;
R6为氢、氘、卤素、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基，或取代或未取代的烷氧基；所述取代的烷基、取代的环烷基、取代的杂环烷基，或取代的烷氧基被如下一个或多个基团取代在任意位置：卤素、羟基、烷基、杂环烷基、环烷基、烷氧基、氨基、芳基、杂芳基、-SRa、-N(Rb)2、-S(O)2N(Rb)2、-NRbC(O)N(Rb)2、-NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C(O)ORb、-(CH2)mOH或-(CH2)mN(Rb)2；R 6 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted alkoxy; substituted An alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, or a substituted alkoxy group is substituted at any position by one or more of the following groups: halogen, hydroxy, alkyl, heterocycloalkyl, cycloalkyl , alkoxy, amino, aryl, heteroaryl, -SR a , -N(R b ) 2 , -S(O) 2 N(R b ) 2 , -NR b C(O)N(R b 2 , -NR b C(O)R a , -C(O)R a , -S(O) 0-2 R a , -C(O)OR b , -(CH 2 ) m OH or -( CH 2 ) m N(R b ) 2 ;
R6a为氢、氘、卤素、羟基、氨基、烷基、-SRa、-ORb、-N(Rb)2、-NRbS(O)2Ra、-S(O)2N(Rb)2、-(CH2)mS(O)0-2CH3、-OS(O)3H、-OP(O)(O-Rb)2、-OC(O)Ra、-OC(O)N(Rb)2、-C(O)N(Rb)2、-(CH2)mC(O)OH、-(CH2)mOH、-(CH2)mN(Rb)2或-(CH2)mC(O)N(Rb)2；R 6a is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, -SR a , -OR b , -N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 2 N (R b ) 2 , -(CH 2 ) m S(O) 0-2 CH 3 , -OS(O) 3 H, -OP(O)(OR b ) 2 , -OC(O)R a ,- OC(O)N(R b ) 2 , -C(O)N(R b ) 2 , -(CH 2 ) m C(O)OH, -(CH 2 ) m OH, -(CH 2 ) m N (R b ) 2 or -(CH 2 ) m C(O)N(R b ) 2 ;
或者，R6和R6a与它们共同连接的C原子一起形成3-8元单环环烷基；Alternatively, R 6 and R 6a together with the C atom to which they are attached form a 3-8 membered monocyclic cycloalkyl group;
R7或R8分别独立地选自氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、或取代或未取代的杂芳基烷基；当所述烷基、芳基、杂芳基、环烷基、杂环烷基、芳基烷基、杂芳基烷基、环烷基烷基或杂环烷基烷基被取代时，可进一步被1～3个选自卤素、羟基、氨基、C1-4烷基、或卤代C1-3烷氧基的取代基取代在任意位置；或者，R7和R8与它们共同连接的N原子一起形成3-8元的单杂环烷基；R 7 or R 8 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl When the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl group is substituted, It may be further substituted at any position by 1 to 3 substituents selected from a halogen, a hydroxyl group, an amino group, a C 1-4 alkyl group, or a halogenated C 1-3 alkoxy group; or, R 7 and R 8 are common thereto The linked N atoms together form a 3-8 membered monoheterocycloalkyl group;
Ra和Rb各自独立地选自氢、烷基、卤代烷基、环烷基、杂环烷基、芳基、杂芳基、杂环烷基烷基、环烷基烷基、芳基烷基、或杂芳基烷基，或者，两个Rb与它们共同连接的N原子一起形成3-8元的单环杂环烷基；R a and R b are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkylalkyl, cycloalkylalkyl, arylalkane Or a heteroarylalkyl group, or two R b together with the N atom to which they are attached together form a 3-8 membered monocyclic heterocycloalkyl group;
n、m和p分别独立地为1、2或3；n, m and p are independently 1, 2 or 3;
q和t分别独立地为0、1或2。q and t are independently 0, 1, or 2, respectively.
所述A环中，所述5-6元杂芳基优选为噻吩基、吡啶基或嘧啶基。In the A ring, the 5-6 membered heteroaryl group is preferably a thienyl group, a pyridyl group or a pyrimidinyl group.
所述R1优选为氢、卤素、羟基、巯基、氰基、C1-3烷氧基、C1-3烷硫基、C1-4烷基(例如，甲基、乙基、正丙基或异丙基)、卤代C1-3烷基(例如，三氟甲基、二氟甲基)和卤代C1-3烷氧基(例如，三氟甲氧基、二氟甲氧基)、-C(O)OH、-C(O)NH2、-S(O)2CH3中的一种或多 种。The R 1 is preferably hydrogen, halogen, hydroxy, decyl, cyano, C 1-3 alkoxy, C 1-3 alkylthio, C 1-4 alkyl (eg, methyl, ethyl, n-propyl) Or isopropyl), halo C 1-3 alkyl (eg, trifluoromethyl, difluoromethyl) and halo C 1-3 alkoxy (eg, trifluoromethoxy, difluoromethyl) One or more of oxy), -C(O)OH, -C(O)NH 2 , -S(O) 2 CH 3 .
所述R1更优选为：H、F、Cl、Br、-CH3、-CN、-OH、-OCH3、-OCF3、-OCHF2和-C(O)NH2中的一种或多种。More preferably, R 1 is one of H, F, Cl, Br, -CH 3 , -CN, -OH, -OCH 3 , -OCF 3 , -OCHF 2 and -C(O)NH 2 or A variety.
所述R4优选为H、甲基、乙基、异丙基或环丙基。The R 4 is preferably H, methyl, ethyl, isopropyl or cyclopropyl.
所述R5优选为H、甲基、乙基、正丙基或异丙基The R 5 is preferably H, methyl, ethyl, n-propyl or isopropyl
所述R5a优选为H、甲基、乙基、正丙基或异丙基。The R 5a is preferably H, methyl, ethyl, n-propyl or isopropyl.
所述R5b优选为H。The R 5b is preferably H.
所述X1、X3、Y或L中，所述R6优选为氢、氘、卤素、取代或未取代的C1-4烷基、取代或未取代的C3-8环烷基、取代或未取代的3-8元杂环烷基，或取代或未取代的C1-4烷氧基。In the X 1 , X 3 , Y or L, the R 6 is preferably hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, A substituted or unsubstituted 3-8 membered heterocycloalkyl group, or a substituted or unsubstituted C 1-4 alkoxy group.
R6中，所述取代的烷基、取代的环烷基、取代的杂环烷基，或取代的烷氧基被如下一个或多个基团取代在任意位置：卤素、羟基、烷基、杂环烷基、环烷基、烷氧基、氨基、芳基、杂芳基、-SRa、-N(Rb)2、-S(O)2N(Rb)2、-NRbC(O)N(Rb)2、-NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C(O)ORb、-(CH2)mOH或-(CH2)mN(Rb)2。In R 6 , the substituted alkyl group, substituted cycloalkyl group, substituted heterocycloalkyl group, or substituted alkoxy group is substituted at any position by one or more of the following groups: halogen, hydroxy, alkyl, Heterocycloalkyl, cycloalkyl, alkoxy, amino, aryl, heteroaryl, -SR a , -N(R b ) 2 , -S(O) 2 N(R b ) 2 , -NR b C (O) N (R b ) 2, -NR b C (O) R a, -C (O) R a, -S (O) 0-2 R a, -C (O) OR b, - ( CH 2 ) m OH or -(CH 2 ) m N(R b ) 2 .
所述X1、X3、Y或L中，所述R6a优选氢、氘、卤素、羟基、氨基、C1-4烷基、-SRa、-ORb、-N(Rb)2、-NRbS(O)2Ra、-S(O)2N(Rb)2、-(CH2)mS(O)0-2CH3、-OS(O)3H、-OP(O)(O-Rb)2、-OC(O)Ra、-OC(O)N(Rb)2、-C(O)N(Rb)2、-(CH2)mC(O)OH、-(CH2)mOH、-(CH2)mN(Rb)2或-(CH2)mC(O)N(Rb)2；或者，R6a和R6与它们共同连接的C原子一起形成3-8元单环环烷基。In the X 1 , X 3 , Y or L, the R 6a is preferably hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, -SR a , -OR b , -N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 2 N(R b ) 2 , -(CH 2 ) m S(O) 0-2 CH 3 , -OS(O) 3 H,- OP(O)(OR b ) 2 , -OC(O)R a , -OC(O)N(R b ) 2 , -C(O)N(R b ) 2 , -(CH 2 ) m C( O) OH, -(CH 2 ) m OH, -(CH 2 ) m N(R b ) 2 or -(CH 2 ) m C(O)N(R b ) 2 ; alternatively, R 6a and R 6 are The C atoms to which they are attached together form a 3-8 membered monocyclic cycloalkyl group.
所述R6或R6a更优选为H、-CH3、-CF3、-CH2CH3或F。More preferably, R 6 or R 6a is H, -CH 3 , -CF 3 , -CH 2 CH 3 or F.
所述X1优选为连接键。X 1 is preferably a linkage.
所述X2优选为-C(O)-、或-S(O)1-2-。The X 2 is preferably -C(O)-, or -S(O) 1-2 -.
所述X3优选为连接键、或-NH-。The X 3 is preferably a linkage, or -NH-.
所述X1、X2和X3优选为如下任一组合：The X 1 , X 2 and X 3 are preferably any combination of the following:
1)X1为连接键、X2为-C(O)-、X3为-NH-；1) X 1 is a linkage, X 2 is -C(O)-, and X 3 is -NH-;
2)X1为连接键、X2为-S(O)2-、X3为-NH-；2) X 1 is a linkage, X 2 is -S(O) 2 -, and X 3 is -NH-;
3)X1为-NH-、X2为-S(O)2-、X3为-NH-。3) X 1 is -NH-, X 2 is -S(O) 2 -, and X 3 is -NH-.
或4)X1为-NH-、X2为-C(O)-、X3为-NH-。Or 4) X 1 is -NH-, X 2 is -C(O)-, and X 3 is -NH-.
所述X1、X2和X3更优选为如下任一组合：X1为连接键、X2为-C(O)-、X3为-NH-。The X 1 , X 2 and X 3 are more preferably any combination of the following: X 1 is a linking bond, X 2 is -C(O)-, and X 3 is -NH-.
所述Y优选为连接键、-CH2-、-CH2CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C(CH3)2-、-CHF-或-CF2-。The Y is preferably a linkage, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -CHF- Or -CF 2 -.
所述L优选为连接键、-CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C(CH3)2-、-CHF-或-CF2-。The L is preferably a linkage, -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -CHF- or -CF 2 -.
所述L更优选为连接键或-O-。More preferably, L is a linkage or -O-.
R2或R3中，所述取代或未取代的烷基优选为取代或未取代的C1-4烷基，更优选为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的丙基、取代或未取代的异丙基；In R 2 or R 3 , the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group, more preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, or a substituted group. Or unsubstituted propyl, substituted or unsubstituted isopropyl;
R2或R3中，所述取代或未取代的芳基优选为取代或未取代的C6-10芳基，更优选为取代或未取代的苯基或取代或未取代的萘基；In R 2 or R 3 , the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted C 6-10 aryl group, more preferably a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group;
R2或R3中，所述取代或未取代的杂芳基优选为取代或未取代的5-10元杂芳基，更优选为取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的嘧啶基、取代或未取代的喹啉基或取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的吡嗪 基、取代或未取代的吡唑基、取代或未取代的吡咯基、取代或未取代的咪唑基、取代或未取代的三氮唑基、取代或未取代的四氮唑基；In R 2 or R 3 , the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-10 membered heteroaryl group, more preferably a substituted or unsubstituted pyridyl group, a substituted or unsubstituted N- group. Oxidized pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted quinolinyl or substituted or unsubstituted isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted Or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazazolyl, substituted or unsubstituted tetrazolyl;
R2或R3中，所述取代或未取代的环烷基优选为取代或未取代的C3-8环烷基，更优选为取代或未取代的C3-8单环环烷基；In R 2 or R 3 , the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group, more preferably a substituted or unsubstituted C 3-8 monocyclic cycloalkyl group;
R2或R3中，所述取代或未取代的杂环烷基优选为取代或未取代的5-8元杂环烷基，更优选为取代或未取代的5-8元单杂环烷基；In R 2 or R 3 , the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 5-8 membered heterocycloalkyl group, more preferably a substituted or unsubstituted 5-8 membered monoheterocycloalkane. base;
当所述的R2或R3为取代的烷基、取代的环烷基、取代的杂环烷基、取代的芳基、取代的杂芳基时可被如下1～3个RA基团取代在任意位置：-OH、-SH、-CN、-NO2、-NH2、卤素、烷硫基、-C(O)N(Rb)2、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-N(Rb)2、-NRbC(O)Ra、-NRbC(O)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC(O)N(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0-2Ra、-S(O)2N(Rb)2、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的杂环烷基、或取代或未取代的杂芳基。When the R 2 or R 3 is a substituted alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group or a substituted heteroaryl group, the following 1 to 3 R A groups may be used. Substitution at any position: -OH, -SH, -CN, -NO 2 , -NH 2 , halogen, alkylthio, -C(O)N(R b ) 2 , -OC(O)R a , -OC (O)OR b , -OC(O)N(R b ) 2 , -C(O)OR b , -C(O)R a , -C(O)N(R b ) 2 , -N(R b ) 2 , -NR b C(O)R a , -NR b C(O)R a , -NR b C(O)OR a , -NR b C(O)N(R b ) 2 , -NR b C (O) N (R b) 2, -NR b S (O) 2 R a, -NR b S (O) 2 N (R b) 2, -S (O) 0-2 R a, - S(O) 2 N(R b ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocycloalkyl, or substituted or unsubstituted heteroaryl.
R2或R3中，所述RA中，所述卤素优选为F、Cl、Br、I；更优选F或Cl；In R 2 or R 3 , in the R A , the halogen is preferably F, Cl, Br, I; more preferably F or Cl;
R2或R3中，所述RA中，所述取代或未取代的烷基优选为取代或未取代的C1-4烷基；更优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。In R 2 or R 3 , in the R A , the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group; more preferably a methyl group, an ethyl group, a n-propyl group or a different group. Propyl, n-butyl, isobutyl, tert-butyl.
R2或R3中，所述RA中，所述取代或未取代的烷氧基优选为取代或未取代的C1-4烷氧基；更优选为甲氧基、乙氧基。In R 2 or R 3 , in the R A , the substituted or unsubstituted alkoxy group is preferably a substituted or unsubstituted C 1-4 alkoxy group; more preferably a methoxy group or an ethoxy group.
R2或R3中，所述RA中，所述取代或未取代的烷硫基优选为取代或未取代的C1-4烷硫基；更优选为甲硫基、乙硫基。In R 2 or R 3 , in the R A , the substituted or unsubstituted alkylthio group is preferably a substituted or unsubstituted C 1-4 alkylthio group; more preferably a methylthio group or an ethylthio group.
R2或R3中，所述RA中，所述取代或未取代的芳基优选为取代或未取代的苯基。In R 2 or R 3 , in the R A , the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted phenyl group.
R2或R3中，所述RA中，所述取代或未取代的杂芳基优选为取代或未取代的5-6元杂芳基。In R 2 or R 3 , in the R A , the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-6 membered heteroaryl group.
R2或R3中，所述RA中，所述取代或未取代的环烷基优选为取代或未取代的C3-8环烷基。In R 2 or R 3 , in the R A , the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group.
R2或R3中，所述RA中，所述取代或未取代的杂环烷基优选为取代或未取代的5-8元杂环烷基。In R 2 or R 3 , in the R A , the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 5-8 membered heterocycloalkyl group.
R2或R3中，所述RA中，所述烷基、烷氧基、芳基、杂芳基、环烷基、或杂环烷基被取代时，可进一步被1-3个选自卤素、羟基、氨基、C1-3烷基、或卤代C1-3烷氧基的取代基取代在任意位置。In R 2 or R 3 , in the R A , when the alkyl group, the alkoxy group, the aryl group, the heteroaryl group, the cycloalkyl group or the heterocycloalkyl group is substituted, it may be further selected from 1 to 3 Substituents from a halogen, a hydroxyl group, an amino group, a C 1-3 alkyl group, or a halogenated C 1-3 alkoxy group are substituted at any position.
R2或R3中，所述R7或R8分别独立地优选为氢、取代或未取代的C1-6烷基、取代或未取代的C3-8环烷基、取代或未取代的3-8元杂环烷基、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的C3-8环烷基C1-3烷基、取代或未取代的3-8元杂环烷基C1-3烷基、取代或未取代的苯基C1-3烷基、或取代或未取代的5-6元杂芳基C1-3烷基；或者，R7和R8与它们共同连接的N原子一起形成3-8元的单杂环烷基。In R 2 or R 3 , R 7 or R 8 are each independently preferably hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted a 3-8 membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted C 3-8 cycloalkyl C 1-3 alkyl group, Substituted or unsubstituted 3-8 membered heterocycloalkyl C 1-3 alkyl, substituted or unsubstituted phenyl C 1-3 alkyl, or substituted or unsubstituted 5-6 membered heteroaryl C 1- 3 alkyl; or, R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered monoheterocycloalkyl group.
所述R7或R8中，当所述烷基、芳基、杂芳基、环烷基、杂环烷基、芳基烷基、杂芳基烷基、环烷基烷基或杂环烷基烷基被取代时，可进一步被1～3个选自卤素、羟基、氨基、C1-4烷基、或卤代C1-3烷氧基的取代基取代在任意位置。In the R 7 or R 8 , when the alkyl group, the aryl group, the heteroaryl group, the cycloalkyl group, the heterocycloalkyl group, the arylalkyl group, the heteroarylalkyl group, the cycloalkylalkyl group or the heterocyclic ring When the alkylalkyl group is substituted, it may be further substituted at any position by 1 to 3 substituents selected from a halogen, a hydroxyl group, an amino group, a C 1-4 alkyl group, or a halogenated C 1-3 alkoxy group.
所述R3更优选为氢、氟、羟基、氰基、C1-4烷基、或C1-3烷氧基。 More preferably, R 3 is hydrogen, fluorine, hydroxy, cyano, C 1-4 alkyl, or C 1-3 alkoxy.
所述R2更优选为取代或未取代的苯基、取代或未取代的5-10元杂芳基。More preferably, R 2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-10 membered heteroaryl group.
所述Ra和Rb各自独立地优选自氢、C1-4烷基、卤代C1-3烷基、C3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、3-8元杂环烷基C1-3烷基、C3-8环烷基C1-3烷基、苯基烷基、或5-6元杂芳基C1-3烷基，或者，两个Rb与它们共同连接的N原子一起形成3-8元的单环杂环烷基。The R a and R b are each independently preferably from hydrogen, C 1-4 alkyl, halo C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl C 1-3 alkyl, C 3-8 cycloalkyl C 1-3 alkyl, phenylalkyl, or 5-6 membered heteroaryl C 1-3 alkyl, or two R b together with the N atom to which they are attached form a 3-8 membered monocyclic heterocycloalkyl group.
所述Ra更优选为氢、甲基、乙基、正丙基、或异丙基。More preferably, R a is hydrogen, methyl, ethyl, n-propyl or isopropyl.
所述Rb更优选为氢、甲基、乙基、正丙基、或异丙基。More preferably, R b is hydrogen, methyl, ethyl, n-propyl or isopropyl.
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式优选为：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000002
Figure PCTCN2017095396-appb-000002
其中，A环、B环、R1、R2、A1～A4、X1～X3、L、Y、U、W、Z、V、q、t和n的定义如前所述。Here, the definitions of the A ring, the B ring, R 1 , R 2 , A 1 to A 4 , X 1 to X 3 , L, Y, U, W, Z, V, q, t and n are as described above.
以下各优选实施方案均包括在式(I-1)的定义中：The following preferred embodiments are all included in the definition of formula (I-1):
在一些优选实施方案中，所述A1～A4为以下任一组合：In some preferred embodiments, the A 1 -A 4 are any combination of the following:
1)A1为C、A2为NR4、O或S、A3为CR5、A4为CH或N；1) A 1 is C, A 2 is NR 4 , O or S, A 3 is CR 5 , and A 4 is CH or N;
2)A1为C、A2为CR5或N、A3为NR4、O或S、A4为CR5a或N；2) A 1 is C, A 2 is CR 5 or N, A 3 is NR 4 , O or S, and A 4 is CR 5a or N;
3)A1为C、A2为CH或N、A3为CR5、A4为NR4、O或S。3) A 1 is C, A 2 is CH or N, A 3 is CR 5 , and A 4 is NR 4 , O or S.
在一些优选实施方案中，所述A1～A4更为以下任一组合：In some preferred embodiments, the A 1 -A 4 are in any combination of the following:
1)A1为C、A2为NR4、A3为CR5、A4为CH或N；1) A 1 is C, A 2 is NR 4 , A 3 is CR 5 , and A 4 is CH or N;
2)A1为C、A2为CR5或N、A3为NR4、A4为CR5a或N；2) A 1 is C, A 2 is CR 5 or N, A 3 is NR 4 , and A 4 is CR 5a or N;
3)A1为C、A2为CH或N、A3为CR5、A4为NR4。3) A 1 is C, A 2 is CH or N, A 3 is CR 5 , and A 4 is NR 4 .
在一些优选实施方案中，所述B环
Figure PCTCN2017095396-appb-000003
为如下任一结构：In some preferred embodiments, the B ring
Figure PCTCN2017095396-appb-000003
Is any of the following structures:
Figure PCTCN2017095396-appb-000004
Figure PCTCN2017095396-appb-000005
Figure PCTCN2017095396-appb-000004
Figure PCTCN2017095396-appb-000005
在一些优选实施方案中，所述B环
Figure PCTCN2017095396-appb-000006
为如下任一结构；In some preferred embodiments, the B ring
Figure PCTCN2017095396-appb-000006
Is any of the following structures;
Figure PCTCN2017095396-appb-000007
Figure PCTCN2017095396-appb-000007
在一些优选实施方案中，X1为连接键、X2为-C(O)-、X3为-NH-。In some preferred embodiments, X 1 is a linkage, X 2 is -C(O)-, and X 3 is -NH-.
在一些优选实施方案中，Y为-CH2-。In some preferred embodiments, Y is -CH 2 -.
在一些优选实施方案中，Y为-CH2CH2-。In some preferred embodiments, Y is -CH 2 CH 2 -.
在一些优选实施方案中，Y为-CH(CH3)-。In some preferred embodiments, Y is -CH (CH 3) -.
在一些优选实施方案中，Y为-C(CH3)2-。In some preferred embodiments, Y is -C (CH 3) 2 -.
在一些优选实施方案中，t为1，q为1。In some preferred embodiments, t is 1 and q is 1.
在一些优选实施方案中，U为CR3，V为CH。In some preferred embodiments, U is CR 3 and V is CH.
在一些优选实施方案中，Z为CH2，W为CH2。In some preferred embodiments, Z is CH 2 and W is CH 2 .
在一些优选实施方案中，L为连接键。In some preferred embodiments, L is a linkage.
在一些优选实施方案中，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基(例如：甲基、乙基、异丙基)、C1-3烷氧基(例如：甲氧基、乙氧基)、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3中的一种或多种；In some preferred embodiments, R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl; The substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of: methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2 , -CN, and -S(O) 2 CH 3 ;
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式优选为：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000008
Figure PCTCN2017095396-appb-000008
A环、B环、R1、R2、A1～A4、X1～X3、L、Y、U、W、Z、V、q、t和n的定义如前所述。The definitions of the A ring, the B ring, R 1 , R 2 , A 1 to A 4 , X 1 to X 3 , L, Y, U, W, Z, V, q, t and n are as described above.
以下各优选实施方案均包括在式(I-2)的定义中：The following preferred embodiments are all included in the definition of formula (I-2):
在一些优选实施方案中，，所述B环
Figure PCTCN2017095396-appb-000009
优选为如下任一结构； In some preferred embodiments, the B ring
Figure PCTCN2017095396-appb-000009
Preferably, it is any of the following structures;
Figure PCTCN2017095396-appb-000010
Figure PCTCN2017095396-appb-000010
在一些优选实施方案中，X1为连接键、X2为-C(O)-、X3为-NH-。In some preferred embodiments, X 1 is a linkage, X 2 is -C(O)-, and X 3 is -NH-.
在一些优选实施方案中，Y为-CH2-。In some preferred embodiments, Y is -CH 2 -.
在一些优选实施方案中，Y为-CH2CH2-。In some preferred embodiments, Y is -CH 2 CH 2 -.
在一些优选实施方案中，t为1，q为1。In some preferred embodiments, t is 1 and q is 1.
在一些优选实施方案中，U为CH，V为CH。In some preferred embodiments, U is CH and V is CH.
在一些优选实施方案中，Z为CH2，W为CH2。In some preferred embodiments, Z is CH 2 and W is CH 2 .
在一些优选实施方案中，L为连接键。In some preferred embodiments, L is a linkage.
在一些优选实施方案中，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基(例如：甲基、乙基、异丙基)、C1-3烷氧基(例如：甲氧基、乙氧基)、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3中的一种或多种。In some preferred embodiments, R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl; The substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2 , -CN, and -S(O) 2 CH 3 .
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式较佳地为：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000011
Figure PCTCN2017095396-appb-000011
其中，W为N或CH；Where W is N or CH;
A2、A3和A4为以下组合：A 2 , A 3 and A 4 are the following combinations:
1)A2为CR5，A3为NR4，A4为N；1) A 2 is CR 5 , A 3 is NR 4 , and A 4 is N;
2)A2为N，A3为NR4，A4为CR5a；2) A 2 is N, A 3 is NR 4 , and A 4 is CR 5a ;
3)A2为CR5，A3为NR4，A4为CR5a；3) A 2 is CR 5 , A 3 is NR 4 , and A 4 is CR 5a ;
4)A2为N，A3为NR4，A4为N；4) A 2 is N, A 3 is NR 4 , and A 4 is N;
或5)A2为N，A3为O或S，A4为CH；Or 5) A 2 is N, A 3 is O or S, and A 4 is CH;
R1、R2、R4、R5、R5a、L、X1～X3、Y、U、V、q和n的定义前所述。The definitions of R 1 , R 2 , R 4 , R 5 , R 5a , L, X 1 to X 3 , Y, U, V, q and n are as described above.
以下各优选实施方案均包括在式(IA)的定义中：The following preferred embodiments are all included in the definition of formula (IA):
在一些优选实施方案中，A2为CR5，A3为NR4，A4为CR5a。In some preferred embodiments, A 2 is CR 5 , A 3 is NR 4 , and A 4 is CR 5a .
在一些优选实施方案中，X1为连接键、X2为-C(O)-、X3为-NH-。In some preferred embodiments, X 1 is a linkage, X 2 is -C(O)-, and X 3 is -NH-.
在一些优选实施方案中，Y为-CH2-。In some preferred embodiments, Y is -CH 2 -.
在一些优选实施方案中，Y为-CH2CH2-。In some preferred embodiments, Y is -CH 2 CH 2 -.
在一些优选实施方案中，Y为-CH(CH3)-。In some preferred embodiments, Y is -CH (CH 3) -.
在一些优选实施方案中，Y为-C(CH3)2-。 In some preferred embodiments, Y is -C (CH 3) 2 -.
在一些优选实施方案中，q为1。In some preferred embodiments, q is one.
在一些优选实施方案中，U为CR3，V为CH。In some preferred embodiments, U is CR 3 and V is CH.
在一些优选实施方案中，L为连接键。In some preferred embodiments, L is a linkage.
在一些优选实施方案中，R3为H或羟基。In some preferred embodiments, R 3 is H or hydroxy.
在一些优选实施方案中，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基(例如：甲基、乙基、异丙基)、C1-3烷氧基(例如：甲氧基、乙氧基)、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3中的一种或多种。In some preferred embodiments, R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl; The substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2 , -CN, and -S(O) 2 CH 3 .
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式较佳地为：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000012
Figure PCTCN2017095396-appb-000012
其中，其中，W为N或CH；R4为H或-CH3；R5为H、甲基、乙基或异丙基；R5a为H、甲基、乙基或异丙基；Wherein, W is N or CH; R 4 is H or -CH 3 ; R 5 is H, methyl, ethyl or isopropyl; R 5a is H, methyl, ethyl or isopropyl;
R1、R2、R3、L、Y和n的定义如前所述。The definitions of R 1 , R 2 , R 3 , L, Y and n are as described above.
以下各优选实施方案均包括在式(IB)的定义中：The following preferred embodiments are all included in the definition of formula (IB):
在一些优选实施方案中，Y为-CH2-。In some preferred embodiments, Y is -CH 2 -.
在一些优选实施方案中，Y为-CH2CH2-。In some preferred embodiments, Y is -CH 2 CH 2 -.
在一些优选实施方案中，Y为-CH(CH3)-。In some preferred embodiments, Y is -CH (CH 3) -.
在一些优选实施方案中，Y为-C(CH3)2-。In some preferred embodiments, Y is -C (CH 3) 2 -.
在一些优选实施方案中，L为连接键。In some preferred embodiments, L is a linkage.
在一些优选实施方案中，R3为H或羟基。In some preferred embodiments, R 3 is H or hydroxy.
在一些优选实施方案中，R5为H或甲基。In some preferred embodiments, R 5 is H or methyl.
在一些优选实施方案中，R5a为H或甲基。In some preferred embodiments, R 5a is H or methyl.
在一些优选实施方案中，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基(例如：甲基、乙基、异丙基)、C1-3烷氧基(例如：甲氧基、乙氧基)、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3中的一种或多种。In some preferred embodiments, R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl; The substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2 , -CN, and -S(O) 2 CH 3 .
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式较佳地为： The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000013
Figure PCTCN2017095396-appb-000013
其中，A2、A3和A4为以下组合：Among them, A 2 , A 3 and A 4 are the following combinations:
1)A2为NR4，A3为CR5，A4为CH；1) A 2 is NR 4 , A 3 is CR 5 , and A 4 is CH;
2)A2为NR4，A3为N，A4为CH；2) A 2 is NR 4 , A 3 is N, and A 4 is CH;
3)A2为S，A3为CH，A4为N；3) A 2 is S, A 3 is CH, and A 4 is N;
或4)A2为O，A3为CH，A4为N；Or 4) A 2 is O, A 3 is CH, and A 4 is N;
R1、R2、R4、R5、L、X1、X2、X3、Y、U、V、W、n和q的定义如前所述。The definitions of R 1 , R 2 , R 4 , R 5 , L, X 1 , X 2 , X 3 , Y, U, V, W, n and q are as described above.
以下各优选实施方案均包括在式(IC)的定义中：The following preferred embodiments are all included in the definition of formula (IC):
在一些优选实施方案中，X1为连接键、X2为-C(O)-、X3为-NH-。In some preferred embodiments, X 1 is a linkage, X 2 is -C(O)-, and X 3 is -NH-.
在一些优选实施方案中，Y为-CH2-。In some preferred embodiments, Y is -CH 2 -.
在一些优选实施方案中，Y为-CH2CH2-。In some preferred embodiments, Y is -CH 2 CH 2 -.
在一些优选实施方案中，Y为-CH(CH3)-。In some preferred embodiments, Y is -CH (CH 3) -.
在一些优选实施方案中，Y为-C(CH3)2-。In some preferred embodiments, Y is -C (CH 3) 2 -.
在一些优选实施方案中，q为1。In some preferred embodiments, q is one.
在一些优选实施方案中，U为CR3，V为CH，R3为H或羟基。In some preferred embodiments, U is CR 3 , V is CH, and R 3 is H or hydroxy.
在一些优选实施方案中，L为连接键。In some preferred embodiments, L is a linkage.
在一些优选实施方案中，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基(例如：甲基、乙基、异丙基)、C1-3烷氧基(例如：甲氧基、乙氧基)、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3中的一种或多种。In some preferred embodiments, R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl; The substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2 , -CN, and -S(O) 2 CH 3 .
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式较佳地为：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000014
Figure PCTCN2017095396-appb-000014
其中，W为N或CH；Where W is N or CH;
R1、R2、R3、R5、L、Y和n的定义如前所述。The definitions of R 1 , R 2 , R 3 , R 5 , L, Y and n are as described above.
以下各优选实施方案均包括在式(ID)的定义中：The following preferred embodiments are included in the definition of formula (ID):
在一些优选实施方案中，Y为-CH2-。In some preferred embodiments, Y is -CH 2 -.
在一些优选实施方案中，Y为-CH(CH3)-。In some preferred embodiments, Y is -CH (CH 3) -.
在一些优选实施方案中，Y为-C(CH3)2-。 In some preferred embodiments, Y is -C (CH 3) 2 -.
在一些优选实施方案中，L为连接键。In some preferred embodiments, L is a linkage.
在一些优选实施方案中，R3为H或羟基。In some preferred embodiments, R 3 is H or hydroxy.
在一些优选实施方案中，R5为H、甲基、乙基、或异丙基。In some preferred embodiments, R 5 is H, methyl, ethyl, or isopropyl.
在一些优选实施方案中，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基(例如：甲基、乙基、异丙基)、C1-3烷氧基(例如：甲氧基、乙氧基)、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3中的一种或多种。In some preferred embodiments, R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl; The substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2 , -CN, and -S(O) 2 CH 3 .
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式较佳地为：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000015
Figure PCTCN2017095396-appb-000015
其中，A2、A3和A4为以下组合：Among them, A 2 , A 3 and A 4 are the following combinations:
1)A2为CH，A3为CH，A4为NR4；1) A 2 is CH, A 3 is CH, and A 4 is NR 4 ;
2)A2为CH，A3为N，A4为CH；2) A 2 is CH, A 3 is N, and A 4 is CH;
3)A2为N，A3为CH，A4为CH；3) A 2 is N, A 3 is CH, and A 4 is CH;
4)A2为N，A3为N，A4为CH；4) A 2 is N, A 3 is N, and A 4 is CH;
或5)A2为N，A3为N，A4为NR4；Or 5) A 2 is N, A 3 is N, and A 4 is NR 4 ;
R1、R2、L、X、Y、U、V和W的定义如前所述。The definitions of R 1 , R 2 , L, X, Y, U, V and W are as described above.
所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其结构通式较佳地为：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
Figure PCTCN2017095396-appb-000016
Figure PCTCN2017095396-appb-000016
其中，A环、R1、R2、L、X1、X2、X3、Y、A1、A2、A3、A4和n的定义前所述。Herein, the definitions of the A ring, R 1 , R 2 , L, X 1 , X 2 , X 3 , Y, A 1 , A 2 , A 3 , A 4 and n are as described above.
所述多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐最佳地为如下任一结构：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
Figure PCTCN2017095396-appb-000017
Figure PCTCN2017095396-appb-000017
Figure PCTCN2017095396-appb-000018
Figure PCTCN2017095396-appb-000018
Figure PCTCN2017095396-appb-000019
Figure PCTCN2017095396-appb-000019
Figure PCTCN2017095396-appb-000020
Figure PCTCN2017095396-appb-000020
Figure PCTCN2017095396-appb-000021
Figure PCTCN2017095396-appb-000021
Figure PCTCN2017095396-appb-000022
Figure PCTCN2017095396-appb-000022
Figure PCTCN2017095396-appb-000023
Figure PCTCN2017095396-appb-000023
Figure PCTCN2017095396-appb-000024
Figure PCTCN2017095396-appb-000024
Figure PCTCN2017095396-appb-000025
Figure PCTCN2017095396-appb-000025
Figure PCTCN2017095396-appb-000026
Figure PCTCN2017095396-appb-000026
Figure PCTCN2017095396-appb-000027
Figure PCTCN2017095396-appb-000027
Figure PCTCN2017095396-appb-000028
Figure PCTCN2017095396-appb-000028
Figure PCTCN2017095396-appb-000029
Figure PCTCN2017095396-appb-000029
Figure PCTCN2017095396-appb-000030
Figure PCTCN2017095396-appb-000030
Figure PCTCN2017095396-appb-000031
Figure PCTCN2017095396-appb-000032
Figure PCTCN2017095396-appb-000031
Figure PCTCN2017095396-appb-000032
本发明还提供了所述多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐的制备方法，其为如下任一方法：The present invention also provides a process for the preparation of the polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, which is any of the following methods:
方法1：method 1:
Figure PCTCN2017095396-appb-000033
Figure PCTCN2017095396-appb-000033
式I-a所示化合物可通过方法1所示的反应式1得到，其中，A环、B环、R1、R2、L、X1、A1、A2、A3、A4、U、V和n定义如上所述。The compound of the formula Ia can be obtained by the reaction formula 1 shown in the method 1, wherein the ring A, the ring B, the R 1 , the R 2 , the L, the X 1 , the A 1 , the A 2 , the A 3 , the A 4 , the U, V and n are defined as described above.
方法1包括如下步骤：将1a和1b所示化合物在碱性条件下通过缩合反应得到I-a所示化合物，缩合反应的条件和步骤可为本领域常规的缩合反应的条件和步骤，本发明特别优选以下反应条件：溶剂优选二氯甲烷，所述的缩合剂优选1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)；所述的碱优选N,N-二异丙基乙胺(DIPEA)或三乙胺(TEA)，反应温度优选0℃～室温，为加快反应速度，还可以向反应体系中加入催化量的4-二甲氨基吡啶。The method 1 comprises the steps of: subjecting the compound represented by 1a and 1b to a compound represented by Ia under a basic condition, and the conditions and steps of the condensation reaction may be the conditions and steps of a conventional condensation reaction in the art, and the present invention is particularly preferred. The following reaction conditions: the solvent is preferably dichloromethane, and the condensing agent is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI); the base is preferably N, N-diisopropylethylamine (DIPEA) or triethylamine (TEA), the reaction temperature is preferably 0 ° C to room temperature, in order to accelerate the reaction rate, a catalytic amount of 4-dimethylaminopyridine can also be added to the reaction system.
方法2：Method 2:
Figure PCTCN2017095396-appb-000034
Figure PCTCN2017095396-appb-000034
式Ib所示化合物可通过方法2所示的反应式2得到，其中，A环、B环、R1、R2、L、X1、A1、A2、A3、A4、U、V和n定义如上所述。The compound of the formula Ib can be obtained by the reaction formula 2 shown in the method 2, wherein the ring A, the ring B, the R 1 , the R 2 , the L, the X 1 , the A 1 , the A 2 , the A 3 , the A 4 , the U, V and n are defined as described above.
方法2包括如下步骤：将2a和1b所示化合物在碱性条件下通过亲核取代反应得到I-b所示化合物，反应的条件和步骤可为本领域常规的条件和步骤，本发明特别优选以下反应条件：溶剂优选二氯甲烷(DCM)；所述的碱优选N,N-二异丙基乙胺(DIPEA)或三乙胺(TEA)，一般情况下为了催化反应进程，可在反应体系中添加催化量的4-二甲氨基吡啶，反应温度优选0℃～室温。The method 2 comprises the steps of: obtaining a compound represented by Ib by nucleophilic substitution reaction under basic conditions, and the conditions and steps of the reaction may be conventional conditions and steps in the art, and the following reactions are particularly preferred in the present invention. Condition: the solvent is preferably dichloromethane (DCM); the base is preferably N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA), in general, in order to catalyze the progress of the reaction, in the reaction system A catalytic amount of 4-dimethylaminopyridine is added, and the reaction temperature is preferably from 0 ° C to room temperature.
在上述方法1～2中，在如式1a、1b、或2a所示化合物中存在其它氨基基团或羟基基团时，该氨基基团或羟基基团均应通过保护基保护，才能避免有副反应。如果存在上述氨基保护基团或羟基保护基团则需要在后续的脱保护步骤后，得到如式Ia、或Ib所示化合物。任何合适的氨基保护基团，例如：叔丁氧羰基(Boc)基团，均可以用于保护氨基基团。如果使用Boc作为保护基，后续的脱保护反应可以在标准条件，例如，对甲苯磺酸/甲醇体系，二氯甲烷/三氟乙酸体系、饱和的氯化氢乙醚溶液、或三氟甲磺酸三甲基硅酯/2,6-二甲基吡啶/二氯甲烷体系中进行；任何合适的羟基保护基团，例如：苄基，均可以用于保护氨基基团，后续的脱保护反应可以在标准条件，例如，钯碳/氢气。 In the above methods 1 and 2, when other amino groups or hydroxyl groups are present in the compound represented by Formula 1a, 1b, or 2a, the amino group or the hydroxyl group should be protected by a protecting group to avoid side effects. If the above amino protecting group or hydroxy protecting group is present, it is necessary to obtain a compound of formula Ia or Ib after the subsequent deprotection step. Any suitable amino protecting group, for example, a tert-butoxycarbonyl (Boc) group, can be used to protect the amino group. If Boc is used as a protecting group, subsequent deprotection reactions can be carried out under standard conditions, for example, p-toluenesulfonic acid/methanol system, dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonate The silyl ester / 2,6-dimethylpyridine / dichloromethane system; any suitable hydroxy protecting group, such as benzyl, can be used to protect the amino group, the subsequent deprotection can be in the standard Conditions, for example, palladium carbon/hydrogen.
所述多环化合物(I)的药学上可接受的盐可通过一般的化学方法合成。The pharmaceutically acceptable salt of the polycyclic compound (I) can be synthesized by a general chemical method.
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。In general, the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
本发明还提供了一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物和药学上可接受的盐中的一种或多种。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprising a polycyclic compound (I), an isomer thereof, a prodrug, a solvent One or more of a compound, a hydrate, a stable isotope derivative, and a pharmaceutically acceptable salt.
所述药物组合物中，所述活性组分还可包括癌症、病毒感染或自身免疫疾病的其它治疗剂。In the pharmaceutical composition, the active ingredient may also include other therapeutic agents for cancer, viral infection or autoimmune diseases.
所述药物组合物中，所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。In the pharmaceutical composition, the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。The pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment. Preferred are liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) and the like.
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。In order to shape the pharmaceutical composition in the form of a tablet, any excipient known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; wetting agents such as glycerin, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Such as pure talc, stearate, boric acid powder and polyethylene glycol. It is also possible to use a usual coating material to prepare a sugar-coated tablet, a gelatin film tablet, a casing tablet, a film-coated tablet, a two-layer film tablet, and a multilayer tablet.
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。In order to shape the pharmaceutical composition in the form of a pill, any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。In order to shape the pharmaceutical composition in the form of a suppository, any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。In order to prepare a pharmaceutical composition in the form of an injection, the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood. Any of the commonly used carriers in the art can also be used in the preparation of the injection. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan. In addition, usual solubilizers, buffers, analgesics, and the like can be added.
本发明中，所述的组合物在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，较佳的为质量百分比30～80％。In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass. %.
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。 In the present invention, the administration method of the pharmaceutical composition is not particularly limited. Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
本发明还提供了所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备吲哚胺2,3-双加氧酶抑制剂中的应用。所述的吲哚胺2,3-双加氧酶抑制剂(IDO抑制剂)是指可以抑制IDO活性或表达(包括IDO的异常活动或过表达)，并逆转IDO-介导的免疫抑制的化合物。所述的IDO抑制剂可以抑制IDO。The present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is used in the preparation of hydrazine Use in indoleamine 2,3-dioxygenase inhibitors. The indoleamine 2,3-dioxygenase inhibitor (IDO inhibitor) refers to inhibiting IDO activity or expression (including abnormal activity or overexpression of IDO) and reversing IDO-mediated immunosuppression. Compound. The IDO inhibitor can inhibit IDO.
本发明还提供了所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备刺激T细胞增殖药物中的应用。The present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for stimulation Application in T cell proliferation drugs.
本发明还提供了所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备治疗、缓解和/或预防由吲哚胺2，3-双加氧酶介导的相关疾病的药物中的应用。所述N-羟基脒类化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物还可和一种或多种其它种类的用于治疗癌症的治疗剂和/或治疗方法联合用于治疗、缓解和/或预防由吲哚胺2，3-双加氧酶介导的相关疾病。所述的2，3-双加氧酶介导的相关疾病是指由2，3-双加氧酶介导的免疫抑制而引起的疾病，所述的疾病可包括：病毒或其它感染(例如：皮肤感染、胃肠道感染、泌尿生殖系统感染、系统性感染等)、癌症、或自身免疫性疾病(例如：类风湿性关节炎、红斑狼疮、银屑病等)。The present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for treatment The use of a medicament for alleviating and/or preventing a disease associated with guanamine 2,3-dioxygenase. The N-hydroxy steroid compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition may also be a Or a variety of other types of therapeutic agents and/or therapeutic methods for treating cancer in combination for treating, ameliorating and/or preventing a disease associated with guanamine 2,3-dioxygenase. The 2,3-dioxygenase-mediated related disease refers to a disease caused by 2,3-dioxygenase-mediated immunosuppression, which may include: a virus or other infection (eg, : skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.), cancer, or autoimmune diseases (eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).
所述其它种类的用于治疗癌症的治疗剂可以和所述的多环化合物(I)做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。The other kind of therapeutic agent for treating cancer may be a therapeutic form for single administration with the polycyclic compound (I), or a therapeutic dosage form for sequential administration.
所述其它种类的用于治疗癌症的治疗剂和/或治疗方法可包括但不限于：微管蛋白抑制剂、烷化剂、拓扑酶I/II抑制剂、铂类化合物、抗代谢类药物、激素和激素类似物、信号转导通路抑制剂、血管生成抑制剂、靶向治疗(例如：特殊的激酶抑制剂)、免疫治疗剂、促凋亡剂、细胞周期信号通路抑制剂和放疗中的一种或多种。The other types of therapeutic agents and/or therapeutic methods for treating cancer may include, but are not limited to, tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum compounds, antimetabolites, Hormone and hormone analogs, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies (eg, specific kinase inhibitors), immunotherapeutics, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiotherapy One or more.
所述微管蛋白抑制剂可选自但不限于：长春碱系列(例如：长春碱、长春新碱、长春瑞滨、长春地辛)、紫杉烷类(多西他赛、紫杉醇)和甲磺酸艾日布林中的一种或多种。The tubulin inhibitor may be selected from, but not limited to, a vinblastine series (eg, vinblastine, vincristine, vinorelbine, vindesine), a taxane (docetaxel, paclitaxel), and a One or more of eribulin sulfonate.
所述烷化剂可选自但不限于：氮芥、乙烯亚胺衍生物、甲烷磺酸酯类、亚硝脲类和三氮烯类中的一种或多种。The alkylating agent may be selected from one or more of the group consisting of nitrogen mustard, ethyleneimine derivative, methanesulfonate, nitrosourea, and triazene.
所述拓扑酶I/II抑制剂可选自但不限于：伊立替康、拓扑替康、阿霉素和右雷佐生中的一种或多种。The topozyme I/II inhibitor may be selected from, but not limited to, one or more of irinotecan, topotecan, doxorubicin, and dexrazoxane.
所述铂类化合物可选自但不限于：顺铂和/或卡铂。The platinum compound may be selected from, but not limited to, cisplatin and/or carboplatin.
所述抗代谢类药物可选自但不限于：叶酸拮抗剂、嘧啶类似物、嘌呤类似物、腺苷脱氨酶抑制剂，例如：甲氨蝶呤、5-氟尿嘧啶、氟脲苷、阿糖胞苷、6-巯基嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁和吉西他滨中的一种或多种。The anti-metabolites may be selected from, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, for example: methotrexate, 5-fluorouracil, fluorouridine, arabinose One or more of cytidine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin, and gemcitabine.
所述免疫治疗剂可选自但不限于：抗肿瘤疫苗(例如：合成肽、DNA疫苗和重组病毒)、溶瘤病毒、免疫刺激抗体、新型佐剂、细胞因子治疗(例如：IL2和GM-CSF)、嵌合抗原受体T细胞治疗法(CAR-T)、小分子免疫调节剂、肿瘤微环境调节剂和抗血管生成因子中的一种或多种。所述的免疫刺激抗体可包括但不限于：1)抑制T细胞活性的蛋白拮抗剂(例如：免疫检查点抑制剂)：CTLA4(例如：ipilimumab和tremelimumab)、PD-1(例如：pembrolizumab和nivolumab)、PD-L1(例如：durvalumab、avelumab和atezolizumab)、LAG3 和TIM3中的一种或多种；1)刺激T细胞活性的蛋白激动剂：GITR、OX40、OX40L、4-1BB(CD137)、CD27和CD40中的一种或多种。The immunotherapeutic agent can be selected from, but not limited to, anti-tumor vaccines (eg, synthetic peptides, DNA vaccines, and recombinant viruses), oncolytic viruses, immunostimulatory antibodies, novel adjuvants, cytokine treatments (eg, IL2 and GM- One or more of CSF), chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulator, tumor microenvironmental modulator, and anti-angiogenic factor. The immunostimulatory antibodies can include, but are not limited to, 1) protein antagonists that inhibit T cell activity (eg, immunological checkpoint inhibitors): CTLA4 (eg, ipilimumab and tremelimumab), PD-1 (eg, pembrolizumab and nivolumab) ), PD-L1 (eg durvalumab, avelumab and atezolizumab), LAG3 And one or more of TIM3; 1) a protein agonist that stimulates T cell activity: one or more of GITR, OX40, OX40L, 4-1BB (CD137), CD27, and CD40.
所述信号转导通路抑制剂(STI)可选自但不限于：BCR/ABL激酶抑制剂、表皮生长因子受体抑制剂、her-2/neu受体抑制剂、AKT家族激酶抑制剂、PI3K信号通路抑制剂、和细胞周期检查点抑制剂。The signal transduction pathway inhibitor (STI) may be selected from, but not limited to, a BCR/ABL kinase inhibitor, an epidermal growth factor receptor inhibitor, a her-2/neu receptor inhibitor, an AKT family kinase inhibitor, PI3K Signal pathway inhibitors, and cell cycle checkpoint inhibitors.
所述血管生成抑制剂可选自但不限于：VEGF/VEGFR信号通路抑制剂、Src家族激酶抑制剂、Src信号通路抑制剂和c-Fes激酶抑制剂中的一种或多种。The angiogenesis inhibitor can be selected from, but not limited to, one or more of a VEGF/VEGFR signaling pathway inhibitor, a Src family kinase inhibitor, a Src signaling pathway inhibitor, and a c-Fes kinase inhibitor.
所述病毒感染可包括：由流感、丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、爱泼斯坦-巴尔病毒(EBV)、脊髓灰质炎病毒、水痘-带状疱疹病毒、柯萨奇病毒、或人类免疫缺陷病毒(HIV)等病毒引起的感染。The viral infection may include: from influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, chickenpox - Infections caused by viruses such as herpes zoster virus, Coxsackie virus, or human immunodeficiency virus (HIV).
所述的癌症可包括但不限于：骨癌、肺癌、胃癌、结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、膀胱癌、子宫颈癌、睾丸癌、肾癌、头颈癌、淋巴癌、白血病和皮肤癌中的一种或多种。The cancer may include, but is not limited to, bone cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, One or more of head and neck cancer, lymphoma, leukemia and skin cancer.
所述的自身免疫性疾病可包括但不限于：类风湿性关节炎、全身性红斑狼疮、混合性结缔组织病(MCTD)、系统硬皮病(包括：CREST综合症)、皮肌炎、结节性脉管炎、肾病(包括：肺出血肾炎综合症、急性肾小球肾炎、原发性膜增殖性肾小球肾炎等)、内分泌相关疾病(包括：I型糖尿病、性腺机能不全、恶性贫血、甲状腺机能亢进等)、肝病(包括：原发性胆汁性肝硬化、自身免疫性胆管炎、自身免疫性肝炎、原发性硬化性胆管炎等)和由于感染引起的自身免疫反应(例如：艾滋病、疟疾等)中的一种或多种。The autoimmune diseases may include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (MCTD), systemic scleroderma (including: CREST syndrome), dermatomyositis, knot Segmental vasculitis, nephropathy (including: pulmonary hemorrhagic nephritis syndrome, acute glomerulonephritis, primary membrane proliferative glomerulonephritis, etc.), endocrine-related diseases (including: type I diabetes, gonadal insufficiency, malignancy) Anemia (including anemia, hyperthyroidism, etc.), liver disease (including: primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.) and autoimmune reactions due to infection (eg One or more of AIDS, malaria, etc.
本发明还提供了一种用所述多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物抑制体系中色氨酸降解的方法，其包括如下步骤：通过给予哺乳动物治疗有效量的如式(I)所示的化合物抑制哺乳动物体内色氨酸的降解；所述的体系为表达IDO的组织、哺乳动物或细胞组织。The present invention also provides a polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition A method of inhibiting tryptophan degradation in a system comprising the steps of inhibiting degradation of tryptophan in a mammal by administering to a mammal a therapeutically effective amount of a compound of formula (I); said system being IDO-expressing Tissue, mammal or cell tissue.
所述哺乳动物，优选人。Said mammal, preferably a human.
本发明中，除非另有说明，取代基名称前未冠有“取代或未取代的”定义的均指未取代的情况，例如：“烷基”是指未取代的烷基，“环烷基”是指未取代的环烷基。In the present invention, unless otherwise stated, the substituent name is not preceded by the definition of "substituted or unsubstituted", and is meant to mean unsubstituted, for example, "alkyl" means unsubstituted alkyl, "cycloalkyl" "" means an unsubstituted cycloalkyl group.
本发明中，除非另有说明，术语“被一个或多个基团取代在任意位置”是指基团上所指定的一个或多个原子的任何一个或者多个氢原子用所指定的基团取代，条件是不超过指定原子的正常化合价，所述取代均为本领域常见的合理取代。例如：被1～3个基团取代在任意位置，是指可以被1个、2个或3个相同或者不同的取代基合理取代在任意位置。In the present invention, unless otherwise indicated, the term "substituted at one position by one or more groups" means that any one or more of the hydrogen atoms of one or more atoms specified on the group are represented by the specified group. Substituted, provided that the normal valence of the specified atom is not exceeded, the substitutions are all reasonable substitutions that are common in the art. For example, substitution of 1 to 3 groups at any position means that one, two or three identical or different substituents may be reasonably substituted at any position.
本发明中，当与取代基的键合显示与连接环中两个原子的键合相交时，那么这样的取代基可键合在环上的任何可键合的环原子。In the present invention, when the bonding to a substituent is shown to intersect the bonding of two atoms in the linking ring, then such a substituent may be bonded to any bondable ring atom on the ring.
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：Unless otherwise stated, the following terms appearing in the specification and claims of the present invention have the following meanings:
术语“烷基”是指包含1-20个碳原子的饱和直链或支链烃基，优选1～10个碳原子，更优选1～8个碳原子，烷基的代表性例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基、4,4-二甲基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体等。The term "alkyl" refers to a saturated straight or branched chain hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, and representative examples of alkyl groups include, but are not limited to, : methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, 4, 4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof.
术语“环烷基”是指包含3-20个碳原子的饱和或部分不饱和(包含1或2个双键)的 单环或多环基团。“单环环烷基”优选3-10元单环烷基，更优选5-8元单环烷基，例如：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基。“多环环烷基”包括“稠合环烷基”和“螺环烷基”，“稠合环烷基”包含稠合到芳基、环烷基、或杂芳基上的单环环烷基环，稠合双环环烷基包括但不限于：苯并环丁烯、2,3-二氢-1-H-茚、2,3-环戊烯并吡啶、5,6-二氢-4H-环戊基[B]噻吩、十氢萘等。“螺环烷基”是指两个环烷基共用一个碳原子形成的双环基团，螺环烷基包括但不限于：螺[2.4]庚基、螺[4.5]癸烷等。单环环烷基或双环环烷基可以通过环上任意的碳原子链接到母体分子上。The term "cycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) containing from 3 to 20 carbon atoms. Monocyclic or polycyclic groups. "monocyclic cycloalkyl" is preferably a 3-10 membered monocycloalkyl group, more preferably a 5-8 membered monocycloalkyl group, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring Octyl, cyclodecyl, cyclododecyl, cyclohexenyl. "Polycyclic cycloalkyl" includes "fused cycloalkyl" and "spirocycloalkyl", and "fused cycloalkyl" includes a monocyclic ring fused to an aryl, cycloalkyl, or heteroaryl group. Alkyl rings, fused bicyclic cycloalkyl groups include, but are not limited to, benzocyclobutene, 2,3-dihydro-1-H-indole, 2,3-cyclopentenopyridine, 5,6-dihydro -4H-cyclopentyl [B] thiophene, decalin, and the like. "Spirocycloalkyl" refers to a bicyclic group formed by the sharing of one carbon atom by two cycloalkyl groups, including but not limited to: spiro[2.4]heptyl, spiro[4.5]decane, and the like. A monocyclic cycloalkyl or bicyclic cycloalkyl group can be attached to the parent molecule through any carbon atom on the ring.
术语“杂环烷基”指由碳原子以及选自氮、氧或硫等杂原子组成的饱和或部分不饱和(包含1或2个双键)的3-20元的非芳香环状基团，此环状基团可为单环或双环基团，在本发明中，杂环烷基中杂原子个数优选1、2、3或4，杂环烷基中的氮、碳或硫原子可任选地被氧化。氮原子可任选进一步被其他基团取代而形成叔胺或季铵盐。“单环杂环烷基”优选3-10元单环杂环烷基，更优选5-8元单环杂环烷基。例如：氮丙啶基、四氢呋喃-2-基、吗啉-4-基、硫代吗啉-4-基、硫代吗啉-S-氧化物-4-基、哌啶-1-基、N-烷基哌啶-4-基、吡咯烷-1-基、N-烷基吡咯烷-2-基、哌嗪-1-基、4-烷基哌嗪-1-基等。“多环杂环烷基”包括“稠合杂环烷基”和“螺杂环基”。“稠合杂环烷基”包含稠合到苯基、杂环烷基、环烷基或杂芳基的单环杂环烷基环，稠合杂环烷基包括但不限于：2,3-二氢苯并呋喃基、1,3-二氢异苯并呋喃基、二氢吲哚基、2,3-二氢苯并[b]噻吩基、二氢苯并哌喃基、1,2,3,4-四氢喹啉基、
Figure PCTCN2017095396-appb-000035
等。“螺杂环基”是指两个杂环烷基或一个环烷基和一个杂环烷基共用一个碳原子形成的双环基团，螺杂环基包括但不限于：
Figure PCTCN2017095396-appb-000036
等。单环杂环烷基和多环杂环烷基可以通过环上任意的环原子链接到母体分子上。上述环原子特指组成环骨架的碳原子和/或氮原子。The term "heterocycloalkyl" refers to a 3-20 membered non-aromatic cyclic group consisting of a carbon atom and a saturated or partially unsaturated (containing 1 or 2 double bonds) consisting of a hetero atom selected from nitrogen, oxygen or sulfur. The cyclic group may be a monocyclic or bicyclic group. In the present invention, the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and a nitrogen, carbon or sulfur atom in the heterocycloalkyl group. It can optionally be oxidized. The nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt. The "monocyclic heterocycloalkyl group" is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 5-8 membered monocyclic heterocycloalkyl group. For example: aziridine, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholine-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl and the like. "Polycycloheterocycloalkyl" includes "fused heterocycloalkyl" and "spiroheterocyclyl". "Fused heterocycloalkyl" includes a monocyclic heterocycloalkyl ring fused to a phenyl, heterocycloalkyl, cycloalkyl or heteroaryl group, including but not limited to: 2,3 - dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indanyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolinyl,
Figure PCTCN2017095396-appb-000035
Wait. "Spiroheterocyclyl" means a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing one carbon atom, and spiroheterocyclyl groups include, but are not limited to:
Figure PCTCN2017095396-appb-000036
Wait. Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be attached to the parent molecule through any ring atom on the ring. The above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
术语“环烷基烷基”是指环烷基与母核结构之间通过烷基连接。由此，“环烷基烷基”包含上述烷基和环烷基的定义。The term "cycloalkylalkyl" refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group. Thus, "cycloalkylalkyl" embraces the definitions of alkyl and cycloalkyl as described above.
术语“杂环烷基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂环烷基烷基”包含上述烷基和杂环烷基的定义。The term "heterocycloalkylalkyl" refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure. Thus, "heterocycloalkylalkyl" embraces the definitions of alkyl and heterocycloalkyl as described above.
术语“烷氧基”指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基，包含烷基氧基、环烷基氧基和杂环烷基氧基。由此，“烷氧基”包含上述烷基、杂环烷基和环烷基的定义。The term "alkoxy" refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group. Thus, "alkoxy" includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
术语“烷硫基”指,环状或者非环状烷基通过硫原子和母体分子相互连接，包含烷基巯基、环烷基巯基和杂环烷基巯基。由此，“烷硫基”包含上述烷基、杂环烷基和环烷基的定义。The term "alkylthio" means that a cyclic or acyclic alkyl group is bonded to each other through a sulfur atom and a parent molecule, and includes an alkyl fluorenyl group, a cycloalkyl fluorenyl group, and a heterocycloalkyl fluorenyl group. Thus, "alkylthio" embraces the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
术语“羟烷基”是指烷基上任意一个氢原子被羟基所取代，包括但不限于：-CH2OH、-CH2CH2OH、-CH2CH2C(CH3)2OH。The term "hydroxyalkyl" refers to an alkyl arbitrary one hydrogen atom is substituted with a hydroxyl group, including but not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C (CH 3) 2 OH.
术语“烯基”指含有至少1个碳碳双键的直链、支链或者环状非芳香烃基。其中可以存在1-3个碳碳双键，优选存在1个碳碳双键。术语“C2-4烯基”是指具有2-4个碳原子的烯基，术语“C2-6烯基”是指具有2-6个碳原子的烯基，包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。所述的烯基可以被取代。The term "alkenyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond. The term "C 2-4 alkenyl" means having 2-4 carbon atoms, an alkenyl group, the term "C 2-6 alkenyl" means an alkenyl radical having 2-6 carbon atoms, include ethenyl, propenyl , butenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted.
术语“炔基”是指含有至少1个碳碳三键的直链、支链或者环状烃基。其中可以存在1-3 个碳碳三键，优选存在1个碳碳三键。术语“C2-6炔基”是指具有2-6个碳原子的炔基，包括乙炔基、丙炔基、丁炔基和3-甲基丁炔基。The term "alkynyl" refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond. The term "C 2-6 alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms, and includes ethynyl, propynyl, butynyl and 3-methylbutynyl.
术语“芳基”是指任何稳定的6-10元单环或双环芳香族基团，例如：苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基等。The term "aryl" refers to any stable 6-10 membered monocyclic or bicyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl.
术语“杂芳基”是指至少1个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团，其可为5-7元单环结构或7-12元双环结构，优选5-6元杂芳基。在本发明中，杂原子个数优选1、2或3，包括但不限于：吡啶基、嘧啶基、哒嗪-3(2H)-酮基、呋喃基、噻吩基、噻唑基、吡咯基、咪唑基、吡唑基、恶唑基、异恶唑基、1,2,5-恶二唑基、1,2,4-恶二唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、四氮唑基、吲唑基、异吲唑基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并[d][1,3]二氧戊环基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、喹唑啉基等。The term "heteroaryl" refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-12 A bicyclic structure, preferably a 5-6 membered heteroaryl group. In the present invention, the number of heteroatoms is preferably 1, 2 or 3, including but not limited to: pyridyl, pyrimidinyl, pyridazine-3(2H)-one, furyl, thienyl, thiazolyl, pyrrolyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1 , 2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolyl, isodecyl, benzofuranyl, benzothienyl, benzo[d][1 , 3] dioxolane, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolinyl and the like.
术语“并环杂芳基”是指单环杂芳基和一个选自单环杂芳基或者单环芳基的基团共用两个相邻环原子所形成的基团，所述“并环杂芳基”为双环基团。所述并环杂芳基优选为8-12元双环基团，包括但不限于：吲唑基、异吲唑基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并噻唑基、喹啉基、异喹啉基、喹唑啉基、1,8-萘啶基、1,5-萘啶基、4-氮杂吲哚基、5-氮杂吲哚基、2-氮杂吲哚基、6-氮杂吲哚基、7-氮杂吲哚基、1H-吡咯并[2,3-B]吡啶基、4-氮杂吲唑基、7-氮杂吲唑基、6-氮杂吲唑基、1H-吡唑并[3,4-C]吡啶等。The term "cyclo-heteroaryl" refers to a group formed by a monocyclic heteroaryl group and a group selected from a monocyclic heteroaryl group or a monocyclic aryl group sharing two adjacent ring atoms, said "co-ring" A heteroaryl group is a bicyclic group. The cycloheteroaryl group is preferably a 8-12 membered bicyclic group including, but not limited to, carbazolyl, isoxazolyl, indolyl, isodecyl, benzofuranyl, benzothienyl, Benzothiazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 4-aza Sulfhydryl, 5-azaindolyl, 2-azaindolyl, 6-azaindolyl, 7-azaindolyl, 1H-pyrrolo[2,3-B]pyridinyl, 4-Azacarbazolyl, 7-azacarbazolyl, 6-azacarbazolyl, 1H-pyrazolo[3,4-C]pyridine, and the like.
术语“芳基烷基”是指芳基与母核结构之间通过烷基连接。由此，“芳基烷基”包含上述烷基和芳基的定义。The term "arylalkyl" refers to an alkyl linkage between the aryl group and the parent core structure. Thus, "arylalkyl" embraces the definition of alkyl and aryl as defined above.
术语“杂芳基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂芳基烷基”包含上述烷基和杂芳基的定义。The term "heteroarylalkyl" refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure. Thus, "heteroarylalkyl" embraces the definitions of alkyl and heteroaryl as defined above.
术语“卤素”表示氟、氯、溴或碘。The term "halogen" means fluoro, chloro, bromo or iodo.
术语“卤代烷基”是指被卤素任意取代的烷基。由此，“卤代烷基”包含以上卤素和烷基的定义。The term "haloalkyl" refers to an alkyl group optionally substituted by halogen. Thus, "haloalkyl" embraces the definitions of the above halo and alkyl.
术语“卤代烷氧基”是指被卤素任意取代的烷氧基。由此，“卤代烷氧基”包含以上卤素和烷氧基的定义。The term "haloalkoxy" refers to an alkoxy group optionally substituted by halogen. Thus, "haloalkoxy" includes the definitions of the above halo and alkoxy.
术语“氨基”是指-NH2，术语“烷基氨基”是指氨基上至少一个氢原子被烷基所取代，包括但不限于：-NHCH2、-NHCH2CH3。术语“氨烷基”是指烷基上任意一个氢原子被氨基所取代，包括但不限于：-CH2NH2、-CH2CH2NH2。由此，“烷基氨基”和“氨烷基”包含上述烷基和氨基的定义。The term "amino" means -NH 2, the term "alkylamino" refers to at least one amino hydrogen atoms are substituted by alkyl groups, including but not limited to: -NHCH 2, -NHCH 2 CH 3 . The term "aminoalkyl" means that any one of the hydrogen atoms on the alkyl group is replaced by an amino group, including but not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 . Thus, "alkylamino" and "aminoalkyl" embrace the definitions of alkyl and amino groups described above.
术语“亚烷基”、“亚烯基”或“亚炔基”是指可以作为连接键连接其他两个基团的烷基、烯基或者炔基，所述亚烷基可以是直链也可以是支链结构，例如-(CH2)q-；所述亚烯基或亚炔基可以是支链、直链或者环状结构。The term "alkylene", "alkenylene" or "alkynylene" refers to an alkyl, alkenyl or alkynyl group which may serve as a linking bond to the other two groups, which may be straight chain as well. It may be a branched structure such as -(CH 2 ) q -; the alkenylene or alkynylene group may be a branched, straight chain or cyclic structure.
符号“＝”表示双键；The symbol "=" indicates a double bond;
本发明所述“室温”是指15-30℃。"Room temperature" as used herein means 15-30 °C.
所述的同位素取代衍生物包括：式I中任意的氢原子被1-5个氘原子取代得到的同位素取代衍生物、式I中任意的碳原子被1-3个碳14原子取代得到的同位素取代衍生物或式I中任意的氧原子被1-3个氧18原子取代得到的同位素取代衍生物。 The isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms. A substituted derivative or an isotopically substituted derivative obtained by substituting an oxygen atom of any of Formula I with 1-3 oxygen atoms.
所述的“前药”是指化合物在体内代谢后转换成原始活性化合物。代表性地讲，前药为非活性物质，或者比活性母体化合物活性小，但可以提供方便的操作、给药或者改善代谢特性。By "prodrug" is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.
本发明所述的“药学上可接受的盐”在Berge，et al.，“Pharmaceutically acceptable salts”，J.Pharm.Sci.,66,1-19(1977)中有讨论，并对药物化学家来说是显而易见，所述的盐是基本上无毒性的，并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄等。本发明所述化合物可以具有酸性基团、碱性基团或两性基团，典型的药学上可接受的盐包括通过本发明化合物和酸反应制备得到的盐，例如：盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、(D，L)-酒石酸，柠檬酸，马来酸，(D，L)-苹果酸，富马酸，丁二酸、琥珀酸盐、乳酸盐、三氟甲磺酸盐、萘-1-磺酸盐、扁桃酸盐、丙酮酸盐、硬脂酸盐、抗坏血酸盐、水杨酸盐。当本发明化合物含有酸性基团时，其药学上可接受的盐还可以包括：碱金属盐，例如钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如和氨、烷基氨类、羟基烷基氨类、氨基酸(赖氨酸、精氨酸)、N-甲基葡糖胺等形成的盐。"Pharmaceutically acceptable salts" as described herein are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like. The compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,L)-malic acid, fumaric acid, succinic acid, succinate, lactate, triflate, naphthalene-1-sulfonate, mandelate, pyruvate, stearin Acid salt, ascorbate, salicylate. When the compound of the present invention contains an acidic group, the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
本发明所述“异构体”是指本发明的式(I)化合物可以有不对称中心和外消旋体、外消旋混合物和单个非对映异构体，所有这些异构体，包括立体异构体、几何异构体均包含在本发明中。在本发明中，式I化合物或其盐以立体异构的形式(例如，其含有一个或多个不对称碳原子)存在时，单独的立体异构体(对映异构体和非对映异构体)以及它们的混合物包括在本发明的范围内。本发明还包括式I表示的化合物或盐的单独异构体，以及与其中一个或多个手性中心反转的异构体的混合物。本发明的范围包括：立体异构体的混合物，以及纯化的对映异构体或对映异构体/非对映异构体富集的混合物。本发明包括所有对映异构体及非对应异构体所有可能的不同组合的立体异构体的混合物。本发明包括上文定义的所有具体基团的立体异构体的全部组合和子集。本发明还包括式I化合物或其盐的几何异构体，所述几何异构体包括顺反异构体。As used herein, "isomer" means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention. In the present invention, a compound of the formula I or a salt thereof, in stereoisomeric form (for example, which contains one or more asymmetric carbon atoms), is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention. The invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted. The scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. The invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers. The invention includes all combinations and subsets of stereoisomers of all the specific groups defined above. The invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention.
本发明所用试剂和原料均市售可得。The reagents and starting materials used in the present invention are commercially available.
具体实施方式detailed description
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.
本发明所有化合物的结构可通过核磁共振(1H NMR)和/或质谱检测(MS)鉴定。The structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
1H NMR化学位移(δ)以PPM记录(10-6)。NMR通过Bruker AVANCE-400光谱仪进行。合适的溶剂是氘代氯仿(CDCl3)，氘代甲醇(MeOD-d4)，氘代二甲亚砜(DMSO-d6)，四甲基硅烷作为内标(TMS)。 The 1 H NMR chemical shift (δ) was recorded in PPM (10 -6 ). NMR was performed on a Bruker AVANCE-400 spectrometer. Suitable solvents are deuterated chloroform (CDCl 3 ), deuterated methanol (MeOD-d 4 ), deuterated dimethyl sulfoxide (DMSO-d 6 ), and tetramethylsilane as internal standard (TMS).
低分辨率质谱(MS)由Agilent 1200HPLC/6120质谱仪测定，使用XBridge C18，4.6×50mm，3.5μm，梯度洗脱条件一：80-5％溶剂A1和20-95％溶剂B1(1.8分钟)，然后95％溶剂 B1和5％溶剂A1(3分钟以上)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A1：0.01％三氟乙酸(TFA)的水溶液；溶剂B1：0.01％三氟乙酸的乙腈溶液；百分数为溶质占溶液的体积百分数。梯度洗脱条件二：80-5％溶剂A2和20-95％溶剂B2(1.5分钟)，然后95％溶剂B2和5％溶剂A2(2分钟以上)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A2：10mM的碳酸氢铵的水溶液；溶剂B2：乙腈。Low resolution mass spectrometry (MS) was determined by an Agilent 1200 HPLC/6120 mass spectrometer using XBridge C18, 4.6 x 50 mm, 3.5 μm, gradient elution conditions: 80-5% solvent A 1 and 20-95% solvent B 1 (1.8 Minutes, then 95% solvent B 1 and 5% solvent A 1 (more than 3 minutes), the percentage being the volume percentage of a solvent to the total solvent volume. Solvent A 1 : an aqueous solution of 0.01% trifluoroacetic acid (TFA); solvent B 1 : a solution of 0.01% trifluoroacetic acid in acetonitrile; the percentage is the volume fraction of the solute in the solution. Gradient elution conditions 2: 80-5% solvent A 2 and 20-95% solvent B 2 (1.5 minutes), then 95% solvent B 2 and 5% solvent A 2 (more than 2 minutes), the percentage is a certain solvent Volume percent of total solvent volume. Solvent A 2 : 10 mM aqueous solution of ammonium hydrogencarbonate; solvent B 2 : acetonitrile.
本发明所有化合物可通过高效液相色谱仪、硅胶柱层析、薄层硅胶板、快速分离机分离或通过超临界流体色谱(SFC)拆分。All of the compounds of the present invention can be separated by high performance liquid chromatography, silica gel column chromatography, thin layer silica gel plates, flash separators or by supercritical fluid chromatography (SFC).
快速分离机(Flash柱层析)(flash system/CheetahTM)使用的是Agela Technologies MP200，配套使用的分离柱为Flash columm Silica-CS(80g)，Cat No.CS140080-0。Rapid separator (Flash column chromatography) (flash system / Cheetah TM) using Agela Technologies MP200, supporting the use of a separation column for Flash columm Silica-CS (80g) , Cat No.CS140080-0.
高效液相色谱仪(prep-HPLC)使用岛津LC-20制备液相色谱，检测波长：214nm&254nm；流速：9.0mL/分钟。色谱柱为：waters xbridge Pre C18，10um，19mm×260mm。洗脱条件(酸性条件)：条件1：30～65％流动相A和70～35％流动相B；条件2：40～60％流动相A和60～40％流动相B；条件10：80～40％流动相A和20～60％流动相B；条件11：15～30％流动相A和85～70％流动相B；流动相A：0.05％三氟乙酸水溶液(百分数为体积百分数)，流动相B：乙腈。洗脱条件(碱性条件)：条件3：65～70％流动相A和35～30％流动相B；条件4：30～55％流动相A和70～45％流动相B；条件5：30～65％流动相A和70～35％流动相B；条件6：40～70％流动相A和60～30％流动相B；条件7：45～75％流动相A和55～25％流动相B；条件8：70～25％流动相A和30～75％流动相B；条件9：70～30％流动相A和30～70％流动相B；条件12：30～45％流动相A和70～55％流动相B；条件13：20～40％流动相A和80～60％流动相B；条件14：20～35％流动相A和80～65％流动相B；条件15：25～40％流动相A和75～60％流动相B；条件16：65～35％流动相A和35～65％流动相B；条件17：25～65％流动相A和75～35％流动相B；条件18：15～35％流动相A和85～65％流动相B；条件19：40～20％流动相A和60～80％流动相B；溶剂A：10mM的碳酸氢铵的水溶液；溶剂B：乙腈。High performance liquid chromatography (prep-HPLC) was carried out using Shimadzu LC-20 preparative liquid chromatography at a detection wavelength of 214 nm & 254 nm; flow rate: 9.0 mL / min. The column is: waters xbridge Pre C18, 10um, 19mm x 260mm. Elution conditions (acidic conditions): Condition 1: 30 to 65% mobile phase A and 70 to 35% mobile phase B; Condition 2: 40 to 60% mobile phase A and 60 to 40% mobile phase B; Condition 10: 80 ~40% mobile phase A and 20-60% mobile phase B; Condition 11: 15-30% mobile phase A and 85-70% mobile phase B; mobile phase A: 0.05% aqueous trifluoroacetic acid solution (percentage percent by volume) , mobile phase B: acetonitrile. Elution conditions (basic conditions): Condition 3: 65 to 70% mobile phase A and 35 to 30% mobile phase B; Condition 4: 30 to 55% mobile phase A and 70 to 45% mobile phase B; Condition 5: 30-65% mobile phase A and 70-35% mobile phase B; Condition 6: 40-70% mobile phase A and 60-30% mobile phase B; Condition 7: 45-75% mobile phase A and 55-25% Mobile phase B; Condition 8: 70 to 25% mobile phase A and 30 to 75% mobile phase B; Condition 9: 70 to 30% mobile phase A and 30 to 70% mobile phase B; Condition 12: 30 to 45% flow Phase A and 70-55% mobile phase B; Condition 13: 20-40% mobile phase A and 80-60% mobile phase B; Condition 14: 20-35% mobile phase A and 80-65% mobile phase B; conditions 15:25-40% mobile phase A and 75-60% mobile phase B; Condition 16: 65-35% mobile phase A and 35-65% mobile phase B; Condition 17: 25-65% mobile phase A and 75~ 35% mobile phase B; Condition 18: 15 to 35% mobile phase A and 85 to 65% mobile phase B; Condition 19: 40 to 20% mobile phase A and 60 to 80% mobile phase B; solvent A: 10 mM carbonic acid An aqueous solution of ammonium hydrogen; solvent B: acetonitrile.
超临界流体色谱(SFC)使用SFC-80(Thar，Waters)，流速为80g/min，柱温为35℃。检测波长为214。手性柱Cellulose-SC 20*250mm,10um(YMC)，流动相为二氧化碳：甲醇(含有0.1％的甲醇氨)＝50:50，样品浓度：12.5mg/mL(甲醇)，进样量：1mL。手性分析使用超临界流体色谱分析仪SFC Method Station(Thar,Waters)，流速为4.0mL/min，柱温为35℃；检测波长为214。手性分析条件A：手性柱Cellulose-SC 4.6×250mm,5um，流动相为二氧化碳：甲醇(含有0.1％的甲醇氨)＝65:35。Supercritical fluid chromatography (SFC) used SFC-80 (Thar, Waters) at a flow rate of 80 g/min and a column temperature of 35 °C. The detection wavelength is 214. Chiral column Cellulose-SC 20*250mm, 10um (YMC), mobile phase is carbon dioxide: methanol (containing 0.1% methanol ammonia) = 50:50, sample concentration: 12.5mg / mL (methanol), injection volume: 1mL . The chiral analysis was performed using a supercritical fluid chromatography analyzer SFC Method Station (Thar, Waters) at a flow rate of 4.0 mL/min, a column temperature of 35 ° C, and a detection wavelength of 214. Chiral analysis conditions A: chiral column Cellulose-SC 4.6 x 250 mm, 5 um, mobile phase carbon dioxide: methanol (containing 0.1% methanol ammonia) = 65:35.
薄层硅胶板是烟台黄海HSGF254或青岛GF254硅胶板。柱层析一般使用烟台黄海200-300目硅胶作为载体。The thin layer silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
实施例1：化合物1.6的合成Example 1: Synthesis of Compound 1.6
Figure PCTCN2017095396-appb-000037
Figure PCTCN2017095396-appb-000037
步骤1：化合物1.1的合成Step 1: Synthesis of Compound 1.1
将膦酰基乙酸三乙酯(6.2g，27.6mmol)溶解在无水四氢呋喃(100mL)中，冷却至-40℃，分批加入叔丁醇钾(3.4g，29.9mmol)，反应体系-40℃搅拌10分钟，然后缓慢升温至0℃，继续搅拌10分钟。之后将体系冷却至-40℃，加入4-苯基环己酮(4.0g，23.0mmol)的四氢呋喃(5mL)溶液。反应体系自然升至室温并搅拌过夜。加入饱和氯化铵水溶液淬灭反应，混合物用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂，得到的残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得化合物1.1(5.0g，产率：89％)为无色油状物。The triethyl phosphonoacetate (6.2 g, 27.6 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), cooled to -40 ° C, and potassium t-butoxide (3.4 g, 29.9 mmol) was added portionwise, the reaction system was -40 ° C Stir for 10 minutes, then slowly warm to 0 ° C and continue stirring for 10 minutes. After the system was cooled to -40 ° C, a solution of 4-phenylcyclohexanone (4.0 g, 23.0 mmol) in tetrahydrofuran (5 mL) was added. The reaction system was naturally warmed to room temperature and stirred overnight. The reaction was quenched with aq. EtOAc EtOAc (EtOAc m. The product was purified by silica gel column chromatography eluting elut elut elut elut elut
步骤2：化合物1.2的合成Step 2: Synthesis of Compound 1.2
将化合物1.1(5.0g，20.5mmol)溶解在甲醇(100mL)中，加入Pd/C(5％，200mg)。然后将反应体系用氢气置换三次并在氢气氛(氢气球)下搅拌过夜。过滤，滤饼用甲醇洗涤，滤液减压浓缩除去溶剂，得到化合物1.2(5.0g，产率：99％)为白色固体。Compound 1.1 (5.0 g, 20.5 mmol) was dissolved in methanol (100 mL) and Pd/C (5%, 200 mg). The reaction system was then replaced with hydrogen three times and stirred under a hydrogen atmosphere (hydrogen balloon) overnight. After filtration, the filter cake was washed with methanol, and the filtrate was evaporated.
步骤3：化合物1.3的合成Step 3: Synthesis of Compound 1.3
将化合物1.2(2.0g，8.12mmol)溶解在四氢呋喃和水的混合溶剂(15mL/5mL)中，加入一水合氢氧化锂(1.4g，32.5mmol)。然后将反应体系在50℃下搅拌3小时。用盐酸溶液(2.0M)调节pH为1～2，有固体析出，过滤，滤饼用水洗涤，干燥得化合物1.3(1.4g，产率：79％)为白色固体。Compound 1.2 (2.0 g, 8.12 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (15 mL/5 mL), and lithium hydroxide monohydrate (1.4 g, 32.5 mmol) was added. The reaction system was then stirred at 50 ° C for 3 hours. The pH was adjusted to 1-2 with a hydrochloric acid solution (2.0M), and a solid was precipitated, filtered, and the filter cake was washed with water and dried to give Compound 1.3 (1.4 g, yield: 79%) as a white solid.
步骤4：化合物1.4的合成Step 4: Synthesis of Compound 1.4
将化合物1.3(1.0g，4.59mmol)溶解在二氯甲烷(15mL)中，加入草酰氯(2.9g，22.9mmol)和两滴N,N-二甲基甲酰胺。反应体系室温搅拌30分钟后，减压蒸馏除去溶剂，将残留物溶解在丙酮中，并加入饱和的叠氮化钠水溶液。然后将反应体系在室温下搅拌1小时。加水，用乙酸乙酯(50mL×3)萃取，合并有机相，并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压蒸馏除去溶剂，得到的残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得化合物1.4(0.9g，产率：81％)为白色固体。Compound 1.3 (1.0 g, 4.59 mmol) was dissolved in dichloromethane (15 mL). After the reaction system was stirred at room temperature for 30 minutes, the solvent was evaporated under reduced pressure, the residue was dissolved in acetone, and a saturated aqueous sodium azide solution was added. The reaction system was then stirred at room temperature for 1 hour. After adding water, the mixture was extracted with ethyl acetate (50 mL×3), and the organic layer was evaporated. /ethyl acetate = 4/1) Compound 1.4 (0.9 g, yield: 81%) was obtained as white solid.
步骤5：化合物1.5的合成Step 5: Synthesis of Compound 1.5
向化合物1.4(800mg，3.29mmol)的甲苯(20mL)溶液中加入叔丁醇(1.2g，16.5mmol)。将反应体系回流搅拌3小时，减压蒸馏除去溶剂，加水，用乙酸乙酯萃取(50mL×2)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压蒸馏除去溶剂，得到的残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得化合物1.5(800mg，产率：84％)为白色固体。To a solution of compound 1.4 (800 mg, 3.29 mmol) in EtOAc (EtOAc) The reaction system was stirred under reflux for 3 hours, and the solvent was evaporated evaporated evaporated. The residue obtained was purified by silica gel column chromatography(lilili
步骤6：化合物1.6的合成Step 6: Synthesis of Compound 1.6
将化合物1.5(800mg，2.77mmol)的盐酸甲醇溶液(4.0M，20mL)加热至40℃，搅拌3小时，减压蒸馏除去溶剂，得到的残留物石油醚洗涤，得到化合物1.6(盐酸盐，600mg，产率：96％)为白色固体。A solution of the compound 1.5 (800 mg, 2.77 mmol) in MeOH (MeOH (MeOH) (MeOH) 600 mg, yield: 96%) as a white solid.
m/z:[M+H]+190m/z: [M+H] + 190
实施例2：化合物1.7的合成Example 2: Synthesis of Compound 1.7
用化合物1.6的合成方法，将步骤1中的膦酰基乙酸三乙酯替换为三乙基2-膦酰基丙酯得到化合物1.7： Substituting the triethyl phosphonoacetate in step 1 with triethyl 2-phosphonylpropyl ester by the synthesis of compound 1.6 to give compound 1.7:
Figure PCTCN2017095396-appb-000038
Figure PCTCN2017095396-appb-000038
实施例3：化合物1.8和1.9的合成Example 3: Synthesis of Compounds 1.8 and 1.9
用化合物1.6的合成方法，用4-(吡啶-4-基)环己酮或4-(2-甲基吡啶-4-基)环己酮和三乙基2-膦酰基丙酯为起始原料得到化合物1.8或1.9：Starting from the synthesis of compound 1.6 with 4-(pyridin-4-yl)cyclohexanone or 4-(2-methylpyridin-4-yl)cyclohexanone and triethyl 2-phosphonylpropyl ester The starting material yields compound 1.8 or 1.9:
Figure PCTCN2017095396-appb-000039
Figure PCTCN2017095396-appb-000039
实施例4：化合物1.10的合成Example 4: Synthesis of Compound 1.10
用化合物1.6的合成方法，将步骤1中的4-苯基环己酮替换为4-(4-(苄氧基)苯基)环己酮得到化合物1.10：Substituting 4-phenylcyclohexanone in step 1 with 4-(4-(benzyloxy)phenyl)cyclohexanone to give compound 1.10 by the synthesis of compound 1.6:
Figure PCTCN2017095396-appb-000040
Figure PCTCN2017095396-appb-000040
实施例5：化合物2.2a和2.2b的合成Example 5: Synthesis of Compounds 2.2a and 2.2b
Figure PCTCN2017095396-appb-000041
Figure PCTCN2017095396-appb-000041
步骤1：化合物2.1a和2.1b的合成：Step 1: Synthesis of Compounds 2.1a and 2.1b:
冰浴条件下，向4-苯基环己酮(1g，5.7mmol)和硝基甲烷(1.75g，28.7mmol)的乙醇(20mL)溶液中滴加乙醇钠(470mg，6.8mmol)的乙醇(10mL)溶液。滴加完毕，反应体系在50℃下搅拌16小时。减压蒸去溶剂，残留物用乙酸乙酯(50mL)溶解后依次用饱和氯化铵水溶液(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝100/1～>5/1)纯化得到化合物2.1a(420mg，产率：31％，极性较小)和化合物2-1b(135mg，产率：8％，极性较大)，均为白色固体。To a solution of 4-phenylcyclohexanone (1 g, 5.7 mmol) and nitromethane (1.75 g, 28.7 mmol) in ethanol (20 mL), EtOAc (EtOAc) 10 mL) solution. After the dropwise addition was completed, the reaction system was stirred at 50 ° C for 16 hours. The solvent was evaporated under reduced pressure. EtOAc EtOAc m. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc/EtOAc/EtOAc/EtOAc) , yield: 8%, more polar), all white solids.
步骤2：化合物2.2a和2.2b的合成Step 2: Synthesis of compounds 2.2a and 2.2b
将化合物2.1a(100mg，0.43mmol)和钯碳(5％，10mg)的乙醇(5mL)混合物在氢气氛(氢气球)下室温搅拌过夜。反应体系过滤，滤液浓缩至干，得到化合物2.2a(87mg，收率：100％)为白色固体。利用化合物2.2a的合成方法，用化合物2.1b(135mg)为起始原料得到化合物2.2b(100mg，产率：86％)为白色固体。A mixture of compound 2.1a (100 mg, 0.43 mmol) and palladium on carbon (5%, 10 mg) in ethanol (5 mL) was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon) overnight. The reaction system was filtered, and the filtrate was concentrated to dryness to afford Compound 2.2a (87mg, yield: 100%) as white solid. Compound 2.2b (100 mg, yield: 86%) was obtained as a white solid using compound 2.2b (135 mg).
实施例6：化合物3.4的合成Example 6: Synthesis of Compound 3.4
Figure PCTCN2017095396-appb-000042
Figure PCTCN2017095396-appb-000042
步骤1：化合物3.2的合成 Step 1: Synthesis of Compound 3.2
冰浴条件下，向化合物3.1(4g，25.6mmol)的甲醇(40mL)溶液中分批加入硼氢化钠(1.26g，33.3mmol)。反应体系在冰浴下搅拌1小时。然后用氯化铵水溶液淬灭反应，乙酸乙酯(3×60mL)萃取，分离出有机相。有机相用饱和食盐水洗涤、过滤，滤液减压浓缩得到化合物3.2(3.6g，产率：90％)为无色油状物。Sodium borohydride (1.26 g, 33.3 mmol) was added portionwise to a solution of compound 3.1 (4 g, 25.6 mmol) in methanol (40 mL). The reaction system was stirred for 1 hour in an ice bath. The reaction was then quenched with aqueous aq. EtOAc (EtOAc (EtOAc) The organic layer was washed with saturated brine and filtered and evaporated, evaporated
步骤2：化合物3.3的合成Step 2: Synthesis of Compound 3.3
冰浴条件下，向化合物3.2(3.1g，19.6mmol)的二甲亚砜(50mL)溶液中加入叔丁醇钾(7.2g，58.9mmol)。反应体系在室温下搅拌1小时，然后再将反应体系冷却至0℃，加入4-氯吡啶盐酸盐(4.4g，29.4mmol)。反应体系室温搅拌过夜，用水淬灭反应，乙酸乙酯(3×50mL)萃取，分离出有机相。有机相用饱和食盐水洗涤，过滤，滤液减压浓缩。残留物用Flash柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物3.3(3.0g，产率：67％)为白色固体。Potassium tert-butoxide (7.2 g, 58.9 mmol) was added to a solution of compound 3.2 (3.1 g, 19.6 mmol) in dimethyl sulfoxide (50 mL). The reaction system was stirred at room temperature for 1 hour, and then the reaction system was cooled to 0 ° C, and 4-chloropyridine hydrochloride (4.4 g, 29.4 mmol) was added. The reaction was stirred at rt over EtOAc (EtOAc)EtOAc The organic layer was washed with brine, filtered and evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut
m/z:[M+H]+236m/z: [M+H] + 236
步骤3：化合物3.4的合成Step 3: Synthesis of Compound 3.4
将化合物3.3(1.8g，7.66mmol)的丙酮(20mL)和盐酸(5mL，6.0M)溶液在45℃下搅拌48小时。然后用氢氧化钠水溶液(6.0M)调节反应体系pH至8～9，乙酸乙酯(3×30mL)萃取，分离出有机相。有机相用饱和食盐水洗涤，过滤，滤液减压浓缩。浓缩物用Flash柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物3.4(1.06g，产率：72％)为无色油状物。A solution of compound 3.3 (1.8 g, 7.66 mmol) in acetone (20 mL) and hydrochloric acid (5 mL, 6.0M) was stirred at 45 ° C for 48 hr. Then, the pH of the reaction system was adjusted to 8 to 9 with an aqueous sodium hydroxide solution (6.0M), and ethyl acetate (3×30 mL) was evaporated to isolate the organic phase. The organic layer was washed with brine, filtered and evaporated. The concentrate was purified by flash column chromatography (EtOAc:EtOAc:EtOAc
m/z:[M+H]+192m/z: [M+H] + 192
实施例7：化合物4.7的合成Example 7: Synthesis of Compound 4.7
Figure PCTCN2017095396-appb-000043
Figure PCTCN2017095396-appb-000043
步骤1：化合物4.1的合成Step 1: Synthesis of Compound 4.1
-78℃，氮气保护下，向化合物3.1(3.0g，19.2mmol)、N-苯基双(三氟甲烷磺酰亚胺)(8.2g，23.1mmol)的甲基叔丁基醚(75mL)溶液中滴加双(三甲基硅基)氨基钠的四氢呋喃溶液(2.0M，11.5mL，23.1mmol)，滴加完毕，将反应体系搅拌1小时。然后将反应液升至室温，搅拌过夜。用饱和氯化铵水溶液淬灭反应，并用乙酸乙酯萃取，有机相用无水硫酸钠干燥、过滤、浓缩得到化合物4.1(6.0g)为浅黄色油状物。To a compound 3.1 (3.0 g, 19.2 mmol), N-phenylbis(trifluoromethanesulfonimide) (8.2 g, 23.1 mmol) of methyl tert-butyl ether (75 mL) A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.0 M, 11.5 mL, 23.1 mmol) was added dropwise, and the mixture was stirred for 1 hour. The reaction was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with EtOAc (EtOAc m.
步骤2：化合物4.2的合成Step 2: Synthesis of Compound 4.2
将化合物4.1(6.0g)、双频哪醇硼酸酯(6.87g，27.1mmol)、醋酸钾(6.13g，62.4mmol)、溴化钠(8.6g，8.33mmol)和Pd(dppf)Cl2(0.76g，1.0mmol)的1,4-二氧六环(65mL)混合物回流搅拌过夜。然后将反应体系冷却至室温，减压除去溶剂，残留物用Flash柱层析纯化(石油醚/乙酸乙酯＝50/1～10/1)得到化合物4.2(3.6g，两步产率：70％)为黄色固体。Compound 4.1 (6.0 g), bispinacol borate (6.87 g, 27.1 mmol), potassium acetate (6.13 g, 62.4 mmol), sodium bromide (8.6 g, 8.33 mmol) and Pd(dppf)Cl 2 (0.76 g, 1.0 mmol) of 1,4-dioxane (65 mL) mixture was stirred at reflux overnight. The reaction system was then cooled to room temperature, and the solvent was evaporated, evaporated, mjjjjjjjjjjj %) is a yellow solid.
步骤3：化合物4.3的合成Step 3: Synthesis of Compound 4.3
氮气保护下，将化合物4.2(3.6g，13.8mmol)、4-溴吡啶(2.1g，13.8mol)、碳酸钾(5.7g，41.4mmol)和Pd(PPh3)4(0.32g，0.28mmol)的水/二氧六环(50mL，4:1)混合物回流搅拌过夜，然后将反应液浓缩，并用乙酸乙酯萃取，有机相用无水硫酸钠干燥、过滤、浓缩得到化合物4.3(2.1g，产率：71％)为浅黄色固体。Compound 4.2 (3.6 g, 13.8 mmol), 4-bromopyridine (2.1 g, 13.8 mol), potassium carbonate (5.7 g, 41.4 mmol) and Pd(PPh 3 ) 4 (0.32 g, 0.28 mmol) under N2. The mixture was stirred with EtOAc EtOAc (EtOAc m. Yield: 71%) as a pale yellow solid.
步骤4：化合物4.4的合成 Step 4: Synthesis of Compound 4.4
向化合物4.3(2.1g，9.67mmol)的甲醇(50mL)溶液中加入Pd/C(200mg，10％)，将该反应体系在氢气氛(氢气球)下室温搅拌过夜。然后将反应体系过滤除去Pd/C，滤液浓缩得到化合物4.4(1.9g，产率：90％)为浅黄色固体。To a solution of Compound 4.3 (2.1 g, 9.67 mmol) in MeOH (50 mL), EtOAc (EtOAc) Then, the reaction system was filtered to remove Pd/C, and the filtrate was concentrated to give Compound 4.4 (1.9 g, yield: 90%) as a pale yellow solid.
m/z:[M+H]+220m/z: [M+H] + 220
步骤5：化合物4.5的合成Step 5: Synthesis of Compound 4.5
将化合物4.4(1.9g，8.66mmol)的盐酸溶液(4.0M，30mL)和丙酮(20mL)混合物在65℃下搅拌过夜。然后将反应体系减压浓缩，残留物用6N氢氧化钠水溶液调pH值＝9，混合物用乙酸乙酯萃取，有机相用无水硫酸钠干燥、过滤、浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝4/1～3/7)纯化得到化合物4.5(800mg，产率：53％)为浅黄色固体。A mixture of compound 4.4 (1.9 g, 8.66 mmol) in EtOAc (EtOAc,EtOAc. The reaction mixture was concentrated under reduced pressure. The residue was purified eluting with EtOAc EtOAc Purification of petroleum ether/ethyl acetate = 4/1 to 3/7) gave Compound 4.5 (800 mg, yield: 53%) as pale yellow solid.
步骤6：化合物4.6的合成Step 6: Synthesis of Compound 4.6
冰浴条件下，向化合物4.5(750mg，4.28mmol)和对甲基苯磺酰甲基异腈(784mg，4.02mmol)的乙二醇二甲醚(20mL)和乙醇(2mL)混合物溶液中加入叔丁醇钾(943mg，7.73mmol)。反应体系室温搅拌过夜，用氯化铵水溶液淬灭反应，然后用乙酸乙酯(3×30mL)萃取，分离出有机相。有机相用饱和食盐水洗涤，过滤，滤液减压浓缩。残留物用Flash柱层析(二氯甲烷/甲醇＝19/1)纯化得到化合物4.6(560mg，产率：70％)为无色油状物。Add to a mixture of compound 4.5 (750 mg, 4.28 mmol) and p-methylbenzenesulfonylmethyl isocyanide (784 mg, 4.02 mmol) in ethylene glycol dimethyl ether (20 mL) and ethanol (2 mL) under ice-bath. Potassium tert-butoxide (943 mg, 7.73 mmol). The reaction was stirred at room temperature overnight, then quenched with EtOAc EtOAc (EtOAc) The organic layer was washed with brine, filtered and evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut
步骤7：化合物4.7的合成Step 7: Synthesis of Compound 4.7
向化合物4.6(560mg，3.01mmol)的甲醇(20mL)溶液中加入Pd/C(50mg，10％)，在氢气氛(氢气球)下室温搅拌过夜。反应液过滤除去Pd/C，滤液浓缩得到化合物4.7(500mg，产率：87％)为浅黄色固体。To a solution of Compound 4.6 (560 mg, 3.01 mmol) in MeOH (20 mL), EtOAc (EtOAc) The reaction solution was filtered to remove Pd/C, and the filtrate was concentrated to give Compound 4.7 (500 mg, yield: 87%) as pale yellow solid.
实施例8：化合物4.8～4.14的合成Example 8: Synthesis of Compounds 4.8 to 4.14
用化合物4.7的合成方法，将步骤3中的4-溴吡啶替换相应的氯化合物或溴化物得到化合物4.8～4.14：Compounds 4.8 to 4.14 are obtained by substituting 4-bromopyridine in step 3 for the corresponding chlorine compound or bromide by the synthesis of compound 4.7:
Figure PCTCN2017095396-appb-000044
Figure PCTCN2017095396-appb-000044
实施例9：化合物4.15的合成Example 9: Synthesis of Compound 4.15
用化合物4.7的合成方法，将步骤6中的化合物4.5替换为化合物3.4得到化合物4.15： Substituting compound 4.5 in step 6 with compound 3.4 to obtain compound 4.15 by the synthesis of compound 4.7:
Figure PCTCN2017095396-appb-000045
Figure PCTCN2017095396-appb-000045
实施例10：化合物4.16的合成Example 10: Synthesis of Compound 4.16
Figure PCTCN2017095396-appb-000046
Figure PCTCN2017095396-appb-000046
氮气保护下，将化合物4.1(2g，6.9mmol)，1-甲基-1H-吡唑-4-硼酸(1.05g，8.3mmol)，Pd(dppf)2Cl2 .CH2Cl2(280mg，0.35mmol)和碳酸钠(2.2g，21mmol)悬浮在1,4-二氧六环(40mL)和水(10mL)中，得到的混合物80℃搅拌4小时。反应混合物冷却至室温，过滤，固体用乙酸乙酯洗涤，滤液减压浓缩，残渣用Flash柱层析(石油醚/乙酸乙酯＝4/1)分离纯化得到化合物4.16(750mg，产率：49％)为无色油状物。Compound 4.1 (2g, 6.9mmol), 1-methyl-1H-pyrazole-4-boronic acid (1.05g, 8.3mmol), Pd(dppf) 2 Cl 2 . CH 2 Cl 2 (280mg, 0.35 mmol) and sodium carbonate (2.2 g, 21 mmol) were suspended in 1,4-dioxane (40 mL) and water (10 mL), and the mixture was stirred at 80 ° C for 4 hours. The reaction mixture was cooled to room temperature, filtered, EtOAc was evaporated,jjjjjjjjjjjjjjj %) is a colorless oil.
m/z:[M+H]+221m/z: [M+H] + 221
实施例11：化合物4.17～4.18的合成Example 11: Synthesis of Compounds 4.17 to 4.18
用化合物4.16的合成方法，将1-甲基-1H-吡唑-4-硼酸替换为4-氰基苯硼酸或4-甲砜基苯硼酸得到化合物4.17～4.18：Substituting 1-methyl-1H-pyrazole-4-boronic acid with 4-cyanobenzeneboronic acid or 4-methylsulfonylbenzeneboronic acid using the synthesis of compound 4.16 to give compounds 4.17 to 4.18:
Figure PCTCN2017095396-appb-000047
Figure PCTCN2017095396-appb-000047
实施例12：化合物4.19～4.21的合成Example 12: Synthesis of Compounds 4.19 to 4.21.
用化合物4.7的合成方法中的步骤4～7，将步骤4中的化合物4.3替换为化合物4.16、4.17或4.18得到化合物4.19～4.21：Substituting the compound 4.3 in the step 4 to the compound 4.16, 4.17 or 4.18 to obtain the compound 4.19 to 4.21 by the steps 4 to 7 in the synthesis method of the compound 4.7:
Figure PCTCN2017095396-appb-000048
Figure PCTCN2017095396-appb-000048
实施例13：化合物4.21a/4.21b的合成Example 13: Synthesis of Compound 4.21a/4.21b
Figure PCTCN2017095396-appb-000049
Figure PCTCN2017095396-appb-000049
用化合物4.6的合成方法，将步骤3中的4-溴吡啶替换为4-氯-6-氟-2-甲基喹啉得到化合物4.20，将4.20用Flash柱层析(石油醚/乙酸乙酯＝6/1～1/1)得到极性较小的化合物4.20a和极性较大的化合物4.20b。 By the synthesis of compound 4.6, 4-bromopyridine in step 3 was replaced with 4-chloro-6-fluoro-2-methylquinoline to give compound 4.20, and 4.20 was flash column chromatography (petroleum ether/ethyl acetate) =6/1 to 1/1) A compound having a relatively small polarity of 4.20a and a compound having a relatively large polarity of 4.20b were obtained.
冰浴冷却下，向化合物4.20a(93mg，0.35mmol)的四氢呋喃(15mL)溶液中缓慢滴加四氢铝锂(2.5M的四氢呋喃溶液，0.70mmol，0.28mL)。反应体系在0℃下搅拌2小时后，加入水(4滴)淬灭反应。滤除固体后，溶液浓缩得到化合物4.21a(110mg，产率：100％)为黄色油状物。用化合物4.21a的合成方法，用化合物4.20b为起始原料得到化合物4.21b。To a solution of the compound 4.20a (93 mg, 0.35 mmol) in tetrahydrofuran (15 mL), EtOAc (EtOAc, EtOAc. After the reaction system was stirred at 0 ° C for 2 hours, water (4 drops) was added to quench the reaction. After filtering off the solid, the solution was concentrated to give compound 4.21a (110 mg, yield: 100%) as a yellow oil. Using the synthesis method of the compound 4.21a, the compound 4.21b was obtained using the compound 4.20b as a starting material.
m/z:[M+H]+273m/z: [M+H] + 273
实施例14：化合物4.8a/4.8b的合成Example 14: Synthesis of Compound 4.8a/4.8b
Figure PCTCN2017095396-appb-000050
Figure PCTCN2017095396-appb-000050
用化合物4.6的合成方法，将步骤3中的4-溴吡啶替换为4-氯-6-氟喹啉得到化合物4.22，将4.22用Flash柱层析(石油醚/乙酸乙酯＝3/1)得到极性较小的化合物4.22a和极性较大的化合物4.22b。用化合物4.21a的合成方法，用化合物4.22a为起始原料得到化合物4.8a；用化合物4.22b为起始原料得到化合物4.8b。By the synthesis of compound 4.6, 4-bromopyridine in step 3 was replaced by 4-chloro-6-fluoroquinoline to give compound 4.22, and 4.22 was flash column chromatography (petroleum ether/ethyl acetate = 3/1). The less polar compound 4.22a and the more polar compound 4.22b were obtained. Using the synthesis method of the compound 4.21a, the compound 4.8a was obtained using the compound 4.22a as a starting material; and the compound 4.8b was obtained using the compound 4.22b as a starting material.
实施例15：化合物4.14a/4.14b的合成Example 15: Synthesis of Compound 4.14a/4.14b
Figure PCTCN2017095396-appb-000051
Figure PCTCN2017095396-appb-000051
用化合物4.6的合成方法，将步骤3中的4-溴吡啶替换为2-甲基-3-氟-4-溴吡啶得到化合物4.23，将4.23用Flash柱层析(石油醚/乙酸乙酯＝3/1)分离得到极性较小的化合物4.23a和极性较大的化合物4.23b。用化合物4.21a的合成方法，用化合物4.23a为起始原料得到化合物4.14a；用化合物4.23b为起始原料得到化合物4.14b。By the synthesis of compound 4.6, 4-bromopyridine in step 3 was replaced by 2-methyl-3-fluoro-4-bromopyridine to give compound 4.23, and 4.23 was flash column chromatography (petroleum ether / ethyl acetate = 3/1) The smaller polar compound 4.23a and the more polar compound 4.23b were isolated. Using the synthesis method of the compound 4.21a, the compound 4.23a was obtained using the compound 4.23a as a starting material; and the compound 4.14b was obtained using the compound 4.23b as a starting material.
实施例16：化合物4.26的合成Example 16: Synthesis of Compound 4.26
Figure PCTCN2017095396-appb-000052
Figure PCTCN2017095396-appb-000052
用化合物4.6的合成方法，将步骤3中的4-溴吡啶替换为2-甲基-4-溴吡啶得到化合物4.25。Substituting 4-bromopyridine in step 3 to 2-methyl-4-bromopyridine to give compound 4.25 by the synthesis of compound 4.6.
化合物4.25(0.5g，2.5mmol)、甲基溴化镁(12.5mmol)溶于四氢呋喃(10.0mL)中，于100℃在微波反应器中反应10分钟。向反应体系中加入钛酸四异丙酯(1.4g，5.0mmol)、甲基溴化镁(5.0mmol)，于50℃在微波反应器中继续反应1小时。向反应体系中加入饱和食盐水(25mL)，用二氯甲烷(100mL)萃取，分液，有机相无水硫酸钠干燥、过滤、浓缩。残留物用Flash柱层析(二氯甲烷/甲醇＝15/1)纯化得到化合物4.26(0.28g，产率：47％)为无色油状物。Compound 4.25 (0.5 g, 2.5 mmol) and methylmagnesium bromide (12.5 mmol) were dissolved in tetrahydrofuran (10.0 mL) and reacted in a microwave reactor at 100 ° C for 10 min. Tetraisopropyl titanate (1.4 g, 5.0 mmol) and methylmagnesium bromide (5.0 mmol) were added to the reaction system, and the reaction was continued at 50 ° C for 1 hour in a microwave reactor. Saturated brine (25 mL) was added to the reaction mixture, and the mixture was evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut
m/z:[M+H]+233m/z: [M+H] + 233
实施例17：化合物4.19b的合成Example 17: Synthesis of Compound 4.19b
Figure PCTCN2017095396-appb-000053
Figure PCTCN2017095396-appb-000053
步骤1：化合物4.28a和4.28b的合成Step 1: Synthesis of Compounds 4.28a and 4.28b
将化合物4.27(1.9g，8.36mmol)的盐酸水溶液(25mL，25mmol，1.0M)和丙酮(25mL)的混合溶液在室温下搅拌2个小时。减压浓缩除去丙酮，残液用乙酸乙酯(100mL×2)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩,残渣用Flash柱层析(石油醚/乙酸乙酯＝4/1)分离纯化得到极性较大的化合物4.28a(1g，产率：56％)和极性较小的化合物4.28b(0.7g，产率：39％)，均为无色液体。A mixed solution of the compound 4.27 (1.9 g, 8.36 mmol) in aqueous hydrochloric acid (25 mL, 25 mmol, 1.0 M) and acetone (25 mL) was stirred at room temperature for 2 hours. The acetone was concentrated under reduced pressure, and the residue was applied ethyl acetate (100 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash column chromatography ( petroleum ether / ethyl acetate = 4/1) to afford the compound 4.28a (1 g). Rate: 56%) and the less polar compound 4.28b (0.7 g, yield: 39%), both being colorless liquid.
m/z:[M+H]+214m/z: [M+H] + 214
步骤2：化合物4.29b的合成Step 2: Synthesis of Compound 4.29b
将化合物4.28b(370mg，1.73mmol)加入甲醇(10mL)中，然后冰水浴下慢慢加入硼氢化钠(66mg，1.73mmol)。该反应体系0～26℃搅拌1个小时后，冰水(50mL)淬灭，用乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物4.29b(314mg，产率：84％)为无色液体。Compound 4.28b (370 mg, 1.73 mmol) was added to MeOH (10 mL), and then sodium borohydride (66 mg, 1.. After the reaction was stirred at 0 to 26 ° C for 1 hour, ice water (50 mL) was evaporated. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated.
m/z:[M+H]+216m/z: [M+H] + 216
步骤3：化合物4.30b的合成Step 3: Synthesis of Compound 4.30b
将化合物4.29b(460mg，2.14mmol)和三乙胺(865mg，8.55mmol)加入二氯甲烷(20mL)中，然后冰水浴下慢慢加入甲基磺酰氯(490mg，4.27mmol)。该反应体系缓慢升至室温并搅拌2个小时后，冰水(10mL)淬灭，有机相分离，水相用乙酸乙酯(50mL)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物4.30b(640mg，粗品)为无色液体。Compound 4.29b (460 mg, 2.14 mmol) and triethylamine (865 mg, 8.55 mmol) were added to dichloromethane (20 mL), and then methanesulfonyl chloride (490 mg, 4.27 mmol) was slowly added in ice water. The reaction was slowly warmed to room temperature and stirred for 2 hr then EtOAc (EtOAc)EtOAc. The combined organic layers were dried with anhydrous sodium sulfate and filtered and evaporated
m/z:[M+H]+294m/z: [M+H] + 294
步骤4：化合物4.31b的合成Step 4: Synthesis of Compound 4.31b
将化合物4.30b(640mg，2.18mmol)和叠氮化钠(710mg，10.9mmol)加入N,N-二甲基甲酰胺(15mL)中，该反应体系100℃搅拌5个小时后，冰水(50mL)淬灭，有机相分离出来，水相用乙酸乙酯(50mL)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物4.31b(480mg，产率：92％)为无色液体。Compound 4.30b (640 mg, 2.18 mmol) and sodium azide (710 mg, 10.9 mmol) were added to N,N-dimethylformamide (15 mL). After stirring at 100 ° C for 5 hours, ice water ( 50 mL) was quenched, the organic phase was separated andEtOAc was evaporated from Et. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and evaporated.
m/z:[M+H]+241m/z: [M+H] + 241
步骤5：化合物4.19b的合成Step 5: Synthesis of Compound 4.19b
将化合物4.31b(480mg，2.0mmol)和钯碳(100mg，10％)加入甲醇(10mL)中，然后在氢气氛(氢气球)下，室温搅拌3小时。过滤，固体用甲醇洗涤，滤液减压浓缩得到化合物4.19b(440mg，粗品)为无色油状物。Compound 4.31b (480 mg, 2.0 mmol) and palladium on carbon (100 mg, 10%) were added to methanol (10 mL), and then stirred under a hydrogen atmosphere (hydrogen balloon) at room temperature for 3 hours. Filtration, the solid was washed with EtOAc (EtOAc)EtOAc.
m/z:[M+H]+215m/z: [M+H] + 215
实施例18：化合物5.3的合成Example 18: Synthesis of Compound 5.3
Figure PCTCN2017095396-appb-000054
Figure PCTCN2017095396-appb-000054
步骤1：化合物5.2的合成Step 1: Synthesis of Compound 5.2
将4-氯-2-甲基吡啶(2.55g，20.0mmol)，化合物5.1(5.14g，24.0mmol)，Pd2(dba)3(458mg，0.5mmol)，BINAP(331mg，0.5mmol)和磷酸钾(5.09g，24.0mmol)悬浮在甲苯(120 mL)中，氮气保护下加热回流4小时。反应混合物冷却至室温，过滤，固体用乙酸乙酯洗涤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝2/3)分离纯化得到化合物5.2(0.96g，产率：15％)为淡黄色油状物体。4-Chloro-2-methylpyridine (2.55 g, 20.0 mmol), compound 5.1 (5.14 g, 24.0 mmol), Pd 2 (dba) 3 (458 mg, 0.5 mmol), BINAP (331 mg, 0.5 mmol) and phosphoric acid Potassium (5.09 g, 24.0 mmol) was suspended in toluene (120 mL). The reaction mixture was cooled to room temperature, filtered, EtOAc EtOAcjjjjjjjj : 15%) is a pale yellow oily substance.
步骤2：化合物5.3的合成Step 2: Synthesis of Compound 5.3
将化合物5.2(305mg，1.0mmol)用乙酸乙酯(10mL)溶解，然后加入氯化氢的1,4-二氧六环溶液(2.5mL，10.0mmol)。该反应体系室温搅拌过夜，过滤、固体用乙酸乙酯(20mL)洗涤，真空干燥后得到化合物5.3(266mg，产率：85％)为淡黄色固体。Compound 5.2 (305 mg, 1.0 mmol) was dissolved in ethyl acetate (10 mL), then EtOAc EtOAc EtOAc. The reaction was stirred with EtOAc (EtOAc)EtOAc.
m/z:[M+H]+206m/z: [M+H] + 206
实施例19：化合物6.3的合成Example 19: Synthesis of Compound 6.3
Figure PCTCN2017095396-appb-000055
Figure PCTCN2017095396-appb-000055
步骤1：化合物6.1的合成Step 1: Synthesis of Compound 6.1
化合物4.12(436mg，2.0mmol)，三乙胺(303mg，3.0mmol)和二碳酸二叔丁酯(480mg，2.2mmol)的二氯甲烷(15mL)溶液在室温下搅拌2小时。减压浓缩除去溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1～4/1)纯化得到化合物6.1(420mg，产率：66％)为无色油状物。A solution of compound 4.12 (436 mg, 2.0 mmol), triethylamine (303 mg, 3.0 mmol) and di-tert-butyl dicarbonate (480 mg, 2.2 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure. EtOAcjjjjjjjjj
m/z:[M+H]+319m/z: [M+H] + 319
步骤2：化合物6.2的合成Step 2: Synthesis of Compound 6.2
化合物6.1(400mg，1.26mmol)溶解在二氯甲烷(15mL)，间氯过氧苯甲酸(282mg，1.64mmol)加入到反应体系中，该反应在室温下搅拌2个小时，加入水(50mL)，二氯甲烷(50mL×2)萃取。合并有机相，用饱和食盐水洗，有机相用无水硫酸钠干燥后减压浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1～1/1)纯化得到化合物6.2(260mg，产率：62％)为白色固体。Compound 6.1 (400 mg, 1.26 mmol) was dissolved in dichloromethane (15 mL) and m-chloroperoxybenzoic acid (282 mg, 1.64 mmol) was added to the reaction system. The reaction was stirred at room temperature for 2 hours, and water (50 mL) was added. Extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine brine The residue was purified by silica gel chromatography chromatography chromatography elut elut elut elut elut
m/z:[M+H]+335m/z: [M+H] + 335
步骤3：化合物6.3的合成Step 3: Synthesis of Compound 6.3
化合物6.2(260mg，0.78mmol)溶解在氯化氢甲醇溶液(7M，10mL)，该反应液在室温下搅拌2个小时，减压浓缩得化合物6.3(170mg，93％)为棕色油状物。Compound 6.2 (260 mg, 0.78 mmol) was dissolved in EtOAc EtOAc (EtOAcjjjjjjjj
m/z:[M+H]+235m/z: [M+H] + 235
实施例20：化合物6.4和6.5a的合成Example 20: Synthesis of Compounds 6.4 and 6.5a
用化合物6.3的合成方法，将化合物4.12替换为化合物4.9或4.14a得到化合物6.4和6.5a：Substituting compound 4.12 with compound 4.9 or 4.14a gives compound 6.4 and 6.5a by the synthesis of compound 6.3:
Figure PCTCN2017095396-appb-000056
Figure PCTCN2017095396-appb-000056
实施例21：化合物7.3的合成 Example 21: Synthesis of Compound 7.3
Figure PCTCN2017095396-appb-000057
Figure PCTCN2017095396-appb-000057
步骤1：化合物7.1的合成Step 1: Synthesis of Compound 7.1
冰浴条件下，向N-氨乙基哌嗪(5.0g，38.7mmol)的四氢呋喃(80mL)溶液加入三氟乙酸乙酯(5.5g，38.7mmol)，将反应体系在室温下搅拌2小时。然后将反应液减压浓缩后得到化合物7.1(9.2g，产率：100％)为无色油状物。To a solution of N-aminoethylpiperazine (5.0 g, 38.7 mmol) in tetrahydrofuran (80 mL) was added ethyl trifluoroacetate (5.5 g, 38.7 mmol), and the mixture was stirred at room temperature for 2 hr. After the reaction mixture was concentrated under reduced pressure, Compound 7.1 (9.2 g, yield: 100%)
m/z:[M+H]+226m/z: [M+H] + 226
步骤2：化合物7.2的合成Step 2: Synthesis of Compound 7.2
向化合物7.1(4.4g，19.5mmol)的乙酸(50mL)溶液中加入4-氯-2-甲基吡啶(2.5g，19.5mmol)，将反应体系在120℃下搅拌16小时。然后将反应液减压浓缩后得到化合物7.2(4.0g，产率：65％)为棕色油状物。4-Chloro-2-methylpyridine (2.5 g, 19.5 mmol) was added to a solution of Compound 7.1 (4.4 g, 19.5 mmol) in EtOAc (50 mL), and the mixture was stirred at 120 ° C for 16 hours. After the reaction mixture was concentrated under reduced pressure, Compound 7.2 (4.0 g, yield: 65%)
m/z:[M+H]+316m/z: [M+H] + 316
步骤3：化合物7.3的合成Step 3: Synthesis of Compound 7.3
化合物7.2(2.0g，6.33mmol)和碳酸钾(4.3g，31.6mmol)溶于甲醇(40mL)和水(20mL)的混合溶剂中，反应体系在室温下搅拌32小时，减压浓缩除去甲醇。残留物用乙酸乙酯稀释，有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用Flash柱层析纯化(二氯甲烷/甲醇＝50/1～10/1)得到化合物7.3(410mg，产率：30％)为黄色油状物。Compound 7.2 (2.0 g, 6.33 mmol) and potassium carbonate (4.3 g, 31.6 mmol) were dissolved in methanol (40 mL) and water (20 mL), and the mixture was stirred at room temperature for 32 hr. The residue was diluted with EtOAc. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut
m/z:[M+H]+221m/z: [M+H] + 221
实施例22：化合物8.2的合成Example 22: Synthesis of Compound 8.2
Figure PCTCN2017095396-appb-000058
Figure PCTCN2017095396-appb-000058
步骤1：肉桂酸甲酯的合成Step 1: Synthesis of methyl cinnamate
冰浴条件下，向肉桂酸(1.0g，6.75mmol)的甲醇(20mL)溶液中滴加草酰氯(2.14g，16.9mmol)，反应体系在室温下搅拌16小时。反应液浓缩除去溶剂，残留物用乙酸乙酯(500mL)溶解，分别用饱和碳酸氢钠水溶液(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥后减压浓缩得到肉桂酸甲酯(1.09g，产率：100％)为黄色油状物。Under ice-cooling, oxalic acid chloride (2.14 g, 16.9 mmol) was added dropwise to a solution of cinnamic acid (1.0 g, 6.75 mmol) in methanol (20 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to drynessnessnessnessnessnessnessnessnessssssssssssssssssssssssssssssss (1.09 g, yield: 100%) was obtained as a yellow oil.
步骤2：化合物8.1的合成Step 2: Synthesis of Compound 8.1
氮气保护下，把肉桂酸甲酯(1.0g，6.1mmol)和对甲基苯磺酰甲基异腈(TosMIC)(1.31g，6.71mmol)溶于四氢呋喃和二甲亚砜(25mL，4:1)的混合溶液中，向反应体系中加入钠氢(60％，370mg，9.15mmol)的四氢呋喃(10mL)悬浮液。滴加完毕后，反应体系加热至80℃搅拌2小时。反应液冷却至室温，加入水(100mL)淬灭反应，乙酸乙酯(50mL×2)萃取。合并有机相，用饱和食盐水洗涤，有机相用无水硫酸钠干燥后减压浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1～1/1)纯化得到化合物8.1(1.1g，产率：90％)为白色固体。Methyl cinnamate (1.0 g, 6.1 mmol) and p-toluenesulfonylmethyl isocyanide (TosMIC) (1.31 g, 6.71 mmol) were dissolved in tetrahydrofuran and dimethyl sulfoxide (25 mL, 4: In a mixed solution of 1), a suspension of sodium hydrogen (60%, 370 mg, 9.15 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture. After the completion of the dropwise addition, the reaction system was heated to 80 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, and then the mixture was evaporated. The combined organic layers were washed with brine brine and evaporated The residue was purified by silica gel chromatography chromatography chromatography elut elut elut elut elut
步骤3：化合物8.2的合成 Step 3: Synthesis of Compound 8.2
化合物8.1(1.1g，5.5mmol)和一水合氢氧化锂(1.84g，44mmol)溶于甲醇(20mL)，四氢呋喃(20mL)和水(10mL)的混合溶剂中，反应体系在80℃下搅拌16小时。冷却至室温后向反应体系中加入水(40mL)，混合物减压浓缩除去有机溶剂。滤去水相中的沉淀。滤液用盐酸(1.0M)调pH至5～6，搅拌30分钟后，过滤，滤饼干燥后得到化合物8.2(450mg，产率：49％)为灰色固体。Compound 8.1 (1.1 g, 5.5 mmol) and lithium hydroxide monohydrate (1.84 g, 44 mmol) were dissolved in methanol (20 mL), tetrahydrofuran (20 mL) and water (10 mL), and the mixture was stirred at 80 ° C. hour. After cooling to room temperature, water (40 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove organic solvent. The precipitate in the aqueous phase was filtered off. The filtrate was adjusted to pH 5-6 with hydrochloric acid (1.0M), stirred for 30 min, filtered, and then filtered and dried to give compound 8.2 (450 mg, yield: 49%) as a grey solid.
m/z:[M+H]+188m/z: [M+H] + 188
实施例23：化合物8.3～8.31的合成Example 23: Synthesis of Compounds 8.3 to 8.31
用化合物8.2的合成方法，将步骤2中的肉桂酸甲酯替换为相应取代的肉桂酸甲酯、取代的肉桂酸乙酯或取代的肉桂酸叔丁酯得到化合物8.3～8.31：By using the synthesis method of compound 8.2, the methyl cinnamate in step 2 is replaced by the corresponding substituted methyl cinnamate, the substituted ethyl cinnamate or the substituted tert-butyl cinnamate to obtain the compound 8.3 to 8.31:
Figure PCTCN2017095396-appb-000059
Figure PCTCN2017095396-appb-000059
化合物编号Compound number R1 R 1 R1a R 1a R1b R 1b R1c R 1c R1d R 1d MSMS
8.38.3 -OCH3 -OCH 3 HH HH HH HH m/z:[M+H]+218m/z: [M+H] + 218
8.48.4 HH -OCH3 -OCH 3 HH HH HH m/z:[M+H]+218m/z: [M+H] + 218
8.58.5 HH ClCl HH HH HH m/z:[M+H]+222m/z: [M+H] + 222
8.68.6 HH HH -OCH2CH3 -OCH 2 CH 3 HH HH m/z:[M+H]+232m/z: [M+H] + 232
8.78.7 HH HH -OCH3 -OCH 3 HH HH m/z:[M+H]+218m/z: [M+H] + 218
8.88.8 HH HH ClCl HH HH m/z:[M+H]+222m/z: [M+H] + 222
8.98.9 -OCF3 -OCF 3 HH HH HH HH m/z:[M+H]+272m/z: [M+H] + 272
8.108.10 FF HH HH HH HH m/z:[M+H]+206m/z: [M+H] + 206
8.118.11 ClCl HH HH HH HH m/z:[M+H]+222m/z: [M+H] + 222
8.128.12 HH HH -OCF3 -OCF 3 HH HH m/z:[M+H]+272m/z: [M+H] + 272
8.138.13 HH FF HH HH HH m/z:[M+H]+206m/z: [M+H] + 206
8.148.14 HH -OCH3 -OCH 3 HH FF HH m/z:[M+H]+236m/z: [M+H] + 236
8.158.15 HH HH -CN-CN HH HH m/z:[M+H]+213m/z: [M+H] + 213
8.168.16 FF FF HH -OCH3 -OCH 3 HH m/z:[M+H]+254m/z: [M+H] + 254
8.178.17 HH -CN-CN HH HH HH m/z:[M+H]+213m/z: [M+H] + 213
8.188.18 -OCH3 -OCH 3 -OCH3 -OCH 3 HH HH HH m/z:[M+H]+248m/z: [M+H] + 248
8.198.19 HH -CH3 -CH 3 HH HH HH m/z:[M+H]+202m/z: [M+H] + 202
8.208.20 HH FF -CN-CN HH HH m/z:[M+H]+231m/z: [M+H] + 231
8.218.21 HH FF -OCH3 -OCH 3 HH HH m/z:[M+H]+236m/z: [M+H] + 236
8.228.22 HH -OCF3 -OCF 3 HH HH HH m/z:[M+H]+272m/z: [M+H] + 272
8.238.23 HH FF -CN-CN HH HH m/z:[M+H]+231m / z: [M + H ] + 231
8.248.24 HH -CN-CN HH FF HH m/z:[M+H]+231m / z: [M + H ] + 231
8.258.25 HH -CN-CN -OCH3 -OCH 3 HH HH m/z:[M+H]+243m/z: [M+H] + 243
8.268.26 FF -OCH3 -OCH 3 HH HH HH m/z:[M+H]+236m/z: [M+H] + 236
8.278.27 HH -OCH3 -OCH 3 FF HH FF m/z:[M+H]+254m/z: [M+H] + 254
8.288.28 FF HH -OCH3 -OCH 3 FF HH m/z:[M+H]+254m/z: [M+H] + 254
8.298.29 FF -OCH3 -OCH 3 FF HH HH m/z:[M+H]+254m/z: [M+H] + 254
8.308.30 HH FF FF -OCH3 -OCH 3 HH m/z:[M+H]+254m/z: [M+H] + 254
8.318.31 HH -OCH3 -OCH 3 -OCH3 -OCH 3 HH HH m/z:[M+H]+248m/z: [M+H] + 248
实施例24：化合物8.32的合成Example 24: Synthesis of Compound 8.32
Figure PCTCN2017095396-appb-000060
Figure PCTCN2017095396-appb-000060
步骤1：化合物8.30的合成Step 1: Synthesis of Compound 8.30
将3,4-二羟基肉桂酸(1.5g，8.33mmol)，苄基溴(6.2g，33.3mmol)和碳酸钾(5.75g，41.7mmol)溶解在N,N-二甲基甲酰胺(50mL)中，反应混合物室温搅拌过夜。反应液用水(500mL)淬灭，加入乙酸乙酯(200mL)萃取，有机层减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝4/1)纯化得到化合物8.30(3.6g，产率：96％)为澄清油状物。3,4-Dihydroxycinnamic acid (1.5 g, 8.33 mmol), benzyl bromide (6.2 g, 33.3 mmol) and potassium carbonate (5.75 g, 41.7 mmol) were dissolved in N,N-dimethylformamide (50 mL) The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc EtOAc EtOAc (EtOAc) , Yield: 96%) as a clear oil.
步骤2：化合物8.31的合成Step 2: Synthesis of Compound 8.31
将化合物8.30(3.6g，8.0mmol)和对甲基苯磺酰甲基异腈(2.3g，12.0mmol)溶解在四氢呋喃(50mL)中，冷却至0℃缓慢加入叔丁醇钾(1.61g，14.4mmol)，反应液0℃下搅拌2小时。然后用水(100mL)淬灭反应，加入乙酸乙酯(200mL)萃取，有机层减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝4/1)纯化得到化合物8.31(2.5g，产率：64％)为黄色固体。The compound 8.30 (3.6 g, 8.0 mmol) and p-methylbenzenesulfonylmethyl isocyanide (2.3 g, 12.0 mmol) were dissolved in tetrahydrofuran (50 mL), and then cooled to 0 ° C slowly, potassium tert-butoxide (1.61 g, 14.4 mmol), the reaction solution was stirred at 0 ° C for 2 hours. The reaction was then quenched with EtOAc (EtOAc (EtOAc)EtOAc. , Yield: 64%) as a yellow solid.
步骤3：化合物8.32的合成Step 3: Synthesis of Compound 8.32
将化合物8.31(0.5g，1.02mmol)和10％钯碳(0.5g)加入到四氢呋喃(30mL)中，反应体系抽真空，氢气置换三次，反应体系在氢气氛下室温搅拌12小时。反应液用硅藻土过滤，滤液减压浓缩得到化合物8.32(307mg，产率：100％)为黑色固体。Compound 8.31 (0.5 g, 1.02 mmol) and 10% palladium on carbon (0.5 g) were added to tetrahydrofuran (30 mL), and the reaction mixture was evaporated, and the mixture was stirred three times with hydrogen, and the reaction mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
实施例25：化合物8.33的合成Example 25: Synthesis of Compound 8.33
根据化合物8.32的合成方法，用3-羟基肉桂酸为起始原料合成化合物8.33：According to the synthesis method of compound 8.32, compound 8.33 was synthesized using 3-hydroxycinnamic acid as a starting material:
Figure PCTCN2017095396-appb-000061
Figure PCTCN2017095396-appb-000061
实施例26：化合物9.2的合成Example 26: Synthesis of Compound 9.2
Figure PCTCN2017095396-appb-000062
Figure PCTCN2017095396-appb-000062
步骤1：化合物9.1的合成：Step 1: Synthesis of Compound 9.1:
向苯甲醛(1.0g，8.4mmol)，氰基乙酸乙酯(0.82g，8.4mmol)和三乙胺盐酸盐(2.86g，20.8mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入叠氮化钠(1.62g，25mmol)，反 应体系加热至100℃并搅拌4小时。反应体系用乙酸乙酯(100mL)稀释后用水和饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1～1/1)纯化得到化合物9.1(1.1g，产率：62％)为白色固体。To a solution of benzaldehyde (1.0 g, 8.4 mmol), ethyl cyanoacetate (0.82 g, 8.4 mmol) and triethylamine hydrochloride (2.86 g, 20.8 mmol) of N,N-dimethylformamide (20 mL) Add sodium azide (1.62g, 25mmol) to the solution, reverse The system was heated to 100 ° C and stirred for 4 hours. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut
步骤2：化合物9.2的合成：Step 2: Synthesis of Compound 9.2:
化合物9.1(1.1g，5.1mmol)和一水合氢氧化锂(1.84g，44mmol)溶于乙醇(20mL)，四氢呋喃(20mL)和水(10mL)的混合溶剂中，加热至50℃搅拌16小时。向反应液中加入水(40mL)，减压浓缩除去大部分有机溶剂。滤去水相中的沉淀。滤液用盐酸(1.0M)调pH至5～6，搅拌30分钟后，过滤，滤饼干燥后得到化合物9.2(450mg，产率：49％)为灰色固体。Compound 9.1 (1.1 g, 5.1 mmol) and lithium hydroxide monohydrate (1.84 g, 44 mmol) were dissolved in ethanol (20 mL), tetrahydrofuran (20 mL) and water (10 mL). Water (40 mL) was added to the reaction mixture, and the mixture was evaporated. The precipitate in the aqueous phase was filtered off. The filtrate was adjusted to pH 5-6 with hydrochloric acid (1.0M). After stirring for 30 min, filtered, and the filter cake was dried to give compound 9.2 (450 mg, yield: 49%) as a gray solid.
m/z:[M+H]+190m/z: [M+H] + 190
实施例27：化合物10.2的合成Example 27: Synthesis of Compound 10.2
Figure PCTCN2017095396-appb-000063
Figure PCTCN2017095396-appb-000063
步骤1：化合物10.1的合成Step 1: Synthesis of Compound 10.1
向乙炔基苯(1.02g，10mmol)和碳酸银(275mg，1.0mmol)的N-甲基吡咯烷酮(15mL)溶液中缓慢加入氰基乙酸乙酯(1.7g，15mmol)，反应体系在80℃下搅拌2小时，冷却至室温后过滤，滤液中加入水(15mL)，并用二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩。残留物用Flash柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物10.1(850mg，产率：40％)为无色油状物。To a solution of ethynylbenzene (1.02 g, 10 mmol) and silver carbonate (275 mg, 1.0 mmol) in N-methylpyrrolidone (15 mL), ethyl cyanoacetate (1.7 g, 15 mmol) was slowly added at 80 ° C After stirring for 2 hours, it was cooled to room temperature, and filtered. Water (15 mL) was evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut
m/z:[M+H]+216m/z: [M+H] + 216
步骤2：化合物10.2的合成Step 2: Synthesis of Compound 10.2
将化合物10.1(850mg，3.9mmol)加入到无水四氢呋喃(15mL)、乙醇(2mL)和水(2mL)的混合溶剂中，该体系于80℃下搅拌12个小时，减压浓缩后，用盐酸(1.0M)调pH＝5～6，固体过滤，滤饼干燥后得到化合物10.2(520mg，产率:71％)为白色固体。The compound 10.1 (850 mg, 3.9 mmol) was added to a mixed solvent of anhydrous tetrahydrofuran (15 mL), ethanol (2 mL) and water (2 mL), and the mixture was stirred at 80 ° C for 12 hours, concentrated under reduced pressure, with hydrochloric acid (1.0 M) The pH was adjusted to 5 to 6. The solid was filtered, and the filter cake was dried to give Compound 10.2 (520 mg, yield: 71%) as a white solid.
m/z:[M+H]+188m/z: [M+H] + 188
实施例28：化合物11.3的合成Example 28: Synthesis of Compound 11.3
Figure PCTCN2017095396-appb-000064
Figure PCTCN2017095396-appb-000064
步骤1：化合物11.1的合成Step 1: Synthesis of Compound 11.1
冰浴条件下，向氨基乙醛缩二乙醇(2g，15.0mmol)和三乙胺(2.13g，21.0mmol)的乙酸乙酯(30mL)溶液中逐滴加入乙酰氯(1.3g，16.5mmol)。该反应体系室温搅拌1小时，然后向反应液中加入乙醇(0.3mL)，继续搅拌1小时，过滤，滤液减压浓缩得化合物5.1(2.5g)为棕色油状物，无需纯化直接用于下一步反应。Acetyl chloride (1.3 g, 16.5 mmol) was added dropwise to a solution of aminoacetaldehyde diethyl acetal (2 g, 15.0 mmol) and triethylamine (2.13 g, 21.0 mmol) in ethyl acetate (30 mL). . The reaction mixture was stirred at room temperature for 1 hour, then ethanol (0.3 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr. reaction.
步骤2：化合物11.2的合成Step 2: Synthesis of Compound 11.2
将化合物11.1(2.5g，14.3mmol)和苯甲酰乙酸乙酯(2.0g，10.4mmol)的三氟乙酸(6 mL)溶液在60℃下搅拌1小时，减压浓缩去除三氟乙酸，残渣溶于乙酸乙酯(50mL)中，分别用水(25mL×2)和饱和碳酸氢钠水溶液(25mL)洗，有机相减压浓缩，所得油状物溶于乙醇(14mL)和氢氧化钠水溶液(2.0M，7mL)中，室温搅拌过夜。反应液用盐酸(2.0M)调至pH＝5～6，并用乙酸乙酯(30mL×3)萃取，有机相用水洗，干燥，浓缩，残留物经硅胶柱层析(石油醚/乙酸乙酯＝10/1～4/1)纯化得到化合物11.2(280mg，两步产率：9％)为淡黄色油状物。Compound 11.1 (2.5 g, 14.3 mmol) and ethyl benzoylacetate (2.0 g, 10.4 mmol) in trifluoroacetic acid (6) The solution was stirred at 60 ° C for 1 hour, and concentrated under reduced pressure to remove trifluoroacetic acid. The residue was dissolved in ethyl acetate (50 mL) and washed with water (25mL×2) and saturated aqueous sodium hydrogen carbonate (25mL) The organic layer was concentrated under reduced vacuo. The reaction mixture was adjusted to pH = 5-6 with EtOAc (EtOAc) (EtOAc) Purification of compound 11.2 (280 mg, mp. yield: 9%)
m/z:[M+H]+216m/z: [M+H] + 216
步骤3：化合物11.3的合成Step 3: Synthesis of Compound 11.3
将化合物11.2(280mg，1.30mmol)和一水合氢氧化锂(254mg，6.05mmol)加入到乙醇(8mL)和水(2mL)的混合溶剂中，加热搅拌回流过夜。反应液减压浓缩除去乙醇，并用盐酸(2.0M)调pH＝5～6。所得固体过滤，滤饼真空干燥后得化合物11.3(180mg，产率：74％)为灰色固体。The compound 11.2 (280 mg, 1.30 mmol) and lithium hydroxide monohydrate (254 mg, 6.05 mmol) were added to a mixed solvent of ethanol (8 mL) and water (2 mL), and stirred under reflux overnight. The reaction solution was concentrated under reduced pressure to remove ethanol, and pH was adjusted to 5 to 6 with hydrochloric acid (2.0M). The obtained solid was filtered, and then filtered and evaporated to dryness.
m/z:[M+H]+188m/z: [M+H] + 188
实施例29：化合物12.2的合成Example 29: Synthesis of Compound 12.2
Figure PCTCN2017095396-appb-000065
Figure PCTCN2017095396-appb-000065
步骤1：3-(吡啶-3-基)丙烯酸乙酯的合成Step 1: Synthesis of ethyl 3-(pyridin-3-yl)acrylate
冰浴条件下，向3-吡啶甲醛(2.14g，20mmol)和膦酰乙酸三乙酯(6.72g，30mmol)的四氢呋喃(40mL)溶液中分批次加入叔丁醇钾(3.36g，30mmol)，该反应体系在80℃下搅拌4小时。将反应体系减压浓缩，残留物溶于乙酸乙酯(100mL)中，依次用饱和氯化铵水溶液(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压浓缩。残留物用硅胶柱色谱(石油醚/乙酸乙酯＝10/1～>1/1)分离得到3-(吡啶-3-基)丙烯酸乙酯(2.3g，产率65％)为浅黄色固体。To a solution of 3-pyridinecarboxaldehyde (2.14 g, 20 mmol) and triethylphosphonoacetate (6.72 g, 30 mmol) in tetrahydrofuran (40 mL) EtOAc (3. The reaction system was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. The residue was purified by silica gel column chromatography (EtOAc (EtOAcEtOAcEtOAcEtOAc .
m/z:[M+H]+178m/z: [M+H] + 178
步骤2：化合物12.1的合成Step 2: Synthesis of Compound 12.1
氮气保护下，把3-(吡啶-3-基)丙烯酸乙酯(2.3g，13.0mmol)和TosMIC(2.64g，6.71mmol)溶于四氢呋喃(40mL)和二甲亚砜(10mL)的混合溶液中，向反应体系中加入钠氢(60％，780mg，19.5mmol)的四氢呋喃(15mL)悬浮液。滴加完毕后，反应体系加热至80℃搅拌2小时。反应液冷至室温，加入水(100mL)淬灭反应，乙酸乙酯(100mL×2)萃取。合并有机相，用饱和食盐水洗，有机相用无水硫酸钠干燥、浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1～1/1)纯化得到化合物12.1(2.39g，产率：85％)为白色固体。A mixed solution of ethyl 3-(pyridin-3-yl)acrylate (2.3 g, 13.0 mmol) and TosMIC (2.64 g, 6.71 mmol) in tetrahydrofuran (40 mL) and dimethyl sulfoxide (10 mL). A suspension of sodium hydrogen (60%, 780 mg, 19.5 mmol) in tetrahydrofuran (15 mL) was added to the reaction mixture. After the completion of the dropwise addition, the reaction system was heated to 80 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature and then quenched with water (100 mL) The organic phase was combined, washed with brine brine and evaporated The residue was purified by silica gel column chromatography eluting elut elut elut elut elut
步骤3：化合物12.2的合成Step 3: Synthesis of Compound 12.2
化合物12.1(2.39g，11.1mmol)和一水合氢氧化锂(3.68g，88mmol)溶于甲醇(30mL)，四氢呋喃(30mL)和水(15mL)的混合溶剂中，反应体系在80℃下搅拌16小时。冷却至室温后向反应体系中加入水(60mL)，减压浓缩除去有机溶剂。滤去水相中的沉淀。滤液用盐酸(1.0M)调pH至5～6，搅拌30分钟后，过滤，滤饼干燥后得到化合物12.2(1.1g，产率：52％)为灰色固体。 Compound 12.1 (2.39 g, 11.1 mmol) and lithium hydroxide monohydrate (3.68 g, 88 mmol) were dissolved in methanol (30 mL), tetrahydrofuran (30 mL) and water (15 mL), and the mixture was stirred at 80 ° C. hour. After cooling to room temperature, water (60 mL) was added to the reaction mixture, and the organic solvent was evaporated. The precipitate in the aqueous phase was filtered off. The filtrate was adjusted to pH 5-6 with hydrochloric acid (1.0M), stirred for 30 min, filtered, and then filtered, and then filtered to afford compound 12.2 (1.1 g, yield: 52%) as a grey solid.
m/z:[M+H]+189m/z: [M+H] + 189
实施例30：化合物12.3～12.6的合成Example 30: Synthesis of Compounds 12.3 to 12.6
用化合物12.2的合成方法，将3-吡啶甲醛替换为嘧啶-5-甲醛、4-吡啶甲醛、5-甲氧基-2-吡啶醛、或3-甲氧基-2-吡啶醛得到化合物12.3～12.6：Substituting 3-pyridinecarboxaldehyde to pyrimidine-5-formaldehyde, 4-pyridinecarboxaldehyde, 5-methoxy-2-pyridine aldehyde, or 3-methoxy-2-pyridine aldehyde by the synthesis of compound 12.2 to obtain compound 12.3 ~12.6:
Figure PCTCN2017095396-appb-000066
Figure PCTCN2017095396-appb-000066
实施例31：化合物13.2的合成Example 31: Synthesis of Compound 13.2
Figure PCTCN2017095396-appb-000067
Figure PCTCN2017095396-appb-000067
步骤1：化合物13.1的合成Step 1: Synthesis of Compound 13.1
将4-苯基恶唑(1g，6.89mmol)和苯丙炔酸乙酯(1.2g，6.89mmol)在封管中，在250℃下反应36小时。然后将反应体系冷却至室温后，直接用Flash柱层析纯化(石油醚/乙酸乙酯＝10/1)得到化合物13.1(1.18g，产率：79％)为无色油状物。4-Phenyloxazole (1 g, 6.89 mmol) and ethyl phenylpropynoate (1.2 g, 6.89 mmol) were placed in a sealed tube and reacted at 250 ° C for 36 hours. After the reaction mixture was cooled to room temperature, it was purified by flash column chromatography (ethyl ether / ethyl acetate = 10/1) to afford compound 13.1 (1.18 g, yield: 79%) as colorless oil.
m/z:[M+H]+217m/z: [M+H] + 217
步骤2：化合物13.2的合成Step 2: Synthesis of Compound 13.2
将化合物13.1(600mg，2.78mmol)和氢氧化锂一水合物(467mg，11.11mmol)的乙醇(8mL)和水(2mL)混合物在80℃下搅拌4小时。减压浓缩除去乙醇，然后用盐酸(1.0M)调pH至4～5，将析出的固体滤出，滤饼用少量水洗涤后真空干燥得到化合物13.2(300mg，产率：57％)为黄色固体。A mixture of compound 13.1 (600 mg, 2.78 mmol) and lithium hydroxide monohydrate (467 mg, 11.11 mmol) in ethanol (8 mL) and water (2 mL) was stirred at 80 ° C for 4 hr. The ethanol was concentrated under reduced pressure, and then the mixture was adjusted to pH 4 to 5 with hydrochloric acid (1.0M), and the precipitated solid was filtered. The filter cake was washed with a small amount of water and dried in vacuo to give compound 13.2 (300 mg, yield: 57%) as yellow. solid.
m/z:[M+H]+189m / z: [M + H ] + 189
实施例32：化合物14.1的合成Example 32: Synthesis of Compound 14.1
Figure PCTCN2017095396-appb-000068
Figure PCTCN2017095396-appb-000068
将1H-咪唑-4-羧酸甲酯(1.0g，7.93mmol)，1-氟-4-硝基苯(1.12g，7.93mmol)和碳酸铯(3.88g，11.9mmol)的N,N-二甲基甲酰胺(25mL)的混合物在80℃下搅拌48小时。然后将反应液冷却至室温，加入水(100mL)淬灭反应，用乙酸乙酯(100mL×2)萃取，合并有机相，用无水硫酸钠干燥、浓缩得到化合物14.1(600mg，产率：31％)为浅黄色固体。 1H-imidazole-4-carboxylic acid methyl ester (1.0 g, 7.93 mmol), 1-fluoro-4-nitrobenzene (1.12 g, 7.93 mmol) and cesium carbonate (3.88 g, 11.9 mmol) of N,N- A mixture of dimethylformamide (25 mL) was stirred at 80 ° C for 48 hours. After the reaction mixture was cooled to room temperature, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated %) is a pale yellow solid.
实施例33：化合物15.2的合成Example 33: Synthesis of Compound 15.2
Figure PCTCN2017095396-appb-000069
Figure PCTCN2017095396-appb-000069
步骤1：化合物15.1的合成Step 1: Synthesis of Compound 15.1
将化合物8.1(300mg，1.49mmol)，碘甲烷(529mg,3.73mmol)，碳酸钾(515mg，3.73mmol)的二甲亚砜(15mL)混合物在室温下搅拌4小时。然后将反应体系倒入水(100mL)中，用乙酸乙酯萃取，有机相用无水硫酸钠干燥、浓缩得到化合物15.1(250mg，产率：77％)为黄色固体。A mixture of compound 8.1 (300 mg, 1.49 mmol), EtOAc (EtOAc, EtOAc, EtOAc) The reaction system was poured into water (100 mL), EtOAc (EtOAc)
步骤2：化合物15.2的合成Step 2: Synthesis of Compound 15.2
向化合物15.1(250mg，1.16mmol)的甲醇(5mL)溶液中加入氢氧化钠水溶液(10mL，4.0M)，将反应体系回流搅拌16小时。然后将反应液冷却至室温，用盐酸(2.0M)调节pH值至3～4，用乙酸乙酯萃取，有机相用无水硫酸钠干燥、浓缩得到化合物15.2(150mg，产率：64％)为黄色固体。A solution of the compound 15.1 (250 mg, 1.16 mmol) in methanol (5 mL) was evaporated. The reaction mixture was cooled to room temperature, and the pH was adjusted to 3 to 4 with EtOAc (EtOAc) (EtOAc) It is a yellow solid.
实施例34：化合物15.3～15.4的合成Example 34: Synthesis of Compounds 15.3 to 15.4
用化合物15.2的合成方法，将化合物8.1替换为1-甲基-4-(2-(三氟甲氧基)苯基)-1H-吡咯-3-羧酸甲酯、或1-甲基-4-(3-(甲氧基)苯基)-1H-吡咯-3-羧酸甲酯得到化合物15.3和15.4：Substituting compound 8.1 with methyl 1-methyl-4-(2-(trifluoromethoxy)phenyl)-1H-pyrrole-3-carboxylate or 1-methyl- by the synthesis of compound 15.2 Methyl 4-(3-(methoxy)phenyl)-1H-pyrrole-3-carboxylate gave compounds 15.3 and 15.4:
Figure PCTCN2017095396-appb-000070
Figure PCTCN2017095396-appb-000070
实施例35：化合物16.4的合成Example 35: Synthesis of Compound 16.4
Figure PCTCN2017095396-appb-000071
Figure PCTCN2017095396-appb-000071
步骤1：化合物16.2的合成：Step 1: Synthesis of Compound 16.2:
将化合物16.1(663mg，2.8mmol)，二氢吡喃(706mg，8.4mmol)和吡啶对甲苯磺酸盐(70mg，0.28mmol)的甲苯(10mL)溶液在45℃下搅拌2小时。反应液减压浓缩除去溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1->4/1)纯化得到化合物16.2(870mg，产率：96％)为无色油状物。A solution of compound 16.1 (663 mg, 2.8 mmol), dihydropyran (706 mg, 8.4 mmol) and pyridine p-toluenesulfonate (70 mg, 0.28 mmol) in toluene (10 mL) was stirred at 45 ° C for 2 hours. The reaction mixture was concentrated to drynessnessnessnessnessnessnessnessnessnessnessnessnessssssssssssssssssssssssssssssss .
m/z:[M+H]+321m/z: [M+H] + 321
步骤2：化合物16.3的合成：Step 2: Synthesis of Compound 16.3:
氮气保护下，把化合物16.2(870mg，2.7mmol)和TosMIC(636mg，3.2mmol)溶于四氢呋喃和二甲亚砜(25mL，4:1)的混合溶液中，向反应体系中加入钠氢(60％，162mg，4.1mmol)的四氢呋喃(10mL)悬浮液。滴加完毕后，反应体系加热至80℃搅拌2小时。反应液冷却至室温，加入水(100mL)淬灭反应，乙酸乙酯(50mL×2)萃取。合并有机相， 用饱和食盐水洗，有机相用无水硫酸钠干燥、减压浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1～1/1)纯化得到化合物16.3(240mg，产率：25％)为白色固体。Under a nitrogen atmosphere, compound 16.2 (870 mg, 2.7 mmol) and TosMIC (636 mg, 3.2 mmol) were dissolved in a mixed solution of tetrahydrofuran and dimethyl sulfoxide (25 mL, 4:1), and sodium hydrogen (60) was added to the reaction system. A suspension of %, 162 mg, 4.1 mmol) in tetrahydrofuran (10 mL). After the completion of the dropwise addition, the reaction system was heated to 80 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, and then the mixture was evaporated. Combine the organic phase, The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut
m/z:[M+H]+360m/z: [M+H] + 360
步骤3：化合物16.4的合成：Step 3: Synthesis of Compound 16.4:
化合物16.3(240mg，0.67mmol)和一水合氢氧化锂(225mg，5.34mmol)加入到乙醇(5mL)，四氢呋喃(5mL)和水(2.5mL)的混合溶剂中，加热至80℃搅拌48小时。向反应液中加入水(20mL)，减压浓缩除去大部分有机溶剂。滤去水相中的沉淀。滤液用盐酸(1.0M)调pH至5～6，搅拌30分钟后，过滤，滤饼干燥后得到化合物16.4(103mg，产率：50％)为黄色固体。Compound 16.3 (240 mg, 0.67 mmol) and lithium hydroxide monohydrate (225 mg, 5.34 mmol) were added to a mixed solvent of ethanol (5 mL), tetrahydrofuran (5 mL) and water (2.5 mL), and the mixture was stirred at 80 ° C for 48 hours. Water (20 mL) was added to the reaction mixture, and the mixture was evaporated. The precipitate in the aqueous phase was filtered off. The filtrate was adjusted to pH 5-6 with hydrochloric acid (1.0M). After stirring for 30 min, filtered, and then filtered, dried to give compound 16.4 (103 mg, yield: 50%) as a yellow solid.
m/z:[M+H]+332m / z: [M + H ] + 332
实施例36：化合物17.4的合成Example 36: Synthesis of Compound 17.4
Figure PCTCN2017095396-appb-000072
Figure PCTCN2017095396-appb-000072
步骤1：化合物17.1的合成Step 1: Synthesis of Compound 17.1
冰浴条件下，向2-溴-1-苯乙酮(5.0g，44.2mmol)的四氢呋喃(25mL)溶液中分批加入纳氢(60％，2.1g，52.5mmol)，反应体系0℃搅拌半小时后，将氰乙酸乙酯(10.0g，52.5mmol)的四氢呋喃(10mL)溶液滴加到上述反应体系中。将反应体系缓慢升至室温，并在室温下搅拌4小时。反应液用水淬灭，然后用乙醚萃取。分离有机相，有机相用无水硫酸镁干燥。过滤，滤液浓缩。残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到化合物17.1(5.5g，产率：54％)为淡黄色固体。Under ice-cooling, a solution of 2-bromo-1-acetophenone (5.0 g, 44.2 mmol) in tetrahydrofuran (25 mL) was added portionwise NaH (60%, 2.1 g, 52.5 mmol), and the mixture was stirred at 0 ° C. After half an hour, a solution of ethyl cyanoacetate (10.0 g, 52.5 mmol) in tetrahydrofuran (10 mL) was added dropwise to the above reaction. The reaction system was slowly warmed to room temperature and stirred at room temperature for 4 hours. The reaction was quenched with water and then extracted with diethyl ether. The organic phase was separated and the organic phase dried over anhydrous magnesium sulfate. Filter and concentrate the filtrate. The residue was purified to silicagel elut elut elut elut elut elut elut
m/z:[M+H]+232m/z: [M+H] + 232
步骤2：化合物17.2的合成Step 2: Synthesis of Compound 17.2
冰浴条件下，将化合物17.1(5.0g，21.6mmol)的盐酸1,4-二氧六环溶液(50mL，4.0M)在室温下搅拌16小时。将反应体系浓缩。残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到化合物17.2(1.0g，产率：19％)为黄色固体。Compound 17.1 (5.0 g, 21.6 mmol) in 1,4-dioxane hydrochloride (50 mL, 4.0 M) was stirred at room temperature for 16 hr. The reaction system was concentrated. The residue was purified with EtOAc EtOAcjjjjjjjjj
m/z:[M+H]+250m/z: [M+H] + 250
步骤3：化合物17.3的合成Step 3: Synthesis of Compound 17.3
将化合物17.2(1.0g，4.0mmol)和钯碳(50mg，5％)的乙醇(15mL)混合物在氢气氛(氢气球)下室温搅拌过夜。反应体系过滤，滤液浓缩至干，得到化合物17.3(800mg，产率：93％)为黄色固体。A mixture of compound 17.2 (1.0 g, 4.0 mmol) and palladium on carbon (50 mg, 5%) in ethanol (15 mL) was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon) overnight. The reaction system was filtered, and the filtrate was concentrated to dryness to afford compound 17.3 (800 mg, yield: 93%) as a yellow solid.
m/z:[M+H]+216m/z: [M+H] + 216
步骤4：化合物17.4的合成Step 4: Synthesis of Compound 17.4
将化合物17.3(800mg，3.7mmol)和一水氢氧化锂(1.25g，29.7mmol)加入到乙醇/四氢呋喃/水(10mL/10mL/5mL)的混合溶剂中，反应体系升温至80℃并搅拌16小时。反应液用盐酸(1.0M)调节pH＝6-7。混合物浓缩至1/4体积，有白色固体析出，过滤，滤饼在50℃下真空干燥得到化合物17.4(160mg，产率：23％)白色固体。Compound 17.3 (800 mg, 3.7 mmol) and lithium hydroxide monohydrate (1.25 g, 29.7 mmol) were added to a mixed solvent of ethanol/tetrahydrofuran/water (10 mL/10 mL/5 mL), and the reaction system was warmed to 80 ° C and stirred 16 hour. The reaction solution was adjusted to pH = 6-7 with hydrochloric acid (1.0M). The mixture was concentrated to 1/4 vol., and a white solid was precipitated, filtered, and the filter cake was dried under vacuum at 50 ° C to afford compound 17.4 (160 mg, yield: 23%) as a white solid.
m/z:[M+H]+188 m/z: [M+H] + 188
实施例37：化合物18.2的合成Example 37: Synthesis of Compound 18.2
Figure PCTCN2017095396-appb-000073
Figure PCTCN2017095396-appb-000073
步骤1：化合物18.1的合成Step 1: Synthesis of Compound 18.1
将4-溴-1H-吡咯-2-羧酸甲酯(1.02g，5.0mmol)，苯硼酸(732mg，6.0mmol)，Pd(dppf)Cl2(176mg，0.25mmol)和碳酸钠水溶液(2.0M，7.5mL，15mmol)加入到1,4二氧六环(50mL)中，反应体系在氮气保护下加热回流搅拌过夜。然后将反应混合物冷却至室温，用冰水(50mL)稀释，乙酸乙酯(2×50mL)萃取，合并有机相后减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物18.1(0.55g，产率：55％)为淡黄色固体。Methyl 4-bromo-1H-pyrrole-2-carboxylate (1.02 g, 5.0 mmol), phenylboronic acid (732 mg, 6.0 mmol), Pd (dppf) Cl 2 (176 mg, 0.25 mmol) and aqueous sodium carbonate (2.0) M, 7.5 mL, 15 mmol) was added to 1,4-dioxane (50 mL). After the reaction mixture was cooled to room temperature, diluted with EtOAc (EtOAc) (EtOAc) /1) Purification gave Compound 18.1 (0.55 g, yield: 55%) as pale yellow solid.
m/z:[M+H]+202m/z: [M+H] + 202
步骤2：化合物18.2的合成Step 2: Synthesis of Compound 18.2
向化合物18.1(201mg，1.0mmol)的甲醇(5.0mL)和四氢呋喃(5.0mL)混合溶液中加入氢氧化锂(126mg，3.0mmol)的水溶液(5.0mL)。反应体系在60℃下搅拌3个小时，然后冷却至室温，用冰水稀释(20mL)，所得的固体过滤，滤饼用冰水洗涤，真空干燥后得到化合物18.2(150mg，产率：80％)为淡黄色固体。A mixed solution of lithium hydroxide (126 mg, 3.0 mmol) (5.0 mL) was added to a mixture of the compound 18.1 (201 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL). The reaction system was stirred at 60 ° C for 3 hours, then cooled to room temperature, diluted with ice water (20 mL), and the obtained solid was filtered, and the filter cake was washed with ice water and dried in vacuo to give compound 18.2 (150 mg, yield: 80%) ) is a pale yellow solid.
m/z:[M+H]+188m/z: [M+H] + 188
实施例38：化合物19.4的合成Example 38: Synthesis of Compound 19.4
Figure PCTCN2017095396-appb-000074
Figure PCTCN2017095396-appb-000074
步骤1：化合物19.1的合成Step 1: Synthesis of Compound 19.1
氮气保护下，将碳酸二甲酯(3.0g，33.3mmol)和钠氢(60％，1.9g，46.6mmol)的甲苯(20mL)溶液加热至110℃,然后向反应体系中滴加3-甲氧基苯乙酮(2.5g，16.6mmol)的甲苯(20mL)溶液，滴加完毕，将反应体系在110℃下搅拌3小时。然后将反应液降温至0℃。用醋酸淬灭反应调节pH＝3。过滤，滤液倒入水中并用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥、过滤、浓缩。残留物用Flash柱层析纯化(石油醚/乙酸乙酯＝50/1～4/1)得到化合物19.1(2.9g，产率：84％)为黄色油状物。Under a nitrogen atmosphere, a solution of dimethyl carbonate (3.0 g, 33.3 mmol) and sodium hydrogen (60%, 1.9 g, 46.6 mmol) in toluene (20 mL) was heated to 110 ° C, then 3-A was added dropwise to the reaction system. A solution of oxyacetophenone (2.5 g, 16.6 mmol) in toluene (20 mL) was added dropwise, and the reaction mixture was stirred at 110 ° C for 3 hours. The reaction was then cooled to 0 °C. The reaction was quenched with acetic acid to adjust pH = 3. After filtration, the filtrate was poured into water and extracted with ethyl acetate. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut
步骤2：化合物19.2的合成Step 2: Synthesis of Compound 19.2
将化合物19.1(2.9g，13.9mmol)在N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)(20mL)中回流1小时。然后将反应体系冷却至室温，减压除去溶剂，残留物用Flash柱层析纯化(二氯甲烷/甲醇＝100/1～95/5)得到化合物19.2(2.9g，产率：78％)为黄色油状物。Compound 19.1 (2.9 g, 13.9 mmol) was refluxed for 1 hour in N,N-dimethylformamide dimethyl acetal (DMF- DMA) (20 mL). Then, the reaction system was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/methanol = 100/1 to 95/5) to afford compound 19.2 (2.9 g, yield: 78%) Yellow oil.
步骤3：化合物19.3的合成Step 3: Synthesis of Compound 19.3
氮气保护下，将化合物19.2(2.9g，10.9mmol)和氨水(873mg，17.4mol)加入甲醇(20mL)中回流3小时，然后将反应液浓缩，得到化合物19.3(2.5g，产率：100％)为浅黄色油状物。Compound 19.2 (2.9 g, 10.9 mmol) and aqueous ammonia (873 mg, 17.4 mol) were added to methanol (20 mL) and refluxed for 3 hours under nitrogen, and then the reaction mixture was concentrated to give compound 19.3 (2.5 g, yield: 100%) ) is a light yellow oil.
步骤4：化合物19.4的合成Step 4: Synthesis of Compound 19.4
化合物19.3(2.6g，10.9mmol)和一水合氢氧化锂(3.7g，87.2mmol)溶于甲醇(20mL)， 四氢呋喃(20mL)和水(10mL)的混合溶剂中，反应体系在80℃下搅拌16小时。冷却至室温后向反应体系中加入水(40mL)，混合物减压浓缩除去有机溶剂。滤去水相中的沉淀。滤液用盐酸(1.0M)调pH至5～6，搅拌30分钟后，过滤，滤饼干燥后用Flash柱层析纯化(二氯甲烷/甲醇＝100/1～95/5)得到化合物19.4(320mg，产率：13.4％)为白色固体。Compound 19.3 (2.6 g, 10.9 mmol) and lithium hydroxide monohydrate (3.7 g, 87.2 mmol) were dissolved in methanol (20 mL). The reaction system was stirred at 80 ° C for 16 hours in a mixed solvent of tetrahydrofuran (20 mL) and water (10 mL). After cooling to room temperature, water (40 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove organic solvent. The precipitate in the aqueous phase was filtered off. The filtrate was adjusted to pH 5-6 with hydrochloric acid (1.0M). After stirring for 30 min, filtered, filtered, dried and purified by flash column chromatography (dichloromethane/methanol = 100/1 to 95/5) 320 mg, yield: 13.4%) was a white solid.
m/z:[M+H]+219m/z: [M+H] + 219
实施例39：化合物19.5～19.6的合成Example 39: Synthesis of Compounds 19.5 to 19.6
用化合物19.4的合成方法，将3-甲氧基苯乙酮替换为苯乙酮或2-甲氧基苯乙酮得到化合物19.5～19.6：Compounds 19.5 to 19.6 were obtained by the synthesis of compound 19.4 by replacing 3-methoxyacetophenone with acetophenone or 2-methoxyacetophenone:
Figure PCTCN2017095396-appb-000075
Figure PCTCN2017095396-appb-000075
化合物编号Compound number R1 R 1 R1a R 1a R1b R 1b MSMS
19.519.5 HH HH HH m/z:[M+H]+189m/z: [M+H] + 189
19.619.6 HH HH 甲氧基Methoxy m/z:[M+H]+219m/z: [M+H] + 219
实施例40：化合物20.3的合成Example 40: Synthesis of Compound 20.3
Figure PCTCN2017095396-appb-000076
Figure PCTCN2017095396-appb-000076
步骤1：化合物20.1的合成Step 1: Synthesis of Compound 20.1
向苯甲酰乙酸乙酯(1.0g，5.20mmol)的丙酮(25mL)溶液中分批加入碳酸钾(1.08g，7.80mmol)和溴代丙酮(1.07g，7.80mmol)，反应体系加热至回流，搅拌16小时后，将反应液冷却至室温，倒入水中，然后用乙酸乙酯萃取。分离有机相，有机相用无水硫酸镁干燥。过滤，滤液浓缩。残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到化合物20.1(750mg，产率：58％)为淡黄色固体。Potassium carbonate (1.08 g, 7.80 mmol) and bromoacetone (1.07 g, 7.80 mmol) were added portionwise to a solution of ethyl benzoylacetate (1.0 g, 5.20 mmol) in acetone (25 mL). After stirring for 16 hours, the reaction solution was cooled to room temperature, poured into water, and then extracted with ethyl acetate. The organic phase was separated and the organic phase dried over anhydrous magnesium sulfate. Filter and concentrate the filtrate. The residue was purified with EtOAcjjjjjjjjjjjj
m/z:[M+H]+249m/z: [M+H] + 249
步骤2：化合物20.2的合成Step 2: Synthesis of Compound 20.2
向化合物20.1(750mg，3.20mmol)的乙醇(15mL)溶液中分批加入40％氨水溶液(2.0mL)反应体系加热至回流，搅拌4小时后，将反应液冷却至室温，倒入水中，然后用乙酸乙酯萃取。分离有机相，有机相用无水硫酸镁干燥。过滤，滤液浓缩。残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物20.2(280mg，产率：40％)为淡黄色固体。To a solution of compound 20.1 (750 mg, 3.20 mmol) in ethanol (15 mL), a 40% aqueous ammonia solution (2.0 mL) was added to the reaction system, and the mixture was heated to reflux. After stirring for 4 hours, the reaction solution was cooled to room temperature and poured into water, then Extract with ethyl acetate. The organic phase was separated and the organic phase dried over anhydrous magnesium sulfate. Filter and concentrate the filtrate. The residue was purified to silicagel elut elut elut elut elut elut elut elut
m/z:[M+H]+230m/z: [M+H] + 230
步骤3：化合物20.3的合成Step 3: Synthesis of Compound 20.3
向化合物20.2(280mg，1.22mmol)的甲醇(5.0mL)和四氢呋喃(5.0mL)混合溶液中加入一水合氢氧化锂(126mg，3.0mmol)的水溶液(5.0mL)。反应体系在60℃下搅拌3个小时，然后冷却至室温，用冰水稀释(20mL)，所得的固体过滤，滤饼用冰水洗涤，真空干燥后得到化合物20.3(120mg，产率：49％)为淡黄色固体。To a mixed solution of the compound 20.2 (280 mg, 1.22 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL), aqueous solution of lithium hydroxide (126 mg, 3.0 mmol) (5.0 mL) was added. The reaction system was stirred at 60 ° C for 3 hours, then cooled to room temperature, diluted with ice water (20 mL), and the obtained solid was filtered, and the filter cake was washed with ice water and dried in vacuo to give compound 20.3 (120 mg, yield: 49%) ) is a pale yellow solid.
m/z:[M+H]+202m/z: [M+H] + 202
实施例41：化合物20.4～20.13的合成 Example 41: Synthesis of Compounds 20.4 to 20.13
用化合物8.2的合成方法，将苯甲酰乙酸乙酯替换为相应取代的苯甲酰乙酸乙酯得到化合物20.5～20.13：By the synthesis of compound 8.2, ethyl benzoylacetate is replaced by the corresponding substituted ethyl benzoylacetate to give compound 20.5 to 20.13:
Figure PCTCN2017095396-appb-000077
Figure PCTCN2017095396-appb-000077
化合物编号Compound number R1 R 1 R1a R 1a R1b R 1b R1c R 1c MSMS
20.420.4 HH HH -OCH3 -OCH 3 HH m/z:[M+H]+232m/z: [M+H] + 232
20.520.5 HH -OCH3 -OCH 3 HH HH m/z:[M+H]+232m/z: [M+H] + 232
20.620.6 HH HH -OCF3 -OCF 3 HH m/z:[M+H]+286m/z: [M+H] + 286
20.720.7 HH -OCF3 -OCF 3 HH HH m/z:[M+H]+286m/z: [M+H] + 286
20.820.8 -OCF3 -OCF 3 HH HH HH m/z:[M+H]+286m/z: [M+H] + 286
20.920.9 HH HH -CN-CN HH m/z:[M+H]+227m/z: [M+H] + 227
20.1020.10 HH HH -CN-CN -OCF3 -OCF 3 m/z:[M+H]+257m/z: [M+H] + 257
20.1120.11 HH HH FF HH m/z:[M+H]+220m/z: [M+H] + 220
20.1220.12 HH -OCH3 -OCH 3 HH -OCH3 -OCH 3 m/z:[M+H]+248m/z: [M+H] + 248
20.1320.13 HH -OCH3 -OCH 3 -OCH3 -OCH 3 HH m/z:[M+H]+248m / z: [M + H ] + 248
实施例42：化合物20.16的合成Example 42: Synthesis of Compound 20.16
用化合物20.3的合成方法，将苯甲酰乙酸乙酯替换为3-氧代-3-(吡啶-3-基)丙酸乙酯得到化合物20.16：By the synthesis of compound 20.3, ethyl benzoylacetate was replaced with ethyl 3-oxo-3-(pyridin-3-yl)propanoate to give compound 20.16:
Figure PCTCN2017095396-appb-000078
Figure PCTCN2017095396-appb-000078
实施例43：化合物20.17～20.18的合成Example 43: Synthesis of Compounds 20.17 to 20.18
用化合物20.3的合成方法，用1-溴-3-甲基-2-丁酮和苯甲酰乙酸乙酯或2-氰基苯甲酰乙酸乙酯反应得到化合物20.17～20.18：The compound 200.3 is reacted with 1-bromo-3-methyl-2-butanone and ethyl benzoylacetate or ethyl 2-cyanobenzoylacetate to give the compound 20.17 to 20.18:
Figure PCTCN2017095396-appb-000079
Figure PCTCN2017095396-appb-000079
化合物编号Compound number R1 R 1 R1a R 1a R1b R 1b MSMS
20.1720.17 HH HH -OCF3 -OCF 3 m/z:[M+H]+314m/z: [M+H] + 314
20.1820.18 HH HH -CN-CN m/z:[M+H]+255m/z: [M+H] + 255
实施例44：化合物20.19的合成Example 44: Synthesis of Compound 20.19
用化合物8.2的合成方法，用2-氰基基苯甲酰乙酸乙酯和1-溴-2-丁酮反应到化合物20.19：Reaction of compound 8.2 with ethyl 2-cyanobenzoylacetate and 1-bromo-2-butanone to compound 20.19:
Figure PCTCN2017095396-appb-000080
Figure PCTCN2017095396-appb-000080
Figure PCTCN2017095396-appb-000081
Figure PCTCN2017095396-appb-000081
实施例45：化合物20.21和20.22的合成Example 45: Synthesis of Compounds 20.21 and 20.22
Figure PCTCN2017095396-appb-000082
Figure PCTCN2017095396-appb-000082
化合物20.20按照化合物20.3的合成方法，用2-氰基-6-甲氧基苯甲酰乙酸甲酯反应得到。将化合物20.20(160mg，0.59mmol)，氢氧化钠(47mg，1.18mmol)溶解在甲醇和水(4mL/4mL)的混合物溶剂中，反应混合物80℃搅拌2小时。反应液用盐酸(1.0M)调pH＝2-3，加入乙酸乙酯(20mL×3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥、过滤、浓缩得到化合物20.21和20.22的混合物(95mg，产率：59％)为白色固体。The compound 20.20 was obtained by the reaction of the compound 20.3 by the reaction of methyl 2-cyano-6-methoxybenzoylacetate. Compound 20.20 (160 mg, 0.59 mmol), sodium hydroxide (47 mg, 1.18 mmol) was dissolved in a solvent mixture of methanol and water (4mL / 4mL), and the mixture was stirred at 80 ° C for 2 hours. The reaction mixture was adjusted to pH 2-3 with hydrochloric acid (1.0M), ethyl acetate (20 mL×3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture of compound 20.21. (95 mg, yield: 59%) was obtained as a white solid.
实施例46：化合物21.3的合成Example 46: Synthesis of Compound 21.3
Figure PCTCN2017095396-appb-000083
Figure PCTCN2017095396-appb-000083
步骤1：化合物21.1的合成Step 1: Synthesis of Compound 21.1
向邻甲氧基苯甲酰氯(9.75mL，77.1mmol)的石油醚(18mL)溶液中分批加入氢氧化钠水溶液(2.08g，52.0mmol，3mL)的水溶液，在0℃下搅拌30分钟，加入乙酰乙酸乙酯(11.4mL，98.1mmol)，然后分批加入氢氧化钠(5.1g，12.8mmol，12mL)的水溶液，反应体系在0℃下搅拌1小时，然后升至35℃搅拌1.6小时，再将反应液冷却至0℃，倒入水中，过滤收集白色固体，用水和石油醚洗涤固体，真空干燥后得到化合物21.1(5.7g，收率32％)为白色粉末。A solution of aqueous sodium hydroxide (2.08 g, 52.0 mmol, 3 mL) was added portionwise to a solution of o-methoxybenzoyl chloride (9.75 mL, 77.1 mmol) in petroleum ether (18 mL) and stirred at 0 ° C for 30 min. Ethyl acetoacetate (11.4 mL, 98.1 mmol) was added, and then an aqueous solution of sodium hydroxide (5.1 g, 12.8 mmol, 12 mL) was added portionwise, and the reaction system was stirred at 0 ° C for 1 hour, then raised to 35 ° C and stirred for 1.6 hours. The reaction solution was cooled to 0 ° C, poured into water, and then filtered, white solid was evaporated, and the solid was washed with water and petroleum ether to afford compound 21.1 (5.7 g, yield 32%) as white powder.
m/z:[M+H]+265m/z: [M+H] + 265
步骤2：化合物21.2的合成Step 2: Synthesis of Compound 21.2
向化合物21.1(5.0g，18.9mmol)的乙醇(50mL)溶液中分批加入85％水合肼溶液(20.0mL)，将反应体系加热回流搅拌4小时后，将反应液冷却至室温，倒入水中，然后用乙酸乙酯萃取。分离有机相，有机相用无水硫酸镁干燥。过滤，滤液浓缩。残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物21.2(2.1g，产率：48％)为淡黄色固体。To a solution of the compound 21.1 (5.0 g, 18.9 mmol) in ethanol (50 mL), 85% hydrazine hydrate solution (20.0 mL) was added portionwise, and the reaction system was heated under reflux for 4 hours, then the reaction solution was cooled to room temperature and poured into water. Then extracted with ethyl acetate. The organic phase was separated and the organic phase dried over anhydrous magnesium sulfate. Filter and concentrate the filtrate. The residue was purified to silicagel elut elut elut elut elut elut elut elut
m/z:[M+H]+231m/z: [M+H] + 231
步骤3：化合物21.3的合成Step 3: Synthesis of Compound 21.3
向化合物21.2(2.1g，9.12mmol)的甲醇(10.0mL)和四氢呋喃(10.0mL)混合溶液中加入氢氧化锂(1.15g，27.4mmol)的水溶液(10.0mL)。反应体系在60℃下搅拌3个小时，然后冷却至室温，用冰水稀释(20mL)，所得的固体过滤，滤饼用冰水洗涤，真空干燥后得到化合物21.3(900mg，产率：49％)为淡黄色固体。To a mixed solution of the compound 21.2 (2.1 g, 9.12 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL), aqueous solution (10.0 mL) of lithium hydroxide (1.15 g, 27.4 mmol) was added. The reaction system was stirred at 60 ° C for 3 hours, then cooled to room temperature, diluted with ice water (20 mL), and the obtained solid was filtered, and the filter cake was washed with ice water and dried in vacuo to give compound 21.3 (900 mg, yield: 49%) ) is a pale yellow solid.
m/z:[M+H]+203m/z: [M+H] + 203
实施例47：化合物22.2的合成 Example 47: Synthesis of Compound 22.2
Figure PCTCN2017095396-appb-000084
Figure PCTCN2017095396-appb-000084
步骤1：化合物22.1的合成Step 1: Synthesis of Compound 22.1
苯甲酰乙酸乙酯(3.0g，15.6mmol)溶解在DMF-DMA(11.2g,93.7mmol)中，反应体系回流搅拌1小时。反应液减压浓缩，残留物用Flash柱层析纯化(石油醚/乙酸乙酯＝2/1)得到化合物22.1(2.9g，产率：75％)为无色油状物。Ethyl benzoylacetate (3.0 g, 15.6 mmol) was dissolved in DMF-DMA (11.2 g, 93.7 mmol), and the mixture was stirred under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj
m/z:[M+H]+248m/z: [M+H] + 248
步骤2：化合物22.2的合成Step 2: Synthesis of Compound 22.2
将化合物22.1(2.9g，11.7mmol)，乙酸钾(1.15g，11.7mmol)和盐酸羟胺(815mg，11.7mmol)溶于乙醚(40mL)和甲醇(20mL)中，反应体系室温搅拌过夜。反应液加入水，乙酸乙酯(3×30mL)萃取，分离出有机相。有机相用饱和食盐水洗涤，过滤、浓缩。残留物用Flash柱层析纯化(石油醚/乙酸乙酯＝4/1)得到化合物22.2(1.55g，产率：61％)为无色油状物。The compound 22.1 (2.9 g, 11.7 mmol), potassium acetate (1.15 g, 11.7 mmol) and hydroxyamine hydrochloride (815 mg, 11.7 mmol) were dissolved in diethyl ether (40 mL) and methanol (20 mL). The reaction mixture was poured into water and ethyl acetate (3×30 mL) The organic phase was washed with brine, filtered and evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut
m/z:[M+H]+218m/z: [M+H] + 218
实施例48：化合物23.3的合成Example 48: Synthesis of Compound 23.3
Figure PCTCN2017095396-appb-000085
Figure PCTCN2017095396-appb-000085
步骤1：化合物23.1的合成Step 1: Synthesis of Compound 23.1
氮气保护下，将2-三氟甲氧基苯甲醛(3.8g，0.20mol)，碳酸氢铵(1.85g，0.24mol)，硝基甲烷(20mL)和醋酸(20mL)的混合物在90℃下搅拌5小时。反应液冷却至室温，加水(50mL)稀释，饱和碳酸氢钠水溶液调节pH＝6-7，乙酸乙酯(50mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝50/1)纯化得到化合物23.1(3.67g，产率：79％)为淡黄色油状物。Mixture of 2-trifluoromethoxybenzaldehyde (3.8 g, 0.20 mol), ammonium hydrogencarbonate (1.85 g, 0.24 mol), nitromethane (20 mL) and acetic acid (20 mL) at 90 ° C under N2 Stir for 5 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), EtOAc (EtOAc) The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj
1HNMR(400MHz,CDCl3):δ8.19(d,J＝13.6Hz,1H),7.66-7.62(m,2H),7.58-7.53(m,1H),7.39(t,J＝7.2Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ): δ 8.19 (d, J = 13.6 Hz, 1H), 7.66-7.62 (m, 2H), 7.58-7.53 (m, 1H), 7.39 (t, J = 7.2 Hz, 2H).
步骤2：化合物23.2的合成Step 2: Synthesis of Compound 23.2
将甲醇钠的甲醇溶液(1.2mL，6.99mmol)缓慢滴加到化合物23.1(1.3g，5.83mmol)和3-氧代丁酸苄酯(1.34g，6.99mmol)的甲醇(20mL)溶液中。反应混合物室温搅拌1小时后，加入氨甲醇溶液(10mL，7.0M)搅拌过夜。反应液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物23.2(500mg，产率：24％)为淡黄色油状物。A solution of sodium methoxide in methanol (1.2 mL, 6.99 mmol) was slowly added dropwise to a solution of Compound 23.1 (1.3 g, 5. <RTIgt; After the reaction mixture was stirred at room temperature for 1 hour, aqueous ammonia (10 mL, 7.0 M) was added and stirred overnight. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj
m/z:[M+H]+376m/z: [M+H] + 376
步骤3：化合物23.3的合成Step 3: Synthesis of Compound 23.3
氮气保护下，将化合物23.2(500mg，1.33mmoL)和钯碳(500mg，10％)下加入到甲醇溶液(30mL)中，氢化过夜。反应混合物过滤，滤液减压浓缩，残留物用Flash柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物23.3(370mg，产率：97％)为白色固体。 Compound 23.2 (500 mg, 1.33 mmoL) and palladium on carbon (500 mg, 10%) were added to a methanol solution (30 mL) under nitrogen and hydrogenated overnight. The reaction mixture was filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
m/z:[M+H]+286m/z: [M+H] + 286
实施例49：化合物23.5的合成Example 49: Synthesis of Compound 23.5
Figure PCTCN2017095396-appb-000086
Figure PCTCN2017095396-appb-000086
步骤1：化合物23.4的合成Step 1: Synthesis of Compound 23.4
3-(2-氰基苯基)丙烯酸乙酯(1.0g，4.97mmol)和2-(4-甲基苯磺酰)丙腈(1.56g，7.46mmol)溶解在四氢呋喃中(10mL)，冰浴下缓慢加入叔丁醇钾(837mg，7.46mmol)，加毕，室温搅拌3小时。减压浓缩，残渣用Flash柱层析(石油醚/乙酸乙酯＝3/1)分离纯化得到化合物23.4(680mg，产率：54％)为棕色固体。Ethyl 3-(2-cyanophenyl)acrylate (1.0 g, 4.97 mmol) and 2-(4-methylbenzenesulfonyl)propanenitrile (1.56 g, 7.46 mmol) were dissolved in tetrahydrofuran (10 mL), ice Potassium tert-butoxide (837 mg, 7.46 mmol) was slowly added under a bath, and the mixture was stirred at room temperature for 3 hours. The organic layer was concentrated under reduced pressure. EtOAcjjjjjjj
m/z:[M+H]+255m/z: [M+H] + 255
步骤3：化合物23.5的合成Step 3: Synthesis of Compound 23.5
化合物23.4(150mg，0.59mmoL)和氢氧化钠(118mg，2.95mmol)溶解在甲醇(10mL)和水(10mL)中，反应体系在90℃下搅拌过夜。减压浓缩除去有机溶剂，残留物用盐酸水溶液(1.0M)调pH至3～4，所得固体过滤，真空干燥后得到化合物23.5(120mg，产率：90％)为黄色固体。Compound 23.4 (150 mg, 0.59 mmol) and sodium hydroxide (118 mg, 2.95 mmol) were dissolved in methanol (10 mL) and water (10 mL), and the mixture was stirred at 90 ° C overnight. The organic solvent was concentrated under reduced pressure. EtOAc EtOAc m.
m/z:[M+H]+227m/z: [M+H] + 227
实施例50：化合物24.2的合成Example 50: Synthesis of Compound 24.2
Figure PCTCN2017095396-appb-000087
Figure PCTCN2017095396-appb-000087
步骤1：化合物24.1的合成Step 1: Synthesis of Compound 24.1
4-溴噻吩-3-羧酸甲酯(400mg，1.84mmol)，2-(三氟甲氧基)苯硼酸(800mg，3.69mmol),四三苯基膦钯(104mg，0.09mmol)和磷酸钾(976mg，4.60mmol)溶于二氧六环(12mL)和水(1.2mL)的混合溶剂中，反应体系在100℃，微波条件下反应1小时。冷却至室温后向反应体系中加入乙酸乙酯(100mL)，有机相用饱和食盐水(30mL×2)洗涤。有机相用无水硫酸钠干燥、过滤、浓缩，残留物用Flash柱层析纯化(石油醚/乙酸乙酯＝30/1～10/1)得到化合物24.1(600mg，产率：95.8％)为无色油状物。Methyl 4-bromothiophene-3-carboxylate (400 mg, 1.84 mmol), 2-(trifluoromethoxy)benzeneboronic acid (800 mg, 3.69 mmol), tetratriphenylphosphine palladium (104 mg, 0.09 mmol) and phosphoric acid Potassium (976 mg, 4.60 mmol) was dissolved in a mixed solvent of dioxane (12 mL) and water (1.2 mL), and the reaction was reacted at 100 ° C for 1 hour under microwave conditions. After cooling to room temperature, ethyl acetate (100 mL) was added to the reaction mixture, and the organic phase was washed with saturated brine (30 mL×2). The organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered and evaporated. Colorless oil.
m/z:[M+H]+303m/z: [M+H] + 303
步骤3：化合物4的合成Step 3: Synthesis of Compound 4
化合物24.1(168mg，0.56mmol)和氢氧化钾(93mg，1.67mmol)溶于甲醇(5mL)，四氢呋喃(5mL)和水(1.5mL)的混合溶剂中，反应体系在70℃下搅拌4小时。冷却至室温后，用盐酸(2.0M)调pH至2～3，混合物用乙酸乙酯(60mL)萃取，有机相用无水硫酸钠干燥后直接浓缩得到化合物24.2(140mg，产率：100％)为黄色固体。The compound 24.1 (168 mg, 0.56 mmol) and potassium hydroxide (93 mg, 1.67 mmol) were dissolved in methanol (5 mL), tetrahydrofuran (5 mL) and water (1.5 mL), and the mixture was stirred at 70 ° C for 4 hours. After cooling to room temperature, the mixture was adjusted to pH 2-3 with EtOAc (EtOAc) (EtOAc) (EtOAc) ) is a yellow solid.
m/z:[M+H]+289m/z: [M+H] + 289
实施例51：化合物24.3的合成Example 51: Synthesis of Compound 24.3
用化合物24.2的合成方法，用3-溴噻酚-2-羧酸甲酯反应得到化合物24.3： Reaction of compound 23.2 with methyl 3-bromothiophene-2-carboxylate affords compound 24.3:
Figure PCTCN2017095396-appb-000088
Figure PCTCN2017095396-appb-000088
实施例52：化合物1-1的合成Example 52: Synthesis of Compound 1-1
Figure PCTCN2017095396-appb-000089
Figure PCTCN2017095396-appb-000089
化合物4-苯基-1H-吡唑-3-羧酸(130mg，0.69mmol)，化合物1.6(156mg，0.69mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(159mg，0.83mmol)混合后悬浮在二氯甲烷(20mL)中，缓慢加入N,N-二异丙基乙胺(DIPEA)(446mg，3.45mmol)和4-二甲氨基吡啶(8.5mg，0.069mmol)。反应体系在室温搅拌过夜后，用冰水淬灭(50mL)反应，并用二氯甲烷(30mL)稀释后分出有机相，有机相用饱和食盐水(25mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用Flash柱层析(石油醚/乙酸乙酯＝2/1)纯化得到化合物1-1(72.5mg，产率：30％)为类白色固体。Compound 4-Phenyl-1H-pyrazole-3-carboxylic acid (130 mg, 0.69 mmol), compound 1.6 (156 mg, 0.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbazide The amine hydrochloride (EDCI) (159 mg, 0.83 mmol) was mixed and suspended in dichloromethane (20 mL). N,N-diisopropylethylamine (DIPEA) (446 mg, 3.45 mmol) and 4- Methylaminopyridine (8.5 mg, 0.069 mmol). After the reaction mixture was stirred at rt EtOAc EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (ethyl ether / ethyl acetate = 2/1) to afford Compound 1-1 (72.5mg, yield: 30%) as white off solid.
m/z:[M+H]+360；1H NMR(400MHz,DMSO-d6):δ13.47(br.s,0.15H),13.28(s,0.85H),8.18-8.20(m,1H),8.07(s,1H),7.58-7.62(m,2H),7.16-7.35(m,8H),3.34-3.37(m,1H),3.11-3.14(m,1H),2.46-2.51(m,1H),1.07-1.86(m,9H)。m/z: [M+H] + 360; 1 H NMR (400 MHz, DMSO-d 6 ): δ 13.47 (br.s, 0.15H), 13.28 (s, 0.85H), 8.18-8.20 (m, 1H), 8.07 (s, 1H), 7.58-7.62 (m, 2H), 7.16-7.35 (m, 8H), 3.34-3.37 (m, 1H), 3.11-3.14 (m, 1H), 2.46-2.51 ( m, 1H), 1.07-1.86 (m, 9H).
实施例53：化合物2-1的合成Example 53: Synthesis of Compound 2-1
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物9.2得到化合物2-1：Compound 2-1 is obtained by substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 9.2 by the synthesis of compound 1-1:
Figure PCTCN2017095396-appb-000090
Figure PCTCN2017095396-appb-000090
m/z:[M+H]+361m/z: [M+H] + 361
实施例54：化合物3-1～3-2的合成Example 54: Synthesis of Compounds 3-1 to 3-2
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物19.4或19.5得到化合物3-1～3-2：By using the synthesis method of the compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid was replaced with the compound 19.4 or 19.5 to obtain the compound 3-1 to 3-2:
Figure PCTCN2017095396-appb-000091
Figure PCTCN2017095396-appb-000091
化合物3-1(130mg，顺反异构体混合物)用硅胶柱层析(石油醚/乙酸乙酯＝4/1～1/1)分离得到极性较小的化合物3-1a(13.8mg，单一立体构型)和极性较大的化合物3-1b(31.5mg，单一立体构型)均为白色固体。The compound 3-1 (130 mg, cis-trans isomer mixture) was separated by silica gel column chromatography ( petroleum ether / ethyl acetate = 4/1 to 1/1) to give the compound 3-1a (13.8 mg, The single stereo configuration) and the more polar compound 3-1b (31.5 mg, single stereo configuration) were all white solids.
m/z:[M+H]+360；3-1a,1H NMR(400MHz,CDCl3):δ8.12(s,1H),7.59-7.64(m,2H),7.48-7.54(m,3H),7.29-7.34(m,2H),7.17-7.26(m,3H),5.60(br.s,1H),3.41(dd,J＝6.0,8.0Hz,2H),2.53-2.62(m,1H),1.56-1.79(m,9H)；3-1b,1H NMR(400MHz,CDCl3):δ10.41(br.s,1H),8.12(s,1H),7.60-7.64(m,2H),7.49-7.53(m,3H),7.29-7.34(m,2H),7.17-7.24(m,3H),5.66(br.s,1H),3.21(dd,J＝6.0,6.4Hz,2H),2.38-2.48(m,1H),1.85-1.94(m, 2H),1.66-1.74(m,2H),1.38-1.48(m,3H),0.95-1.08(m,2H)。m/z: [M+H] + 360; 3-1a, 1 H NMR (400MHz, CDCl 3 ): δ 8.12 (s, 1H), 7.59-7.64 (m, 2H), 7.48-7.54 (m, 3H), 7.29-7.34 (m, 2H), 7.17-7.26 (m, 3H), 5.60 (br.s, 1H), 3.41 (dd, J = 6.0, 8.0 Hz, 2H), 2.53-2.62 (m, 1H), 1.56-1.79 (m, 9H); 3-1b, 1 H NMR (400MHz, CDCl 3 ): δ 10.41 (br.s, 1H), 8.12 (s, 1H), 7.60-7.64 (m, 2H), 7.49-7.53 (m, 3H), 7.29-7.34 (m, 2H), 7.17-7.24 (m, 3H), 5.66 (br.s, 1H), 3.21 (dd, J = 6.0, 6.4 Hz, 2H), 2.38-2.48 (m, 1H), 1.85-1.94 (m, 2H), 1.66-1.74 (m, 2H), 1.38-1.48 (m, 3H), 0.95-1.08 (m, 2H).
Figure PCTCN2017095396-appb-000092
Figure PCTCN2017095396-appb-000092
化合物3-2(186mg，顺反异构体混合物)经prep-HPLC(分离条件1)得到化合物3-2a(16.6mg，出峰时间：19.0～20.0分钟，单一立体构型)和3-2b(8.9mg，出峰时间：18.5～19.0分钟，单一立体构型)，均为白色固体。Compound 3-2 (186 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 3-2a (16.6 mg, peak time: 19.0 to 20.0 min, single stereo configuration) and 3-2b (8.9 mg, peak time: 18.5 to 19.0 minutes, single stereo configuration), all white solids.
m/z:[M+H]+390；3-2a,1H NMR(400MHz,CD3OD):δ7.98(s,1H),7.35-7.39(m,1H),7.20-7.30(m,6H),7.14-7.17(m,1H),7.00-7.01(m,1H),3.84(s,3H),3.45(d,J＝7.6Hz,2H),2.57-2.62(m,1H),1.61-1.96(m,9H)；3-2b,1H NMR(400MHz,CD3OD):δ8.00(s,1H),7.38-7.42(t,J＝8.0Hz,1H),7.20-7.29(m,6H),7.14-7.17(m,1H),7.02-7.03(m,1H),3.86(s,3H),3.21(d,J＝6.8Hz,2H),2.44-2.50(m,1H),1.84-1.90(m,4H),1.44-1.62(m,3H),1.07-1.17(m,2H)。m/z: [M+H] + 390; 3-2a, 1 H NMR (400 MHz, CD 3 OD): δ 7.98 (s, 1H), 7.35-7.39 (m, 1H), 7.20-7.30 (m) , 6H), 7.14-7.17 (m, 1H), 7.00-7.01 (m, 1H), 3.84 (s, 3H), 3.45 (d, J = 7.6 Hz, 2H), 2.57-2.62 (m, 1H), 1.61-1.96 (m, 9H); 3-2b, 1 H NMR (400 MHz, CD 3 OD): δ 8.00 (s, 1H), 7.38-7.42 (t, J = 8.0 Hz, 1H), 7.20-7.29 (m, 6H), 7.14-7.17 (m, 1H), 7.02-7.03 (m, 1H), 3.86 (s, 3H), 3.21 (d, J = 6.8 Hz, 2H), 2.44-2.50 (m, 1H) ), 1.84-1.90 (m, 4H), 1.44-1.62 (m, 3H), 1.07-1.17 (m, 2H).
实施例55：化合物4-1～4-2的合成Example 55: Synthesis of Compounds 4-1 to 4-2
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物19.6和化合物4.7或4.9反应得到化合物4-1～4-2：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid was replaced with compound 19.6 and compound 4.7 or 4.9 to give compound 4-1 to 4-2:
Figure PCTCN2017095396-appb-000093
Figure PCTCN2017095396-appb-000093
化合物4-1(187mg，顺反异构体混合物)经prep-HPLC(分离条件1)得到化合物4-1a(20mg，出峰时间：18.5～20.0分钟，单一立体构型)和4-1b(12mg，出峰时间：16.3～18.0分钟，单一立体构型)，均为白色固体。Compound 4-1 (187 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 4-1a (20 mg, peak time: 18.5 to 20.0 minutes, single stereo configuration) and 4-1b ( 12 mg, peak time: 16.3 to 18.0 minutes, single stereo configuration), all white solids.
m/z:[M+H]+391；4-1a,1H NMR(400MHz,CD3OD):δ7.98(s,1H),7.41-7.51(m,2H),7.08-7.28(m,6H),3.84(s,3H),3.14(d,J＝6.4Hz,2H),2.39-2.46(m,1H),1.40-1.87(m,7H),0.98-1.09(m,2H)；4-1b,1HNMR(400MHz,CD3OD):δ7.98(s,1H),7.40-7.49(m,2H),7.05-7.28(m,6H),3.82(s,3H),3.38(d,J＝7.6Hz,2H),2.54-2.59(m,1H),1.60-1.86(m,9H)。m/z: [M+H] + 391; 4-1a, 1 H NMR (400 MHz, CD 3 OD): δ 7.98 (s, 1H), 7.41 - 7.51 (m, 2H), 7.08-7.28 (m) , 6H), 3.84 (s, 3H), 3.14 (d, J = 6.4 Hz, 2H), 2.39-2.46 (m, 1H), 1.40-1.87 (m, 7H), 0.98-1.09 (m, 2H); 4-1b, 1 H NMR (400 MHz, CD 3 OD): δ 7.98 (s, 1H), 7.40-7.49 (m, 2H), 7.05-7.28 (m, 6H), 3.82 (s, 3H), 3.38 ( d, J = 7.6 Hz, 2H), 2.54-2.59 (m, 1H), 1.60-1.86 (m, 9H).
Figure PCTCN2017095396-appb-000094
Figure PCTCN2017095396-appb-000094
化合物4-2(187mg，顺反异构体混合物)经prep-HPLC(分离条件1)得到化合物4-2a(28mg，出峰时间：17.0～18.5分钟，单一立体构型)和4-2b(16mg，出峰时间：18.7～19.0分钟，单一立体构型)，均为白色固体。Compound 4-2 (187 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 4-2a (28 mg, peak time: 17.0 to 18.5 minutes, single stereo configuration) and 4-2b ( 16 mg, peak time: 18.7 to 19.0 minutes, single stereo configuration), all white solids.
m/z:[M+H]+405；4-2a,1H NMR(400MHz,CD3OD):δ8.56(d,J＝6.0Hz,1H),7.77-8.08(m,3H),7.41-7.49(m,2H),7.06-7.16(m,2H),3.85(s,3H),3.38(s,2H),3.17(d,J＝6.8Hz,2H),2.77(s,3H),1.09-1.98(m,8H)；4-2b,1H NMR(400MHz,CD3OD):δ8.56(d,J＝6.4Hz,1H),7.80-7.97(m,3H),7.40-7.46(m,2H),7.06-7.15(m,2H),3.82(s,3H),3.40(d,J＝8.0 Hz,2H),3.32(s,1H),2.88-2.93(m,1H),2.76(s,3H),1.68-1.92(m,8H)。m/z: [M+H] + 405; 4-2a, 1 H NMR (400 MHz, CD 3 OD): δ 8.56 (d, J = 6.0 Hz, 1H), 7.77-8.08 (m, 3H), 7.41-7.49 (m, 2H), 7.06-7.16 (m, 2H), 3.85 (s, 3H), 3.38 (s, 2H), 3.17 (d, J = 6.8 Hz, 2H), 2.77 (s, 3H) , 1.09-1.98 (m, 8H); 4-2b, 1 H NMR (400MHz, CD 3 OD): δ 8.56 (d, J = 6.4 Hz, 1H), 7.80-7.97 (m, 3H), 7.40- 7.46 (m, 2H), 7.06-7.15 (m, 2H), 3.82 (s, 3H), 3.40 (d, J = 8.0 Hz, 2H), 3.32 (s, 1H), 2.88-2.93 (m, 1H) , 2.76 (s, 3H), 1.68-1.92 (m, 8H).
实施例56：化合物5-1的合成Example 56: Synthesis of Compound 5-1
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物13.2得到化合物5-1：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 13.2 to obtain compound 5-1 by the synthesis of compound 1-1:
Figure PCTCN2017095396-appb-000095
Figure PCTCN2017095396-appb-000095
化合物5-1(200mg，顺反异构体混合物)用硅胶柱层析(二氯甲烷/甲醇＝100/1～10/1)分离得到极性较小的化合物5-1a(29.1mg，单一立体构型)和极性较大的化合物5-1b(21.3mg，单一立体构型)均为白色固体。Compound 5-1 (200 mg, cis-trans isomer mixture) was separated by silica gel column chromatography (dichloromethane/methanol = 100/1 to 10/1) to afford compound 5-1a (29.1 mg, single The stereo configuration) and the more polar compound 5-1b (21.3 mg, single stereo configuration) were both white solids.
m/z:[M+H]+360；5-1a,1H NMR(400MHz,CDCl3):δ8.07(d,J＝1.6Hz,1H),7.39-7.50(m,6H),7.29-7.33(m,2H),7.18-7.23(m,3H),5.50(s,1H),3.35-3.39(m,2H),2.55-2.58(m,1H),1.65-1.71(m,5H),1.44-1.56(m,4H)；5-1b,1H NMR(400MHz,CDCl3):δ8.08(d,J＝1.6Hz,1H),7.42-7.50(m,6H),7.29-7.33(m,2H),7.19-7.23(m,3H),5.55(s,1H),3.15-3.19(m,2H),2.38-2.45(m,1H),1.83-1.89(m,2H),1.61-1.64(m,2H),1.33-1.44(m,3H),0.89-1.01(m,2H)。m/z: [M+H] + 360; 5-1a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.07 (d, J = 1.6 Hz, 1H), 7.39-7.50 (m, 6H), 7.29 -7.33 (m, 2H), 7.18-7.23 (m, 3H), 5.50 (s, 1H), 3.35-3.39 (m, 2H), 2.55-2.58 (m, 1H), 1.65-1.71 (m, 5H) , 1.44-1.56 (m, 4H); 5-1b, 1 H NMR (400MHz, CDCl 3 ): δ 8.08 (d, J = 1.6 Hz, 1H), 7.42-7.50 (m, 6H), 7.29-7.33 (m, 2H), 7.19-7.23 (m, 3H), 5.55 (s, 1H), 3.15-3.19 (m, 2H), 2.38-2.45 (m, 1H), 1.83-1.89 (m, 2H), 1.61 -1.64 (m, 2H), 1.33-1.44 (m, 3H), 0.89-1.01 (m, 2H).
实施例57：化合物6-1～6-36的合成Example 57: Synthesis of Compounds 6-1 to 6-36
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、8.10、8.12、8.13、8.14、8.15、8.18、8.32、8.33、8.22、8.23、8.24、8.25、8.21、8.26、8.27、8.28、12.2、12.3、12.4、12.5、12.6、15.2、15.3或16.4和化合物1.6或1.7反应得到化合物6-1～6-36：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 1-1 for compound 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 8.10, 8.12, 8.13, 8.14 , 8.15, 8.18, 8.32, 8.33, 8.22, 8.23, 8.24, 8.25, 8.21, 8.26, 8.27, 8.28, 12.2, 12.3, 12.4, 12.5, 12.6, 15.2, 15.3 or 16.4 and compound 1.6 or 1.7 give compound 6- 1~6-36:
Figure PCTCN2017095396-appb-000096
Figure PCTCN2017095396-appb-000096
将化合物6-1(125mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝4/1～1/1)得到极性较小的化合物6-1a(9.5mg，单一立体构型)和极性较大的化合物6-1b(44.7mg，单一立体构型)，均为白色固体。The compound 6-1 (125 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 4/1 to 1/1) to afford compound 6-1a (9.5 mg, The single stereo configuration) and the more polar compound 6-1b (44.7 mg, single stereo configuration) were all white solids.
m/z:[M+H]+359；6-1a,1H NMR(400MHz,CDCl3):δ8.72(s,1H),7.49(t,J＝6.4Hz,1H),7.27-7.46(m,7H),7.13-7.23(m,3H),6.74(t,J＝6.4Hz,1H),5.52(br.s,1H),3.34(dd,J＝6.0,7.2Hz,2H),2.47-2.57(m,1H),1.55-1.63(m,5H),1.41-1.52(m,4H)；6-1b,1H NMR(400MHz,CDCl3):δ8.81(s,1H),7.48(t,J＝6.8Hz,1H),7.27-7.47(m,7H),7.15-7.23(m,3H),6.74(t,J＝6.0Hz,1H),5.58(br.s,1H),3.14(dd,J＝6.0,6.4Hz,2H),2.33-2.43(m,1H),1.80-1.88(m,2H),1.55-1.62(m,2H),1.30-1.43(m,3H),0.87-0.99(m,2H)。m/z: [M+H] + 359; 6-1a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.72 (s, 1H), 7.49 (t, J = 6.4 Hz, 1H), 7.27-7.46 (m,7H), 7.13 - 7.23 (m, 3H), 6.74 (t, J = 6.4 Hz, 1H), 5.52 (br.s, 1H), 3.34 (dd, J = 6.0, 7.2 Hz, 2H), 2.47-2.57 (m, 1H), 1.55-1.63 (m, 5H), 1.41-1.52 (m, 4H); 6-1b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.81 (s, 1H), 7.48 (t, J = 6.8 Hz, 1H), 7.27-7.47 (m, 7H), 7.15-7.23 (m, 3H), 6.74 (t, J = 6.0 Hz, 1H), 5.58 (br.s, 1H) , 3.14 (dd, J = 6.0, 6.4 Hz, 2H), 2.33 - 2.43 (m, 1H), 1.80-1.88 (m, 2H), 1.55-1.62 (m, 2H), 1.30-1.43 (m, 3H) , 0.87-0.99 (m, 2H).
Figure PCTCN2017095396-appb-000097
Figure PCTCN2017095396-appb-000097
将化合物6-2(85mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4) 得到极性较小的化合物2-2a(42mg，单一立体构型)和极性较大的化合物2-2b(39mg，单一立体构型)，均为白色固体。Compound 6-2 (85 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 9/1 to 1/4) The less polar compound 2-2a (42 mg, single stereo configuration) and the more polar compound 2-2b (39 mg, single stereo configuration) were obtained as white solids.
m/z:[M+H]+389；6-2a,1H NMR(400MHz,CDCl3):δ8.57(br.s,1H),6.96-7.52(m,10H),6.74-6.75(m,1H),5.66-5.69(m,1H),3.80(s,3H),3.32-3.35(m,2H),2.48-2.56(m,1H),1.40-1.66(m,9H)；6-2b,1H NMR(400MHz,CDCl3):δ8.58(br.s,1H),6.99-7.52(m,11H),6.73-6.75(m,1H),5.72-5.75(m,1H),3.82(s,3H),3.12-3.15(m,2H),2.35-2.43(m,1H),1.82-1.87(m,2H),1.56-1.61(m,1H),1.30-1.41(m,3H),0.86-0.97(m,2H)。m/z: [M+H] + 389; 6-2a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.57 (br.s, 1H), 6.96-7.52 (m, 10H), 6.74-6.75 ( m, 1H), 5.66-5.69 (m, 1H), 3.80 (s, 3H), 3.32-3.35 (m, 2H), 2.48-2.56 (m, 1H), 1.40-1.66 (m, 9H); 2b, 1 H NMR (400MHz, CDCl3): δ 8.58 (br.s, 1H), 6.99-7.52 (m, 11H), 6.73-6.75 (m, 1H), 5.72-5.75 (m, 1H), 3.82 (s, 3H), 3.12-3.15 (m, 2H), 2.35-2.43 (m, 1H), 1.82-1.87 (m, 2H), 1.56-1.61 (m, 1H), 1.30-1.41 (m, 3H) , 0.86-0.97 (m, 2H).
Figure PCTCN2017095396-appb-000098
Figure PCTCN2017095396-appb-000098
将化合物6-3(90mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物6-3a(35mg，单一立体构型)和极性较大的化合物6-3b(40mg，单一立体构型)，均为白色固体。The compound 6-3 (90 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 9/1 to 1/4) to give a less polar compound 6-3a (35 mg, single The stereo configuration) and the more polar compound 6-3b (40 mg, single stereo configuration) were all white solids.
m/z:[M+H]+393；6-3a,1H NMR(400MHz,CDCl3):δ9.58(br.s,1H),7.16-7.51(m,10H),6.74-6.76(m,1H),5.32-5.35(m,1H),3.33-3.36(m,2H),2.49-2.57(m,1H),1.39-1.65(m,9H)；6-3b,1H NMR(400MHz,CDCl3):δ9.38(br.s,1H),7.19-7.54(m,10H),6.75-6.77(m,1H),5.38-5.41(m,1H),3.14-3.17(m,2H),2.35-2.43(m,1H),1.82-1.89(m,2H),1.54-1.60(m,2H),1.30-1.42(m,3H),0.87-0.97(m,2H)。m/z: [M+H] + 393; 6-3a, 1 H NMR (400 MHz, CDCl 3 ): δ 9.58 (br.s, 1H), 7.16-7.51 (m, 10H), 6.74-6.76 ( m,1H),5.32-5.35(m,1H),3.33-3.36(m,2H), 2.49-2.57(m,1H),1.39-1.65(m,9H);6-3b, 1 H NMR(400MHz , CDCl 3 ): δ 9.38 (br.s, 1H), 7.19-7.54 (m, 10H), 6.75-6.77 (m, 1H), 5.38-5.41 (m, 1H), 3.14 - 3.17 (m, 2H) ), 2.35-2.43 (m, 1H), 1.82-1.89 (m, 2H), 1.54-1.60 (m, 2H), 1.30-1.42 (m, 3H), 0.87-0.97 (m, 2H).
Figure PCTCN2017095396-appb-000099
Figure PCTCN2017095396-appb-000099
将化合物6-4(85mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物6-4a(44mg，单一立体构型)和极性较大的化合物6-4b(29mg，单一立体构型)，均为白色固体。Compound 6-4 (85 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 9/1 to 1/4) to give compound 6-4a (44 mg, The stereo configuration) and the more polar compound 6-4b (29 mg, single stereo configuration) were both white solids.
m/z:[M+H]+443；6-4a,1H NMR(400MHz,CDCl3):δ9.38(br.s,1H),7.19-7.54(m,10H),6.75-6.77(m,1H),5.38-5.41(m,1H),3.14-3.17(m,2H),2.35-2.43(m,1H),1.82-1.89(m,2H),1.54-1.60(m,2H),1.30-1.42(m,3H),0.87-0.97(m,2H)；6-4b,1H NMR(400MHz,CDCl3):δ8.88(br.s,1H),7.45-7.54(m,3H),7.19-7.33(m,7H),6.77-6.79(m,1H),5.49-5.52(m,1H),3.18-3.22(m,2H),2.38-2.46(m,1H),1.87-1.90(m,2H),1.66-1.70(m,2H),1.35-1.46(m,3H),0.98-1.05(m,2H)。m/z: [M+H] + 443; 6-4a, 1 H NMR (400MHz, CDCl 3 ): δ 9.38 (br.s, 1H), 7.19-7.54 (m, 10H), 6.75-6.77 ( m, 1H), 5.38-5.41 (m, 1H), 3.14-3.17 (m, 2H), 2.35-2.43 (m, 1H), 1.82-1.89 (m, 2H), 1.54-1.60 (m, 2H), 1.30-1.42 (m, 3H), 0.87-0.97 (m, 2H); 6-4b, 1 H NMR (400MHz, CDCl 3 ): δ 8.88 (br.s, 1H), 7.45-7.54 (m, 3H) ), 7.19-7.33 (m, 7H), 6.77-6.79 (m, 1H), 5.49-5.52 (m, 1H), 3.18-3.22 (m, 2H), 2.38-2.46 (m, 1H), 1.87-1.90 (m, 2H), 1.66-1.70 (m, 2H), 1.35-1.46 (m, 3H), 0.98-1.05 (m, 2H).
Figure PCTCN2017095396-appb-000100
Figure PCTCN2017095396-appb-000100
将化合物6-5(62mg，顺反异构体混合物)经硅胶柱色谱分离(二氯甲烷/甲醇＝10/1)得到极性较小的化合物6-5a(3.6mg，单一立体构型)和极性较大的化合物6-5b(2.6mg，单一立体构型)，均为白色固体。 The compound 6-5 (62 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (dichloromethane/methanol = 10/1) to afford compound 6-5a (3.6 mg, single stereo configuration). The more polar compound 6-5b (2.6 mg, single stereo configuration) was a white solid.
m/z:[M+H]+393；6-5a,1H NMR(400MHz,CD3OD):δ7.44-7.45(m,1H),7.35-7.37(m,1H),7.22-7.33(m,7H),7.13-7.17(m,1H),6.90(d,J＝2.4Hz,1H),3.41(d,J＝7.6Hz,2H),2.59-2.62(m,1H),1.92-1.94(m,1H),1.62-1.80(m,8H)；6-5b,1H NMR(400MHz,CD3OD):δ7.45-7.46(m,1H),7.32-7.39(m,2H),7.13-7.29(m,7H),6.90(d,J＝2.4Hz,1H),3.17(d,J＝6.4Hz,2H),2.43-2.50(m,1H),2.02-2.07(m,1H),1.81-1.90(m,4H),1.46-1.62(m,4H)。m/z: [M+H] + 393; 6-5a, 1 H NMR (400 MHz, CD 3 OD): δ 7.44-7.45 (m, 1H), 7.35-7.37 (m, 1H), 7.22-7.33 (m, 7H), 7.13-7.17 (m, 1H), 6.90 (d, J = 2.4 Hz, 1H), 3.41 (d, J = 7.6 Hz, 2H), 2.59 - 2.62 (m, 1H), 1.92 1.94 (m, 1H), 1.62-1.80 (m, 8H); 6-5b, 1 H NMR (400 MHz, CD 3 OD): δ 7.45-7.46 (m, 1H), 7.32-7.39 (m, 2H) , 7.13 - 7.29 (m, 7H), 6.90 (d, J = 2.4 Hz, 1H), 3.17 (d, J = 6.4 Hz, 2H), 2.43-2.50 (m, 1H), 2.02-2.07 (m, 1H) ), 1.81-1.90 (m, 4H), 1.46-1.62 (m, 4H).
Figure PCTCN2017095396-appb-000101
Figure PCTCN2017095396-appb-000101
将化合物6-6(78mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝2/3)得到极性较小的化合物6-6a(3.5mg，单一立体构型)和极性较大的化合物6-6b(4.4mg，单一立体构型)，均为白色固体。The compound 6-6 (78 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give a less polar compound 6-6a (3.5 mg, single stereo configuration) And the more polar compound 6-6b (4.4 mg, single stereo configuration), both as white solids.
m/z:[M+H]+403；6-6a,1H NMR(400MHz,DMSO-d6):δ11.1(s,1H),7.14-7.30(m,7H),6.77-6.85(m,4H),3.91-3.97(m,2H),3.24(t,J＝6.4Hz,2H),1.98-2.01(m,2H),1.45-1.78(m,8H),1.21-1.34(m,3H)；6-6b,1H NMR(400MHz,DMSO-d6):δ11.1(s,1H),7.15-7.30(m,7H),6.88-6.99(m,3H),6.75-6.77(m,1H),3.93-3.98(m,2H),2.97(t,J＝6.4Hz,2H),2.38-2.44(m,1H),1.96-2.03(m,1H),1.66-1.77(m,4H),1.34-1.54(m,4H),1.21-1.26(m,3H)。m/z: [M+H] + 403; 6-6a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.1 (s, 1H), 7.14-7.30 (m, 7H), 6.77-6.85 ( m, 4H), 3.91-3.97 (m, 2H), 3.24 (t, J = 6.4 Hz, 2H), 1.98-2.01 (m, 2H), 1.45-1.78 (m, 8H), 1.21-1.34 (m, 3H); 6-6b, 1 H NMR (400MHz, DMSO-d 6 ): δ11.1 (s, 1H), 7.15-7.30 (m, 7H), 6.88-6.99 (m, 3H), 6.75-6.77 ( m,1H),3.93-3.98(m,2H), 2.97(t,J=6.4Hz,2H), 2.38-2.44(m,1H),1.96-2.03(m,1H),1.66-1.77(m, 4H), 1.34-1.54 (m, 4H), 1.21-1.26 (m, 3H).
Figure PCTCN2017095396-appb-000102
Figure PCTCN2017095396-appb-000102
将化合物6-7(100mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝4/1～>1/1)得到极性较小的化合物6-7a(32mg，单一立体构型)和极性较大的化合物6-7b(27mg，单一立体构型)，均为白色固体。The compound 6-7 (100 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 4/1 to > 1/1) to give the compound 6-7a (32 mg, The single stereo configuration) and the more polar compound 6-7b (27 mg, single stereo configuration) were all white solids.
m/z:[M+H]+389；6-7a,1H NMR(400MHz,DMSO-d6):δ11.12(s,1H),7.43(t,J＝6.0Hz,1H),7.34-7.39(m,2H),7.15-7.32(m,6H),6.82-6.88(m,3H),3.74(s,3H),3.27(t,J＝6.4Hz,2H),2.53-2.60(m,1H),1.83-1.92(m,1H),1.50-1.75(m,8H)；6-7b,1H NMR(400MHz,DMSO-d6):δ11.13(s,1H),7.35-7.40(m,2H),7.20-7.34(m,6H),7.14-7.20(m,1H),6.85-6.91(m,2H),6.83(t,J＝2.4Hz,1H),3.75(s,3H),3.03(t,J＝6.4Hz,2H),2.40-2.47(m,1H),1.73-1.84(m,4H),1.33-1.52(m,3H),0.95-1.10(m,2H)。m/z: [M+H] + 389; 6-7a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.12 (s, 1H), 7.43 (t, J = 6.0 Hz, 1H), 7.34 -7.39(m,2H),7.15-7.32(m,6H),6.82-6.88(m,3H),3.74(s,3H), 3.27(t,J=6.4Hz,2H),2.53-2.60(m , 1H), 1.83-1.92 (m, 1H), 1.50-1.75 (m, 8H); 6-7b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.13 (s, 1H), 7.35-7.40 (m, 2H), 7.20-7.34 (m, 6H), 7.14-7.20 (m, 1H), 6.85-6.91 (m, 2H), 6.83 (t, J = 2.4 Hz, 1H), 3.75 (s, 3H) ), 3.03 (t, J = 6.4 Hz, 2H), 2.40-2.47 (m, 1H), 1.73-1.84 (m, 4H), 1.33-1.52 (m, 3H), 0.95-1.10 (m, 2H).
Figure PCTCN2017095396-appb-000103
Figure PCTCN2017095396-appb-000103
将化合物6-8(100mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝4/1～>1/1)得到极性较小的化合物6-8a(33.4mg，单一立体构型)和极性较大的化合物6-8b(30.3mg，单一立体构型)，均为白色固体。 The compound 6-8 (100 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 -> 1 / 1) to give the compound 6-8a (33.4 mg) , single stereo configuration) and the more polar compound 6-8b (30.3 mg, single stereo configuration), both as white solids.
m/z:[M+H]+389；6-8a,1H NMR(400MHz,DMSO-d6):δ11.18(s,1H),7.52(t,J＝6.0Hz,1H),7.22-7.32(m,4H),7.14-7.21(m,3H),6.99-7.07(m,2H),6.93-6.97(m,1H),6.71-6.77(m,1H),3.73(s,3H),3.24-3.30(m,2H),2.54-2.60(m,1H),1.84-1.93(m,1H),1.50-1.75(m,8H)；6-8b,1H NMR(400MHz,CDCl3):δ8.64(s,1H),7.51(t,J＝6.4Hz,1H),7.26-7.39(m,3H),7.17-7.24(m,3H),7.05(br.d,J＝7.6Hz,1H),6.99-7.02(m,1H),6.90-6.95(m,1H),6.77(t,J＝6.4Hz,1H),5.67(br.s,1H),3.85(s,3H),3.18(t,J＝6.0Hz,2H),2.36-2.47(m,1H),1.87(br.d,J＝11.6Hz,2H),1.65(br.d,J＝11.6Hz,2H),1.33-1.46(m,3H),0.91-1.14(m,2H)。m/z: [M+H] + 389; 6-8a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.18 (s, 1H), 7.52 (t, J = 6.0 Hz, 1H), 7.22 -7.32(m,4H),7.14-7.21(m,3H),6.99-7.07(m,2H),6.93-6.97(m,1H),6.71-6.77(m,1H),3.73(s,3H) , 3.24-3.30 (m, 2H), 2.54-2.60 (m, 1H), 1.84-1.93 (m, 1H), 1.50-1.75 (m, 8H); 6-8b, 1 H NMR (400 MHz, CDCl 3 ) : δ 8.64 (s, 1H), 7.51 (t, J = 6.4 Hz, 1H), 7.26-7.39 (m, 3H), 7.17-7.24 (m, 3H), 7.05 (br.d, J = 7.6 Hz) , 1H), 6.99-7.02 (m, 1H), 6.90-6.95 (m, 1H), 6.77 (t, J = 6.4 Hz, 1H), 5.67 (br.s, 1H), 3.85 (s, 3H), 3.18 (t, J = 6.0 Hz, 2H), 2.36-2.47 (m, 1H), 1.87 (br.d, J = 11.6 Hz, 2H), 1.65 (br.d, J = 11.6 Hz, 2H), 1.33 -1.46 (m, 3H), 0.91-1.14 (m, 2H).
Figure PCTCN2017095396-appb-000104
Figure PCTCN2017095396-appb-000104
将化合物6-9(100mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝4/1～1/1)得到极性较小的化合物6-9a(20mg，单一立体构型)和极性较大的化合物6-9b(5mg，单一立体构型)，均为白色固体。The compound 6-9 (100 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 4/1 to 1/1) to give a less polar compound 6-9a (20 mg, single The stereo configuration) and the more polar compound 6-9b (5 mg, single stereo configuration) were all white solids.
m/z:[M+H]+377；6-9a,1H NMR(400MHz,CDCl3):δ8.53(s,2H),7.31-7.50(m,4H),7.12-7.27(m,5H),6.75(t,J＝2.4Hz,1H),5.52(s,1H),2.91-3.19(m,3H),2.41(m,1H),1.88(d,J＝11.4Hz,2H),0.96-1.43(m,6H)；6-9b,1H NMR(400MHz,CDCl3):δ8.57(s,2H),7.30-7.49(m,4H),7.08-7.24(m,5H),6.74(t,J＝2.4Hz,1H),5.45(s,1H),3.36-3.39(m,2H),1.65-2.57(m,6H),0.90-1.35(m,4H)。m/z: [M+H] + 377; 6-9a, 1 H NMR (400MHz, CDCl 3 ): δ 8.53 (s, 2H), 7.31-7.50 (m, 4H), 7.12-7.27 (m, 5H), 6.75 (t, J = 2.4 Hz, 1H), 5.52 (s, 1H), 2.91-3.19 (m, 3H), 2.41 (m, 1H), 1.88 (d, J = 11.4 Hz, 2H), 0.96-1.43 (m, 6H); 6-9b, 1 H NMR (400MHz, CDCl 3 ): δ 8.57 (s, 2H), 7.30-7.49 (m, 4H), 7.08-7.24 (m, 5H), 6.74 (t, J = 2.4 Hz, 1H), 5.45 (s, 1H), 3.36-3.39 (m, 2H), 1.65-2.57 (m, 6H), 0.90-1.35 (m, 4H).
Figure PCTCN2017095396-appb-000105
Figure PCTCN2017095396-appb-000105
m/z:[M+H]+360；1H NMR(400MHz,DMSO-d6):δ11.44(s,1H),8.40-8.43(m,2H),7.88-7.93(m,1H),7.49-7.52(m,2H),7.23-7.32(m,6H),7.15-7.19(m,1H),3.30-3.34(m,2H),3.08(t,J＝6.4Hz,1H),1.81-1.87(m,2H),1.66-1.70(m,2H),1.58-1.61(m,3H),1.41-1.45(m,1H),1.10-1.24(m,1H)。m / z: [M + H ] + 360; 1 H NMR (400MHz, DMSO-d 6): δ11.44 (s, 1H), 8.40-8.43 (m, 2H), 7.88-7.93 (m, 1H) , 7.49-7.52 (m, 2H), 7.23-7.32 (m, 6H), 7.15-7.19 (m, 1H), 3.30-3.34 (m, 2H), 3.08 (t, J = 6.4 Hz, 1H), 1.81 -1.87 (m, 2H), 1.66-1.70 (m, 2H), 1.58-1.61 (m, 3H), 1.41-1.45 (m, 1H), 1.10-1.24 (m, 1H).
Figure PCTCN2017095396-appb-000106
Figure PCTCN2017095396-appb-000106
将化合物6-11(550mg，顺反异构体混合物)经SFC分离得到化合物6-11a(159mg，手性分析保留时间：1.75分钟，单一立体构型)和化合物6-11b(218mg，手性分析保留时间：2.33分钟，单一立体构型)，均为白色固体。Compound 6-11 (550 mg, cis and trans isomer mixture) was isolated by SFC to give compound 6-11a (159 mg, chiral analysis retention time: 1.75 min, single stereo configuration) and compound 6-11b (218 mg, chiral Analytical retention time: 2.33 minutes, single stereo configuration), all white solids.
m/z:[M+H]+360；6-11a,1H NMR(400MHz,DMSO-d6):δ11.35(s,1H),8.62(d,J＝1.6Hz,1H),8.34(dd,J＝1.6,4.8Hz,1H),7.79-7.86(m,2H),7.21-7.36(m,6H),7.13-7.20(m,1H),7.04-7.08(m,1H),3.29(t,J＝6.8Hz,2H),2.52-2.59(m,1H),1.91(br.s,1H),1.50-1.76(m, 8H)；6-11b,1H NMR(400MHz,DMSO-d6):δ11.36(s,1H),8.63(d,J＝1.2Hz,1H),8.35(dd,J＝1.6,4.8Hz,1H),7.77-7.87(m,2H),7.34-7.38(m,1H),7.19-7.32(m,5H),7.12-7.19(m,1H),7.03-7.07(m,1H),3.04(t,J＝6.4Hz,2H),2.40-2.48(m,1H),1.76-1.88(m,4H),1.54(br.s,1H),1.34-1.48(m,2H),0.98-1.12(m,2H)。m/z: [M+H] + 360; 6-11a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.35 (s, 1H), 8.62 (d, J = 1.6 Hz, 1H), 8.34 (dd, J=1.6, 4.8 Hz, 1H), 7.79-7.86 (m, 2H), 7.21-7.36 (m, 6H), 7.13-7.20 (m, 1H), 7.04-7.08 (m, 1H), 3.29 (t, J = 6.8 Hz, 2H), 2.52-2.59 (m, 1H), 1.91 (br.s, 1H), 1.50-1.76 (m, 8H); 6-11b, 1 H NMR (400 MHz, DMSO- d 6 ): δ 11.36 (s, 1H), 8.63 (d, J = 1.2 Hz, 1H), 8.35 (dd, J = 1.6, 4.8 Hz, 1H), 7.77 - 7.87 (m, 2H), 7.34 7.38 (m, 1H), 7.19-7.32 (m, 5H), 7.12-7.19 (m, 1H), 7.03-7.07 (m, 1H), 3.04 (t, J = 6.4 Hz, 2H), 2.40-2.48 ( m, 1H), 1.76-1.88 (m, 4H), 1.54 (br.s, 1H), 1.34-1.48 (m, 2H), 0.98-1.12 (m, 2H).
Figure PCTCN2017095396-appb-000107
Figure PCTCN2017095396-appb-000107
m/z:[M+H]+361；1H NMR(400MHz,DMSO-d6):δ11.51(s,1H),8.97,8.96(two s,1H),8.87,8.85(two s,2H),7.93(t,J＝6.0Hz,1H),7.49,7.45(two dd,J＝2.4,2.8Hz,1H),7.13-7.33(m,6H),3.30,3.07(two dd,J＝6.0,6.4Hz,2H),2.42-2.50(m,1H),1.36-1.89(m,8H),1.00-1.14(m,1H)。m/z: [M+H] + 361; 1 H NMR (400MHz, DMSO-d 6 ): δ 11.51 (s, 1H), 8.97, 8.96 (two s, 1H), 8.87, 8.85 (two s, 2H), 7.93 (t, J = 6.0 Hz, 1H), 7.49, 7.45 (two dd, J = 2.4, 2.8 Hz, 1H), 7.13 - 7.33 (m, 6H), 3.30, 3.07 (two dd, J = 6.0, 6.4 Hz, 2H), 2.42-2.50 (m, 1H), 1.36-1.89 (m, 8H), 1.00-1.14 (m, 1H).
Figure PCTCN2017095396-appb-000108
Figure PCTCN2017095396-appb-000108
m/z:[M+H]+390；1H NMR(400MHz,DMSO-d6):δ11.45(s,1H),10.98,10.94(two t,J＝5.2Hz,1H),8.21,8.17(two d,J＝2.8Hz,1H),7.78,7.76(two d,J＝8.8Hz,1H),7.43-7.50(m,1H),7.37-7.41(m,2H),7.14-7.32(m,5H),3.87,3.84(two s,3H),3.40(dd,J＝6.0,8.0Hz,0.7H),3.27(t,J＝6.0Hz,1.3H),2.41-2.50(m,1H),1.40-2.00(m,8H),1.09-1.22(m,1H)。m / z: [M + H ] + 390; 1 H NMR (400MHz, DMSO-d 6): δ11.45 (s, 1H), 10.98,10.94 (two t, J = 5.2Hz, 1H), 8.21, 8.17 (two d, J=2.8 Hz, 1H), 7.78, 7.76 (two d, J=8.8 Hz, 1H), 7.43-7.50 (m, 1H), 7.37-7.41 (m, 2H), 7.14-7.32 ( m, 5H), 3.87, 3.84 (two s, 3H), 3.40 (dd, J = 6.0, 8.0 Hz, 0.7H), 3.27 (t, J = 6.0 Hz, 1.3H), 2.41-2.50 (m, 1H) ), 1.40-2.00 (m, 8H), 1.09-1.22 (m, 1H).
Figure PCTCN2017095396-appb-000109
Figure PCTCN2017095396-appb-000109
m/z:[M+H]+390；1H NMR(400MHz,DMSO-d6):δ12.45(s,1H),9.17(s,1H),8.52(t,J＝4.4Hz,1H),8.26(s,1H),7.78,7.76(two d,J＝8.8Hz,1H),7.43-7.50(m,1H),7.37-7.41(m,2H),7.14-7.32(m,5H),3.87,3.84(two s,3H),3.40(dd,J＝6.0Hz,8.0Hz,0.7H),3.27(t,J＝6.0Hz,1.3H),2.41-2.50(m,1H),1.40-2.00(m,8H),1.09-1.22(m,1H)。m/z: [M+H] + 390; 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.45 (s, 1H), 9.17 (s, 1H), 8.52 (t, J = 4.4 Hz, 1H) ), 8.26 (s, 1H), 7.78, 7.76 (two d, J = 8.8 Hz, 1H), 7.43-7.50 (m, 1H), 7.37-7.41 (m, 2H), 7.14-7.32 (m, 5H) , 3.87, 3.84 (two s, 3H), 3.40 (dd, J = 6.0 Hz, 8.0 Hz, 0.7H), 3.27 (t, J = 6.0 Hz, 1.3H), 2.41-2.50 (m, 1H), 1.40 -2.00 (m, 8H), 1.09-1.22 (m, 1H).
Figure PCTCN2017095396-appb-000110
Figure PCTCN2017095396-appb-000110
将化合物6-15(55mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物2-13a(21mg，单一立体构型)和极性较大的化合物2-13b(15mg，单一立体构型)，均为白色固体。The compound 6-15 (55 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 9/1 to 1/4) to give a less polar compound 2-13a (21 mg, single The stereo configuration) and the more polar compound 2-13b (15 mg, single stereo configuration) were all white solids.
m/z:[M+H]+373；6-15a,1H NMR(400MHz,CDCl3):δ7.17-7.44(m,10H),6.55(d,J＝2.8Hz,1H),5.46-5.51(m,1H),3.71(s,3H),3.33-3.36(m,2H),2.50-2.58(m,1H),1.45-1.68(m,10H)；6-15b,1H NMR(400MHz,CDCl3):δ7.19-7.44(m,10H),6.55(d,J＝2.8Hz,1H), 5.50-5.59(m,1H),3.71(s,3H),3.13-3.17(m,2H),2.37-2.44(m,1H),1.85-1.88(m,3H),1.61-1.64(m,2H),1.31-1.44(m,3H),0.89-1.00(m,2H)。m/z: [M+H] + 373; 6-15a, 1 H NMR (400MHz, CDCl 3 ): δ 7.17-7.44 (m, 10H), 6.55 (d, J = 2.8 Hz, 1H), 5.46 -5.51 (m, 1H), 3.71 (s, 3H), 3.33-3.36 (m, 2H), 2.50-2.58 (m, 1H), 1.45-1.68 (m, 10H); 6-15b, 1 H NMR ( 400MHz, CDCl 3 ): δ 7.19-7.44 (m, 10H), 6.55 (d, J = 2.8 Hz, 1H), 5.50-5.59 (m, 1H), 3.71 (s, 3H), 3.13-3.17 (m , 2H), 2.37-2.44 (m, 1H), 1.85-1.88 (m, 3H), 1.61-1.64 (m, 2H), 1.31-1.44 (m, 3H), 0.89-1.00 (m, 2H).
Figure PCTCN2017095396-appb-000111
Figure PCTCN2017095396-appb-000111
将化合物6-16(30mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物6-16a(6.1mg，单一立体构型)和极性较大的化合物2-16b(18.9mg，单一立体构型)，均为白色固体。The compound 6-16 (30 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 9/1 to 1/4) to give the compound 6-16a (6.1 mg, The single stereo configuration) and the more polar compound 2-16b (18.9 mg, single stereo configuration) were all white solids.
m/z:[M+H]+373；6-16a,1H NMR(400MHz,CDCl3):δ8.99(br.s,1H),7.15-7.49(m,12H),6.74-6.75(m,1H),5.29-5.32(m,1H),4.33-4.36(m,1H),2.60-2.67(m,1H),1.87-1.97(m,1H),1.14-1.70(m,7H),1.02(d,J＝6.4Hz,3H)；6-16b,1H NMR(400MHz,CDCl3):δ9.40(br.s,1H),7.18-7.49(m,12H),6.75-6.77(m,1H),5.45-5.48(m,1H),3.97-4.06(m,1H),2.33-2.41(m,1H),1.02-1.88(m,7H),0.98(d,J＝6.8Hz,3H),0.78-0.92(m,1H)。m/z: [M+H] + 373; 6-16a, 1 H NMR (400MHz, CDCl 3 ): δ 8.99 (br.s, 1H), 7.15-7.49 (m, 12H), 6.74-6.75 ( m,1H), 5.29-5.32 (m,1H),4.33-4.36 (m,1H), 2.60-2.67 (m,1H),1.87-1.97 (m,1H),1.14-1.70 (m,7H), 1.02 (d, J = 6.4 Hz, 3H); 6-16b, 1 H NMR (400MHz, CDCl 3 ): δ 9.40 (br.s, 1H), 7.18-7.49 (m, 12H), 6.75-6.77 ( m, 1H), 5.45-5.48 (m, 1H), 3.97-4.06 (m, 1H), 2.33-2.41 (m, 1H), 1.02-1.88 (m, 7H), 0.98 (d, J = 6.8 Hz, 3H), 0.78-0.92 (m, 1H).
Figure PCTCN2017095396-appb-000112
Figure PCTCN2017095396-appb-000112
将化合物6-17(150mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1～1/1)得到极性较小的化合物6-17a(26mg，单一立体构型)和极性较大的化合物6-17b(15mg，单一立体构型)，均为白色固体。The compound 6-17 (150 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to give the compound 6-17a (26 mg, The stereo configuration) and the more polar compound 6-17b (15 mg, single stereo configuration) were all white solids.
m/z:[M+H]+403；6-17a,1H NMR(400MHz,CDCl3):δ9.26(br.s,1H),7.51(br.s,1H),7.37-7.42(m,1H),7.28-7.33(m,2H),7.17-7.22(m,3H),6.99-7.07(m,2H),6.72(br.s,1H),5.72(d,J＝9.2Hz,1H),3.95-3.99(m,1H),3.81(s,3H),2.29-2.36(m,1H),1.81-1.86(m,2H),1.48-1.63(m,2H),1.26-1.36(m,3H),1.14-1.19(m,1H),0.99-1.06(m,1H),0.95(d,J＝7.2Hz,3H),0.75-0.79(m,1H)；6-17b,1H NMR(400MHz,CDCl3):δ8.99(br.s,1H),7.54(br.s,1H),7.37-7.42(m,1H),7.15-7.30(m,5H),6.97-7.04(m,2H),6.72(br.s,1H),5.76(d,J＝8.8Hz,1H),4.23-4.29(m,1H),3.79(s,3H),2.58-2.63(m,1H),1.82-1.86(m,1H),1.56-1.69(m,4H),1.37-1.48(m,2H),1.26-1.33(m,2H),1.08-1.13(m,1H),0.99(d,J＝6.4Hz,3H)。m/z: [M+H] + 403; 6-17a, 1 H NMR (400MHz, CDCl 3 ): δ 9.26 (br.s, 1H), 7.51 (br.s, 1H), 7.37-7.42 ( m,1H), 7.28-7.33 (m, 2H), 7.17-7.22 (m, 3H), 6.99-7.07 (m, 2H), 6.72 (br.s, 1H), 5.72 (d, J = 9.2 Hz, 1H), 3.95-3.99 (m, 1H), 3.81 (s, 3H), 2.29-2.36 (m, 1H), 1.81-1.86 (m, 2H), 1.48-1.63 (m, 2H), 1.26-1.36 ( m,3H),1.14-1.19(m,1H),0.99-1.06(m,1H),0.95(d,J=7.2Hz,3H),0.75-0.79(m,1H);6-17b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.99 (br.s, 1H), 7.54 (br.s, 1H), 7.37-7.42 (m, 1H), 7.15-7.30 (m, 5H), 6.97-7.04 ( m, 2H), 6.72 (br.s, 1H), 5.76 (d, J = 8.8 Hz, 1H), 4.23-4.29 (m, 1H), 3.79 (s, 3H), 2.58-2.63 (m, 1H) , 1.82-1.86 (m, 1H), 1.56-1.69 (m, 4H), 1.37-1.48 (m, 2H), 1.26-1.33 (m, 2H), 1.08-1.13 (m, 1H), 0.99 (d, J = 6.4 Hz, 3H).
Figure PCTCN2017095396-appb-000113
Figure PCTCN2017095396-appb-000113
将化合物6-18(160mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝2/1～1/3)得到极性较小的化合物6-18a(60mg，单一立体构型)和极性较大的化合物6-18b(75mg，单一立体构型)，均为白色固体。The compound 6-18 (160 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 2/1 to 1/3) to give the compound 6-18a (60 mg, single The stereo configuration) and the more polar compound 6-18b (75 mg, single stereo configuration) were all white solids.
m/z:[M+H]+503 m/z: [M+H] + 503
Figure PCTCN2017095396-appb-000114
Figure PCTCN2017095396-appb-000114
将化合物6-19(670mg，顺反异构体混合物)经Flash柱层析(石油醚/乙酸乙酯＝1/1)得到极性较大的化合物6-19a(27.7mg，单一立体构型)和极性较小的化合物6-19b(25.6mg，单一立体构型)，均为白色固体。The compound 6-19 (670 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the compound 6-19a (27.7 mg, single stereo configuration). And the less polar compound 6-19b (25.6 mg, single stereo configuration), both as white solids.
m/z:[M+H]+443；6-19a,1HNMR(400MHz,DMSO-d6):δ11.23(s,1H),7.47(t,J＝5.8Hz,1H),7.40-7.13(m,10H),6.81(t,J＝2.4Hz,1H),2.98(t,J＝6.4Hz,2H),2.46-2.40(m,1H),1.80(d,J＝11.2Hz,4H),1.49-1.23(m,3H),1.05-0.95(m,2H)；6-19b,1HNMR(400MHz,DMSO-d6):δ11.23(s,1H),7.54(t,J＝5.8Hz,1H),7.38-7.13(m,10H),6.82(t,J＝2.4Hz,1H),3.22(t,J＝6.8Hz,2H),2.54-2.51(m,1H),1.85(d,J＝3.2Hz,1H),1.67-1.61(m,4H),1.55-1.49(m,4H)。m/z: [M+H] + 443; 6-19a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.23 (s, 1H), 7.47 (t, J = 5.8 Hz, 1H), 7.40- 7.13 (m, 10H), 6.81 (t, J = 2.4 Hz, 1H), 2.98 (t, J = 6.4 Hz, 2H), 2.46-2.40 (m, 1H), 1.80 (d, J = 11.2 Hz, 4H) ), 1.49-1.23 (m, 3H), 1.05-0.95 (m, 2H); 6-19b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.23 (s, 1H), 7.54 (t, J = 5.8 Hz, 1H), 7.38-7.13 (m, 10H), 6.82 (t, J = 2.4 Hz, 1H), 3.22 (t, J = 6.8 Hz, 2H), 2.54-2.51 (m, 1H), 1.85 ( d, J = 3.2 Hz, 1H), 1.67-1.61 (m, 4H), 1.55-1.49 (m, 4H).
Figure PCTCN2017095396-appb-000115
Figure PCTCN2017095396-appb-000115
化合物6-20(201mg，顺反异构体混合物)经prep-TLC(石油醚/乙酸乙酯＝1/1)得到极性较大的化合物6-20a(5mg，单一立体构型)和极性较小的化合物6-20b(12mg，单一立体构型)，均为白色固体。Compound 6-20 (201 mg, cis-trans isomer mixture) was subjected to prep-TLC (petroleum ether/ethyl acetate = 1/1) to give the compound 6-20a (5 mg, single stereo configuration) and The less potent compound 6-20b (12 mg, single stereo configuration) was a white solid.
m/z:[M+H]+554；6-20a,1HNMR(400MHz,DMSO-d6):δ7.43(t,J＝5.8Hz,1H),7.38-7.13(m,10H),6.80(d,J＝2.4Hz,1H),3.66(s,3H),2.97(t,J＝6.4Hz,2H),2.46-2.40(m,1H),1.79-1.76(m,4H),1.47-1.32(m,3H),1.04-0.98(m,2H)；6-20b,1HNMR(400MHz,DMSO-d6):δ7.51(t,J＝5.8Hz,1H),7.36-7.13(m,10H),6.80(d,J＝2.4Hz,1H),3.66(s,3H),3.20(t,J＝6.8Hz,2H),1.83-1.82(m,1H),1.66-1.51(m,8H),1.26-1.21(m,1H)。m/z: [M+H] + 554; 6-20a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.43 (t, J = 5.8 Hz, 1H), 7.38-7.13 (m, 10H), 6.80 (d, J = 2.4 Hz, 1H), 3.66 (s, 3H), 2.97 (t, J = 6.4 Hz, 2H), 2.46-2.40 (m, 1H), 1.79-1.76 (m, 4H), 1.47 -1.32 (m, 3H), 1.04-0.98 (m, 2H); 6-20b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.51 (t, J = 5.8 Hz, 1H), 7.36-7.13 ( m, 10H), 6.80 (d, J = 2.4 Hz, 1H), 3.66 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 1.83-1.82 (m, 1H), 1.66-1.51 (m , 8H), 1.26-1.21 (m, 1H).
Figure PCTCN2017095396-appb-000116
Figure PCTCN2017095396-appb-000116
将化合物6-21(142mg，顺反异构体混合物)经prep-TLC分离(二氯甲烷/乙酸乙酯＝1/1)得到极性较小的化合物6-21a(18mg，单一立体构型)和极性较大的化合物6-21b(33.2mg，单一立体构型)，均为白色固体。The compound 6-21 (142 mg, cis-trans isomer mixture) was separated by prep-TLC (dichloromethane/ethyl acetate = 1/1) to give the less polar compound 6-21a (18 mg, single stereo configuration) And the more polar compound 6-21b (33.2 mg, single stereo configuration), both as white solids.
m/z:[M+H]+377；6-21a,1HNMR(400MHz,CD3OD):δ7.24-7.18(m,1H),7.15-7.11(m,4H),7.07-7.02(m,2H),6.86-6.83(m,1H),6.79(s,1H),3.30(d,J＝8.0Hz,2H),2.47(s,1H),1.82-1.78(m,1H),1.65(m,3H),1.57-1.52(m,6H),1.19(s,1H)；6-21b,1H-NMR(400MHz,CD3OD):δ7.26-7.21(m,1H),7.16-7.13(m,4H),7.10-7.03(m,3H),6.87-6.86(m,1H),6.79-6.78(d,J＝4.0Hz,1H),3.06(d,J＝4.0Hz,2H),2.35(m,1H),1.78-1.70(m,4H),1.42-1.35(m,3H),1.19(s,1H),1.01-1.97(m,2H)。 m/z: [M+H]+377; 6-21a, 1 H NMR (400 MHz, CD 3 OD): δ 7.24-7.18 (m, 1H), 7.15-7.11 (m, 4H), 7.07-7.02 ( m, 2H), 6.86-6.83 (m, 1H), 6.79 (s, 1H), 3.30 (d, J = 8.0 Hz, 2H), 2.47 (s, 1H), 1.82-1.78 (m, 1H), 1.65 (m, 3H), 1.57-1.52 (m, 6H), 1.19 (s, 1H); 6-21b, 1 H-NMR (400 MHz, CD 3 OD): δ 7.26-7.21 (m, 1H), 7.16 -7.13 (m, 4H), 7.10-7.03 (m, 3H), 6.87-6.86 (m, 1H), 6.79-6.78 (d, J = 4.0 Hz, 1H), 3.06 (d, J = 4.0 Hz, 2H) ), 2.35 (m, 1H), 1.78-1.70 (m, 4H), 1.42-1.35 (m, 3H), 1.19 (s, 1H), 1.01-1.97 (m, 2H).
Figure PCTCN2017095396-appb-000117
Figure PCTCN2017095396-appb-000117
将化合物6-22(289mg，顺反异构体混合物)经Flash柱层析(石油醚/乙酸乙酯＝2/3)得到极性较大的化合物6-22a(55.9mg，单一立体构型)和极性较小的化合物6-22b(41.2mg，单一立体构型)，均为白色固体。The compound 6-22 (289 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give the compound 6-22a (55.9 mg, single stereo configuration). And the less polar compound 6-22b (41.2 mg, single stereo configuration), both as white solids.
m/z:[M+H]+407；6-22a,1HNMR(400MHz,DMSO-d6):δ11.27(s,1H),7.69(t,J＝6.0Hz,1H),7.29-7.14(m,6H),7.06(t,J＝2.4Hz,1H),6.93-6.89(m,2H),6.63-6.59(m,1H),3.74(s,3H),3.05(t,J＝6.4Hz,2H),2.46-2.41(m,1H),1.84-1.79(m,4H),1.55-1.51(m,1H),1.46-1.36(m,2H),1.10-1.01(m,2H)；6-22b,1HNMR(400MHz,DMSO-d6):δ11.26(s,1H),7.74-7.72(m,1H),7.30-7.14(m,6H),7.07(t,J＝2.0Hz,1H),6.92-6.88(m,2H),6.61-6.57(m,1H),3.74(s,3H),3.29(t,J＝6.8Hz,2H),2.57-2.50(m,1H),1.92-1.90(m,1H),1.75-1.52(m,8H)。m/z: [M+H] + 407; 6-22a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.27 (s, 1H), 7.69 (t, J = 6.0 Hz, 1H), 7.29- 7.14(m,6H),7.06(t,J=2.4Hz,1H),6.93-6.89(m,2H),6.63-6.59(m,1H),3.74(s,3H),3.05(t,J= 6.4 Hz, 2H), 2.46-2.41 (m, 1H), 1.84-1.79 (m, 4H), 1.55-1.51 (m, 1H), 1.46-1.36 (m, 2H), 1.10-1.01 (m, 2H) ; 6-22b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.26 (s, 1H), 7.74 - 7.72 (m, 1H), 7.30-7.14 (m, 6H), 7.07 (t, J = 2.0) Hz, 1H), 6.92-6.88 (m, 2H), 6.61-6.57 (m, 1H), 3.74 (s, 3H), 3.29 (t, J = 6.8 Hz, 2H), 2.57-2.50 (m, 1H) , 1.92-1.90 (m, 1H), 1.75-1.52 (m, 8H).
Figure PCTCN2017095396-appb-000118
Figure PCTCN2017095396-appb-000118
将化合物6-23(302mg，顺反异构体混合物)经Flash柱层析(二氯甲烷/甲醇＝50/1)得到极性较大的化合物6-23a(20.6mg，单一立体构型)和极性较小的化合物6-23b(10mg，单一立体构型)，均为白色固体。The compound 6-23 (302 mg, cis-trans isomer mixture) was subjected to flash column chromatography (dichloromethane / methanol = 50/1) to give the compound 6-23a (20.6 mg, single stereo configuration). The less polar compound 6-23b (10 mg, single stereo configuration) was a white solid.
m/z:[M+H]+384；6-23a,1H NMR(400MHz,DMSO-d6):δ11.39(s,1H),7.75-7.70(m,2H),7.62-7.58(m,1H),7.43-7.37(m,3H),7.29-7.14(m,5H),6.60(t,J＝2.0Hz,1H),3.00(t,J＝6.0Hz,2H),2.51-2.41(m,1H),1.83-1.78(m,4H),1.53-1.52(m,1H),1.44-1.34(m,2H),1.06-0.97(m,2H)；6-23b,1H NMR(400MHz,DMSO-d6):δ11.38(s,1H),7.74-7.71(m,2H),7.60-7.56(m,1H),7.41-7.35(m,3H),7.29-7.14(m,5H),6.96(t,J＝2.0Hz,1H),3.24(t,J＝7.2Hz,2H),2.51-2.49(m,1H),1.90-1.88(m,1H),1.67-1.50(m,8H)。m/z: [M+H] + 384; 6-23a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.39 (s, 1H), 7.75-7.70 (m, 2H), 7.62-7.58 ( m,1H), 7.43-7.37 (m, 3H), 7.29-7.14 (m, 5H), 6.60 (t, J = 2.0 Hz, 1H), 3.00 (t, J = 6.0 Hz, 2H), 2.51-2.41 (m, 1H), 1.83-1.78 (m, 4H), 1.53-1.52 (m, 1H), 1.44-1.34 (m, 2H), 1.06-0.97 (m, 2H); 6-23b, 1 H NMR ( 400MHz, DMSO-d 6 ): δ11.38 (s, 1H), 7.74-7.71 (m, 2H), 7.60-7.56 (m, 1H), 7.41-7.35 (m, 3H), 7.29-7.14 (m, 5H), 6.96 (t, J = 2.0 Hz, 1H), 3.24 (t, J = 7.2 Hz, 2H), 2.51-2.49 (m, 1H), 1.90 - 1.88 (m, 1H), 1.67-1.50 (m , 8H).
Figure PCTCN2017095396-appb-000119
Figure PCTCN2017095396-appb-000119
将化合物6-24(210mg，顺反异构体混合物)经prep-TLC(石油醚/乙酸乙酯＝1/1)得到极性较大的化合物6-24a(27.1mg，单一立体构型)和极性较小的化合物6-24b(26.5mg，单一立体构型)，均为白色固体。The compound 6-24 (210 mg, cis-trans isomer mixture) was subjected to prep-TLC (petroleum ether/ethyl acetate = 1/1) to give the compound 6-24a (27.1 mg, single stereo configuration). The less polar compound 6-24b (26.5 mg, single stereo configuration) was a white solid.
m/z:[M+H]+425；6-24a,1HNMR(400MHz,DMSO-d6):δ11.31(s,1H),7.77-7.71(m,1H),7.31-7.11(m,9H),3.87(s,3H),3.09-3.04(m,2H),2.04-1.95(m,1H),1.85-1.78(m,4H),1.61-1.49(m,1H),1.49-1.35(m,2H),1.13-1.01(m,2H)；6-24b,1HNMR(400MHz,DMSO-d6):δ11.31(s,1H),7.80-7.75(m,1H),7.32-7.08(m,9H),3.85(s,3H),3.31-3.27(m,2H),1.96-1.87(m,1H),1.82-1.52(m,9H)。 m/z: [M+H] + 425; 6-24a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.31 (s, 1H), 7.77-7.71 (m, 1H), 7.31-7.11 (m) , 9H), 3.87 (s, 3H), 3.09-3.04 (m, 2H), 2.04-1.95 (m, 1H), 1.85-1.78 (m, 4H), 1.61-1.49 (m, 1H), 1.49-1.35 (m, 2H), 1.13-1.01 (m, 2H); 6-24b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.31 (s, 1H), 7.80-7.75 (m, 1H), 7.32 7.08 (m, 9H), 3.85 (s, 3H), 3.31-3.27 (m, 2H), 1.96-1.87 (m, 1H), 1.82-1.52 (m, 9H).
Figure PCTCN2017095396-appb-000120
Figure PCTCN2017095396-appb-000120
将化合物6-25(190mg，顺反异构体混合物)经prep-TLC(石油醚/乙酸乙酯＝1/1)得到极性较大的化合物6-25a(20.2mg，单一立体构型)和极性较小的化合物6-25b(5.4mg，单一立体构型)，均为白色固体。Compound 6-25 (190 mg, cis-trans isomer mixture) was subjected to prep-TLC (petroleum ether/ethyl acetate = 1/1) to give the compound 6-25a (20.2 mg, single stereo configuration). The less polar compound 6-25b (5.4 mg, single stereo configuration) was a white solid.
m/z:[M+H]+384；6-25a,1HNMR(400MHz,DMSO-d6):δ11.36(s,1H),7.89(s,1H),7.85-7.80(m,2H),7.61(d,J＝7.6Hz,1H),7.52-7.46(m,1H),7.34-7.31(m,1H),7.31-7.21(m,4H),7.19-7.11(m,2H),3.10-3.04(m,2H),2.05-1.95(m,1H),1.87-1.77(m,4H),1.62-1.51(m,1H),1.49-1.36(m,2H),1.13-1.01(m,2H)；6-25b,1HNMR(400MHz,DMSO-d6):δ11.36(s,1H),7.89(s,1H),7.86-7.83(m,1H),7.80(d,J＝8.0Hz,1H),7.60(d,J＝7.6Hz,1H),7.50-7.45(m,1H),7.30-7.22(m,5H),7.19-7.12(m,2H),3.30-3.25(m,2H),2.10-1.88(m,2H),1.75-1.53(m,8H)。m/z: [M+H] + 384; 6-25a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.36 (s, 1H), 7.89 (s, 1H), 7.85-7.80 (m, 2H) ), 7.61 (d, J = 7.6 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.34 - 7.31 (m, 1H), 7.31 - 7.21 (m, 4H), 7.19 - 7.11 (m, 2H), 3.10-3.04 (m, 2H), 2.05-1.95 (m, 1H), 1.87-1.77 (m, 4H), 1.62-1.51 (m, 1H), 1.49-1.36 (m, 2H), 1.13-1.01 (m , 2H); 6-25b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.36 (s, 1H), 7.89 (s, 1H), 7.86-7.83 (m, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50-7.45 (m, 1H), 7.30-7.22 (m, 5H), 7.19-7.12 (m, 2H), 3.30-3.25 (m) , 2H), 2.10 - 1.88 (m, 2H), 1.75-1.53 (m, 8H).
Figure PCTCN2017095396-appb-000121
Figure PCTCN2017095396-appb-000121
将化合物6-26(388mg，顺反异构体混合物)经Flash柱层析(石油醚/乙酸乙酯＝3/7)得到极性较大的化合物6-26a(7.2mg，单一立体构型)和极性较小的化合物6-26b(32.8mg，单一立体构型)，均为白色固体。Compound 6-26 (388 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether/ethyl acetate = 3/7) to give the compound 6-26a (7.2 mg, single stereo configuration). And the less polar compound 6-26b (32.8 mg, single stereo configuration), both as white solids.
m/z:[M+H]+419；6-26a,1HNMR(400MHz,DMSO-d6):δ11.13(s,1H),7.28-7.25(m,3H),7.21-7.20(m,3H),7.15(t,J＝7.2Hz,1H),7.09(d,J＝2.0Hz,1H),6.97(dd,J＝1.6,8.0Hz,1H),6.89-6.85(m,2H),3.74-3.73(m,6H),3.03(t,J＝6.2Hz,2H),2.45-2.39(m,1H)1.78-1.74(m,4H),1.48-1.32(m,3H),1.06-0.96(m,2H)；6-26b,1HNMR(400MHz,DMSO-d6):δ11.13(s,1H),7.39(t,J＝6.0Hz,1H),7.30-7.14(m,6H),7.08(d,J＝2.0Hz,1H),6.96(dd,J＝2.0,8.0Hz,1H),6.88-6.84(m,2H),3.72-3.71(m,6H),3.26(t,J＝6.8Hz,2H),2.56-2.53(m,1H),1.85-1.80(m,1H),1.72-1.50(m,8H)。m/z: [M+H] + 419; 6-26a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.13 (s, 1H), 7.28-7.25 (m, 3H), 7.21-7.20 (m) , 3H), 7.15 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 1.6, 8.0 Hz, 1H), 6.89-6.85 (m, 2H) , 3.74-3.73 (m, 6H), 3.03 (t, J = 6.2 Hz, 2H), 2.45-2.39 (m, 1H) 1.78-1.74 (m, 4H), 1.48-1.32 (m, 3H), 1.06- 0.96 (m, 2H); 6-26b , 1 HNMR (400MHz, DMSO-d 6): δ11.13 (s, 1H), 7.39 (t, J = 6.0Hz, 1H), 7.30-7.14 (m, 6H ), 7.08 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 2.0, 8.0 Hz, 1H), 6.88-6.84 (m, 2H), 3.72-3.71 (m, 6H), 3.26 (t, J = 6.8 Hz, 2H), 2.56-2.53 (m, 1H), 1.85-1.80 (m, 1H), 1.72-1.50 (m, 8H).
Figure PCTCN2017095396-appb-000122
Figure PCTCN2017095396-appb-000122
m/z:[M+H]+391；1HNMR(400MHz,DMSO-d6):δ11.07-11.05(m,1H),8.75-8.70(m,2H),7.28-7.08(m,6H),6.92(t,J＝6.4Hz,1H),6.82(d,J＝1.6Hz,1H),6.72-6.63(m,3H),3.24(t,J＝6.8Hz,1H),3.01(t,J＝6.2Hz,1H),2.45-2.39(m,1H),1.79-1.34(m,8H),1.02-0.96(m,1H)。 m/z: [M+H] + 391; 1 H NMR (400MHz, DMSO-d 6 ): δ 11.07-11.05 (m, 1H), 8.75-8.70 (m, 2H), 7.28-7.08 (m, 6H) ), 6.92 (t, J = 6.4 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.72 - 6.63 (m, 3H), 3.24 (t, J = 6.8 Hz, 1H), 3.01 (t , J = 6.2 Hz, 1H), 2.45-2.39 (m, 1H), 1.79-1.34 (m, 8H), 1.02-0.96 (m, 1H).
Figure PCTCN2017095396-appb-000123
Figure PCTCN2017095396-appb-000123
将化合物6-28(197mg，顺反异构体混合物)经Flash柱层析(二氯甲烷/甲醇＝50/1)得到极性较大的化合物6-28a(18.0mg，单一立体构型)和极性较小的化合物6-28b(15.0mg，单一立体构型)，均为白色固体。Compound 6-28 (197 mg, cis-trans isomer mixture) was subjected to flash column chromatography (dichloromethane/methanol = 50/1) to afford compound 6-28a (18.0 mg, single stereo configuration). The less polar compound 6-28b (15.0 mg, single stereo configuration) was a white solid.
m/z:[M+H]+375；6-28a,1HNMR(400MHz,DMSO-d6):δ11.16(s,1H),9.21(s,1H),7.30-7.17(m,7H),7.09(t,J＝7.6Hz,1H),6.86-6.84(m,3H),6.62-6.60(m,1H),3.04(t,J＝6.4Hz,2H),2.49-2.41(m,1H),1.87-1.76(m,4H),1.42-1.38(m,3H),1.04-1.00(m,2H)；6-28b,1HNMR(400MHz,DMSO-d6):δ11.14(s,1H),9.17(s,1H),9.38(t,J＝6.0Hz,1H),7.30-7.22(m,6H),7.05(t,J＝7.6Hz,1H),6.85-6.82(m,3H),6.58-6.56(m,1H),3.26(t,J＝6.8Hz,2H),2.56-2.51(m,1H),1.85-1.84(m,1H),1.69-1.51(m,8H)。m/z: [M+H] + 375; 6-28a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.16 (s, 1H), 9.21 (s, 1H), 7.30-7.17 (m, 7H) ), 7.09 (t, J = 7.6 Hz, 1H), 6.86-6.84 (m, 3H), 6.62-6.60 (m, 1H), 3.04 (t, J = 6.4 Hz, 2H), 2.49-2.41 (m, 1H), 1.87-1.76 (m, 4H), 1.42-1.38 (m, 3H), 1.04-1.00 (m, 2H); 6-28b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.14 (s , 1H), 9.17 (s, 1H), 9.38 (t, J = 6.0 Hz, 1H), 7.30-7.22 (m, 6H), 7.05 (t, J = 7.6 Hz, 1H), 6.85-6.82 (m, 3H), 6.58-6.56 (m, 1H), 3.26 (t, J = 6.8 Hz, 2H), 2.56-2.51 (m, 1H), 1.85-1.84 (m, 1H), 1.69-1.51 (m, 8H) .
Figure PCTCN2017095396-appb-000124
Figure PCTCN2017095396-appb-000124
将化合物6-29(486mg，顺反异构体混合物)经prep-HPLC(分离条件19)得到化合物6-29b(35.6mg，出峰时间：17.0～18.0分钟，单一立体构型)为白色固体。Compound 6-29 (486 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 19) to give compound 6-29b (35.6 mg, peak time: 17.0 to 18.0 min, single stereo configuration) as a white solid. .
m/z:[M+H]+443；6-29b,1H NMR(400MHz,CD3OD):δ7.44-7.38(m,2H),7.34(s,1H),7.29-7.23(m,5H),7.17-7.10(m,2H),6.94-7.93(d,J＝4.0Hz,1H),3.43-3.41(d,J＝8.0Hz,2H),2.61-2.56(m,1H),1.97-1.91(m,1H),1.83-1.63(m,8H)。m/z: [M+H] + 443; 6-29b, 1 H NMR (400 MHz, CD 3 OD): δ 7.44 - 7.38 (m, 2H), 7.34 (s, 1H), 7.29-7.23 (m) , 5H), 7.17-7.10 (m, 2H), 6.94-7.93 (d, J = 4.0 Hz, 1H), 3.43-3.41 (d, J = 8.0 Hz, 2H), 2.61-2.56 (m, 1H), 1.97-1.91 (m, 1H), 1.83-1.63 (m, 8H).
Figure PCTCN2017095396-appb-000125
Figure PCTCN2017095396-appb-000125
将化合物6-30(303mg，顺反异构体混合物)经Flash柱层析(石油醚/乙酸乙酯＝2/3)得到极性较小的化合物6-30b(20.0mg，单一立体构型)为白色固体。Compound 6-30 (303 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give the less polar compound 6-30b (20.0 mg, single stereo configuration) ) is a white solid.
m/z:[M+H]+402；6-30a,1HNMR(400MHz,CD3OD):δ7.56-7.61(m,1H),7.11-7.36(m,8H),6.99(s,1H),3.38(d,J＝7.6Hz,2H),3.38(s,1H),1.98-2.02(m,2H),1.64-1.77(m,7H)。m/z: [M+H] + 402; 6-30a, 1 H NMR (400 MHz, CD 3 OD): δ 7.56-7.61 (m, 1H), 7.11-7.36 (m, 8H), 6.99 (s, 1H), 3.38 (d, J = 7.6 Hz, 2H), 3.38 (s, 1H), 1.98-2.02 (m, 2H), 1.64-1.77 (m, 7H).
Figure PCTCN2017095396-appb-000126
Figure PCTCN2017095396-appb-000126
将化合物6-31(118mg，顺反异构体混合物)经prep-TLC(石油醚/乙酸乙酯＝1/2)得到极性较小的化合物6-31a(21.3mg，单一立体构型)和极性较大的化合物6-31b(9.5mg，单一立体构型)，均为白色固体。 Compound 6-31 (118 mg, cis-trans isomer mixture) was subjected to prep-TLC (petroleum ether/ethyl acetate = 1/2) to give the less polar compound 6-31a (21.3 mg, single stereo configuration) The more polar compound 6-31b (9.5 mg, single stereo configuration) was a white solid.
m/z:[M+H]+402；6-31a,1H NMR(400MHz,CD3OD):δ7.64-7.65(m,1H),7.52-7.56(m,1H),7.33-7.36(m,1H),7.29(d,J＝2.0Hz,1H),7.27(d,J＝4.4Hz,4H),7.12-7.17(m,1H),7.07(d,J＝2.0Hz,1H),3.46(d,J＝8.0Hz,2H),2.58-2.63(m,1H),1.99-2.05(m,1H),1.67-1.84(m,8H)；6-31b,1H NMR(400MHz,CD3OD):δ7.65-7.66(m,1H),7.53-7.57(m,1H),7.35-7.38(m,1H),7.23-7.31(m,5H),7.13-7.21(m,1H),7.07(d,J＝2.0Hz,1H),3.21(d,J＝6.8Hz,2H),2.47-2.53(m,1H),1.92(d,J＝7.6Hz,4H),1.62-1.71(m,1H),1.49-1.58(m,2H),1.13-1.23(m,2H)。m/z: [M+H] + 402; 6-31a, 1 H NMR (400 MHz, CD 3 OD): δ 7.64 - 7.65 (m, 1H), 7.52 - 7.56 (m, 1H), 7.33 - 7.36 (m, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 4.4 Hz, 4H), 7.12 - 7.17 (m, 1H), 7.07 (d, J = 2.0 Hz, 1H) , 3.46 (d, J = 8.0 Hz, 2H), 2.58-2.63 (m, 1H), 1.99-2.05 (m, 1H), 1.67-1.84 (m, 8H); 6-31b, 1 H NMR (400 MHz, CD 3 OD): δ 7.65-7.66 (m, 1H), 7.53-7.57 (m, 1H), 7.35-7.38 (m, 1H), 7.23-7.31 (m, 5H), 7.13-7.21 (m, 1H) ), 7.07 (d, J = 2.0 Hz, 1H), 3.21 (d, J = 6.8 Hz, 2H), 2.47 - 2.53 (m, 1H), 1.92 (d, J = 7.6 Hz, 4H), 1.62-1.71 (m, 1H), 1.49-1.58 (m, 2H), 1.13-1.23 (m, 2H).
Figure PCTCN2017095396-appb-000127
Figure PCTCN2017095396-appb-000127
将化合物6-32(155mg，顺反异构体混合物)经prep-TLC(石油醚/乙酸乙酯＝1/3)得到极性较小的化合物6-32a(11.5mg，单一立体构型)和极性较大的化合物6-32b(20.3mg，单一立体构型)，均为白色固体。The compound 6-32 (155 mg, cis-trans isomer mixture) was subjected to prep-TLC (petroleum ether / ethyl acetate = 1/3) to give the less polar compound 6-32a (11.5 mg, single stereo configuration) The more polar compound, 6-32b (20.3 mg, single stereo configuration), was a white solid.
m/z:[M+H]+414；6-32a,1H NMR(400MHz,CD3OD):δ7.56-7.63(m,2H),7.32(d,J＝2.4Hz,1H),7.22-7.28(m,5H),7.13-7.16(m,1H),6.92(d,J＝2.4Hz,1H),3.68(s,3H),3.39(d,J＝7.6Hz,2H),2.57-2.59(m,1H),1.90-1.92(m,1H),1.64-1.75(m,8H)；6-32b,1H NMR(400MHz,CD3OD):δ7.59-7.64(m,2H),7.33(d,J＝2.0Hz,1H),7.20-7.29(m,5H),7.13-7.17(m,1H),6.91(d,J＝2.4Hz,1H),3.68(s,3H),3.15(d,J＝6.8Hz,2H),2.43-2.49(m,1H),1.78-1.89(m,4H),1.45-1.57(m,3H),1.02-1.13(m,2H)。m/z: [M+H] + 414; 6-32a, 1 H NMR (400 MHz, CD 3 OD): δ 7.56-7.63 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.22-7.28 (m, 5H), 7.13-7.16 (m, 1H), 6.92 (d, J = 2.4 Hz, 1H), 3.68 (s, 3H), 3.39 (d, J = 7.6 Hz, 2H), 2.57 -2.59 (m, 1H), 1.90 - 1.92 (m, 1H), 1.64-1.75 (m, 8H); 6-32b, 1 H NMR (400 MHz, CD 3 OD): δ 7.59 - 7.64 (m, 2H) ), 7.33 (d, J = 2.0 Hz, 1H), 7.20-7.29 (m, 5H), 7.13-7.17 (m, 1H), 6.91 (d, J = 2.4 Hz, 1H), 3.68 (s, 3H) , 3.15 (d, J = 6.8 Hz, 2H), 2.43-2.49 (m, 1H), 1.78-1.89 (m, 4H), 1.45-1.57 (m, 3H), 1.02-1.13 (m, 2H).
Figure PCTCN2017095396-appb-000128
Figure PCTCN2017095396-appb-000128
将化合物6-33(542mg，顺反异构体混合物)经硅胶柱层析(石油醚/乙酸乙酯＝1/9～3/7)得到极性较小的化合物6-33a(25mg，单一立体构型)和极性较大的化合物6-33b(25mg，单一立体构型)，均为白色固体。Compound 6-33 (542 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petrole ether/ethyl acetate = 1/9 to 3/7) to give compound 6-33a (25 mg, single The stereo configuration) and the more polar compound 6-33b (25 mg, single stereo configuration) were both white solids.
m/z:[M+H]+407；6-33a,1HNMR(400MHz,DMSO-d6):δ11.11(s,1H),7.41-7.27(m,1H),7.29-7.20(m,5H),7.17-7.15(m,1H),7.09-7.07(m,1H),7.01-6.97(m,2H),6.83-6.81(m,1H),3.62(s,3H),3.25-3.21(m,2H),2.51-2.50(m,1H),1.81(m,1H),1.67-1.52(m,8H)；6-33b,1HNMR(400MHz,DMSO-d6):δ11.21(s,1H),7.29-7.20(m,8H),7.17-7.13(m,2H),6.82-6.81(m,1H),3.63(s,3H),3.01-2.98(m,2H),2.51-2.49(m,1H),1.81-1.72(m,4H),1.40-1.36(m,3H),1.01-0.98(m,2H)。m/z: [M+H] + 407; 6-33a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.11 (s, 1H), 7.41-7.27 (m, 1H), 7.29-7.20 (m) , 5H), 7.17-7.15 (m, 1H), 7.09-7.07 (m, 1H), 7.01-6.97 (m, 2H), 6.83-6.81 (m, 1H), 3.62 (s, 3H), 3.25-3.21 (m, 2H), 2.51-2.50 (m, 1H), 1.81 (m, 1H), 1.67-1.52 (m, 8H); 6-33b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.21. s, 1H), 7.29-7.20 (m, 8H), 7.17-7.13 (m, 2H), 6.82-6.81 (m, 1H), 3.63 (s, 3H), 3.01-2.98 (m, 2H), 2.51- 2.49 (m, 1H), 1.81-1.72 (m, 4H), 1.40-1.36 (m, 3H), 1.01 - 0.98 (m, 2H).
Figure PCTCN2017095396-appb-000129
Figure PCTCN2017095396-appb-000129
将化合物6-34(486mg，顺反异构体混合物)经硅胶柱层析(石油醚/乙酸乙酯＝1/9～3/7) 得到极性较小的化合物6-34a(20mg，单一立体构型)和极性较大的化合物6-34b(20mg，单一立体构型)，均为白色固体。Compound 6-34 (486 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petrole ether/ethyl acetate = 1/9 to 3/7) The less polar compound 6-34a (20 mg, single stereo configuration) and the more polar compound 6-34b (20 mg, single stereo configuration) were obtained as white solids.
m/z:[M+H]+407；6-34a,1HNMR(400MHz,DMSO-d6):δ11.21(s,1H),7.60(s,1H),7.30-7.22(m,6H),7.18-7.16(m,1H),7.10-7.05(m,1H),7.00-6.96(m,2H),3.79(s,3H),3.29-3.26(m,2H),2.51-2.49(m,1H),1.72-1.68(m,1H),1.65-1.53(m,8H)；6-34b,1HNMR(400MHz,DMSO-d6):δ11.21(s,1H),7.53(s,1H),7.30-6.99(m,8H),6.96-6.95(m,2H),3.82(s,3H),3.06-3.02(m,2H),2.50-2.49(m,1H),1.80-1.77(m,4H),1.60-1.37(m,3H),1.05-1.03(m 2H)。m/z: [M+H] + 407; 6-34a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.21. (s, 1H), 7.60 (s, 1H), 7.30-7.22 (m, 6H) ), 7.18-7.16 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.96 (m, 2H), 3.79 (s, 3H), 3.29-3.26 (m, 2H), 2.51-2.49 (m , 1H), 1.72-1.68 (m, 1H), 1.65-1.53 (m, 8H); 6-34b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.21 (s, 1H), 7.53 (s, 1H), 7.30-6.99 (m, 8H), 6.96-6.95 (m, 2H), 3.82 (s, 3H), 3.06-3.02 (m, 2H), 2.50-2.49 (m, 1H), 1.80-1.77 ( m, 4H), 1.60-1.37 (m, 3H), 1.05-1.03 (m 2H).
Figure PCTCN2017095396-appb-000130
Figure PCTCN2017095396-appb-000130
将化合物6-35(489mg，顺反异构体混合物)经硅胶柱层析(石油醚/乙酸乙酯＝1/9～1/1)得到极性较小的化合物6-35a(50mg，单一立体构型)和极性较大的化合物6-35b(53mg，单一立体构型)，均为白色固体。The compound 6-35 (489 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petrole ether / ethyl acetate = 1 / 9 to 1 / 1) to give the compound 6-35a (50 mg, single The stereo configuration) and the more polar compound 6-35b (53 mg, single stereo configuration) were both white solids.
m/z:[M+H]+425；6-35a,1H NMR(400MHz,DMSO-d6):δ11.36(s,1H),7.39-7.37(m,1H),7.29-7.28(m,1H),7.27-7.22(m,4H),7.24-7.23(m,1H),7.22-7.21(m,1H),6.90-6.87(m,2H),3.81(s,3H),3.24-3.23(m,2H),2.52(m,1H),1.65-1.62(m,1H),1.57-1.53(m,8H)；6-35b,1H NMR(400MHz,DMSO-d6):δ11.36(s,1H),7.59-7.58(m,1H),7.41-7.40(m,1H),7.27-7.16(m,6H),7.04-6.97(m,1H),6.95-6.92(m,1H),6.87-6.86(m,1H),3.82(s,3H),2.99-2.97(m,2H),2.52-2.50(m，1H),1.81-1.78(m,4H),1.41-1.38(m,3H),1.03-1.01(m,2H)。m/z: [M+H] + 425; 6-35a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.36 (s, 1H), 7.39-7.37 (m, 1H), 7.29-7.28 ( m,1H), 7.27-7.22 (m, 4H), 7.24-7.23 (m, 1H), 7.22-7.21 (m, 1H), 6.90-6.87 (m, 2H), 3.81 (s, 3H), 3.24- 3.23 (m, 2H), 2.52 (m, 1H), 1.65-1.62 (m, 1H), 1.57-1.53 (m, 8H); 6-35b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11. 36(s,1H), 7.59-7.58(m,1H), 7.41-7.40(m,1H), 7.27-7.16(m,6H),7.04-6.97(m,1H),6.95-6.92(m,1H) ), 6.87-6.86 (m, 1H), 3.82 (s, 3H), 2.99-2.97 (m, 2H), 2.52-2.50 (m, 1H), 1.81-1.78 (m, 4H), 1.41-1.38 (m , 3H), 1.03-1.01 (m, 2H).
Figure PCTCN2017095396-appb-000131
Figure PCTCN2017095396-appb-000131
将化合物6-36(489mg，顺反异构体混合物)经硅胶柱层析(石油醚/乙酸乙酯＝1/4～1/1)得到极性较小的化合物6-36a(50mg，单一立体构型)为白色固体。The compound 6-36 (489 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petrole ether / ethyl acetate = 1/4 to 1 / 1) to give the compound 6-36a (50 mg, single The stereo configuration) is a white solid.
m/z:[M+H]+425；6-36a,1H NMR(400MHz,DMSO-d6):δ11.16(s,1H),7.42-7.45(m,1H),7.16-7.31(m,7H),7.05-7.10(m,1H),6.82-6.84(m,1H),3.66(s,3H),3.22-3.25(m,2H),2.53-2.57(m,1H),1.82-1.90(m,1H),1.51-1.72(m,8H)。m/z: [M+H] + 425; 6-36a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.16 (s, 1H), 7.42-7.45 (m, 1H), 7.16-7.31 ( m,7H),7.05-7.10(m,1H),6.82-6.84(m,1H),3.66(s,3H),3.22-3.25(m,2H),2.53-2.57(m,1H),1.82- 1.90 (m, 1H), 1.51-1.72 (m, 8H).
实施例58：化合物6-38a/6-38b的合成Example 58: Synthesis of compound 6-38a/6-38b
Figure PCTCN2017095396-appb-000132
Figure PCTCN2017095396-appb-000132
冰浴条件下，化合物6-22a(95mg，0.23mmol)的无水二氯甲烷(20mL)溶液中缓慢滴加三溴化硼的二氯甲烷溶液(1.17mL，1.17mmol)。反应混合物在此温度下反应5个小时， 加冰水(25mL)淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤(30mL)，无水硫酸钠干燥、过滤，浓缩，残渣用(正己烷/乙酸乙酯＝5/1)重结晶得到化合物6-38a(29.5mg，产率：32％)为类白色固体。A solution of boron tribromide in dichloromethane (1.17 mL, 1.17 mmol) was slowly added dropwise to a solution of compound 6-22a (95 mg, 0.23 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture is reacted at this temperature for 5 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc) Crystallization gave compound 6-38a (29.5 mg, yield: 32%) as an off white solid.
利用化合物6-38a的合成方法，用化合物6-22b(150mg)为起始原料合成化合物6-38b(84.1mg，产率：58％)，为类白色固体。Compound 6-38b (84.1 mg, yield: 58%) was obtained from compound 6-bb (150 mg).
m/z:[M+H]+393；6-38a,1HNMR(400MHz,DMSO-d6):δ11.22(s,1H),9.68(s,1H),7.57(t,J＝5.6Hz,1H),7.30-7.15(m,6H),6.96-6.94(m,1H),6.73-6.71(m,2H),6.39-6.36(m,1H),3.05(t,J＝6.4Hz,2H),2.51-2.43(m,1H),1.80(d,J＝10.8Hz,4H),1.54-1.53(m,1H),1.46-1.40(m,2H),1.10-1.04(m,2H)；6-38b,1HNMR(400MHz,DMSO-d6):δ11.22(s,1H),9.65(s,1H),7.64(t,J＝5.6Hz,1H),7.31-7.15(m,6H),6.96(t,J＝2.4Hz,1H),6.72(d,J＝2.0Hz,1H),6.70-6.69(m,1H),6.36(dt,J＝2.0,10.8Hz,1H),3.29(t,J＝6.4Hz,1H),2.55-2.50(m,1H),1.92-1.90(m,1H),1.75-1.56(m,8H)。m/z: [M+H] + 393; 6-38a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.22 (s, 1H), 9.68 (s, 1H), 7.57 (t, J = 5.6 Hz, 1H), 7.30-7.15 (m, 6H), 6.96-6.94 (m, 1H), 6.73-6.71 (m, 2H), 6.39-6.36 (m, 1H), 3.05 (t, J = 6.4 Hz, 2H), 2.51-2.43 (m, 1H), 1.80 (d, J = 10.8 Hz, 4H), 1.54-1.53 (m, 1H), 1.46-1.40 (m, 2H), 1.10.10.04 (m, 2H) ;6-38b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.22 (s, 1H), 9.65 (s, 1H), 7.64 (t, J = 5.6 Hz, 1H), 7.31-7.15 (m, 6H), 6.96 (t, J = 2.4 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.70-6.69 (m, 1H), 6.36 (dt, J = 2.0, 10.8 Hz, 1H), 3.29 (t, J = 6.4 Hz, 1H), 2.55-2.50 (m, 1H), 1.92-1.90 (m, 1H), 1.75-1.56 (m, 8H).
实施例59：化合物6-39b的合成Example 59: Synthesis of Compound 6-39b
利用化合物6-38a的合成方法，用化合物6-24b为起始原料合成化合物6-39b：Synthesis of compound 6-39b using compound 6-bb as a starting material by the synthesis of compound 6-38a:
Figure PCTCN2017095396-appb-000133
Figure PCTCN2017095396-appb-000133
m/z:[M+H]+411；1H NMR(400MHz,CD3OD):δ7.27-7.24(m,5H),7.16-7.15(m,1H),6.84-6.83(d,J＝4.0Hz,1H),6.80-6.73(m,2H),3.43-3.41(d,J＝8.0Hz,1H),2.68-2.59(m,1H),1.77-1.74(m,1H),1.68-1.64(m,9H)。m/z: [M+H] + 411; 1 H NMR (400 MHz, CD 3 OD): δ 7.27-7.24 (m, 5H), 7.16-7.15 (m, 1H), 6.84-6.83 (d, J =4.0 Hz, 1H), 6.80-6.73 (m, 2H), 3.43-3.41 (d, J = 8.0 Hz, 1H), 2.68-2.59 (m, 1H), 1.77-1.74 (m, 1H), 1.68- 1.64 (m, 9H).
实施例60：化合物6-40a/6-40b的合成Example 60: Synthesis of Compound 6-40a/6-40b
利用化合物6-38a的合成方法，用化合物6-34a或6-34b为起始原料合成化合物6-40a和6-40b。Compounds 6-40a and 6-40b were synthesized by the synthesis of compound 6-38a using compound 6-34a or 6-34b as a starting material.
Figure PCTCN2017095396-appb-000134
Figure PCTCN2017095396-appb-000134
m/z:[M+H]+393；6-40a,1HNMR(400MHz,DMSO-d6):δ11.10(s,1H),9.58(s,1H),7.48(m,1H),7.29-7.16(m,6H),7.06-7.00(m,2H),6.99-6.81(m,2H),3.34-3.25(m,2H),2.53-2.50(m,1H),1.87(br.s,1H),1.70-1.53(m,8H)；6-40b,1HNMR(400MHz,DMSO-d6):δ11.10(s,1H),9.63(s,1H),7.37-7.36(m,1H),7.28-7.16(m,6H),7.07-7.00(m,2H),6.84-6.82(m,2H),3.05-3.02(m,2H),2.50-2.49(m,1H),1.81-1.75(m,4H),1.42-1.39(m,3H),1.04-1.03(m,2H)。m/z: [M+H] + 393; 6-40a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.10 (s, 1H), 9.58 (s, 1H), 7.48 (m, 1H), 7.29-7.16(m,6H),7.06-7.00(m,2H),6.99-6.81(m,2H),3.34-3.25(m,2H),2.53-2.50(m,1H),1.87(br.s , 1H), 1.70-1.53 (m, 8H); 6-40b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.10 (s, 1H), 9.63 (s, 1H), 7.37-7.36 (m, 1H), 7.28-7.16 (m, 6H), 7.07-7.00 (m, 2H), 6.84-6.82 (m, 2H), 3.05-3.02 (m, 2H), 2.50-2.49 (m, 1H), 1.81- 1.75 (m, 4H), 1.42-1.39 (m, 3H), 1.04-1.03 (m, 2H).
实施例61：化合物6-49a的合成Example 61: Synthesis of Compound 6-49a
利用化合物6-38a的合成方法，用化合物6-36a为起始原料合成化合物6-49a： Synthesis of compound 6-49a using compound 6-38a as a starting material by the synthesis of compound 6-38a:
Figure PCTCN2017095396-appb-000135
Figure PCTCN2017095396-appb-000135
m/z:[M+H]+411；1H NMR(400MHz,CD3OD):δ7.34-7.33(d,J＝4.0Hz,1H),7.29-7.24(m,4H),7.17-7.13(m,1H),7.09-7.04(m,1H),6.79-6.74(m,2H),3.43-3.40(d,J＝8.0Hz,2H),3.35-3.30(m,1H),1.93-1.91(m,1H),1.78-1.63(m,8H)。m/z: [M+H] + 411; 1 H NMR (400 MHz, CD 3 OD): δ 7.34 - 7.33 (d, J = 4.0 Hz, 1H), 7.29-7.24 (m, 4H), 7.17- 7.13 (m, 1H), 7.09-7.04 (m, 1H), 6.79-6.74 (m, 2H), 3.43-3.40 (d, J = 8.0 Hz, 2H), 3.35-3.30 (m, 1H), 1.93 1.91 (m, 1H), 1.78-1.63 (m, 8H).
实施例62：化合物6-41a/6-41b的合成Example 62: Synthesis of compound 6-41a/6-41b
Figure PCTCN2017095396-appb-000136
Figure PCTCN2017095396-appb-000136
将化合物6-18a(60mg，0.12mmol)和吡啶对甲苯磺酸盐(12mg，0.012mmol)的甲醇(5mL)溶液在室温下搅拌16小时。减压除去溶剂，残留物用硅胶柱层析(二氯甲烷/甲醇＝100/1～>10:1)纯化得到化合物6-41a(28mg，产率：56％)为白色固体。A solution of compound 6-18a (60 mg, 0.12 mmol) and EtOAc m. The solvent was removed under reduced pressure and the crystallijjjjjjjjjj
利用化合物6-41a的合成方法，用化合物6-18b(75mg)为起始原料合成化合物6-41b(35mg，产率：56％)，为白色固体。Compound 6-41b (35 mg, yield: 56%) was obtained from compound 6-bb (75 mg).
m/z:[M+H]+419；6-41a,1H NMR(400MHz,DMSO-d6):δ11.11(s,1H),7.13-7.32(m,9H),6.97(d,J＝8.0Hz,1H),6.82-6.90(m,2H),4.71(t,J＝6.4Hz,1H),3.94(t,J＝5.2Hz,2H),3.60-3.67(m,2H),2.98(t,J＝6.4Hz,2H),2.36-2.45(m,1H),1.62-1.80(m,4H),1.29-1.45(m,3H),0.88-1.02(m,2H)；6-41b,1H NMR(400MHz,DMSO-d6):δ11.12(s,1H),7.28(t,J＝7.2Hz,2H),7.11-7.24(m,7H),6.99(d,J＝7.6Hz,1H),6.89(dt,J＝0.8,7.2Hz,1H),6.83(t,J＝6.4Hz,1H),4.70(t,J＝5.6Hz,1H),3.95(t,J＝5.2Hz,2H),3.60-3.67(m,2H),3.21(t,J＝6.8Hz,2H),1.80(br.s,1H),1.42-1.71(m,8H)。m/z: [M+H] + 419; 6-41a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.11 (s, 1H), 7.13 - 7.32 (m, 9H), 6.97 (d, J=8.0 Hz, 1H), 6.82-6.90 (m, 2H), 4.71 (t, J = 6.4 Hz, 1H), 3.94 (t, J = 5.2 Hz, 2H), 3.60-3.67 (m, 2H), 2.98 (t, J = 6.4 Hz, 2H), 2.36-2.45 (m, 1H), 1.62-1.80 (m, 4H), 1.29-1.45 (m, 3H), 0.88-1.02 (m, 2H); 41b, 1 H NMR (400MHz, DMSO-d 6): δ11.12 (s, 1H), 7.28 (t, J = 7.2Hz, 2H), 7.11-7.24 (m, 7H), 6.99 (d, J = 7.6 Hz, 1H), 6.89 (dt, J = 0.8, 7.2 Hz, 1H), 6.83 (t, J = 6.4 Hz, 1H), 4.70 (t, J = 5.6 Hz, 1H), 3.95 (t, J = 5.2 Hz, 2H), 3.60-3.67 (m, 2H), 3.21 (t, J = 6.8 Hz, 2H), 1.80 (br.s, 1H), 1.42-1.71 (m, 8H).
实施例63：化合物6-42a/6-42b的合成Example 63: Synthesis of compound 6-42a/6-42b
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸和化合物2.2a或2.2b反应得到化合物6-42a/6-42b：4-phenyl-1H-pyrazole-3-carboxylic acid is reacted with compound 2.2a or 2.2b to give compound 6-42a/6-42b by the synthesis of compound 1-1:
Figure PCTCN2017095396-appb-000137
Figure PCTCN2017095396-appb-000137
m/z:[M+H]+375；6-42a,1H NMR(400MHz,DMSO-d6):δ11.26(s,1H),7.42-7.48(m,2H),7.13-7.35(m,10H),6.94(t,J＝2.0Hz,1H),4.39(s,1H),3.17(d,J＝6.0Hz,2H),2.37-2.48(m,1H),1.70-1.84(m,2H),1.50-1.63(m,4H),1.32-1.44(m,2H)；6-42b,1H NMR(400MHz,DMSO-d6):δ11.27(s,1H),7.40-7.45(m,2H),7.21-7.34(m,8H),7.14-7.20(m,2H),6.94(t,J＝2.0Hz,1H),4.73(s,1H),3.41(d,J＝6.0Hz,2H),1.55-1.79(m,6H),1.43(dt,J＝4.4,12.8Hz,2H)。m/z: [M+H] + 375; 6-42a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.26 (s, 1H), 7.42 - 7.48 (m, 2H), 7.13 - 7.35 ( m, 10H), 6.94 (t, J = 2.0 Hz, 1H), 4.39 (s, 1H), 3.17 (d, J = 6.0 Hz, 2H), 2.37-2.48 (m, 1H), 1.70-1.84 (m , 2H), 1.50-1.63 (m, 4H), 1.32-1.44 (m, 2H); 6-42b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.27 (s, 1H), 7.40-7.45 (m, 2H), 7.21-7.34 (m, 8H), 7.14-7.20 (m, 2H), 6.94 (t, J = 2.0 Hz, 1H), 4.73 (s, 1H), 3.41 (d, J = 6.0) Hz, 2H), 1.55-1.79 (m, 6H), 1.43 (dt, J = 4.4, 12.8 Hz, 2H).
实施例64：化合物6-43的合成 Example 64: Synthesis of compound 6-43
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物23.3得到化合物22-1：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid to compound 23.3 by the synthesis of compound 1-1 gives compound 22-1:
Figure PCTCN2017095396-appb-000138
Figure PCTCN2017095396-appb-000138
将化合物6-43(190mg，顺反异构体混合物)经Flash柱层析(石油醚/乙酸乙酯＝1/2)得到化合物6-43a(32.1mg，极性较大，单一立体构型)和6-43b(16.0mg，极性较小，单一立体构型)，均为白色固体。Compound 6-43 (190 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether / ethyl acetate = 1/2) to afford compound 6-43a (32.1 mg, mp. And 6-43b (16.0 mg, less polar, single stereo configuration), all white solids.
m/z:[M+H]+457；6-43a,1H NMR(400MHz,DMSO-d6):δ11.03(s,1H),7.40-7.16(m,9H),6.82(t,J＝6.0Hz,1H),6.68(d,J＝2.4Hz,1H),2.98(t,J＝6.0Hz,2H),2.44-2.35(m,1H),2.34(s,3H),1.75(d,J＝10.8Hz,2H),1.66(d,J＝10.8Hz,2H),1.40-1.33(m,3H),0.96-0.92(m,2H)；6-43b,1H NMR(400MHz,DMSO-d6):δ11.01(s,1H),7.39-7.14(m,9H),6.99(t,J＝6.0Hz,1H),6.69(d,J＝2.4Hz,1H),3.22(t,J＝7.2Hz,2H),2.51-2.48(m,1H),2.32(s,3H),1.78-1.76(m,1H),1.65-1.46(m,8H)。m/z: [M+H] + 457; 6-43a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.03 (s, 1H), 7.40-7.16 (m, 9H), 6.82 (t, J=6.0 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 2.98 (t, J=6.0 Hz, 2H), 2.44-2.35 (m, 1H), 2.34 (s, 3H), 1.75 ( d, J = 10.8 Hz, 2H), 1.66 (d, J = 10.8 Hz, 2H), 1.40-1.33 (m, 3H), 0.96-0.92 (m, 2H); 6-43b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.01 (s, 1H), 7.39-7.14 (m, 9H), 6.99 (t, J = 6.0 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 3.22 ( t, J = 7.2 Hz, 2H), 2.51-2.48 (m, 1H), 2.32 (s, 3H), 1.78-1.76 (m, 1H), 1.65-1.46 (m, 8H).
实施例65：化合物6-44～6-46的合成Example 65: Synthesis of compound 6-44-6-46
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.4和化合物4.19、4.21或1.10反应得到化合物6-44～6-46：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 8.4 and compound 4.19, 4.21 or 1.10 to give compound 6-44-6-46:
Figure PCTCN2017095396-appb-000139
Figure PCTCN2017095396-appb-000139
将化合物6-44(100mg，顺反异构体混合物)经prep-TLC(石油醚/乙酸乙酯＝2/3)得到极性较大的化合物6-44a(16.3mg，单一立体构型)和极性较小的化合物6-44b(18.3mg，单一立体构型)，均为白色固体。The compound 6-44 (100 mg, cis-trans isomer mixture) was subjected to prep-TLC (petroleum ether / ethyl acetate = 2 / 3) to give the compound 6-44a (16.3 mg, single stereo configuration). The less polar compound 6-44b (18.3 mg, single stereo configuration) was a white solid.
m/z:[M+H]+414；6-44a,1HNMR(400MHz,DMSO-d6):δ11.13(s,1H),7.67(d,J＝8.0Hz,2H),7.43-7.35(m,3H),7.16-7.10(m,2H),6.99-6.92(m,2H),6.89-6.86(m,1H),6.71-6.64(m,1H),3.66(s,3H),3.00-2.94(m,2H),2.53-2.45(m,1H),1.77-1.68(m,4H),1.51-1.28(m,3H),1.04-0.91(m,2H)；6-44b,1HNMR(400MHz,DMSO-d6):δ11.20(s,1H),7.76(d,J＝8.0Hz,2H),7.57-7.52(m,1H),7.46(d,J＝8.0Hz,2H),7.22-7.14(m,2H),7.06-6.98(m,2H),6.97-6.94(m,1H),6.77-6.72(m,1H),3.72(s,3H),3.31-3.24(m,2H),2.71-2.62(m,1H),1.94-1.84(m,1H),1.78-1.51(m,8H)。m/z: [M+H] + 414; 6-44a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.13 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.43 7.35 (m, 3H), 7.16-7.10 (m, 2H), 6.99-6.92 (m, 2H), 6.89-6.86 (m, 1H), 6.71-6.64 (m, 1H), 3.66 (s, 3H), 3.00-2.94 (m, 2H), 2.53-2.45 (m, 1H), 1.77-1.68 (m, 4H), 1.51-1.28 (m, 3H), 1.04-0.91 (m, 2H); 6-44b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.20 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.57-7.52 (m, 1H), 7.46 (d, J = 8.0 Hz, 2H) ), 7.22 - 7.14 (m, 2H), 7.06 - 6.98 (m, 2H), 6.97 - 6.94 (m, 1H), 6.77 - 6.72 (m, 1H), 3.72 (s, 3H), 3.31-3.24 (m , 2H), 2.71-2.62 (m, 1H), 1.94-1.84 (m, 1H), 1.78-1.51 (m, 8H).
Figure PCTCN2017095396-appb-000140
Figure PCTCN2017095396-appb-000140
化合物6-45(145mg，顺反异构体混合物)经prep-HPLC(分离条件9)得到化合物6-45a(2.3mg，出峰时间：16.8～17.5分钟，单一立体构型)和6-45b(0.6mg，出峰时间：18.0～18.8分钟，单一立体构型)，均为白色固体。 Compound 6-45 (145 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 9) to give compound 6-45a (2.3 mg, peak time: 16.8 to 17.5 minutes, single stereo configuration) and 6-45b (0.6 mg, peak time: 18.0 to 18.8 minutes, single stereo configuration), all white solids.
m/z:[M+H]+467；6-45a,1H NMR(400MHz,CD3OD):δ7.87-7.85(d,J＝8.0Hz,2H),7.50-7.47(d,J＝12.0Hz,2H),7.31-7.27(m,2H),7.00-6.97(m,2H),6.88-6.85(m,1H),6.81-6.80(d,J＝4.0Hz,1H),3.80(s,3H),3.15-3.13(d,J＝8.0Hz,2H),3.09(s,3H),2.62-2.55(m,2H),1.88-1.85(d,J＝6.0Hz,2H),1.76-1.72(d,J＝16.0Hz,2H),1.50-1.46(m,3H),1.09-1.00(m,2H)；6-45b,1H NMR(400MHz,CD3OD):δ7.77-7.73(d,J＝16.0Hz,2H),7.44-7.42(d,J＝8.0Hz,2H),7.18-7.14(m,2H),6.89-6.86(m,2H),6.74(m,1H),6.72(m,1H),3.68(s,3H),3.28-3.26(d,J＝8.0Hz,2H),2.99(s,3H),2.61-2.59(m,1H),1.94(m,1H),1.73(m,2H),1.69-1.63(m,2H),1.57-1.56(m,1H),1.53-1.51(m,4H)。m/z: [M+H] + 467; 6-45a, 1 H NMR (400 MHz, CD 3 OD): δ 7.87-7.85 (d, J = 8.0 Hz, 2H), 7.50-7.47 (d, J =12.0 Hz, 2H), 7.31-7.27 (m, 2H), 7.00-6.97 (m, 2H), 6.88-6.85 (m, 1H), 6.81-6.80 (d, J = 4.0 Hz, 1H), 3.80 ( s, 3H), 3.15-3.13 (d, J = 8.0 Hz, 2H), 3.09 (s, 3H), 2.62-2.55 (m, 2H), 1.88-1.85 (d, J = 6.0 Hz, 2H), 1.76 -1.72 (d, J = 16.0 Hz, 2H), 1.50-1.46 (m, 3H), 1.09-1.00 (m, 2H); 6-45b, 1 H NMR (400 MHz, CD 3 OD): δ 7.77- 7.73 (d, J = 16.0 Hz, 2H), 7.44 - 7.42 (d, J = 8.0 Hz, 2H), 7.18-7.14 (m, 2H), 6.89-6.86 (m, 2H), 6.74 (m, 1H) , 6.72 (m, 1H), 3.68 (s, 3H), 3.28-3.26 (d, J = 8.0 Hz, 2H), 2.99 (s, 3H), 2.61-2.59 (m, 1H), 1.94 (m, 1H) ), 1.73 (m, 2H), 1.69-1.63 (m, 2H), 1.57-1.56 (m, 1H), 1.53-1.51 (m, 4H).
Figure PCTCN2017095396-appb-000141
Figure PCTCN2017095396-appb-000141
m/z:[M+H]+495m/z: [M+H] + 495
实施例66：化合物6-47b的合成Example 66: Synthesis of Compound 6-47b
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.12和化合物4.19b反应得到化合物6-47b：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 8.12 and compound 4.19b to give compound 6-47b:
Figure PCTCN2017095396-appb-000142
Figure PCTCN2017095396-appb-000142
m/z:[M+H]+468；1H NMR(400MHz,DMSO-d6):δ11.24(s,1H),7.75(d,J＝8.4Hz,2H),7.55(t,J＝5.6Hz,1H),7.45(d,J＝8.0Hz,2H),7.39-7.26(m,5H),6.82(t,J＝2.0Hz,1H),3.24(t,J＝6.8Hz,2H),2.67-2.62(m,1H),1.86-1.85(m,1H),1.72-1.50(m,8H)。m/z: [M+H] + 468; 1 H NMR (400MHz, DMSO-d 6 ): δ 11.24 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 5.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.39-7.26 (m, 5H), 6.82 (t, J = 2.0 Hz, 1H), 3.24 (t, J = 6.8 Hz, 2H) ), 2.67-2.62 (m, 1H), 1.86-1.85 (m, 1H), 1.72-1.50 (m, 8H).
实施例67：化合物6-48的合成Example 67: Synthesis of Compound 6-48
Figure PCTCN2017095396-appb-000143
Figure PCTCN2017095396-appb-000143
化合物6-46(200mg，0.40mmol)溶解在甲醇(15ml)中，氢气氛下加入Pd/C(40mg)，该反应体系在30℃下搅拌3小时，硅藻土过滤浓缩得粗产品，粗品过柱纯化(二氯甲烷/甲醇＝100/1～10/1)得到较大极性的化合物6-48a(28mg)和较小极性的6-48b(20mg)，均为白色固体。The compound 6-46 (200 mg, 0.40 mmol) was dissolved in methanol (15 ml), and Pd/C (40 mg) was added under a hydrogen atmosphere. The reaction system was stirred at 30 ° C for 3 hours, and concentrated by celite to give a crude product. Purification by column chromatography (dichloromethane/methanol = 100/1 to 10/1) gave compound 6-48a (28 mg), which was a more polar, and 6-48b (20 mg) of lesser.
m/z:[M+H]+405；6-48a,1HNMR(400MHz,CD3OD):δ7.27-7.31(m,2H),6.96-7.00(m,4H),6.89(dd,J＝2.0,8.4Hz,1H),6.79(d,J＝2.0Hz,1H),6.68(d,J＝8.4Hz,2H),3.80(s,3H),3.11(d,J＝6.4Hz,2H),2.29-2.35(m,1H),1.67-1.80(m,4H),1.31-1.43(m,3H),0.92-1.02(m,2H)；6-48b,1HNMR(400MHz,CD3OD):δ7.23-7.27(m,2H),6.95-7.04(m,4H),6.84(dd,J＝2.0,8.8Hz,1H),6.80(d,J＝2.0Hz,1H),6.67(d,J＝8.8Hz,2H),3.77(s,3H),3.33(d,J＝9.6Hz,2H),2.43-2.48(m,1H),1.55-1.77(m,9H)。m/z: [M+H] + 405; 6-48a, 1 H NMR (400 MHz, CD 3 OD): δ 7.27-7.31 (m, 2H), 6.96-7.00 (m, 4H), 6.89 (dd, J = 2.0, 8.4 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.11 (d, J = 6.4 Hz, 2H), 2.29-2.35 (m, 1H), 1.67-1.80 (m, 4H), 1.31-1.43 (m, 3H), 0.92-1.02 (m, 2H); 6-48b, 1 H NMR (400 MHz, CD 3 OD): δ7.23-7.27 (m, 2H), 6.95-7.04 (m, 4H), 6.84 (dd, J = 2.0, 8.8 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.33 (d, J = 9.6 Hz, 2H), 2.43-2.48 (m, 1H), 1.55-1.77 (m, 9H).
实施例68：化合物7-1～7-9的合成Example 68: Synthesis of Compounds 7-1 to 7-9
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.2、8.3、8.4、8.5、 8.7、8.8、8.11或15.2和化合物4.7或1.8反应得到化合物7-1～7-9：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compounds 8.2, 8.3, 8.4, 8.5 by the synthesis of compound 1-1 8.7, 8.8, 8.11 or 15.2 and compound 4.7 or 1.8 are reacted to give compounds 7-1 to 7-9:
Figure PCTCN2017095396-appb-000144
Figure PCTCN2017095396-appb-000144
将化合物7-1(80mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物7-1a(35mg，单一立体构型)和极性较大的化合物7-1b(35mg，单一立体构型)，均为白色固体。The compound 7-1 (80 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 9/1 to 1/4) to give the compound 7-1a (35 mg, The stereo configuration) and the more polar compound 7-1b (35 mg, single stereo configuration) were all white solids.
m/z:[M+H]+360；7-1a,1H NMR(400MHz,CDCl3):δ8.37-8.39(m,2H),7.29-7.39(m,5H),7.13-7.15(m,2H),6.68-6.69(m,1H),3.35(br.s,1H),3.23-3.26(m,2H),2.49-2.56(m,1H),1.36-1.64(m,9H)；7-1b,1H NMR(400MHz,CDCl3):δ8.60-8.68(m,1H),8.49-8.51(m,2H),7.35-7.52(m,5H),7.10-7.12(m,2H),6.76-6.77(m,1H),5.54-5.61(m,1H),3.14-3.18(m,2H),2.36-2.44(m,1H),1.85-1.88(m,2H),1.27-1.41(m,4H),0.90-1.01(m,2H)。m/z: [M+H] + 360; 7-1a, 1 H NMR (400MHz, CDCl 3 ): δ 8.37-8.39 (m, 2H), 7.29-7.39 (m, 5H), 7.13 - 7.15 ( m, 2H), 6.68-6.69 (m, 1H), 3.35 (br.s, 1H), 3.23-3.26 (m, 2H), 2.49-2.56 (m, 1H), 1.36-1.64 (m, 9H); 7-1b, 1 H NMR (400MHz, CDCl 3 ): δ 8.60-8.68 (m, 1H), 8.49-8.51 (m, 2H), 7.35-7.52 (m, 5H), 7.10-7.12 (m, 2H) ), 6.76-6.77 (m, 1H), 5.54-5.61 (m, 1H), 3.14 - 3.18 (m, 2H), 2.36-2.44 (m, 1H), 1.85-1.88 (m, 2H), 1.27-1.41 (m, 4H), 0.90-1.01 (m, 2H).
Figure PCTCN2017095396-appb-000145
Figure PCTCN2017095396-appb-000145
将化合物7-2(79mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物7-2a(25mg，单一立体构型)和极性较大的化合物7-2b(35mg，单一立体构型)，均为白色固体。The compound 7-2 (79 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 9/1 to 1/4) to give a less polar compound 7-2a (25 mg, single The stereo configuration) and the more polar compound 7-2b (35 mg, single stereo configuration) were both white solids.
m/z:[M+H]+390；7-2a,1H NMR(400MHz,CDCl3):δ8.94(br.s,1H),8.48-8.51(m,2H),7.49-7.51(m,1H),7.28-7.40(m,2H),6.98-7.14(m,4H),6.73-6.74(m,1H),5.74-5.77(m,1H),3.81(s,3H),3.12-3.15(m,2H),2.34-2.42(m,1H),1.82-1.86(m,3H),1.59-1.63(m,2H),1.29-1.39(m,2H),0.86-0.97(m,2H)；7-2b,1H NMR(400MHz,CDCl3):δ8.71(br.s,1H),8.48-8.51(m,2H),7.50-7.51(m,1H),7.25-7.39(m,2H),6.97-7.15(m,4H),6.73-6.75(m,1H),5.67-5.69(m,1H),3.80(s,3H),3.28-3.31(m,2H),2.51-2.58(m,1H),1.58-1.66(m,5H),1.38-1.52(m,4H)。m/z: [M+H] + 390; 7-2a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.94 (br.s, 1H), 8.48-8.51 (m, 2H), 7.49-7.51 ( m,1H), 7.28-7.40 (m, 2H), 6.98-7.14 (m, 4H), 6.73-6.74 (m, 1H), 5.74-5.77 (m, 1H), 3.81 (s, 3H), 3.12 3.15 (m, 2H), 2.34 - 2.42 (m, 1H), 1.82-1.86 (m, 3H), 1.59-1.63 (m, 2H), 1.29-1.39 (m, 2H), 0.86-0.97 (m, 2H) 7-2b, 1 H NMR (400MHz, CDCl 3 ): δ 8.71 (br.s, 1H), 8.48-8.51 (m, 2H), 7.50-7.51 (m, 1H), 7.25-7.39 (m) , 2H), 6.97-7.15 (m, 4H), 6.73-6.75 (m, 1H), 5.67-5.69 (m, 1H), 3.80 (s, 3H), 3.28-3.31 (m, 2H), 2.51-2.58 (m, 1H), 1.58-1.66 (m, 5H), 1.38-1.52 (m, 4H).
Figure PCTCN2017095396-appb-000146
Figure PCTCN2017095396-appb-000146
将化合物7-3(40mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物7-3a(27.2mg，单一立体构型)和极性较大的化合物7-3b(6.6mg，单一立体构型)，均为白色固体。The compound 7-3 (40 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 9/1 to 1/4) to obtain the compound 7-3a (27.2 mg, The single stereo configuration) and the more polar compound 7-3b (6.6 mg, single stereo configuration) were all white solids.
m/z:[M+H]+390；7-3a,1H NMR(400MHz,CDCl3):δ8.75(d,J＝6.4Hz,2H),8.65(br.s,1H),7.66(d,J＝6.4Hz,2H),7.52-7.54(m,1H),7.32-7.38(m,2H),6.92-7.05(m,3H),6.78-6.79(m,1H),5.73-5.75(m,1H),3.84(m,3H),3.18-3.22(m,2H),1.94-1.97(m,2H),1.75-1.78(m,2H),1.38-1.49(m,3H),1.01-1.08(m,2H)；7-3b,1H NMR(400MHz,CDCl3):δ8.55 (br.s,1H),8.50(d,J＝6.0Hz,2H),7.51-7.52(m,1H),7.31-7.35(m,1H),7.14-7.16(d,J＝6.4Hz,2H),6.89-7.04(m,3H),6.76-6.78(m,1H),5.57-5.62(m,1H),3.84(s,3H),3.32-3.36(m,2H),2.54-2.61(m,1H),1.44-1.72(m,9H)。m/z: [M+H] + 390; 7-3a, 1 H NMR (400MHz, CDCl 3 ): δ 8.75 (d, J = 6.4 Hz, 2H), 8.65 (br.s, 1H), 7.66 (d, J = 6.4 Hz, 2H), 7.52 - 7.54 (m, 1H), 7.32 - 7.38 (m, 2H), 6.92 - 7.05 (m, 3H), 6.78 - 6.79 (m, 1H), 5.73-5.75 (m, 1H), 3.84 (m, 3H), 3.18-3.22 (m, 2H), 1.94-1.97 (m, 2H), 1.75-1.78 (m, 2H), 1.38-1.49 (m, 3H), 1.01 -1.08 (m, 2H); 7-3b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.55 (br.s, 1H), 8.50 (d, J = 6.0 Hz, 2H), 7.51 - 7.52 (m) ,1H),7.31-7.35(m,1H),7.14-7.16(d,J=6.4Hz,2H),6.89-7.04(m,3H),6.76-6.78(m,1H),5.57-5.62(m , 1H), 3.84 (s, 3H), 3.32-3.36 (m, 2H), 2.54-2.61 (m, 1H), 1.44-1.72 (m, 9H).
Figure PCTCN2017095396-appb-000147
Figure PCTCN2017095396-appb-000147
将化合物7-4(25mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝9/1～1/4)得到极性较小的化合物7-4a(9.7mg，单一立体构型)和极性较大的化合物7-4b(6.5mg，单一立体构型)，均为白色固体。Compound 7-4 (25 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petrole ether / ethyl acetate = 9/1 to 1/4) to afford compound 7-4a (9.7 mg, The single stereo configuration) and the more polar compound 7-4b (6.5 mg, single stereo configuration) were all white solids.
m/z:[M+H]+374；7-4a,1H NMR(400MHz,CDCl3):δ8.47-8.50(m,2H),7.28-7.44(m,6H),7.09-7.12(m,2H),6.55-6.56(m,1H),5.52-5.55(m,1H),3.71(s,3H),3.12-3.15(m,2H),2.36-2.40(m,1H),1.84-1.87(m,2H),1.63-1.67(m,2H),1.30-1.40(m,3H),0.89-0.99(m,2H)；7-4b,1H NMR(400MHz,CDCl3):δ8.47-8.50(m,2H),7.28-7.44(m,6H),7.09-7.12(m,2H),6.55-6.56(m,1H),5.52-5.55(m,1H),3.71(s,3H),3.12-3.15(m,2H),2.36-2.40(m,1H),1.84-1.87(m,2H),1.63-1.67(m,2H),1.30-1.40(m,3H),0.89-0.99(m,2H)。m/z: [M+H] + 374; 7-4a, 1 H NMR (400MHz, CDCl 3 ): δ 8.47-8.50 (m, 2H), 7.28-7.44 (m, 6H), 7.09-7.12 ( m, 2H), 6.55-6.56 (m, 1H), 5.52-5.55 (m, 1H), 3.71 (s, 3H), 3.12-3.15 (m, 2H), 2.36-2.40 (m, 1H), 1.84- 1.87 (m, 2H), 1.63-1.67 (m, 2H), 1.30-1.40 (m, 3H), 0.89-0.99 (m, 2H); 7-4b, 1 H NMR (400 MHz, CDCl 3 ): δ 8. 47-8.50 (m, 2H), 7.28-7.44 (m, 6H), 7.09-7.12 (m, 2H), 6.55-6.56 (m, 1H), 5.52-5.55 (m, 1H), 3.71 (s, 3H) ), 3.12-3.15 (m, 2H), 2.36-2.40 (m, 1H), 1.84-1.87 (m, 2H), 1.63-1.67 (m, 2H), 1.30-1.40 (m, 3H), 0.89-0.99 (m, 2H).
Figure PCTCN2017095396-appb-000148
Figure PCTCN2017095396-appb-000148
化合物7-5(190mg，顺反异构体混合物)经prep-HPLC(分离条件1)得到化合物7-5a(24.6mg，出峰时间：11.5～13.0分钟，单一立体构型)和7-5b(39mg，出峰时间：10.0～11.5分钟，单一立体构型)，均为白色固体。Compound 7-5 (190 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 7-5a (24.6 mg, peak time: 11.5 to 13.0 min, single stereo configuration) and 7-5b (39 mg, peak time: 10.0 to 11.5 minutes, single stereo configuration), all white solids.
m/z:[M+H]+394；7-5a,1H NMR(400MHz,CD3OD):δ8.42-8.43(m,2H),7.45-7.46(m,1H),7.32-7.39(m,4H),7.24-7.28(m,2H),6.91(d,J＝2.4Hz,1H),3.20(d,J＝6.8Hz,2H),2.54-2.60(m,1H),1.86-1.94(m,4H),1.48-1.65(m,3H),1.10-1.19(m,2H)；7-5b,1H NMR(400MHz,CD3OD):δ8.42-8.43(m,2H),7.43-7.44(m,1H),7.21-7.39(m,6H),6.92(d,J＝2.4Hz,1H),3.42(d,J＝7.6Hz,2H),2.66-2.72(m,1H),1.91-1.96(m,1H),1.78-1.88(m,2H),1.62-1.73(m,6H)。m/z: [M+H] + 394; 7-5a, 1 H NMR (400 MHz, CD 3 OD): δ 8.42-8.43 (m, 2H), 7.45-7.46 (m, 1H), 7.32-7.39 (m, 4H), 7.24-7.28 (m, 2H), 6.91 (d, J = 2.4 Hz, 1H), 3.20 (d, J = 6.8 Hz, 2H), 2.54 - 2.60 (m, 1H), 1.86- 1.94 (m, 4H), 1.48-1.65 (m, 3H), 1.10-1.19 (m, 2H); 7-5b, 1 H NMR (400 MHz, CD 3 OD): δ 8.42 - 8.43 (m, 2H) , 7.43-7.44 (m, 1H), 7.21-7.39 (m, 6H), 6.92 (d, J = 2.4 Hz, 1H), 3.42 (d, J = 7.6 Hz, 2H), 2.66-2.72 (m, 1H) ), 1.91-1.96 (m, 1H), 1.78-1.88 (m, 2H), 1.62-1.73 (m, 6H).
Figure PCTCN2017095396-appb-000149
Figure PCTCN2017095396-appb-000149
化合物7-6(108mg，顺反异构体混合物)经prep-HPLC(分离条件2)得到化合物7-6a(11.1mg，出峰时间：11.5～13.0分钟，单一立体构型)和7-6b(7.3mg，出峰时间：10.0～11.5分钟，单一立体构型)，均为白色固体。Compound 7-6 (108 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 2) to give compound 7-6a (11.1 mg, peak time: 11.5 to 13.0 min, single stereo configuration) and 7-6b (7.3 mg, peak time: 10.0 to 11.5 minutes, single stereo configuration), all white solids.
m/z:[M+H]+394；7-6a,1H NMR(400MHz,CD3OD):δ8.42-8.43(m,2H),7.41-7.43(m,2H),7.33-7.37(m,4H),7.29(d,J＝2.4Hz,1H),6.88(d,J＝2.0Hz,1H),3.18(d,J＝6.4Hz,2 H),2.52-2.60(m,1H),1.82-1.94(m,4H),1.46-1.62(m,3H),1.06-1.16(m,2H)；7-6b,1HNMR(400MHz,CD3OD):δ8.42-8.44(m,2H),7.37-7.42(m,4H),7.31-7.34(m,2H),7.27(d,J＝2.0Hz,1H),6.89(d,J＝2.4Hz,1H),3.40(d,J＝8.0Hz,2H),2.67-2.72(m,1H),1.76-1.95(m,3H),1.66-1.73(m,6H)。m/z: [M+H] + 394; 7-6a, 1 H NMR (400 MHz, CD 3 OD): δ 8.42 - 8.43 (m, 2H), 7.41 - 7.43 (m, 2H), 7.33 - 7.37 (m, 4H), 7.29 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 3.18 (d, J = 6.4 Hz, 2 H), 2.52 - 2.60 (m, 1H) ), 1.82-1.94 (m, 4H), 1.46-1.62 (m, 3H), 1.06-1.16 (m, 2H); 7-6b, 1 H NMR (400 MHz, CD 3 OD): δ 8.42 - 8.44 (m , 2H), 7.37-7.42 (m, 4H), 7.31-7.34 (m, 2H), 7.27 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 3.40 (d, J = 8.0 Hz, 2H), 2.67-2.72 (m, 1H), 1.76-1.95 (m, 3H), 1.66-1.73 (m, 6H).
Figure PCTCN2017095396-appb-000150
Figure PCTCN2017095396-appb-000150
将化合物7-7(85mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1～1/1)得到极性较小的化合物7-7a(16.2mg，单一立体构型)和极性较大的化合物7-7b(5.7mg，单一立体构型)，均为白色固体。The compound 7-7 (85 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to afford the compound 7-7a (16.2 mg, The single stereo configuration) and the more polar compound 7-7b (5.7 mg, single stereo configuration) were all white solids.
m/z:[M+H]+394；7-7a,1H NMR(400MHz,CDCl3):δ8.74(br.s,1H),8.50-8.52(m,2H),7.51-7.55(m,2H),7.42-7.46(m,1H),7.33-7.38(m,2H),7.11-7.12(m,2H),6.76-6.78(m,1H),5.32-5.38(m,1H),3.13-3.16(m,2H),2.35-2.43(m,1H),1.83-1.86(m,2H),1.58-1.63(m,2H),1.27-1.40(m,3H),0.87-0.97(m,2H)；7-7b,1H NMR(400MHz,CDCl3):δ8.75(d,J＝6.4Hz,2H),8.65(br.s,1H),7.66(d,J＝6.4Hz,2H),7.52-7.54(m,1H),7.32-7.38(m,2H),6.92-7.05(m,3H),6.78-6.79(m,1H),5.73-5.75(m,1H),3.84(m,3H),3.18-3.22(m,2H),1.94-1.97(m,2H),1.75-1.78(m,2H),1.38-1.49(m,3H),1.01-1.08(m,2H)。m/z: [M+H] + 394; 7-7a, 1 H NMR (400MHz, CDCl 3 ): δ 8.74 (br.s, 1H), 8.50-8.52 (m, 2H), 7.51-7.55 ( m, 2H), 7.42-7.46 (m, 1H), 7.33-7.38 (m, 2H), 7.11-7.12 (m, 2H), 6.76-6.78 (m, 1H), 5.32-5.38 (m, 1H), 3.13-3.16(m,2H), 2.35-2.43(m,1H),1.83-1.86(m,2H), 1.58-1.63(m,2H),1.27-1.40(m,3H),0.87-0.97(m , 2H); 7-7b, 1 H NMR (400MHz, CDCl 3 ): δ 8.75 (d, J = 6.4 Hz, 2H), 8.65 (br.s, 1H), 7.66 (d, J = 6.4 Hz, 2H), 7.52-7.54 (m, 1H), 7.32-7.38 (m, 2H), 6.92-7.05 (m, 3H), 6.78-6.79 (m, 1H), 5.73-5.75 (m, 1H), 3.84 ( m, 3H), 3.18-3.22 (m, 2H), 1.94-1.97 (m, 2H), 1.75-1.78 (m, 2H), 1.38-1.49 (m, 3H), 1.01-1.08 (m, 2H).
Figure PCTCN2017095396-appb-000151
Figure PCTCN2017095396-appb-000151
m/z:[M+H]+404；1H NMR(400MHz,CDCl3):δ8.65-8.76(m,2H),7.55-7.64(m,2H),7.31-7.43(m,2H),7.00-7.07(m,2H),6.75-6.75(m,1H),5.79(d,J＝8.8Hz,1H),3.97-4.03(m,1H),3.83(s,3H),3.35-3.42(m,1H),2.56-2.62(m,1H),1.88-1.95(m,2H),1.63-1.73(m,2H),1.21-1.41(m,3H),1.06-1.10(m,1H),0.95(m,J＝6.8Hz,3H)。m/z: [M+H] + 404; 1 H NMR (400MHz, CDCl 3 ): δ 8.65-8.76 (m, 2H), 7.55-7.64 (m, 2H), 7.31-7.43 (m, 2H) , 7.00-7.07 (m, 2H), 6.75-6.75 (m, 1H), 5.79 (d, J = 8.8 Hz, 1H), 3.97-4.03 (m, 1H), 3.83 (s, 3H), 3.35-3.42 (m, 1H), 2.56-2.62 (m, 1H), 1.88-1.95 (m, 2H), 1.63-1.73 (m, 2H), 1.21-1.41 (m, 3H), 1.06-1.10 (m, 1H) , 0.95 (m, J = 6.8 Hz, 3H).
Figure PCTCN2017095396-appb-000152
Figure PCTCN2017095396-appb-000152
m/z:[M+H]+404；1H NMR(400MHz,DMSO-d6):δ11.15(s,1H),8.45(d,J＝5.6Hz,2H),7.36(d,J＝8.8Hz,2H),7.22-7.24(m,3H),6.89-6.94(m,3H),6.82-6.84(m,1H),3.78-3.82(m,1H),3.75(s,3H),2.42-2.45(m,1H),1.79-1.82(m,3H),1.71-1.74(m,1H),1.32-1.41(m,3H),1.07-1.11(m,1H),0.98-1.04(m,4H)。m/z: [M+H] + 404; 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.15 (s, 1H), 8.45 (d, J = 5.6 Hz, 2H), 7.36 (d, J) = 8.8 Hz, 2H), 7.22-7.24 (m, 3H), 6.89-6.94 (m, 3H), 6.82-6.84 (m, 1H), 3.78-3.82 (m, 1H), 3.75 (s, 3H), 2.42-2.45(m,1H), 1.79-1.82(m,3H),1.71-1.74(m,1H),1.32-1.41(m,3H),1.07-1.11(m,1H),0.98-1.04(m , 4H).
实施例69：化合物8-1～8-7的合成Example 69: Synthesis of Compounds 8-1 to 8-7
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.2、8.7、8.4、8.13、8.15、8.12或8.17和化合物4.8反应得到化合物8-1～8-7： By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced with compound 8.2, 8.7, 8.4, 8.13, 8.15, 8.12 or 8.17 and compound 4.8 to give compound 8-1~ 8-7:
Figure PCTCN2017095396-appb-000153
Figure PCTCN2017095396-appb-000153
将化合物8-1(180mg，顺反异构体混合物)经硅胶柱色谱分离(二氯甲烷/甲醇＝100/1～10/1)得到极性较小的化合物8-1a(42mg，单一立体构型)和极性较大的化合物8-1b(40mg，单一立体构型)，均为白色固体。The compound 8-1 (180 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (dichloromethane/methanol = 100/1 to 10/1) to give a less polar compound 8-1a (42 mg, single solid The configuration and the more polar compound 8-1b (40 mg, single stereo configuration) were both white solids.
m/z:[M+H]+428；8-1a,1H NMR(400MHz,DMSO-d6):δ11.22(s,1H),8.81(d,J＝4.4Hz,1H),8.07-8.12(m,1H),7.97-8.00(m,1H),7.65-7.70(m,1H),7.53-7.56(m,1H),7.45-7.48(m,3H),7.24-7.32(m,3H),7.15-7.20(m,1H),6.93-6.94(m,1H),3.26-3.30(m,1H),3.08-3.11(m,2H),1.83-1.92(m,4H),1.49-1.61(m,3H),1.16-1.32(m,2H)；8-1b,1H NMR(400MHz,DMSO-d6):δ8.91(s,1H),8.81(d,J＝4.8Hz,1H),8.11-8.15(m,1H),7.63-7.66(m,1H),7.41-7.53(m,6H),7.32-7.38(m,2H),6.76-6.78(m,1H),5.55-5.58(m,1H),3.41-3.44(m,2H),3.14-3.22(m,1H),1.72-1.76(m,4H),1.64-1.72(m,5H)。m/z: [M+H] + 428; 8-1a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.22 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.07 -8.12(m,1H), 7.97-8.00(m,1H), 7.65-7.70(m,1H),7.53-7.56(m,1H),7.45-7.48(m,3H),7.24-7.32(m, 3H), 7.15-7.20 (m, 1H), 6.93-6.94 (m, 1H), 3.26-3.30 (m, 1H), 3.08-3.11 (m, 2H), 1.83-1.92 (m, 4H), 1.49- 1.61 (m, 3H), 1.16-1.32 (m, 2H); 8-1b, 1 H NMR (400MHz, DMSO-d 6 ): δ 8.91 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.11-8.15 (m, 1H), 7.63-7.66 (m, 1H), 7.41-7.53 (m, 6H), 7.32-7.38 (m, 2H), 6.76-6.78 (m, 1H), 5.55- 5.58 (m, 1H), 3.41-3.44 (m, 2H), 3.14 - 3.22 (m, 1H), 1.72-1.76 (m, 4H), 1.64-1.72 (m, 5H).
Figure PCTCN2017095396-appb-000154
Figure PCTCN2017095396-appb-000154
将化合物8-2(120mg，顺反异构体混合物)经硅胶柱色谱分离(二氯甲烷/甲醇＝100/1～10/1)得到极性较小的化合物8-2a(15mg，单一立体构型)和极性较大的化合物8-2b(14mg，单一立体构型)，均为白色固体。The compound 8-2 (120 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (dichloromethane/methanol = 100/1 to 10/1) to give a less polar compound 8-2a (15 mg, single solid The configuration and the more polar compound 8-2b (14 mg, single stereo configuration) were all white solids.
m/z:[M+H]+458；8-2a,1H NMR(400MHz,CDCl3):δ9.63(s,1H),8.81(d,J＝4.4Hz,1H),8.11-8.15(m,1H),7.62-7.66(m,1H),7.46-7.51(m,2H),7.33-7.42(m,2H),7.26(d,J＝4.8Hz,1H),7.01-7.08(m,2H),6.74-6.75(m,1H),5.85-5.88(m,1H),3.82(s,3H),3.19-3.23(m,2H),2.99-3.05(m,1H),1.96(d,J＝12.4Hz,2H),1.66-1.69(m,2H),1.39-1.51(m,3H),1.00-1.10(m,2H)；8-2b,1H NMR(400MHz,CDCl3):δ9.38(s,1H),8.79(d,J＝4.8Hz,1H),8.11-8.14(m,1H),7.62-7.65(m,1H),7.45-7.50(m,2H),7.35-7.39(m,1H),7.29-7.32(m,2H),6.97-7.04(m,2H),6.73-6.75(m,1H),5.74-5.77(m,1H),3.80(s,3H),3.38-3.41(m,2H),3.12-3.21(m,1H),1.57-1.74(m,9H)。m/z: [M+H] + 458; 8-2a, 1 H NMR (400MHz, CDCl 3 ): δ 9.63 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.11 - 8.15 (m, 1H), 7.62-7.66 (m, 1H), 7.46-7.51 (m, 2H), 7.33-7.42 (m, 2H), 7.26 (d, J = 4.8 Hz, 1H), 7.01-7.08 (m , 2H), 6.74-6.75 (m, 1H), 5.85-5.88 (m, 1H), 3.82 (s, 3H), 3.19-3.23 (m, 2H), 2.99-3.05 (m, 1H), 1.96 (d) , J = 12.4 Hz, 2H), 1.66-1.69 (m, 2H), 1.39-1.51 (m, 3H), 1.00 - 1.10 (m, 2H); 8-2b, 1 H NMR (400 MHz, CDCl 3 ): δ 9.38 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.11-8.14 (m, 1H), 7.62-7.65 (m, 1H), 7.45-7.50 (m, 2H), 7.35- 7.39 (m, 1H), 7.29-7.32 (m, 2H), 6.97-7.04 (m, 2H), 6.73-6.75 (m, 1H), 5.74-5.77 (m, 1H), 3.80 (s, 3H), 3.38-3.41 (m, 2H), 3.12-3.21 (m, 1H), 1.57-1.74 (m, 9H).
Figure PCTCN2017095396-appb-000155
Figure PCTCN2017095396-appb-000155
将化合物8-3(205mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物8-3a(50mg，出峰时间：19.0～19.8分钟，单一立体构型)和8-3b(46mg，出峰时间：20.0～20.8分钟，单一立体构型)，均为白色固体。Compound 8-3 (205 mg, cis-trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 8-3a (50 mg, peak time: 19.0 to 19.8 minutes, single stereo configuration) and 8-3b (46 mg, peak time: 20.0 to 20.8 minutes, single stereo configuration), all white solids.
m/z:[M+H]+458；8-3a,1HNMR(400MHz,CD3OD):δ8.64(d,J＝4.8Hz,1H),7.97(dd,J＝5.2,8.8Hz,1H),7.76(dd,J＝2.8,10.8Hz,1H),7.46-7.51(m,1H),7.35(d,J＝4.8Hz,1H), 7.18-7.22(m,2H),6.89-6.92(m,2H),6.75-6.78(m,1H),6.71(d,J＝2.4Hz,1H),3.69(s,3H),3.12-3.16(m,1H),3.10(d,J＝6.4Hz,2H),1.87(d,J＝12.0Hz,2H),1.69(d,J＝10.8Hz,2H),1.43-1.53(m,3H),1.06-1.16(m,2H)；8-3b,1HNMR(400MHz,CD3OD):δ8.64(d,J＝4.8Hz,1H),7.97(dd,J＝5.6,9.2Hz,1H),7.76(dd,J＝2.8,10.4Hz,1H),7.45-7.50(m,1H),7.42(d,J＝4.8Hz,1H),7.13-7.18(m,2H),6.86-6.90(m,2H),6.70-6.73(m,2H),3.67(s,3H),3.33(d,J＝7.6Hz,2H),3.22-3.23(m,1H),1.83(s,1H),1.29-1.72(m,8H)。m/z: [M+H] + 458; 8-3a, 1 H NMR (400 MHz, CD 3 OD): δ 8.64 (d, J = 4.8 Hz, 1H), 7.97 (dd, J = 5.2, 8.8 Hz) , 1H), 7.76 (dd, J = 2.8, 10.8 Hz, 1H), 7.46-7.51 (m, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.18-7.22 (m, 2H), 6.89- 6.92 (m, 2H), 6.75-6.78 (m, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.69 (s, 3H), 3.12-3.16 (m, 1H), 3.10 (d, J = 6.4 Hz, 2H), 1.87 (d, J = 12.0 Hz, 2H), 1.69 (d, J = 10.8 Hz, 2H), 1.43-1.53 (m, 3H), 1.06-1.16 (m, 2H); 3b, 1 H NMR (400 MHz, CD 3 OD): δ 8.64 (d, J = 4.8 Hz, 1H), 7.97 (dd, J = 5.6, 9.2 Hz, 1H), 7.76 (dd, J = 2.8, 10.4 Hz) , 1H), 7.45-7.50 (m, 1H), 7.42 (d, J = 4.8 Hz, 1H), 7.13-7.18 (m, 2H), 6.86-6.90 (m, 2H), 6.70-6.73 (m, 2H) ), 3.67 (s, 3H), 3.33 (d, J = 7.6 Hz, 2H), 3.22-3.23 (m, 1H), 1.83 (s, 1H), 1.29 - 1.72 (m, 8H).
Figure PCTCN2017095396-appb-000156
Figure PCTCN2017095396-appb-000156
将化合物8-4(233mg，顺反异构体混合物)经prep-TLC分离(二氯甲烷/乙酸乙酯＝1/1)得到极性较小的化合物8-4a(14mg，单一立体构型)和极性较大的化合物8-4b(8mg，单一立体构型)，均为白色固体。The compound 8-4 (233 mg, cis-trans isomer mixture) was separated by prep-TLC (dichloromethane/ethyl acetate = 1/1) to give the less polar compound 8-4a (14 mg, single stereo configuration) And the more polar compound 8-4b (8 mg, single stereo configuration), both as a white solid.
m/z:[M+H]+446；8-4a,1HNMR(400MHz,CD3OD):δ8.77(d,J＝4.0Hz,1H),8.11-8.07(m,1H),7.90(dd,J＝8.0,4.0Hz,1H),7.63-7.58(m,1H),7.50(d,J＝4.0Hz,1H),7.39-7.34(m,1H),7.29-7.26(m,2H),7.21(d,J＝8.0Hz,1H),7.00-6.96(m,1H),6.92(d,J＝4.0Hz,1H),3.25(d,J＝8.0Hz,2H),2.05-1.91(m,5H),1.69-1.60(m,3H),1.37-1.20(m,2H)；8-4b,1HNMR(400MHz,CD3OD):δ8.77(d,J＝4.0Hz,1H),8.11-8.07(m,1H),7.91(dd,J＝12.0,4.0Hz,1H),7.63-7.56(m,2H),7.35-7.23(m,3H),7.19(d,J＝8.0Hz,1H),6.97-6.91(m,2H),3.48(d,J＝8.0Hz,2H),3.41-3.36(m,1H),2.09-2.02(m,1H),1.90-1.80(m,8H)。m/z: [M+H] + 446; 8-4a, 1 H NMR (400 MHz, CD 3 OD): δ 8.77 (d, J = 4.0 Hz, 1H), 8.11 - 8.07 (m, 1H), 7.90 (dd, J=8.0, 4.0 Hz, 1H), 7.63-7.58 (m, 1H), 7.50 (d, J=4.0 Hz, 1H), 7.39-7.34 (m, 1H), 7.29-7.26 (m, 2H) ), 7.21 (d, J = 8.0 Hz, 1H), 7.00-6.96 (m, 1H), 6.92 (d, J = 4.0 Hz, 1H), 3.25 (d, J = 8.0 Hz, 2H), 2.05-1.91 (m, 5H), 1.69-1.60 (m, 3H), 1.37-1.20 (m, 2H); 8-4b, 1 H NMR (400 MHz, CD 3 OD): δ 8.77 (d, J = 4.0 Hz, 1H) ), 8.11 - 8.07 (m, 1H), 7.91 (dd, J = 12.0, 4.0 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.35 - 7.23 (m, 3H), 7.19 (d, J = 8.0) Hz, 1H), 6.97-6.91 (m, 2H), 3.48 (d, J = 8.0 Hz, 2H), 3.41-3.36 (m, 1H), 2.09-2.02 (m, 1H), 1.90- 1.80 (m, 8H).
Figure PCTCN2017095396-appb-000157
Figure PCTCN2017095396-appb-000157
将化合物8-5(236mg，顺反异构体混合物)经Flash柱层析分离(二氯甲烷/甲醇＝20/1)得到极性较大的化合物8-5a(15.6mg，单一立体构型)和极性较小的化合物8-5b(22.4mg，单一立体构型)，均为白色固体。Compound 8-5 (236 mg, cis-trans isomer mixture) was subjected to flash column chromatography (dichloromethane/methanol = 20/1) to afford compound 8-5a (15.6 mg, single stereo configuration). And the less polar compound 8-5b (22.4 mg, single stereo configuration), both as a white solid.
m/z:[M+H]+453；8-5a,1HNMR(400MHz,DMSO-d6):δ11.40(s,1H),8.81(d,J＝4.4Hz,1H),8.10(dd,J＝6.0,9.2Hz,H),7.97(dd,J＝2.4,10.8Hz,H),7.78(t,J＝5.6Hz,1H),7.73(d,J＝7.6Hz,1H),7.67(dt,J＝2.1,8.8Hz,1H),7.59(t,J＝8.0Hz,1H),7.47-7.36(m,4H),6.97(s,1H),3.35-3.30(m,3H),2.02-2.00(m,1H),1.76-1.64(m,8H)；8-5b,1HNMR(400MHz,DMSO-d6):δ11.41(s,1H),8.81(d,J＝4.4Hz,1H),8.09(dd,J＝5.6,8.8Hz,1H),7.98(dd,J＝2.0,10.8Hz,1H),7.78-7.74(m,2H),7.70-7.59(m,2H),7.45-7.38(m,4H),6.97(s,1H),3.33-3.27(m,1H),3.06(t,J＝6.0Hz,2H),1.91-1.86(m,4H),1.61-1.51(m,3H),1.31-1.24(m,2H)。m/z: [M+H] + 453; 8-5a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.40 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.10 ( Dd, J = 6.0, 9.2 Hz, H), 7.97 (dd, J = 2.4, 10.8 Hz, H), 7.78 (t, J = 5.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.67 (dt, J = 2.1, 8.8 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.47-7.36 (m, 4H), 6.97 (s, 1H), 3.35-3.30 (m, 3H) , 2.02-2.00 (m, 1H), 1.76-1.64 (m, 8H); 8-5b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.41 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.09 (dd, J=5.6, 8.8 Hz, 1H), 7.98 (dd, J=2.0, 10.8 Hz, 1H), 7.78-7.74 (m, 2H), 7.70-7.59 (m, 2H) , 7.45-7.38 (m, 4H), 6.97 (s, 1H), 3.33 - 3.27 (m, 1H), 3.06 (t, J = 6.0 Hz, 2H), 1.91-1.86 (m, 4H), 1.61-1.51 (m, 3H), 1.31-1.24 (m, 2H).
Figure PCTCN2017095396-appb-000158
Figure PCTCN2017095396-appb-000158
将化合物8-6(205mg，顺反异构体混合物)经prep-HPLC(分离条件15)得到化合物8-6a(15.9mg，出峰时间：21.4～22.0分钟，单一立体构型)和8-6b(12.8mg，出峰时间：22.3～23.1分钟，单一立体构型)，均为白色固体。Compound 8-6 (205 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 15) to give compound 8-6a (15.9 mg, peak time: 21.4 to 22.0 minutes, single stereo configuration) and 8- 6b (12.8 mg, peak time: 22.3 to 23.1 minutes, single stereo configuration), all white solids.
m/z:[M+H]+512；8-6a,1HNMR(400MHz,DMSO-d6):δ11.24(s,1H),8.81(d,J＝4.4Hz,1H),8.10-8.06(m,1H),7.98-7.94(m,1H),7.68-7.63(m,1H),7.53(t,J＝6.0Hz,1H),7.45(d,J＝4.8Hz,1H),7.41-7.39(m,1H),7.33-7.28(m,4H),6.83(t,J＝2.4Hz,1H),3.05(t,J＝6.0Hz,2H),1.90-1.82(m,4H),1.55-1.46(m,2H),1.29-1.23(m,4H)；8-6b,1HNMR(400MHz,DMSO-d6):δ11.30(s,1H),8.86(d,J＝4.4Hz,1H),8.16-8.12(m,1H),8.02-7.99(m,1H),7.74-7.69(m,1H),7.66(t,J＝5.6Hz,1H),7.49(d,J＝4.4Hz,1H),7.45-7.43(m,1H),7.38-7.31(m,4H),6.89(t,J＝2.0Hz,1H),3.36-3.34(m,2H),2.00-1.68(m,10H)。m/z: [M+H] + 512; 8-6a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.24 (s, 1H), 8.81 (d, J = 4.4 Hz, 1H), 8.10- 8.06 (m, 1H), 7.98-7.94 (m, 1H), 7.68-7.63 (m, 1H), 7.53 (t, J = 6.0 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.41 -7.39(m,1H),7.33-7.28(m,4H),6.83(t,J=2.4Hz,1H),3.05(t,J=6.0Hz,2H),1.90-1.82(m,4H), 1.55-1.46 (m, 2H), 1.29-1.23 (m, 4H); 8-6b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.30 (s, 1H), 8.86 (d, J = 4.4 Hz) , 1H), 8.16-8.12 (m, 1H), 8.02-7.99 (m, 1H), 7.74-7.69 (m, 1H), 7.66 (t, J = 5.6 Hz, 1H), 7.49 (d, J = 4.4 Hz, 1H), 7.45-7.43 (m, 1H), 7.38-7.31 (m, 4H), 6.89 (t, J = 2.0 Hz, 1H), 3.36-3.34 (m, 2H), 2.00-1.68 (m, 10H).
Figure PCTCN2017095396-appb-000159
Figure PCTCN2017095396-appb-000159
将化合物8-7(211mg，顺反异构体混合物)经prep-TLC分离(石油醚/乙酸乙酯＝3/10)得到极性较大的化合物8-7a(3.7mg，单一立体构型)和极性较小的化合物8-7b(8.0mg，单一立体构型)，均为白色固体。The compound 8-7 (211 mg, cis-trans isomer mixture) was separated by prep-TLC (petroleum ether / ethyl acetate = 3/10) to give the compound 8-7a (3.7 mg, single stereo configuration) And the less polar compound 8-7b (8.0 mg, single stereo configuration), both as white solids.
m/z:[M+H]+453；8-7a,1HNMR(400MHz,DMSO-d6):δ11.37(s,1H),8.82(d,J＝4.4Hz,1H),8.12-8.05(m,1H),7.99-7.95(m,1H),7.91-7.85(m,2H),7.82-7.78(m,1H),7.71-7.63(m,1H),7.61-7.57(m,1H),7.50-7.45(m,2H),7.34-7.31(m,1H),7.14-7.12(m,1H),3.40-3.35(m,2H),2.05-1.95(m,2H),1.85-1.64(m,8H)；8-7b,1HNMR(400MHz,DMSO-d6):δ11.37(s,1H),8.82-8.80(m,1H),8.12-8.06(m,1H),8.01-7.97(m,1H),7.95-7.92(m,1H),7.90-7.85(m,1H),7.85-7.81(m,1H),7.70-7.64(m,1H),7.63-7.59(m,1H),7.53-7.44(m,2H),7.36-7.33(m,1H),7.14-7.11(m,1H),3.15-3.10(m,2H),2.04-1.85(m,6H),1.70-1.40(m,4H)。m/z: [M+H] + 453; 8-7a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.37 (s, 1H), 8.82 (d, J = 4.4 Hz, 1H), 8.12 8.05 (m, 1H), 7.99-7.95 (m, 1H), 7.91-7.85 (m, 2H), 7.82-7.78 (m, 1H), 7.71-7.63 (m, 1H), 7.61-7.57 (m, 1H) ), 7.50-7.45 (m, 2H), 7.34 - 7.31 (m, 1H), 7.14 - 7.12 (m, 1H), 3.40-3.35 (m, 2H), 2.05-1.95 (m, 2H), 1.85-1.64 (m, 8H); 8-7b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.37 (s, 1H), 8.82-8.80 (m, 1H), 8.12-8.06 (m, 1H), 8.01 7.97 (m, 1H), 7.95-7.92 (m, 1H), 7.90-7.85 (m, 1H), 7.85-7.81 (m, 1H), 7.70-7.64 (m, 1H), 7.63-7.59 (m, 1H) ), 7.53-7.44 (m, 2H), 7.36-7.33 (m, 1H), 7.14-7.11 (m, 1H), 3.15-3.10 (m, 2H), 2.04-1.85 (m, 6H), 1.70-1.40 (m, 4H).
实施例70：化合物8-10a～8-16a的合成Example 70: Synthesis of Compound 8-10a-8-16a
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物23.5或8.19、8.21、8.16、8.29、8.30或8.31和化合物4.8a反应得到化合物8-10a～8-16a：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 23.5 or 8.19, 8.21, 8.16, 8.29, 8.30 or 8.31 and compound 4.8a to give compound 8-10a. ~8-16a:
Figure PCTCN2017095396-appb-000160
Figure PCTCN2017095396-appb-000160
Figure PCTCN2017095396-appb-000161
Figure PCTCN2017095396-appb-000161
Figure PCTCN2017095396-appb-000162
Figure PCTCN2017095396-appb-000162
实施例71：化合物8-19a～8-20a的合成Example 71: Synthesis of Compound 8-19a-8-20a
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.7、8.16和化合物4.21a反应得到化合物8-19a～8-20a：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 8.7, 8.16 and compound 4.21a to give compound 8-19a-8-20a:
Figure PCTCN2017095396-appb-000163
Figure PCTCN2017095396-appb-000163
Figure PCTCN2017095396-appb-000164
Figure PCTCN2017095396-appb-000164
实施例72：化合物8-21a～8-23a的合成Example 72: Synthesis of compound 8-21a-8-23a
利用化合物6-38a的合成方法，用化合物8-13a、8-12a或8-16a为起始原料合成化合物8-21a～8-23a：The compound 8-21a-8-23a was synthesized by the synthesis method of the compound 6-38a using the compound 8-13a, 8-12a or 8-16a as a starting material:
Figure PCTCN2017095396-appb-000165
Figure PCTCN2017095396-appb-000165
Figure PCTCN2017095396-appb-000166
Figure PCTCN2017095396-appb-000166
实施例73：化合物9-1～9-6的合成Example 73: Synthesis of Compounds 9-1 to 9-6
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.2～8.3、8.7、15.4或8.4和化合物4.9或1.9反应得到化合物9-1～9-6：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 8.2-8.3, 8.7, 15.4 or 8.4 and compound 4.9 or 1.9 to give compound 9-1-9- 6:
Figure PCTCN2017095396-appb-000167
Figure PCTCN2017095396-appb-000167
将化合物9-1(153mg，顺反异构体混合物)经硅胶柱色谱分离(二氯甲烷/甲醇＝10/1)得到极性较小的化合物9-1a(25.8mg，单一立体构型)和极性较大的化合物9-1b(3.5mg，单一立体构型)，均为白色固体。 The compound 9-1 (153 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (dichloromethane/methanol = 10/1) to give a less polar compound 9-1a (25.8 mg, single stereo configuration) The more polar compound 9-1b (3.5 mg, single stereo configuration) was a white solid.
m/z:[M+H]+374；9-1a,1H NMR(400MHz,CD3OD):δ8.56(d,J＝6.4Hz,1H),7.83(s,1H),7.77-7.79(m,1H),7.26-7.45(m,6H),6.84(d,J＝1.6Hz,1H),3.17(d,J＝6.4Hz,2H),2.79-2.83(m,1H),2.77(s,3H),2.02-2.06(m,1H),1.95-1.98(m,2H),1.82-1.85(m,2H),1.50-1.64(m,4H)；9-1b,1H NMR(400MHz,CD3OD):δ8.56(d,J＝6.4Hz,1H),7.86(s,1H),7.80-7.82(m,1H),7.23-7.44(m,6H),6.85(d,J＝2.0Hz,1H),3.42(d,J＝8.0Hz,2H),2.88-2.92(m,1H),2.76(s,3H),1.68-1.90(m,9H)。m/z: [M+H] + 374; 9-1a, 1 H NMR (400 MHz, CD 3 OD): δ 8.56 (d, J = 6.4 Hz, 1H), 7.83 (s, 1H), 7.77- 7.79 (m, 1H), 7.26-7.45 (m, 6H), 6.84 (d, J = 1.6 Hz, 1H), 3.17 (d, J = 6.4 Hz, 2H), 2.79-2.83 (m, 1H), 2.77 (s, 3H), 2.02-2.06 (m, 1H), 1.95-1.98 (m, 2H), 1.82-1.85 (m, 2H), 1.50-1.64 (m, 4H); 9-1b, 1 H NMR ( 400MHz, CD 3 OD): δ 8.56 (d, J = 6.4 Hz, 1H), 7.86 (s, 1H), 7.80-7.82 (m, 1H), 7.23 - 7.44 (m, 6H), 6.85 (d, J = 2.0 Hz, 1H), 3.42 (d, J = 8.0 Hz, 2H), 2.88-2.92 (m, 1H), 2.76 (s, 3H), 1.68-1.90 (m, 9H).
Figure PCTCN2017095396-appb-000168
Figure PCTCN2017095396-appb-000168
将化合物9-2(80mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1)得到极性较小的化合物9-2a(13mg，单一立体构型)和极性较大的化合物9-2b(12mg，单一立体构型)，均为白色固体。The compound 9-2 (80 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give a less polar compound 9-2a (13 mg, single stereo configuration) The more polar compound 9-2b (12 mg, single stereo configuration) was a white solid.
m/z:[M+H]+404；9-2a,1H NMR(400MHz,DMSO-d6):δ11.14(s,1H),8.31(d,J＝5.2Hz,1H),7.36-7.39(m,3H),7.23(t,J＝2.4Hz,1H),7.11(s,1H),7.04(d,J＝5.2Hz,1H),6.87-6.89(m,2H),6.83-6.85(m,1H),3.74(s,3H),3.01-3.04(m,2H),2.43-2.46(m,4H),1.77-1.80(m,4H),1.38-1.44(m,3H),1.00-1.03(m,2H)；9-2b,1H NMR(400MHz,DMSO-d6):δ11.14(s,1H),8.32(d,J＝5.2Hz,1H),7.44-7.47(m,1H),7.36(d,J＝8.2Hz,2H),7.20(t,J＝2.4Hz,1H),7.13(s,1H),7.05-7.07(m,1H),6.84-6.86(m,3H),3.74(s,3H),3.23-3.26(m,2H),2.43-2.44(m,4H),1.81-1.85(m,1H),1.68-1.71(m,2H),1.56-1.57(m,6H)。m/z: [M+H] + 404; 9-2a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.14 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.36 -7.39(m,3H), 7.23(t,J=2.4Hz,1H),7.11(s,1H),7.04(d,J=5.2Hz,1H),6.87-6.89(m,2H),6.83- 6.85 (m, 1H), 3.74 (s, 3H), 3.01-3.04 (m, 2H), 2.43-2.46 (m, 4H), 1.77-1.80 (m, 4H), 1.38-1.44 (m, 3H), 1.00-1.03 (m, 2H); 9-2b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.14 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.44 - 7.47 ( m,1H), 7.36 (d, J=8.2Hz, 2H), 7.20 (t, J=2.4Hz, 1H), 7.13(s,1H), 7.05-7.07(m,1H),6.84-6.86(m ,3H), 3.74(s,3H),3.23-3.26(m,2H),2.43-2.44(m,4H),1.81-1.85(m,1H),1.68-1.71(m,2H),1.56-1.57 (m, 6H).
Figure PCTCN2017095396-appb-000169
Figure PCTCN2017095396-appb-000169
将化合物9-3(207mg，顺反异构体混合物)经硅胶柱色谱分离(二氯甲烷/甲醇＝95/5)得到极性较小的化合物9-3a(58mg，单一立体构型)和极性较大的化合物9-3b(40mg，单一立体构型)，均为白色固体。The compound 9-3 (207 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (dichloromethane/methanol = 95/5) to give the less polar compound 9-3a (58 mg, single stereo configuration) and The more polar compound 9-3b (40 mg, single stereo configuration) was a white solid.
m/z:[M+H]+404；9-3a,1H NMR(400MHz,DMSO-d6):δ11.09-11.15(m,1H),8.64-8.70(s,1H),7.71-7.84(m,2H),7.18-7.26(m,3H),6.89-7.00(m,3H),6.72-6.76(m,1H),3.68(s,3H),2.97-3.01(m,2H),2.66(s,3H),1.78-1.87(m,2H),1.68-1.76(m,2H),1.37-1.50(m,3H),1.22-1.26(m,1H),0.91-1.03(m,2H)；9-3b,1H NMR(400MHz,DMSO-d6):δ11.09-11.16(m,1H),8.63-8.70(s,1H),7.78-7.84(m,1H),7.71-7.75(m,1H),7.13-7.23(m,3H),7.03-7.07(m,1H),6.96(d,J＝8.0Hz,1H),6.86-6.90(m,1H),6.74-6.76(m,1H),3.66(s,3H),3.20-3.23(m,2H),2.76-2.86(m,1H),2.67(s,3H),1.54-1.80(m,8H),1.20-1.26(m,1H)。m/z: [M+H] + 404; 9-3a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.09-11.15 (m, 1H), 8.64-8.70 (s, 1H), 7.71 7.84 (m, 2H), 7.18-7.26 (m, 3H), 6.89-7.00 (m, 3H), 6.72-6.76 (m, 1H), 3.68 (s, 3H), 2.97-3.01 (m, 2H), 2.66(s,3H), 1.78-1.87(m,2H), 1.68-1.76(m,2H),1.37-1.50(m,3H),1.22-1.26(m,1H),0.91-1.03(m,2H) 9-3b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.09-11.16 (m, 1H), 8.63-8.70 (s, 1H), 7.78-7.84 (m, 1H), 7.71-7.75 (m, 1H), 7.13 - 7.23 (m, 3H), 7.03-7.07 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.86-6.90 (m, 1H), 6.74 - 6.76 (m , 1H), 3.66 (s, 3H), 3.20-3.23 (m, 2H), 2.76-2.86 (m, 1H), 2.67 (s, 3H), 1.54-1.80 (m, 8H), 1.20-1.26 (m , 1H).
Figure PCTCN2017095396-appb-000170
Figure PCTCN2017095396-appb-000170
m/z:[M+H]+418；1H NMR(400MHz,CDCl3):δ8.73-8.77(m,1H),8.70(d,J＝6.0Hz,1H),7.52-7.54(m,1H),7.30-7.43(m,4H),6.96-7.07(m,2H),6.74-6.76(m,1H),5.72(d,J＝9.2Hz,1H),3.95-4.02(m,1H),3.82(s,3H),2.83(m,3H),2.49-2.58(m,1H),1.84-1.93(m,2H),1.60-1.73(m,2H),1.17-1.39(m,3H),0.99-1.12(m,1H),0.94(d,J＝6.8Hz,3H),0.82-0.89(m,1H)。m/z: [M+H] + 418; 1 H NMR (400 MHz, CDCl 3 ): δ 8.83 - 8.77 (m, 1H), 8.70 (d, J = 6.0 Hz, 1H), 7.52-7.54 (m) , 1H), 7.30-7.43 (m, 4H), 6.96-7.07 (m, 2H), 6.74-6.76 (m, 1H), 5.72 (d, J = 9.2 Hz, 1H), 3.95-4.02 (m, 1H) ), 3.82 (s, 3H), 2.83 (m, 3H), 2.49-2.58 (m, 1H), 1.84-1.93 (m, 2H), 1.60-1.73 (m, 2H), 1.7-1.39 (m, 3H) ), 0.99-1.12 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.82 - 0.89 (m, 1H).
Figure PCTCN2017095396-appb-000171
Figure PCTCN2017095396-appb-000171
将化合物9-5(205mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物9-5a(43.7mg，出峰时间：14.7～15.2分钟，单一立体构型)和9-5b(28.0mg，出峰时间：15.5～16.2分钟，单一立体构型)，均为白色固体。Compound 9-5 (205 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 5) to give compound 9-5a (43.7 mg, peak time: 14.7 to 15.2 minutes, single stereo configuration) and 9- 5b (28.0 mg, peak time: 15.5 to 16.2 minutes, single stereo configuration), all white solids.
m/z:[M+H]+418；9-5a,1HNMR(400MHz,CD3OD):δ8.25(d,J＝4.8Hz,1H),6.72-7.23(m,8H),3.76-3.77(m,4H),3.67(s,3H),3.30(s,1H),2.55-2.60(m,1H),2.48(s,3H),1.55-1.79(m,9H)；9-5b,1HNMR(400MHz,CD3OD):δ8.25(d,J＝5.2Hz,1H),7.27(t,J＝8.0Hz,1H),7.17(d,J＝2.4Hz,1H),7.14(s,1H),7.08(d,J＝5.2Hz,1H),6.94-6.97(m,2H),6.86(dd,J＝2.4,8.4Hz,1H),6.73(d,J＝2.4Hz,1H),3.79(s,3H),3.69(s,3H),3.11(d,J＝6.4Hz,2H),2.48(s,3H),2.42-2.45(m,1H),1.83(d,J＝11.2Hz,2H),1.73(d,J＝11.2Hz,2H),1.37-1.48(m,3H),0.96-1.06(m,2H)。m/z: [M+H] + 418; 9-5a, 1 H NMR (400 MHz, CD 3 OD): δ 8.25 (d, J = 4.8 Hz, 1H), 6.72-7.23 (m, 8H), 3.76 -3.77 (m, 4H), 3.67 (s, 3H), 3.30 (s, 1H), 2.55-2.60 (m, 1H), 2.48 (s, 3H), 1.55-1.79 (m, 9H); 9-5b , 1 H NMR (400 MHz, CD 3 OD): δ 8.25 (d, J = 5.2 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.14 (s, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.94 - 6.97 (m, 2H), 6.86 (dd, J = 2.4, 8.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 3.11 (d, J = 6.4 Hz, 2H), 2.48 (s, 3H), 2.42 - 2.45 (m, 1H), 1.83 (d, J) =11.2 Hz, 2H), 1.73 (d, J = 11.2 Hz, 2H), 1.37-1.48 (m, 3H), 0.96-1.06 (m, 2H).
Figure PCTCN2017095396-appb-000172
Figure PCTCN2017095396-appb-000172
将化合物9-6(210mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物9-6a(50mg，出峰时间：13.2～13.9分钟，单一立体构型)和9-6b(30mg，出峰时间：14.1～14.8分钟，单一立体构型)，均为类白色固体。Compound 9-6 (210 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 5) to give compound 9-6a (50 mg, peak time: 13.2 to 13.9 minutes, single stereo configuration) and 9-6b (30 mg, peak time: 14.1 to 14.8 minutes, single stereo configuration), all white-like solids.
m/z:[M+H]+404；9-6a,1HNMR(400MHz,CD3OD):δ8.26(d,J＝4.8Hz,1H),7.26-7.30(m,2H),7.15(s,1H),7.08(d,J＝5.2Hz,1H),6.96-6.99(m,2H),6.84-6.87(m,1H),6.80(d,J＝2.4Hz,1H),3.79(s,3H),3.12(d,J＝6.8Hz,2H),2.48(s,3H),2.41-2.46(m,1H),1.85(d,J＝11.6Hz,2H),1.72(d,J＝10.8Hz,2H),1.38-1.49(m,3H),0.96-1.07(m,2H)；9-6b,1HNMR(400MHz,CD3OD):δ8.26(d,J＝5.2Hz,1H),7.26(d,J＝2.4Hz,1H),7.19-7.24(m,2H),7.11-7.12(m,1H),6.95-6.98(m,2H),6.80-6.83(m,2H),3.77(s,3H),3.35(d,J＝7.6Hz,2H),2.56-2.63(m,1H),2.48(s,3H),1.56-1.81(m,9H)。m/z: [M+H] + 404; 9-6a, 1 H NMR (400 MHz, CD 3 OD): δ 8.26 (d, J = 4.8 Hz, 1H), 7.26-7.30 (m, 2H), 7.15 (s, 1H), 7.08 (d, J = 5.2 Hz, 1H), 6.96-6.99 (m, 2H), 6.84 - 6.87 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 3.79 ( s, 3H), 3.12 (d, J = 6.8 Hz, 2H), 2.48 (s, 3H), 2.41-2.46 (m, 1H), 1.85 (d, J = 11.6 Hz, 2H), 1.72 (d, J) = 10.8 Hz, 2H), 1.38-1.49 (m, 3H), 0.96-1.07 (m, 2H); 9-6b, 1 H NMR (400 MHz, CD 3 OD): δ 8.26 (d, J = 5.2 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.19-7.24 (m, 2H), 7.11-7.12 (m, 1H), 6.95-6.98 (m, 2H), 6.80-6.83 (m, 2H) , 3.77 (s, 3H), 3.35 (d, J = 7.6 Hz, 2H), 2.56 - 2.63 (m, 1H), 2.48 (s, 3H), 1.56-1.81 (m, 9H).
实施例74：化合物9-7的合成Example 74: Synthesis of Compound 9-7
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物23.3和化合物4.9反应得到化合物9-7： By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 23.3 and compound 4.9 to give compound 9-7:
Figure PCTCN2017095396-appb-000173
Figure PCTCN2017095396-appb-000173
将化合物9-7(245mg，顺反异构体混合物)经prep-HPLC(分离条件11)得到化合物9-7a(43.7mg，出峰时间：11.5～12.5分钟，单一立体构型)和9-7b(28.0mg，出峰时间：12.5～13.8分钟，单一立体构型)，均为白色固体。Compound 9-7 (245 mg, cis-trans isomer mixture) was subjected to prep-HPLC (isolation condition 11) to give compound 9-7a (43.7 mg, peak time: 11.5 to 12.5 min, single stereo configuration) and 9- 7b (28.0 mg, peak time: 12.5 to 13.8 minutes, single stereo configuration), all white solids.
m/z:[M+H]+472；9-7a,1H NMR(400MHz,DMSO-d6):δ11.05(s,1H),8.65(d,J＝5.6Hz,1H),7.80(s,1H),7.73(d,J＝5.6Hz,1H),7.40-7.32(m,4H),6.92(t,J＝5.6Hz,1H),6.69(d,J＝2.4Hz,1H),2.99(t,J＝6.0Hz,2H),2.72-2.68(m,1H),2.66(s,3H),2.34(s,3H),1.81(d,J＝11.6Hz,2H),1.71(d,J＝11.6Hz,2H),1.47-1.38(m,3H),1.02-0.93(m,2H)；9-7b,1H NMR(400MHz,DMSO-d6):δ11.03(s,1H),7.73-7.81(m,2H),8.66(s,1H),7.39-7.26(m,4H),7.03(d,J＝5.2Hz,1H),6.69(d,J＝2.8Hz,1H),3.22(t,J＝6.4Hz,2H),2.84-2.76(m,1H),2.66(s,3H),2.31(s,3H),1.78-1.48(m,9H)。m/z: [M+H] + 472; 9-7a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.05 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.40-7.32 (m, 4H), 6.92 (t, J = 5.6 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H) , 2.99 (t, J = 6.0 Hz, 2H), 2.72 - 2.68 (m, 1H), 2.66 (s, 3H), 2.34 (s, 3H), 1.81 (d, J = 11.6 Hz, 2H), 1.71 ( d, J = 11.6 Hz, 2H), 1.47-1.38 (m, 3H), 1.02-0.93 (m, 2H); 9-7b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.03 (s, 1H), 7.73-7.81 (m, 2H), 8.66 (s, 1H), 7.39-7.26 (m, 4H), 7.03 (d, J = 5.2 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H) ), 3.22 (t, J = 6.4 Hz, 2H), 2.84 - 2.76 (m, 1H), 2.66 (s, 3H), 2.31 (s, 3H), 1.78-1.48 (m, 9H).
实施例75：化合物10-1的合成Example 75: Synthesis of Compound 10-1
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物8.2和化合物4.15反应得到化合物10-1：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 8.2 and compound 4.15 to give compound 10-1:
Figure PCTCN2017095396-appb-000174
Figure PCTCN2017095396-appb-000174
m/z:[M+H]+376；1H NMR(400MHz,DMSO-d6):δ11.24(s,1H),8.69(s,2H),7.52-7.59(m,3H),7.43-7.46(m,2H),7.23-7.30(m,3H),7.15-7.19(m,1H),6.93-6.94(m,1H),4.70-5.02(m,1H),3.03-3.09(m,2H),2.09-2.15(m,1H),1.91-1.96(m,1H),1.77-1.84(m,1H),1.38-1.70(m,4H),1.28-1.34(m,1H),1.08-1.18(m,1H)。m/z: [M+H] + 376; 1 H NMR (400MHz, DMSO-d 6 ): δ 11.24 (s, 1H), 8.69 (s, 2H), 7.52-7.59 (m, 3H), 7.43 -7.46 (m, 2H), 7.23-7.30 (m, 3H), 7.15-7.19 (m, 1H), 6.93-6.94 (m, 1H), 4.70-5.02 (m, 1H), 3.03-3.09 (m, 2H), 2.09-2.15 (m, 1H), 1.91-1.96 (m, 1H), 1.77-1.84 (m, 1H), 1.38-1.70 (m, 4H), 1.28-1.34 (m, 1H), 1.08- 1.18 (m, 1H).
实施例76：化合物11-1的合成Example 76: Synthesis of Compound 11-1
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物10.2得到化合物11-1：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 10.2 to obtain compound 11-1 by the synthesis of compound 1-1:
Figure PCTCN2017095396-appb-000175
Figure PCTCN2017095396-appb-000175
化合物11-1(300mg，顺反异构体混合物)用Flash柱层析(石油醚/乙酸乙酯＝5/1)分离得到极性较小的化合物11-1a(10mg，单一立体构型)和极性较大的化合物11-1b(25mg，单一立体构型)，均为白色固体。Compound 11-1 (300 mg, cis-trans isomer mixture) was separated by flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 11-1a (10 mg, single stereo configuration). The more polar compound 11-1b (25 mg, single stereo configuration) was a white solid.
m/z:[M+H]+359；11-1a,1H NMR(400MHz,CD3OD):δ7.42-7.46(m,4H),7.34-7.37(m,1H),7.21-7.28(m,4H),7.13-7.17(m,1H),6.94(d,J＝2.8Hz,1H),6.21(d,J＝2.4Hz,1H),3.32(m,J＝2.4Hz,2H),2.52-2.58(m,1H),1.55-1.70(m,9H)；11-1b,1H NMR(400MHz,CDCl3):δ9.63(s,1H),7.46-7.51(m,4H),7.39-7.43(m,1H),7.29-7.33(m,2H),7.19-7.22(m,3H),6.95(t,J＝2.8Hz,1H),6.26(t,J＝2.8Hz,1H),5.82(s,1H),3.18(t,J＝6.0Hz,2H), 2.37-2.44(m,1H),1.88(d,J＝11.2Hz,2H),1.63-1.75(m,4H),1.38-1.42(m,3H)。m/z: [M+H] + 359; 11-1a, 1 H NMR (400 MHz, CD 3 OD): δ 7.42-7.46 (m, 4H), 7.34-7.37 (m, 1H), 7.21-7.28 (m, 4H), 7.13-7.17 (m, 1H), 6.94 (d, J = 2.8 Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 3.32 (m, J = 2.4 Hz, 2H) , 2.52-2.58 (m, 1H), 1.55-1.70 (m, 9H); 11-1b, 1 H NMR (400MHz, CDCl 3 ): δ 9.63 (s, 1H), 7.46-7.51 (m, 4H) , 7.39-7.43 (m, 1H), 7.29-7.33 (m, 2H), 7.19-7.22 (m, 3H), 6.95 (t, J = 2.8 Hz, 1H), 6.26 (t, J = 2.8 Hz, 1H) ), 5.82 (s, 1H), 3.18 (t, J = 6.0 Hz, 2H), 2.37-2.44 (m, 1H), 1.88 (d, J = 11.2 Hz, 2H), 1.63-1.75 (m, 4H) , 1.38-1.42 (m, 3H).
实施例77：化合物12-1的合成Example 77: Synthesis of Compound 12-1
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物11.3得到化合物12-1：Compound 12-1 is obtained by substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 11.3 by the synthesis of compound 1-1:
Figure PCTCN2017095396-appb-000176
Figure PCTCN2017095396-appb-000176
化合物12-1(156mg，顺反异构体混合物)用Flash柱层析(石油醚/乙酸乙酯＝1/1)分离得到极性较小的化合物12-1a(11mg，单一立体构型)和极性较大的化合物12-1b(36mg，单一立体构型)，均为白色固体。Compound 12-1 (156 mg, cis-trans isomer mixture) was isolated by flash column chromatography (petrole ether / ethyl acetate = 1 / 1) to afford compound 12-1a (11 mg, single stereo configuration). The more polar compound 12-1b (36 mg, single stereo configuration) was a white solid.
m/z:[M+H]+359；12-1a,1H NMR(400MHz,CDCl3):δ8.55(s,1H),7.54-7.58(m,2H),7.36-7.46(m,3H),7.29-7.33(m,2H),7.17-7.24(m,3H),6.80-6.81(m,1H),6.67-6.69(m,1H),5.59-5.63(m,1H),3.39-3.42(m,2H),2.53-2.60(m,1H),1.74-1.80(m,1H),1.65-1.73(m,5H),1.54-1.58(m,3H)；12-1b,1H NMR(400MHz,CDCl3):δ8.61(s,1H),7.55-7.58(m,2H),7.38-7.48(m,3H),7.29-7.33(m,2H),7.19-7.24(m,3H),6.80-6.81(m,1H),6.67-6.68(m,1H),5.66-5.68(m,1H),3.18-3.21(m,2H),2.39-2.47(m,1H),1.87-1.90(m,2H),1.68-1.74(m,3H),1.31-1.61(m,4H)。m/z: [M+H] + 359; 12-1a, 1 H NMR (400MHz, CDCl 3 ): δ 8.55 (s, 1H), 7.54 - 7.58 (m, 2H), 7.36-7.46 (m, 3H), 7.29-7.33 (m, 2H), 7.17-7.24 (m, 3H), 6.80-6.81 (m, 1H), 6.67-6.69 (m, 1H), 5.59-5.63 (m, 1H), 3.39- 3.42 (m, 2H), 2.53-2.60 (m, 1H), 1.74-1.80 (m, 1H), 1.65-1.73 (m, 5H), 1.54-1.58 (m, 3H); 12-1b, 1 H NMR (400MHz, CDCl 3 ): δ 8.61 (s, 1H), 7.55-7.58 (m, 2H), 7.38-7.48 (m, 3H), 7.29-7.33 (m, 2H), 7.19-7.24 (m, 3H) ), 6.80-6.81 (m, 1H), 6.67-6.68 (m, 1H), 5.66-5.68 (m, 1H), 3.18-3.21 (m, 2H), 2.39-2.47 (m, 1H), 1.87-1.90 (m, 2H), 1.68-1.74 (m, 3H), 1.31-1.61 (m, 4H).
实施例78：化合物13-1～13-8、13-10～13-13的合成Example 78: Synthesis of Compounds 13-1 to 13-8, 13-10 to 13-13
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.3、20.4、20.5、20.6、、20.16、20.9、20.11、20.12或20.13和化合物1.6或1.7反应得到化合物13-1～13-8、13-10～13-13：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid for compound 20.3, 20.4, 20.5, 20.6, 20.16, 20.9, 20.11, 20.12 or 20.13 and compound 1.6 or 1.7 by the synthesis of compound 1-1 The reaction gave compounds 13-1 to 13-8, 13-10 to 13-13:
Figure PCTCN2017095396-appb-000177
Figure PCTCN2017095396-appb-000177
化合物13-1(220mg，顺反异构体混合物)用Flash柱层析(石油醚/乙酸乙酯＝2/1)分离得到极性较小的化合物13-1a(35mg，单一立体构型)和极性较大的化合物13-1b(25mg，单一立体构型)，均为白色固体。Compound 13-1 (220 mg, cis-trans isomer mixture) was isolated by flash column chromatography (petrole ether / ethyl acetate = 2 / 1) to afford compound 13-1a (35 mg, single stereo configuration). The more polar compound 13-1b (25 mg, single stereo configuration) was a white solid.
m/z:[M+H]+373；13-1a,1H NMR(400MHz,CDCl3):δ8.02(br.s,1H),7.54-7.56(m,2H),7.37-7.47(m,3H),7.30-7.33(m,2H),7.19-7.21(m,3H),6.35(br.s,1H),5.68(br.s,1H),3.19-3.22(m,2H),2.40-2.46(m,1H),2.32(s,3H),1.87-1.90(m,2H),1.36-1.40(m,5H),0.97-1.08(m,2H)；13-1b,1H NMR(400MHz,CDCl3):δ8.02(br.s,1H),7.52-7.55(m,2H),7.31-7.45(m,4H),7.18-7.24(m,3H),6.34(br.s,1H),5.62(br.s,1H),3.39-3.42(m,2H),2.53-2.60(m,1H),2.32(s,3H),1.74-1.78(m,2H),1.49-1.73(m,8H)。m/z: [M+H] + 373; 13-1a, 1 H NMR (400MHz, CDCl 3 ): δ 8.02 (br.s, 1H), 7.54 - 7.56 (m, 2H), 7.37-7.47 ( m, 3H), 7.30-7.33 (m, 2H), 7.19-7.21 (m, 3H), 6.35 (br.s, 1H), 5.68 (br.s, 1H), 3.19-3.22 (m, 2H), 2.40-2.46(m,1H), 2.32(s,3H),1.87-1.90(m,2H),1.36-1.40(m,5H),0.97-1.08(m,2H);13-1b, 1 H NMR (400MHz, CDCl 3 ): δ 8.02 (br.s, 1H), 7.52-7.55 (m, 2H), 7.31-7.45 (m, 4H), 7.18-7.24 (m, 3H), 6.34 (br.s) , 1H), 5.62 (br.s, 1H), 3.39-3.42 (m, 2H), 2.53-2.60 (m, 1H), 2.32 (s, 3H), 1.74-1.78 (m, 2H), 1.49-1.73 (m, 8H).
Figure PCTCN2017095396-appb-000178
Figure PCTCN2017095396-appb-000178
将化合物13-2(90mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1～1/1)得到极性较小的化合物13-2a(11.1mg，单一立体构型)和极性较大的化合物13-2b(8.3mg， 单一立体构型)，均为白色固体。The compound 13-2 (90 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to afford the compound 13-2a (11.1 mg, Single stereo configuration) and the more polar compound 13-2b (8.3 mg, Single stereo configuration), all white solids.
m/z:[M+H]+403；13-2a,1H NMR(400MHz,CDCl3):δ8.45(br.s,1H),7.48-7.52(m,1H),7.31-7.38(m,3H),7.19-7.21(m,3H),6.99-7.05(m,2H),6.34-6.35(m,1H),5.75-5.78(m,1H),3.88(s,3H),3.17-3.19(m,2H),2.39-2.43(m,1H),2.31(s,3H),1.86-1.89(m,2H),1.69-1.72(m,2H),1.35-1.45(m,3H),0.98-1.05(m,2H)；13-2b,1H NMR(400MHz,CDCl3):δ8.43(br.s,1H),7.47-7.50(m,1H),7.30-7.36(m,2H),7.17-7.24(m,3H),6.99-7.03(m,2H),6.34-6.35(m,1H),5.72-5.75(m,1H),3.87(s,3H),3.37-3.41(m,2H),2.51-2.59(m,3H),2.31(m,3H),1.63-1.77(m,5H),1.52-1.56(m,4H)。m/z: [M+H] + 403; 13-2a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.45 (br.s, 1H), 7.48-7.52 (m, 1H), 7.31-7. m, 3H), 7.19-7.21 (m, 3H), 6.99-7.05 (m, 2H), 6.34-6.35 (m, 1H), 5.75-5.78 (m, 1H), 3.88 (s, 3H), 3.17- 3.19 (m, 2H), 2.39-2.43 (m, 1H), 2.31 (s, 3H), 1.86-1.89 (m, 2H), 1.69-1.72 (m, 2H), 1.35-1.45 (m, 3H), 0.98-1.05 (m, 2H); 13-2b, 1 H NMR (400MHz, CDCl 3 ): δ 8.43 (br.s, 1H), 7.47-7.50 (m, 1H), 7.30-7.36 (m, 2H) ), 7.17-7.24 (m, 3H), 6.99-7.03 (m, 2H), 6.34-6.35 (m, 1H), 5.72-5.75 (m, 1H), 3.87 (s, 3H), 3.37-3.41 (m , 2H), 2.51-2.59 (m, 3H), 2.31 (m, 3H), 1.63-1.77 (m, 5H), 1.52-1.56 (m, 4H).
Figure PCTCN2017095396-appb-000179
Figure PCTCN2017095396-appb-000179
化合物13-3(182mg，顺反异构体混合物)经prep-HPLC(分离条件3)得到化合物13-3a(15.5mg，出峰时间：9.5～10.0分钟，单一立体构型)和13-3b(31.3mg，出峰时间：9.0～9.5分钟，单一立体构型)，均为白色固体。Compound 13-3 (182 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 3) to give compound 13-3a (15.5 mg, peak time: 9.5 to 10.0 min, single stereo configuration) and 13-3b (31.3 mg, peak time: 9.0-9.5 minutes, single stereo configuration), all white solids.
m/z:[M+H]+403；1H NMR(400MHz,DMSO-d6):δ11.0(s,1H),7.62(t,J＝6.0Hz,1H),7.17-7.31(m,7H),6.78-6.80(m,1H),6.12(s,1H),3.75(s,3H),3.28(t,J＝6.8Hz,2H),2.20(s,3H),1.98-2.01(m,1H),1.85-1.95(m,1H),1.54-1.81(m,8H)；1H NMR(400MHz,DMSO-d6):δ11.1(s,1H),7.59(t,J＝6.0Hz,1H),7.15-7.29(m,7H),6.80-6.82(m,1H),6.14(s,1H),3.77(s,3H),3.05(t,J＝6.0Hz,2H),2.20(s,3H),1.98-2.01(m,1H),1.81(d,J＝10.8Hz,4H),1.53-1.54(m,1H),1.36-1.44(m,2H),1.00-1.08(m,2H)。m/z: [M+H] + 403; 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.0 (s, 1H), 7.62 (t, J = 6.0 Hz, 1H), 7.17-7.31 (m) , 7H), 6.78-6.80 (m, 1H), 6.12 (s, 1H), 3.75 (s, 3H), 3.28 (t, J = 6.8 Hz, 2H), 2.20 (s, 3H), 1.98-2.01 ( m, 1H), 1.85-1.95 (m, 1H), 1.54-1.81 (m, 8H); 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.1 (s, 1H), 7.59 (t, J = 6.0 Hz, 1H), 7.15-7.29 (m, 7H), 6.80-6.82 (m, 1H), 6.14 (s, 1H), 3.77 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H), 2.20(s,3H), 1.98-2.01(m,1H),1.81(d,J=10.8Hz,4H),1.53-1.54(m,1H),1.36-1.44(m,2H),1.00-1.08( m, 2H).
Figure PCTCN2017095396-appb-000180
Figure PCTCN2017095396-appb-000180
将化合物13-4(276mg，顺反异构体混合物)经Flash柱层析分离(石油醚/乙酸乙酯＝1/2)得到极性较大的化合物13-4a(14mg，单一立体构型)和极性较小的化合物13-4b(18mg，单一立体构型)，均为白色固体。The compound 13-4 (276 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether / ethyl acetate = 1/2) to give the compound 13-4a (14 mg, single stereo configuration). And the less polar compound 13-4b (18 mg, single stereo configuration), both as white solids.
m/z:[M+H]+398；13-4a,1HNMR(400MHz,DMSO-d6):δ11.34(s,1H),8.27(t,J＝5.8Hz,1H),7.57-7.53(m,2H),7.51-7.46(m,2H),7.30-7.26(m,2H),7.22-7.15(m,3H),6.19(d,J＝1.6Hz,1H),3.05(t,J＝6.2Hz,2H),2.47-2.41(m,1H),2.19(s,3H),1.79-1.71(m,4H),1.48-1.25(m,3H),1.05-0.95(m,2H)；13-4b,1HNMR(400MHz,DMSO-d6):δ11.33(s,1H),8.29(t,J＝5.6Hz,1H),7.57-7.52(m,2H),7.50-7.47(m,2H),7.29(t,J＝7.2Hz,2H),7.24-7.22(m,2H),7.18-7.15(m,1H),6.17(s,1H),3.30-3.27(m,2H),2.53-2.51(m,1H),2.16(s,3H),1.85-1.84(m,1H),1.68-1.53(m,8H)。m/z: [M+H] + 398; 13-4a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.34 (s, 1H), 8.27 (t, J = 5.8 Hz, 1H), 7.57- 7.53 (m, 2H), 7.51-7.46 (m, 2H), 7.30-7.26 (m, 2H), 7.22-7.15 (m, 3H), 6.19 (d, J = 1.6 Hz, 1H), 3.05 (t, J=6.2 Hz, 2H), 2.47-2.41 (m, 1H), 2.19 (s, 3H), 1.79-1.71 (m, 4H), 1.48-1.25 (m, 3H), 1.05-0.95 (m, 2H) 13-4b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.33 (s, 1H), 8.29 (t, J = 5.6 Hz, 1H), 7.57-7.52 (m, 2H), 7.50-7.47 ( m, 2H), 7.29 (t, J = 7.2 Hz, 2H), 7.24 - 7.22 (m, 2H), 7.18-7.15 (m, 1H), 6.17 (s, 1H), 3.30-3.27 (m, 2H) , 2.53-2.51 (m, 1H), 2.16 (s, 3H), 1.85-1.84 (m, 1H), 1.68-1.53 (m, 8H).
Figure PCTCN2017095396-appb-000181
Figure PCTCN2017095396-appb-000181
将化合物13-5(559mg，顺反异构体混合物)经Flash柱层析分离(石油醚/乙酸乙酯＝ 9/1～1/2)得到极性较小的化合物13-5a(26mg，单一立体构型)和极性较大的化合物13-5b(30mg，单一立体构型)，均为白色固体。Compound 13-5 (559 mg, cis-trans isomer mixture) was separated by flash column chromatography (petroleum ether / ethyl acetate = 9/1 to 1/2) The less polar compound 13-5a (26 mg, single stereo configuration) and the more polar compound 13-5b (30 mg, single stereo configuration) were obtained as white solids.
m/z:[M+H]+391；13-5a,1H NMR(400MHz,DMSO-d6):δ11.08(s,1H),7.54-7.51(m,1H),7.43-7.39(m,1H),7.34-7.27(m,3H),7.23-7.22(m,2H),7.19-7.14(m,3H),6.23-6.22(m,1H),3.30-3.21(m,3H),2.20(s,3H),1.88(br.s,1H),1.69-1.52(m,8H)；13-5b,1H NMR(400MHz,DMSO-d6):δ11.08(s,1H),7.50-7.41(m,2H),7.36-7.15(m,8H),6.24(d,J＝2.0Hz,1H),2.99(t,J＝6.4Hz,2H),2.51-2.41(m,1H),2.20(s,3H),1.80-1.77(m,4H),1.56-1.35(m,3H),1.06-0.96(m,2H)。m/z: [M+H] + 391; 13-5a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.08 (s, 1H), 7.54 - 7.51 (m, 1H), 7.43 - 7.39 ( m,1H),7.34-7.27(m,3H),7.23-7.22(m,2H),7.19-7.14(m,3H),6.23-6.22(m,1H), 3.30-3.21(m,3H), 2.20 (s, 3H), 1.88 (br.s, 1H), 1.69-1.52 (m, 8H); 13-5b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.08 (s, 1H), 7.50-7.41 (m, 2H), 7.36-7.15 (m, 8H), 6.24 (d, J = 2.0 Hz, 1H), 2.99 (t, J = 6.4 Hz, 2H), 2.51-2.41 (m, 1H) , 2.20 (s, 3H), 1.80-1.77 (m, 4H), 1.56-1.35 (m, 3H), 1.06-0.96 (m, 2H).
Figure PCTCN2017095396-appb-000182
Figure PCTCN2017095396-appb-000182
将化合物13-6(623mg，顺反异构体混合物)经Flash柱层析分离(石油醚/乙酸乙酯＝1/2)得到极性较小的化合物13-6a(85mg，单一立体构型)和极性较大的化合物13-6b(85mg，单一立体构型)，均为白色固体。The compound 13-6 (623 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether / ethyl acetate = 1/2) to afford the compound 13-6a (85 mg, single stereo configuration) And the more polar compound 13-6b (85 mg, single stereo configuration), both as white solids.
m/z:[M+H]+391；13-6a,1HNMR(400MHz,DMSO-d6):δ11.17(s,1H),7.74(t,J＝5.6Hz,1H),7.55-7.15(m,8H),7.04(dt,J＝1.2,8.0Hz,1H)，6.17(d,J＝1.6Hz,1H),3.29(t,J＝7.2Hz,2H),2.54-2.52(m,1H),2.22(s,3H),1.92(br.s,1H),1.73-1.52(m,8H)；13-6b,1HNMR(400MHz,DMSO-d6):δ11.17(s,1H),7.73(t,J＝6.0Hz,1H),7.57-7.14(m,8H),7.054(dt,J＝1.6,8.0Hz,1H)，6.20(d,J＝2.0Hz,1H),3.05(t,J＝6.4Hz,2H),2.51-2.43(m,1H),2.22(s,3H),1.84-1.80(m,4H),1.58-1.55(m,1H),1.46-1.36(m,2H),1.11-1.02(m,2H)。m/z: [M+H] + 391; 13-6a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.17 (s, 1H), 7.74 (t, J = 5.6 Hz, 1H), 7.55- 7.15 (m, 8H), 7.04 (dt, J = 1.2, 8.0 Hz, 1H), 6.17 (d, J = 1.6 Hz, 1H), 3.29 (t, J = 7.2 Hz, 2H), 2.54-2.52 (m) , 1H), 2.22 (s, 3H), 1.92 (br.s, 1H), 1.73-1.52 (m, 8H); 13-6b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.17 (s, 1H), 7.73 (t, J = 6.0 Hz, 1H), 7.57-7.14 (m, 8H), 7.054 (dt, J = 1.6, 8.0 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 3.05 (t, J = 6.4 Hz, 2H), 2.51-2.43 (m, 1H), 2.22 (s, 3H), 1.84-1.80 (m, 4H), 1.58-1.55 (m, 1H), 1.46-1.36 ( m, 2H), 1.11-1.02 (m, 2H).
Figure PCTCN2017095396-appb-000183
Figure PCTCN2017095396-appb-000183
将化合物13-7(187mg，顺反异构体混合物)经Flash柱层析分离(石油醚/乙酸乙酯＝1/1)得到极性较小的化合物13-7a(31mg，单一立体构型)为白色固体。The compound 13-7 (187 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether/ethyl acetate = 1/1) to afford the compound 13-7a (31 mg, single stereo configuration). ) is a white solid.
m/z:[M+H]+433；13-7a,1H NMR(400MHz,CD3OD):δ7.28-7.25(m,4H),7.16-7.11(m,1H),6.71-6.70(d,J＝4.0Hz,2H),6.43-6.42(t,J＝2.5Hz,1H),6.14(d,J＝1.0Hz,1H),3.79(s,6H),3.40-3.38(d,J＝8.0Hz,2H),2.61-2.53(m,1H),2.26(d,J＝1.0Hz,3H),1.95-1.88(m,1H),1.80-1.52(m,8H)。m/z: [M+H] + 433; 13-7a, 1 H NMR (400 MHz, CD 3 OD): δ 7.28-7.25 (m, 4H), 7.16-7.11 (m, 1H), 6.71-6.70 (d, J = 4.0 Hz, 2H), 6.43 - 6.42 (t, J = 2.5 Hz, 1H), 6.14 (d, J = 1.0 Hz, 1H), 3.79 (s, 6H), 3.40-3.38 (d, J = 8.0 Hz, 2H), 2.61-2.53 (m, 1H), 2.26 (d, J = 1.0 Hz, 3H), 1.95-1.88 (m, 1H), 1.80-1.52 (m, 8H).
Figure PCTCN2017095396-appb-000184
Figure PCTCN2017095396-appb-000184
将化合物13-8(180mg，顺反异构体混合物)经Flash柱层析分离(石油醚/乙酸乙酯＝1/1)得到极性较小的化合物13-8a(15.2mg，单一立体构型)为白色固体。The compound 13-8 (180 mg, cis-trans isomer mixture) was subjected to flash column chromatography (petroleum ether/ethyl acetate = 1/1) to afford the compound 13-8a (15.2 mg, single stereostructure). Type) is a white solid.
m/z:[M+H]+433；13-8a,1H NMR(400MHz,CD3OD):δ7.25-7.21(m,4H),7.15-7.09(m, 2H),7.06(d,J＝2.0Hz,1H),6.94-6.91(dd,J＝8.0,4.0Hz,1H),6.22(s,1H),3.86(s,3H),3.61(s,3H),3.33(m,2H),2.57-2.50(m,1H),2.26(s,3H),1.84-1.75(m,1H),1.70-1.50(m,8H)。m/z: [M+H] + 433; 13-8a, 1 H NMR (400 MHz, CD 3 OD): δ 7.25-7.21 (m, 4H), 7.15-7.09 (m, 2H), 7.06 (d) , J=2.0 Hz, 1H), 6.94-6.91 (dd, J=8.0, 4.0 Hz, 1H), 6.22 (s, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 3.33 (m, 2H), 2.57-2.50 (m, 1H), 2.26 (s, 3H), 1.84-1.75 (m, 1H), 1.70-1.50 (m, 8H).
Figure PCTCN2017095396-appb-000185
Figure PCTCN2017095396-appb-000185
将化合物13-10(90mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1～1/1)得到极性较小的化合物13-10a(13.7mg，单一立体构型)和极性较大的化合物13-10b(10.4mg，单一立体构型)，均为白色固体。The compound 13-10 (90 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to afford the compound 13-10a (13.7 mg, The single stereo configuration) and the more polar compound 13-10b (10.4 mg, single stereo configuration) were all white solids.
m/z:[M+H]+417；13-10a,1H NMR(400MHz,CDCl3):δ8.37(br.s,1H),7.38-7.46(m,2H),7.29-7.33(m,2H),7.18-7.22(m,3H),7.01-7.07(m,2H),6.38(d,J＝1.6Hz,1H),5.82(d,J＝8.8Hz,1H),3.99-4.05(m,1H),3.88(s,3H),2.33-2.39(m,1H),2.32(s,3H),1.85-1.89(m,2H),1.58-1.72(m,2H),1.31-1.39(m,3H),1.05-1.10(m,1H),1.03(d,J＝6.8Hz,3H),0.91-0.94(m,1H)；13-10b,1H NMR(400MHz,CDCl3):δ8.41(br.s,1H),7.47-7.50(m,1H),7.25-7.37(m,5H),7.16-7.20(m,1H),6.98-7.02(m,2H),6.33-6.34(m,1H),5.49(d,J＝9.2Hz,1H),4.31-4.38(m,1H),3.87(s,3H),2.60-2.65(m,1H),2.31(s,3H),1.87-1.93(m,1H),1.31-1.72(m,8H),1.07(d,J＝6.8Hz,3H)。m/z: [M+H] + 417; 13-10a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.37 (br.s, 1H), 7.38-7.46 (m, 2H), 7.29-7.33 ( m, 2H), 7.18-7.22 (m, 3H), 7.01-7.07 (m, 2H), 6.38 (d, J = 1.6 Hz, 1H), 5.82 (d, J = 8.8 Hz, 1H), 3.99-4.05 (m, 1H), 3.88 (s, 3H), 2.33-2.39 (m, 1H), 2.32 (s, 3H), 1.85-1.89 (m, 2H), 1.58-1.72 (m, 2H), 1.31-1.39 (m, 3H), 1.05-1.10 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.91 - 0.94 (m, 1H); 13-10b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.41 (br.s, 1H), 7.47-7.50 (m, 1H), 7.25-7.37 (m, 5H), 7.16-7.20 (m, 1H), 6.98-7.02 (m, 2H), 6.33-6.34 (m, 1H), 5.49 (d, J = 9.2 Hz, 1H), 4.31-4.38 (m, 1H), 3.87 (s, 3H), 2.60-2.65 (m, 1H), 2.31 (s, 3H), 1.87-1.93 (m, 1H), 1.31-1.72 (m, 8H), 1.07 (d, J = 6.8 Hz, 3H).
Figure PCTCN2017095396-appb-000186
Figure PCTCN2017095396-appb-000186
将化合物13-11(188mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1～1/2)得到极性较小的化合物13-11a(32mg，单一立体构型)和极性较大的化合物13-11b(75mg，单一立体构型)，均为白色固体。The compound 13-11 (188 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/2) to give the compound 13-11a (32 mg, single The stereo configuration) and the more polar compound 13-11b (75 mg, single stereo configuration) were all white solids.
m/z:[M+H]+417；13-11a,1H NMR(400MHz,DMSO-d6):δ11.04(s,1H),7.37(d,J＝8.8Hz,1H),7.13-7.33(m,8H),6.75-6.81(m,1H),6.10(br.s,1H),4.19-4.30(m,1H),3.73(s,3H),2.59(br.s,1H),2.20(s,3H),1.36-1.86(m,9H),1.09(d,J＝6.8Hz,3H)；13-11b,1H NMR(400MHz,DMSO-d6):δ11.05(s,1H),7.13-7.31(m,9H),6.79-6.84(m,1H),6.14(br.s,1H),3.74-3.84(m,4H),2.37-2.47(m,1H),2.21(s,3H),1.74-1.89(m,4H),1.30-1.47(m,3H),1.00-1.16(m,5H)。m/z: [M+H] + 417; 13-11a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.04 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.13 -7.33 (m, 8H), 6.75-6.81 (m, 1H), 6.10 (br.s, 1H), 4.19-4.30 (m, 1H), 3.73 (s, 3H), 2.59 (br.s, 1H) , 2.20 (s, 3H), 1.36-1.86 (m, 9H), 1.09 (d, J = 6.8 Hz, 3H); 13-11b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.05 (s , 1H), 7.13-7.31 (m, 9H), 6.79-6.84 (m, 1H), 6.14 (br.s, 1H), 3.74-3.84 (m, 4H), 2.37-2.47 (m, 1H), 2.21. (s, 3H), 1.74-1.89 (m, 4H), 1.30-1.47 (m, 3H), 1.00-1.16 (m, 5H).
Figure PCTCN2017095396-appb-000187
Figure PCTCN2017095396-appb-000187
m/z:[M+H]+471；1H NMR(400MHz,DMSO-d6):δ11.08(s,1H),7.32-7.50(m,4H),7.13-7.31(m,5H),7.04(d,J＝8.8Hz,1H),6.26(d,J＝2.0Hz,1H),3.65-3.77(m,1H),2.35-2.45(m,1H),2.20(s,3H),1.73-1.87(m,4H),1.29-1.45(m,3H),0.95-1.12(m,5H)。 m/z: [M+H] + 471; 1 H NMR (400MHz, DMSO-d 6 ): δ 11.08 (s, 1H), 7.32-7.50 (m, 4H), 7.13 - 7.31 (m, 5H) , 7.04 (d, J = 8.8 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H), 3.65-3.77 (m, 1H), 2.35-2.45 (m, 1H), 2.20 (s, 3H), 1.73-1.87 (m, 4H), 1.29-1.45 (m, 3H), 0.95-1.12 (m, 5H).
Figure PCTCN2017095396-appb-000188
Figure PCTCN2017095396-appb-000188
m/z:[M+H]+388；1H NMR(400MHz,DMSO-d6):δ11.2(s,1H),8.76(s,1H),8.42(d,J＝3.6Hz,1H),8.00(d,J＝8.0Hz,1H),7.14-7.43(m,7H),6.30(s,1H),3.77-3.81(m,1H),2.23(s,3H),1.98-2.01(m,1H),1.82-1.84(m,4H),1.37-1.45(m,3H),1.08-1.12(m,4H)。m/z: [M+H] + 388; 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.2 (s, 1H), 8.76 (s, 1H), 8.42 (d, J = 3.6 Hz, 1H) ), 8.00 (d, J = 8.0 Hz, 1H), 7.14 - 7.43 (m, 7H), 6.30 (s, 1H), 3.77-3.81 (m, 1H), 2.23 (s, 3H), 1.98-2.01 ( m, 1H), 1.82-1.84 (m, 4H), 1.37-1.45 (m, 3H), 1.08-1.12 (m, 4H).
实施例79：化合物14-1～14-7的合成Example 79: Synthesis of Compounds 14-1 to 14-7
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.8、20.5、20.6、20.4、20.7、20.16或20.9和化合物4.9反应得到化合物14-1～14-7：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 20.8, 20.5, 20.6, 20.4, 20.7, 20.16 or 20.9 and compound 4.9 by the synthesis of compound 1-1 to give compound 14-1~ 14-7:
Figure PCTCN2017095396-appb-000189
Figure PCTCN2017095396-appb-000189
化合物14-1(160mg，顺反异构体混合物)经prep-HPLC(分离条件4)得到化合物14-1a(25mg，出峰时间：10.5～11.5分钟，单一立体构型)和14-1b(15.2mg，出峰时间：9.5～10.5分钟，单一立体构型)，均为白色固体。Compound 14-1 (160 mg, cis and trans isomer mixture) was subjected to prep-HPLC (separation condition 4) to give compound 14-1a (25 mg, peak time: 10.5 to 11.5 min, single stereo configuration) and 14-1b ( 15.2 mg, peak time: 9.5 to 10.5 minutes, single stereo configuration), all white solids.
m/z:[M+H]+389；14-1a,1H NMR(400MHz,DMSO-d6):δ11.3(s,1H),8.76(s,1H),8.42(d,J＝4.0Hz,1H),8.31(d,J＝5.2Hz,1H),7.99-8.00(m,1H),7.77(t,J＝5.6Hz,1H),7.35-7.38(m,1H),7.11(s,1H),7.05(d,J＝4.8Hz,1H),6.28(s,1H),3.05(t,J＝6.4Hz,2H),2.42(s,3H),2.23(s,3H),1.97-2.03(m,1H),1.79-1.82(m,4H),1.51-1.56(m,1H),1.35-1.44(m,2H),1.00-1.08(m,2H)；14-1b,1H NMR(400MHz,DMSO-d6):δ11.3(s,1H),8.75(d,J＝2.0Hz,1H),8.39-8.41(m,1H),8.32(d,J＝5.2Hz,1H),7.96-7.99(m,1H),7.77(t,J＝6.0Hz,1H),7.34-7.37(m,1H),7.13(s,1H),7.06(d,J＝5.6Hz,1H),6.26(s,1H),3.27(t,J＝7.2Hz,2H),2.43(s,3H),2.23(s,3H),1.98-2.01(m,1H),1.88-1.91(m,1H),1.66-1.73(m,2H),1.54-1.61(m,6H)。m/z: [M+H] + 389; 14-1a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.3 (s, 1H), 8.76 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.99-8.00 (m, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.35-7.38 (m, 1H), 7.11 ( s, 1H), 7.05 (d, J = 4.8 Hz, 1H), 6.28 (s, 1H), 3.05 (t, J = 6.4 Hz, 2H), 2.42 (s, 3H), 2.23 (s, 3H), 1.97-2.03(m,1H), 1.79-1.82(m,4H), 1.51-1.56(m,1H),1.35-1.44(m,2H),1.00-1.08(m,2H);14-1b, 1 H NMR (400MHz, DMSO-d 6): δ11.3 (s, 1H), 8.75 (d, J = 2.0Hz, 1H), 8.39-8.41 (m, 1H), 8.32 (d, J = 5.2Hz, 1H), 7.96-7.99 (m, 1H), 7.77 (t, J = 6.0 Hz, 1H), 7.34 - 7.37 (m, 1H), 7.13 (s, 1H), 7.06 (d, J = 5.6 Hz, 1H) ), 6.26 (s, 1H), 3.27 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 2.23 (s, 3H), 1.98-2.01 (m, 1H), 1.88-1.91 (m, 1H), 1.66-1.73 (m, 2H), 1.54-1.61 (m, 6H).
Figure PCTCN2017095396-appb-000190
Figure PCTCN2017095396-appb-000190
将化合物14-2(188mg，顺反异构体混合物)经硅胶柱色谱分离(二氯甲烷/甲醇＝100/1～10/1)得到极性较大的化合物13-11a(25mg，单一立体构型)和极性较小的化合物13-11b(23mg，单一立体构型)，均为白色固体。The compound 14-2 (188 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (dichloromethane/methanol = 100/1 to 10/1) to give the compound 13-11a (25 mg, single solid). The configuration and the less polar compound 13-11b (23 mg, single stereo configuration) were both white solids.
m/z:[M+H]+418；14-2a,1H NMR(400MHz,CDCl3):δ8.38(d,J＝4.8Hz,1H),8.15(s,1H),7.33-7.38(m,1H),7.09-7.13(m,2H),6.98(s,1H),6.91-6.94(m,2H),6.34(d,J＝2.4Hz,1H),5.66-5.70(m,1H),3.84(s,3H),3.18-3.22(m,2H),2.53(s,3H),2.34-2.41(m,1H),2.31(s,3H),1.81-1.91(m,2H),1.74-1.80(m,2H),1.33-1.52(m,3H),0.97-1.07(m,2H)；14-2b,1H NMR(400MHz,CDCl3):δ8.38(d,J＝5.6Hz,1H),8.05(s,1H),7.32-7.36(m,1H), 7.08-7.12(m,2H),7.04(s,1H),6.90-6.97(m,2H),6.34-6.35(m,1H),5.59-5.62(m,1H),3.84(s,3H),3.37-3.41(m,2H),2.55(s,3H),2.31(s,3H),1.54-1.79(m,10H)。m/z: [M+H] + 418; 14-2a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.38 (d, J = 4.8 Hz, 1H), 8.15 (s, 1H), 7.33-7.38 (m, 1H), 7.09-7.13 (m, 2H), 6.98 (s, 1H), 6.91-6.94 (m, 2H), 6.34 (d, J = 2.4 Hz, 1H), 5.66-5.70 (m, 1H) ), 3.84 (s, 3H), 3.18-3.22 (m, 2H), 2.53 (s, 3H), 2.34-2.41 (m, 1H), 2.31 (s, 3H), 1.81-1.91 (m, 2H), 1.74-1.80 (m, 2H), 1.33-1.52 (m, 3H), 0.97-1.07 (m, 2H); 14-2b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.38 (d, J = 5.6) Hz, 1H), 8.05 (s, 1H), 7.32-7.36 (m, 1H), 7.08-7.12 (m, 2H), 7.04 (s, 1H), 6.90-6.97 (m, 2H), 6.34-6.35 ( m,1H), 5.59-5.62 (m, 1H), 3.84 (s, 3H), 3.37-3.41 (m, 2H), 2.55 (s, 3H), 2.31 (s, 3H), 1.54-1.79 (m, 10H).
Figure PCTCN2017095396-appb-000191
Figure PCTCN2017095396-appb-000191
将化合物14-3(188mg，顺反异构体混合物)经硅胶柱色谱分离(二氯甲烷/甲醇＝100/1～10/1)得到极性较大的化合物14-3a(6.5mg，单一立体构型)和极性较小的化合物14-3b(5.6mg，单一立体构型)，均为白色固体。The compound 14-3 (188 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (dichloromethane/methanol = 100/1 to 10/1) to give the compound 14-3a (6.5 mg, single The stereo configuration) and the less polar compound 14-3b (5.6 mg, single stereo configuration) were both white solids.
m/z:[M+H]+472；14-3a,1H NMR(400MHz,CDCl3):δ8.38(d,J＝5.2Hz,1H),8.21(s,1H),7.62-7.64(m,1H),7.34-7.44(m,3H),6.98(s,1H),6.92(d,J＝5.2Hz,1H),6.28(d,J＝2.4Hz,1H),5.57-5.60(m,1H),3.18-3.22(m,2H),2.54(s,3H),2.36-2.42(m,1H),2.33(s,3H),1.85-1.89(m,2H),1.75-1.79(m,2H),147-1.50(m,1H),1.33-1.44(m,2H),0.98-1.08(m,2H)；14-3b,1H NMR(400MHz,CDCl3):δ8.38(d,J＝5.2Hz,1H),8.21(s,1H),7.61-7.63(m,1H),7.33-7.43(m,3H),7.02(s,1H),6.95(d,J＝5.6Hz,1H),6.27(d,J＝2.4Hz,1H),5.48-5.51(m,1H),3.37-3.40(m,2H),2.54(s,3H),2.33(s,3H),1.62-1.81(m,6H),1.54-1.58(m,4H)。m/z: [M+H] + 472; 14-3a, 1 H NMR (400MHz, CDCl 3 ): δ 8.38 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 7.62-7.64 (m, 1H), 7.34-7.44 (m, 3H), 6.98 (s, 1H), 6.92 (d, J = 5.2 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 5.57-5.60 ( m,1H), 3.18-3.22 (m, 2H), 2.54 (s, 3H), 2.36-2.42 (m, 1H), 2.33 (s, 3H), 1.85-1.89 (m, 2H), 1.75-1.79 ( m, 2H), 147-1.50 (m, 1H), 1.33-1.44 (m, 2H), 0.98-1.08 (m, 2H); 14-3b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.38 ( d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 7.61 - 7.63 (m, 1H), 7.33 - 7.43 (m, 3H), 7.02 (s, 1H), 6.95 (d, J = 5.6 Hz) , 1H), 6.27 (d, J = 2.4 Hz, 1H), 5.48-5.51 (m, 1H), 3.37-3.40 (m, 2H), 2.54 (s, 3H), 2.33 (s, 3H), 1.62- 1.81 (m, 6H), 1.54-1.58 (m, 4H).
Figure PCTCN2017095396-appb-000192
Figure PCTCN2017095396-appb-000192
将化合物14-4(223mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物14-4a(73mg，出峰时间：16.8～17.2分钟，单一立体构型)和14-4b(71mg，出峰时间：17.3～18.0分钟，单一立体构型)，均为白色固体。Compound 14-4 (223 mg, cis-trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 14-4a (73 mg, peak time: 16.8 to 17.2 minutes, single stereo configuration) and 14-4b. (71 mg, peak time: 17.3 to 18.0 minutes, single stereo configuration), all white solids.
m/z:[M+H]+418；14-4a,1HNMR(400MHz,CD3OD):δ8.25(d,J＝5.6Hz,1H),7.30-7.38(m,2H),6.98-7.14(m,4H),6.17(d,J＝0.8Hz,1H),3.80(s,3H),3.07(d,J＝6.4Hz,2H),2.48(s,3H),2.38-2.45(m,1H),2.22(s,3H),1.82(d,J＝10.8Hz,2H),1.68(d,J＝13.6Hz,2H),1.35-1.46(m,3H),0.92-1.03(m,2H)；14-4b,1HNMR(400MHz,CD3OD):δ8.25(d,J＝5.6Hz,1H),7.26-7.35(m,2H),6.92-7.18(m,4H),6.16(d,J＝0.8Hz,1H),3.79(s,3H),3.59(s,1H),2.54-2.61(m,1H),2.48(s,3H),2.22-2.23(m,4H),1.53-1.77(m,9H)。m/z: [M+H] + 418; 14-4a, 1 H NMR (400 MHz, CD 3 OD): δ 8.25 (d, J = 5.6 Hz, 1H), 7.30-7.38 (m, 2H), 6.98 -7.14 (m, 4H), 6.17 (d, J = 0.8 Hz, 1H), 3.80 (s, 3H), 3.07 (d, J = 6.4 Hz, 2H), 2.48 (s, 3H), 2.38-2.45 ( m,1H), 2.22(s,3H),1.82(d,J=10.8Hz,2H),1.68(d,J=13.6Hz,2H),1.35-1.46(m,3H),0.92-1.03(m , 2H); 14-4b, 1 H NMR (400MHz, CD 3 OD): δ 8.25 (d, J = 5.6 Hz, 1H), 7.26-7.35 (m, 2H), 6.92-7.18 (m, 4H), 6.16 (d, J = 0.8 Hz, 1H), 3.79 (s, 3H), 3.59 (s, 1H), 2.54-2.61 (m, 1H), 2.48 (s, 3H), 2.22-2.23 (m, 4H) , 1.53-1.77 (m, 9H).
Figure PCTCN2017095396-appb-000193
Figure PCTCN2017095396-appb-000193
将化合物14-5(191mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物14-5a(73mg，出峰时间：19.0～19.8分钟，单一立体构型)和14-5b(71mg，出峰时间：19.9～20.3分钟，单一立体构型)，均为白色固体。Compound 14-5 (191 mg, cis-trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 14-5a (73 mg, peak time: 19.0 to 19.8 minutes, single stereo configuration) and 14-5b (71 mg, peak time: 19.9 to 20.3 minutes, single stereo configuration), all white solids.
m/z:[M+H]+472；14-5a,1HNMR(400MHz,CD3OD):δ8.25(d,J＝5.6Hz,1H),7.41-7.52(m,3H),7.07-7.16(m,3H),6.16(d,J＝0.8Hz,1H),3.16(d,J＝6.8Hz,2H),2.48(s,4H),2.26(d,J＝0.8Hz,3H),1.88(d,J＝10.8Hz,4H),1.43-1.65(m,3H),1.08-1.18(m,2H)；14-5b, 1HNMR(400MHz,CD3OD):δ8.25(d,J＝5.6Hz,1H),7.39-7.51(m,3H),7.12-7.21(m,3H),6.15(d,J＝0.8Hz,1H),3.39(d,J＝8.0Hz,2H),2.59-2.64(m,1H),2.48(s,3H),2.26(s,3H),1.62-1.98(m,9H)。m/z: [M+H] + 472; 14-5a, 1 H NMR (400 MHz, CD 3 OD): δ 8.25 (d, J = 5.6 Hz, 1H), 7.41 - 7.52 (m, 3H), 7.07 -7.16 (m, 3H), 6.16 (d, J = 0.8 Hz, 1H), 3.16 (d, J = 6.8 Hz, 2H), 2.48 (s, 4H), 2.26 (d, J = 0.8 Hz, 3H) , 1.88 (d, J = 10.8 Hz, 4H), 1.43-1.65 (m, 3H), 1.08-1.18 (m, 2H); 14-5b, 1 H NMR (400 MHz, CD 3 OD): δ 8.25 (d , J=5.6 Hz, 1H), 7.39-7.51 (m, 3H), 7.12-7.21 (m, 3H), 6.15 (d, J = 0.8 Hz, 1H), 3.39 (d, J = 8.0 Hz, 2H) , 2.59-2.64 (m, 1H), 2.48 (s, 3H), 2.26 (s, 3H), 1.62-1.98 (m, 9H).
Figure PCTCN2017095396-appb-000194
Figure PCTCN2017095396-appb-000194
将化合物14-6(137mg，顺反异构体混合物)经prep-HPLC(分离条件6)得到化合物14-6a(36.3mg，出峰时间：14.5～15.0分钟，单一立体构型)和14-6b(12.0mg，出峰时间：14.0～14.5分钟，单一立体构型)，均为白色固体。Compound 14-6 (137 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 6) to give compound 14-6a (36.3 mg, peak time: 14.5 to 15.0 min, single stereo configuration) and 14- 6b (12.0 mg, peak time: 14.0 to 14.5 minutes, single stereo configuration), all white solid.
m/z:[M+H]+472；14-6a,1H NMR(400MHz,CDCl3):δ8.37(d,J＝5.2Hz,1H),8.09(s,1H),7.59-7.63(m,2H),7.24-7.25(m,2H),6.96(s,1H),6.89-6.90(m,1H),6.21-6.22(m,1H),5.66-5.68(m,1H),3.24(t,J＝6.4Hz,2H),2.52(s,3H),2.36-2.40(m,1H),2.30(s,3H),1.80-1.89(m,4H),1.49-1.56(m,1H),1.35-1.45(m,2H),1.01-1.10(m,2H)；14-6b,1H NMR(400MHz,CDCl3):δ8.37(s,1H),8.11(s,1H),7.60(d,J＝8.8Hz,2H),7.23-7.25(m,2H),7.02(s,1H),6.94-6.95(m,1H),6.20-6.21(m,1H),5.55-5.57(m,1H),3.41(t,J＝6.4Hz,2H),2.52-2.58(m,4H),2.30(s,3H),1.81-1.83(m,1H),1.53-1.75(m,8H)。m/z: [M+H] + 472; 14-6a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.37 (d, J = 5.2 Hz, 1H), 8.09 (s, 1H), 7.59-7.63 (m, 2H), 7.24-7.25 (m, 2H), 6.96 (s, 1H), 6.89-6.90 (m, 1H), 6.21-6.22 (m, 1H), 5.66-5.68 (m, 1H), 3.24 (t, J = 6.4 Hz, 2H), 2.52 (s, 3H), 2.36-2.40 (m, 1H), 2.30 (s, 3H), 1.80-1.89 (m, 4H), 1.49-1.56 (m, 1H) ), 1.35-1.45 (m, 2H), 1.01-1.10 (m, 2H); 14-6b, 1 H NMR (400MHz, CDCl 3 ): δ 8.37 (s, 1H), 8.11 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.23 - 7.25 (m, 2H), 7.02 (s, 1H), 6.94 - 6.95 (m, 1H), 6.20 - 6.21 (m, 1H), 5.55 - 5.57 ( m,1H), 3.41 (t, J = 6.4 Hz, 2H), 2.52-2.58 (m, 4H), 2.30 (s, 3H), 1.81-1.83 (m, 1H), 1.53-1.75 (m, 8H) .
Figure PCTCN2017095396-appb-000195
Figure PCTCN2017095396-appb-000195
将化合物14-7(284mg，顺反异构体混合物)经prep-HPLC(分离条件14)得到化合物14-7a(30.1mg，出峰时间：16.2～17.0分钟，单一立体构型)和14-7b(16.8mg，出峰时间：17.0～17.8分钟，单一立体构型)，均为白色固体。Compound 14-7 (284 mg, cis-trans isomer mixture) was subjected to prep-HPLC (isolation condition 14) to give compound 14-7a (30.1 mg, peak time: 16.2 to 17.0 min, single stereo configuration) and 14- 7b (16.8 mg, peak time: 17.0 to 17.8 minutes, single stereo configuration), all white solids.
m/z:[M+H]+413；14-7a,1H NMR(400MHz,DMSO-d6):δ11.33(s,1H),8.31(d,J＝5.2Hz,1H),8.28(t,J＝5.6Hz,1H),7.54-7.52(m,2H),7.48-7.46(m,2H),7.09(s,1H),7.04-7.02(m,1H),6.18(s,1H),3.29-3.27(m,1H),3.07-3.05(m,2H),2.42(s,3H),2.18(s,3H),1.78(t,J＝14.0Hz,4H),1.73-1.71(m,1H),1.37-1.34(m,2H),1.00-0.97(m,2H)；14-7b,1H NMR(400MHz,DMSO-d6):δ11.32(s,1H),8.32(d,J＝5.2Hz,1H),8.29(t,J＝5.6Hz,1H),7.56-7.55(m,2H),7.54-7.52(m,2H),7.11(s,1H),7.04-7.03(m,1H),6.16(s,1H),3.28-3.27(m,1H),3.25-3.24(m,2H),2.45(s,3H),2.15(s,3H),1.83-1.81(m,1H),1.37-1.34(m,2H),1.55-1.23(m,6H)。m/z: [M+H] + 413; 14-7a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.33 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.28 (t, J = 5.6 Hz, 1H), 7.54 - 7.52 (m, 2H), 7.48-7.46 (m, 2H), 7.09 (s, 1H), 7.04-7.02 (m, 1H), 6.18 (s, 1H) ), 3.29-3.27 (m, 1H), 3.07-3.05 (m, 2H), 2.42 (s, 3H), 2.18 (s, 3H), 1.78 (t, J = 14.0 Hz, 4H), 1.73-1.71 ( m, 1H), 1.37-1.34 (m, 2H), 1.00-0.97 (m, 2H); 14-7b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.32 (s, 1H), 8.32 ( d, J=5.2 Hz, 1H), 8.29 (t, J=5.6 Hz, 1H), 7.56-7.55 (m, 2H), 7.54-7.52 (m, 2H), 7.11 (s, 1H), 7.04-7.03 (m, 1H), 6.16 (s, 1H), 3.28-3.27 (m, 1H), 3.25-3.24 (m, 2H), 2.45 (s, 3H), 2.15 (s, 3H), 1.83-1.81 (m , 1H), 1.37-1.34 (m, 2H), 1.55-1.23 (m, 6H).
实施例80：化合物14-10的合成Example 80: Synthesis of Compound 14-10
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6和化合物4.26反应得到化合物14-10：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 20.6 and compound 4.26 to give compound 14-10:
Figure PCTCN2017095396-appb-000196
Figure PCTCN2017095396-appb-000196
m/z:[M+H]+500；1H NMR(400MHz,CD3OD)δ8.54(d,J＝8.0Hz,1H),7.82(s,1H),7.77(d,J＝4.0Hz,1H),7.55-7.40(m,4H),6.22(s,1H),2.78-2.73(m,4H),2.27(s,3H),2.17-2.11(m,1H),1.97(d,J＝12.0Hz,2H),1.85(d,J＝16.0Hz,2H),1.58-1.49(m,2H),1.25-1.14(m,8H)。m/z: [M+H] + 500; 1 H NMR (400 MHz, CD 3 OD) δ 8.54 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 4.0) Hz, 1H), 7.55-7.40 (m, 4H), 6.22 (s, 1H), 2.78-2.73 (m, 4H), 2.27 (s, 3H), 2.17-2.11 (m, 1H), 1.97 (d, J = 12.0 Hz, 2H), 1.85 (d, J = 16.0 Hz, 2H), 1.58-1.49 (m, 2H), 1.25-1.14 (m, 8H).
实施例81：化合物14-11～14-12的合成Example 81: Synthesis of Compounds 14-11 to 14-12
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6、20.4和化合物4.12反应得到化合物26-1：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid was replaced with compound 20.6, 20.4 and compound 4.12 to give compound 26-1:
Figure PCTCN2017095396-appb-000197
Figure PCTCN2017095396-appb-000197
将化合物14-11(192mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物14-11a(60mg，出峰时间：17.6～18.2分钟，单一立体构型)和14-11b(50mg，出峰时间：18.3～19.2分钟，单一立体构型)，均为类白色固体。Compound 14-11 (192 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 14-11a (60 mg, peak time: 17.6 to 18.2 minutes, single stereo configuration) and 14-11b (50 mg, peak time: 18.3 to 19.2 minutes, single stereo configuration), all white-like solids.
m/z:[M+H]+486；14-11a,1H NMR(400MHz,CD3OD):δ7.32-7.52(m,4H),6.93(s,2H),6.21(d,J＝0.8Hz,1H),3.10(d,J＝6.8Hz,2H),2.44(s,6H),2.39-2.42(m,1H),2.26(d,J＝0.4Hz,3H),1.83(d,J＝10.4Hz,4H),1.39-1.56(m,3H),1.01-1.11(m,2H)；14-11b,1H NMR(400MHz,CD3OD):δ7.49-7.51(m,1H),7.30-7.42(m,3H),6.97(s,2H),6.20(d,J＝0.4Hz,1H),3.33(d,J＝7.6Hz,2H),2.51-2.59(m,1H),2.43(s,6H),2.25(d,J＝0.4Hz,3H),1.57-1.90(m,9H)。m/z: [M+H] + 486; 14-11a, 1 H NMR (400 MHz, CD 3 OD): δ 7.32-7.52 (m, 4H), 6.93 (s, 2H), 6.21. (d, J =0.8 Hz, 1H), 3.10 (d, J = 6.8 Hz, 2H), 2.44 (s, 6H), 2.39 - 2.42 (m, 1H), 2.26 (d, J = 0.4 Hz, 3H), 1.83 (d , J = 10.4 Hz, 4H), 1.39-1.56 (m, 3H), 1.01-1.11 (m, 2H); 14-11b, 1 H NMR (400 MHz, CD 3 OD): δ 7.49 - 7.51 (m, 1H), 7.30-7.42 (m, 3H), 6.97 (s, 2H), 6.20 (d, J = 0.4 Hz, 1H), 3.33 (d, J = 7.6 Hz, 2H), 2.51-2.59 (m, 1H) ), 2.43 (s, 6H), 2.25 (d, J = 0.4 Hz, 3H), 1.57-1.90 (m, 9H).
Figure PCTCN2017095396-appb-000198
Figure PCTCN2017095396-appb-000198
将化合物14-12(213mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物14-12a(30mg，出峰时间：15.5～16.0分钟，单一立体构型)和14-12b(40mg，出峰时间：16.2～16.6分钟，单一立体构型)，均为类白色固体。Compound 14-12 (213 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 14-12a (30 mg, peak time: 15.5 to 16.0 min, single stereo configuration) and 14-12b (40 mg, peak time: 16.2 to 16.6 minutes, single stereo configuration), all white-like solids.
m/z:[M+H]+432；14-12a,1H NMR(400MHz,CD3OD):δ7.30-7.38(m,2H),7.08(d,J＝8.0Hz,1H),7.00(t,J＝7.6Hz,1H),6.91(s,2H),6.17(s,1H),3.80(d,J＝1.2Hz,3H),3.07(d,J＝6.4Hz,2H),2.44(s,6H),2.34-2.40(m,1H),2.23(s,3H),1.79(d,J＝12.0Hz,2H),1.67(d,J＝11.2Hz,2H),1.34-1.44(m,3H),0.91-1.01(m,2H)；14-12b,1H NMR(400MHz,CD3OD):δ7.28-7.35(m,2H),7.05(d,J＝8.0Hz,1H),6.95-6.98(m,3H),6.16(s,1H),3.79(s,3H),3.28-3.29(m,2H),2.48-2.54(m,1H),2.43(s,6H),2.23(s,3H),1.52-1.77(m,9H)。m/z: [M+H] + 432; 14-12a, 1 H NMR (400 MHz, CD 3 OD): δ 7.30-7.38 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.91 (s, 2H), 6.17 (s, 1H), 3.80 (d, J = 1.2 Hz, 3H), 3.07 (d, J = 6.4 Hz, 2H), 2.44(s,6H), 2.34-2.40(m,1H), 2.23(s,3H), 1.79(d,J=12.0Hz,2H),1.67(d,J=11.2Hz,2H),1.34-1.44 (m, 3H), 0.91-1.01 (m, 2H); 14-12b, 1 H NMR (400 MHz, CD 3 OD): δ 7.28-7.35 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.95-6.98 (m, 3H), 6.16 (s, 1H), 3.79 (s, 3H), 3.28-3.29 (m, 2H), 2.48-2.54 (m, 1H), 2.43 (s, 6H) , 2.23 (s, 3H), 1.52-1.77 (m, 9H).
实施例82：化合物14-13a和14-13b的合成Example 82: Synthesis of compounds 14-13a and 14-13b
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6和化合物4.14a、4.14b反应得到化合物14-13a和14-13b： By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 20.6 and compound 4.14a, 4.14b to give compounds 14-13a and 14-13b:
Figure PCTCN2017095396-appb-000199
Figure PCTCN2017095396-appb-000199
m/z:[M+H]+490；14-13a,1H NMR(400MHz,CD3OD):δ8.15(d,J＝5.2Hz,1H),7.53(dd,J＝2.0Hz,J＝7.2Hz,1H),7.37-7.45(m,2H),7.34(d,J＝7.6Hz,1H),7.28-7.31(m,1H),6.24(s,1H),3.40(d,J＝7.6Hz,2H),2.96-3.00(m,1H),2.49(d,J＝3.2Hz,3H),2.28(s,3H),1.92-2.00(m,1H),1.62-1.82(m,8H)；14-13b,1H NMR(400MHz,CD3OD):δ8.15(d,J＝5.2Hz,1H),7.54(dd,J＝2.0Hz,1H),7.35-7.46(m,3H),7.21-7.23(m,1H),6.24(s,1H),3.14(d,J＝6.8Hz,2H),2.85-2.91(m,1H),2.49(d,J＝3.2Hz,3H),2.29(s,3H),1.87(d,J＝11.6Hz,4H),1.48-1.60(m,3H),1.07-1.16(m,2H)。m/z: [M+H] + 490; 14-13a, 1 H NMR (400 MHz, CD 3 OD): δ 8.15 (d, J = 5.2 Hz, 1H), 7.53 (dd, J = 2.0 Hz, J=7.2 Hz, 1H), 7.37-7.45 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.28-7.31 (m, 1H), 6.24 (s, 1H), 3.40 (d, J) = 7.6 Hz, 2H), 2.96-3.00 (m, 1H), 2.49 (d, J = 3.2 Hz, 3H), 2.28 (s, 3H), 1.92-2.00 (m, 1H), 1.62-1.82 (m, 8H); 14-13b, 1 H NMR (400MHz, CD 3 OD): δ 8.15 (d, J = 5.2 Hz, 1H), 7.54 (dd, J = 2.0 Hz, 1H), 7.35-7.46 (m, 3H), 7.21-7.23 (m, 1H), 6.24 (s, 1H), 3.14 (d, J = 6.8 Hz, 2H), 2.85-2.91 (m, 1H), 2.49 (d, J = 3.2 Hz, 3H) ), 2.29 (s, 3H), 1.87 (d, J = 11.6 Hz, 4H), 1.48-1.60 (m, 3H), 1.07-1.16 (m, 2H).
实施例83：化合物15-1～15-2的合成Example 83: Synthesis of Compound 15-1 to 15-2
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6、20.4化合物5.3反应得到化合物15-1～15-2：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 20.6, 20.4 compound 5.3 to give compound 15-1 to 15-2:
Figure PCTCN2017095396-appb-000200
Figure PCTCN2017095396-appb-000200
Figure PCTCN2017095396-appb-000201
Figure PCTCN2017095396-appb-000201
实施例84：化合物21-1～21-4的合成Example 84: Synthesis of Compounds 21-1 to 21-4
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6、20.9、20.19、20.5、20.21和化合物4.8反应得到化合物21-1～21-4：In the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid was replaced with compounds 20.6, 20.9, 20.19, 20.5, 20.21. and compound 4.8 to give compounds 21-1 to 21-4:
Figure PCTCN2017095396-appb-000202
Figure PCTCN2017095396-appb-000202
将化合物21-1(192mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物21-1a(30mg，出峰时间：19.5～20.3分钟，单一立体构型)和21-1b(28mg，出峰时间：20.6～21.3分钟，单一立体构型)，均为白色固体。Compound 21-1 (192 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 5) to give compound 21-1a (30 mg, peak time: 19.5 to 20.3 minutes, single stereo configuration) and 21-1b (28 mg, peak time: 20.6 to 21.3 minutes, single stereo configuration), all white solids.
m/z:[M+H]+526；21-1a,1H NMR(400MHz,CD3OD):δ8.64(d,J＝4.4Hz,1H),7.97(dd,J＝5.6Hz,J＝9.6Hz,1H),7.76(dd,J＝2.8,J＝10.8Hz,1H),7.23-7.51(m,6H),6.13(d,J＝0.8 Hz,1H),3.13-3.17(m,1H),3.08(d,J＝6.8Hz,2H),2.17(d,J＝0.8Hz,3H),1.92(d,J＝12Hz,2H),1.83(dd,J＝2,2.4Hz,2H),1.45-1.57(m,3H),1.16-1.23(m,2H)；21-1b,1H NMR(400MHz,CD3OD):δ8.63(d,J＝4.8Hz,1H),7.96(dd,J＝5.6,J＝9.2Hz,1H),7.76(dd,J＝2.4,J＝10.4Hz,1H),7.20-7.50(m,6H),6.13(d,J＝1.2Hz,1H),3.32(d,J＝8Hz,2H),3.22-3.23(m,1H),2.16(d,J＝0.4Hz,3H),1.93(s,1H),1.64-1.75(m,8H)。m/z: [M+H] + 526; 21-1a, 1 H NMR (400 MHz, CD 3 OD): δ 8.64 (d, J = 4.4 Hz, 1H), 7.97 (dd, J = 5.6 Hz, J = 9.6 Hz, 1H), 7.76 (dd, J = 2.8, J = 10.8 Hz, 1H), 7.23 - 7.51 (m, 6H), 6.13 (d, J = 0.8 Hz, 1H), 3.13 - 3.17 (m , 1H), 3.08 (d, J = 6.8 Hz, 2H), 2.17 (d, J = 0.8 Hz, 3H), 1.92 (d, J = 12 Hz, 2H), 1.83 (dd, J = 2, 2.4 Hz, 2H), 1.45-1.57 (m, 3H), 1.16-1.23 (m, 2H); 21-1b, 1 H NMR (400 MHz, CD 3 OD): δ 8.63 (d, J = 4.8 Hz, 1H), 7.96 (dd, J = 5.6, J = 9.2 Hz, 1H), 7.76 (dd, J = 2.4, J = 10.4 Hz, 1H), 7.20-7.50 (m, 6H), 6.13 (d, J = 1.2 Hz, 1H), 3.32 (d, J = 8 Hz, 2H), 3.22-3.23 (m, 1H), 2.16 (d, J = 0.4 Hz, 3H), 1.93 (s, 1H), 1.64-1.75 (m, 8H) .
Figure PCTCN2017095396-appb-000203
Figure PCTCN2017095396-appb-000203
将化合物21-2(320mg，顺反异构体混合物)经prep-HPLC(分离条件16)得到化合物21-2a(15.5mg，出峰时间：21.0～21.8分钟，单一立体构型)和21-2b(5.3mg，出峰时间：21.9～22.4分钟，单一立体构型)，均为白色固体。Compound 21-2 (320 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 16) to give compound 21-2a (15.5 mg, peak time: 21.0 to 21.8 minutes, single stereo configuration) and 21- 2b (5.3 mg, peak time: 21.9 to 22.4 minutes, single stereo configuration), all white solids.
m/z:[M+H]+467；21-2a,1H NMR(400MHz,DMSO-d6):δ11.36(s,1H),8.82(d,J＝4.4Hz,1H),8.34(t,J＝5.2Hz,1H),8.11-8.07(m,1H),7.99-7.95(m,1H),7.77-7.65(m,1H),7.57-7.54(m,2H),7.52-7.50(m,1H),7.47(d,J＝2.0Hz,1H),7.45(d,J＝4.8Hz,1H),6.18(d,J＝1.6Hz,1H),3.12(t,J＝6.0Hz,2H),2.20(s,3H),1.90(d,J＝12.0Hz,2H),1.79(d,J＝1.2Hz,2H),1.58-1.46(m,3H),1.29-1.20(m,3H)；21-2b,1H NMR(400MHz,DMSO-d6):δ11.34(s,1H),8.83(d,J＝4.4Hz,1H),8.34(t,J＝5.2Hz,1H),8.11-8.07(m,1H),7.99-7.95(m,1H),7.70-7.64(m,1H),7.58-7.54(m,2H),7.51-7.50(m,1H),7.48(d,J＝2.0Hz,1H),7.46(d,J＝4.8Hz,1H),6.18(d,J＝1.6Hz,1H),3.30-3.28(m,3H),2.14(s,3H),1.95-1.93(m,1H),1.78-1.65(m,8H)。m/z: [M+H] + 467; 21-2a, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.36 (s, 1H), 8.82 (d, J = 4.4 Hz, 1H), 8.34 (t, J = 5.2 Hz, 1H), 8.11 - 8.07 (m, 1H), 7.99 - 7.95 (m, 1H), 7.77 - 7.65 (m, 1H), 7.57 - 7.54 (m, 2H), 7.52 - 7.50 (m, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H), 3.12 (t, J = 6.0 Hz) , 2H), 2.20 (s, 3H), 1.90 (d, J = 12.0 Hz, 2H), 1.79 (d, J = 1.2 Hz, 2H), 1.58-1.46 (m, 3H), 1.29-1.20 (m, 3H); 21-2b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.34 (s, 1H), 8.83 (d, J = 4.4 Hz, 1H), 8.34 (t, J = 5.2 Hz, 1H) ), 8.11-8.07 (m, 1H), 7.99-7.95 (m, 1H), 7.70-7.64 (m, 1H), 7.58-7.54 (m, 2H), 7.51-7.50 (m, 1H), 7.48 (d) , J=2.0 Hz, 1H), 7.46 (d, J=4.8 Hz, 1H), 6.18 (d, J=1.6 Hz, 1H), 3.30-3.28 (m, 3H), 2.14 (s, 3H), 1.95 -1.93 (m, 1H), 1.78-1.65 (m, 8H).
Figure PCTCN2017095396-appb-000204
Figure PCTCN2017095396-appb-000204
m/z:[M+H]+481；1H NMR(400MHz,DMSO-d6):δ11.35(s,1H),8.83(d,J＝4.8Hz,1H),8.33(d,J＝5.6Hz,1H),8.11-8.07(m,1H),7.98(dd,J＝2.8,10.8Hz,1H),7.69-7.64(m,1H),7.58-7.44(m,5H),6.19(d,J＝2.4Hz,1H),3.37-3.25(m,4H),2.48-2.46(m,1H),1.95-1.94(m,1H),1.75-1.65(m,8H),1.13-1.09(m,3H)。m/z: [M+H] + 481; 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.35 (s, 1H), 8.83 (d, J = 4.8 Hz, 1H), 8.33 (d, J) = 5.6 Hz, 1H), 8.11 - 8.07 (m, 1H), 7.98 (dd, J = 2.8, 10.8 Hz, 1H), 7.69-7.64 (m, 1H), 7.58-7.44 (m, 5H), 6.19 ( d, J = 2.4 Hz, 1H), 3.37-3.25 (m, 4H), 2.48-2.46 (m, 1H), 1.95-1.94 (m, 1H), 1.75-1.65 (m, 8H), 1.13-1.09 ( m, 3H).
Figure PCTCN2017095396-appb-000205
Figure PCTCN2017095396-appb-000205
将化合物21-4(350mg，顺反异构体混合物)经prep-HPLC(分离条件18)得到21-4a(25.0mg，出峰时间：17.3～18.5分钟，单一立体构型)和化合物21-4b(36.5mg，出峰时间：16.2～17.1分钟，单一立体构型)，均为黄色固体。Compound 21-4 (350 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 18) to give 21-4a (25.0 mg, peak time: 17.3 to 18.5 minutes, single stereo configuration) and compound 21- 4b (36.5 mg, peak time: 16.2 to 17.1 minutes, single stereo configuration), all yellow solid.
m/z:[M+H]+472；21-4a,1HNMR(400MHz,DMSO-d6):δ11.06(s,1H),8.97(d,J＝4.8Hz,1H),8.19-8.10(m,2H),7.83-7.79(m,1H),7.65-7.62(m,2H),7.25-7.17(m,3H),6.80-6.77(m,1H),6.14(d,J＝2.0Hz,1H),3.74(s,3H),3.43(br.s,1H),3.36-3.33(m,2H),2.21(s,3H),2.01(br.s,1H),1.80-1.66(m,8H)；21-4b,1HNMR(400MHz,DMSO-d6):δ11.06(s,1H),8.97(d,J＝4.8 Hz,1H),8.20-8.15(m,2H),7.85-7.80(m,1H),7.67(d,J＝5.2Hz,1H),7.64-7.61(m,1H),7.27-7.19(m,3H),6.82-6.79(m,1H),6.16(d,J＝2.0Hz,1H),3.75(s,3H),3.44-3.38(m,1H),3.11-3.08(m,2H),2.21(s,3H),1.92-1.85(m,4H),1.63-1.52(m,3H),1.34-1.25(m,2H)。m/z: [M+H] + 472; 21-4a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.06 (s, 1H), 8.97 (d, J = 4.8 Hz, 1H), 8.19- 8.10(m,2H),7.83-7.79(m,1H), 7.65-7.62(m,2H), 7.25-7.17(m,3H), 6.80-6.77(m,1H), 6.14(d,J=2.0 Hz, 1H), 3.74 (s, 3H), 3.43 (br.s, 1H), 3.36-3.33 (m, 2H), 2.21 (s, 3H), 2.01 (br.s, 1H), 1.80-1.66 ( m,8H); 21-4b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.06 (s, 1H), 8.97 (d, J = 4.8 Hz, 1H), 8.20-8.15 (m, 2H), 7.85-7.80(m,1H), 7.67(d,J=5.2Hz,1H), 7.64-7.61(m,1H), 7.27-7.19(m,3H),6.82-6.79(m,1H),6.16( d, J = 2.0 Hz, 1H), 3.75 (s, 3H), 3.44 - 3.38 (m, 1H), 3.11-3.08 (m, 2H), 2.21 (s, 3H), 1.92-1.85 (m, 4H) , 1.63-1.52 (m, 3H), 1.34-1.25 (m, 2H).
Figure PCTCN2017095396-appb-000206
Figure PCTCN2017095396-appb-000206
m/z:[M+H]+514m/z: [M+H] + 514
实施例85：化合物21-11a～21-13a的合成Example 85: Synthesis of compounds 21-11a to 21-13a
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.10、20.12或20.13和化合物4.8a反应得到化合物21-11a～21-13a：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 20.10, 20.12 or 20.13 and compound 4.8a by compound 1-1 to give compound 21-11a-21-13a:
Figure PCTCN2017095396-appb-000207
Figure PCTCN2017095396-appb-000207
Figure PCTCN2017095396-appb-000208
Figure PCTCN2017095396-appb-000208
实施例86：化合物21-15a的合成Example 86: Synthesis of Compound 21-15a
利用化合物6-38a的合成方法，用化合物21-12a为起始原料合成化合物21-15a：The compound 21-15a was synthesized by the synthesis method of the compound 6-38a using the compound 21-12a as a starting material:
Figure PCTCN2017095396-appb-000209
Figure PCTCN2017095396-appb-000209
m/z:[M+H]+474；1H NMR(400MHz,CD3OD):δ8.66-8.64(d,J＝8.0Hz,1H),7.99-7.95(m,1H),7.78-7.74(m,1H),7.51-7.46(m,1H),7.45-7.43(d,J＝8.0Hz,1H),6.34-6.33(d,J＝4.0Hz,2H),6.15-6.14(m,1H),6.06(s,1H),3.34-3.32(d,J＝8.0Hz,2H),3.28-3.24(m,1H),2.13(s,3H),1.89(s,1H),1.74-1.65(m,8H)。m/z: [M+H] + 474; 1 H NMR (400 MHz, CD 3 OD): δ 8.66 - 8.64 (d, J = 8.0 Hz, 1H), 7.99 - 7.95 (m, 1H), 7.78- 7.74 (m, 1H), 7.51-7.46 (m, 1H), 7.45-7.43 (d, J = 8.0 Hz, 1H), 6.34-6.33 (d, J = 4.0 Hz, 2H), 6.15-6.14 (m, 1H), 6.06 (s, 1H), 3.34-3.32 (d, J = 8.0 Hz, 2H), 3.28-3.24 (m, 1H), 2.13 (s, 3H), 1.89 (s, 1H), 1.74-1.65 (m, 8H).
实施例87：化合物21-16a和21-17a的合成Example 87: Synthesis of Compounds 21-16a and 21-17a
Figure PCTCN2017095396-appb-000210
Figure PCTCN2017095396-appb-000210
利用化合物1-1的合成方法，用化合物20.21和20.22的混合物和化合物4.8a反应得到化合物2-16a和2-17a的混合物，经prep-HPLC分离得到化合物2-16a和2-17a。By the synthesis of the compound 1-1, a mixture of the compounds 20.21 and 20.22 and the compound 4.8a are reacted to obtain a mixture of the compounds 2-16a and 2-17a, and the compounds 2-16a and 2-17a are obtained by prep-HPLC.
2-16a：m/z:[M+H]+515；2-17a：m/z:[M+H]+497。2-16a: m/z: [M+H] + 515; 2-17a: m/z: [M+H] + 497.
实施例88：化合物22-1～22-4的合成Example 88: Synthesis of Compounds 22-1 to 22-4
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6和化合物4.10、4.11、4.13或4.20反应得到化合物22-1～22-4：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 20.6 and compound 4.10, 4.11, 4.13 or 4.20 to give compound 22-1 to 22-4:
Figure PCTCN2017095396-appb-000211
Figure PCTCN2017095396-appb-000211
将化合物22-1(160mg，顺反异构体混合物)经prep-HPLC(分离条件12)得到化合物22-1a(18.5mg，出峰时间：9.2～10.1分钟，单一立体构型)和22-1b(7.8mg，出峰时间：10.2～11.0分钟，单一立体构型)，均为白色固体。Compound 22-1 (160 mg, cis and trans isomer mixture) was subjected to prep-HPLC (separation condition 12) to give compound 22-1a (18.5 mg, peak time: 9.2 to 10.1 min, single stereo configuration) and 22- 1b (7.8 mg, peak time: 10.2 to 11.0 minutes, single stereo configuration), all white solid.
m/z:[M+H]+459；22-1a,1H NMR(400MHz,DMSO-d6):δ11.08(s,1H),9.10(t,J＝3.2Hz,1H),7.67(d,J＝3.2Hz,2H),7.48-7.32(m,5H),6.23(d,J＝1.6Hz,1H),2.99(t,J＝6.4Hz,2H),2.87-2.81(m,1H),2.21(s,3H),1.89(d,J＝11.6Hz,2H),1.81(d,J＝10.8Hz,2H),1.58-1.49(m,3H),1.10-0.99(m,2H)；22-1b,1H NMR(400MHz,DMSO-d6):δ11.07(s,1H),9.10(t,J＝3.2Hz,1H),7.67(d,J＝3.2Hz,2H),7.49-7.30(m,5H),6.21(d,J＝2.0Hz,1H),3.16(t,J＝6.8Hz,2H),2.98-2.93(m,1H),2.19(s,3H),1.92-1.83(m,3H),1.67-1.63(m,2H),1.57-1.55(m,4H)。m/z: [M+H] + 459; 22-1a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.08 (s, 1H), 9.10 (t, J = 3.2 Hz, 1H), 7.67 (d, J = 3.2 Hz, 2H), 7.48-7.32 (m, 5H), 6.23 (d, J = 1.6 Hz, 1H), 2.99 (t, J = 6.4 Hz, 2H), 2.87 - 2.81 (m, 1H), 2.21 (s, 3H), 1.89 (d, J = 11.6 Hz, 2H), 1.81 (d, J = 10.8 Hz, 2H), 1.58-1.49 (m, 3H), 1.10-0.99 (m, 2H) 22-1b, 1 H NMR (400MHz, DMSO-d 6 ): δ 11.07 (s, 1H), 9.10 (t, J = 3.2 Hz, 1H), 7.67 (d, J = 3.2 Hz, 2H) , 7.49-7.30 (m, 5H), 6.21 (d, J = 2.0 Hz, 1H), 3.16 (t, J = 6.8 Hz, 2H), 2.98-2.93 (m, 1H), 2.19 (s, 3H), 1.92-1.83 (m, 3H), 1.67-1.63 (m, 2H), 1.57-1.55 (m, 4H).
Figure PCTCN2017095396-appb-000212
Figure PCTCN2017095396-appb-000212
将化合物22-2(274mg，顺反异构体混合物)经prep-HPLC(分离条件13)得到化合物22-2a(46.3mg，出峰时间：14.7～15.5分钟，单一立体构型)和22-2b(32.7mg，出峰时间：15.6～16.3分钟，单一立体构型)，均为白色固体。Compound 22-2 (274 mg, cis-trans isomer mixture) was subjected to prep-HPLC (isolation condition 13) to give compound 22-2a (46.3 mg, peak time: 14.7 to 15.5 minutes, single stereo configuration) and 22- 2b (32.7 mg, peak time: 15.6 to 16.3 minutes, single stereo configuration), all white solids.
m/z:[M+H]+473；22-2a,1H NMR(400MHz,DMSO-d6):δ11.07(s,1H),7.48-7.32(m,7H),6.23(d,J＝2.0Hz,1H),2.99(t,J＝6.4Hz,2H),2.81-2.75(m,1H),2.56(s,3H),2.19(s,3H),1.88-1.79(m,4H),1.55-1.45(m,3H),1.08-0.98(m,2H)；22-2b,1H NMR(400MHz, DMSO-d6):δ11.06(s,1H),7.49-7.30(m,7H),6.21(d,J＝1.2Hz,1H),3.15(t,J＝6.8Hz,2H),2.92-2.87(m,1H),2.56(s,3H),2.19(s,3H),1.90-1.83(m,3H),1.64-1.52(m,6H)。m/z: [M+H] + 473; 22-2a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.07 (s, 1H), 7.48-7.32 (m, 7H), 6.23 (d, J=2.0 Hz, 1H), 2.99 (t, J=6.4 Hz, 2H), 2.81-2.75 (m, 1H), 2.56 (s, 3H), 2.19 (s, 3H), 1.88-1.79 (m, 4H) ), 1.55-1.45 (m, 3H), 1.08-0.98 (m, 2H); 22-2b, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.06 (s, 1H), 7.49-7.30 (m) , 7H), 6.21 (d, J = 1.2 Hz, 1H), 3.15 (t, J = 6.8 Hz, 2H), 2.92 - 2.87 (m, 1H), 2.56 (s, 3H), 2.19 (s, 3H) , 1.90 - 1.83 (m, 3H), 1.64-1.52 (m, 6H).
Figure PCTCN2017095396-appb-000213
Figure PCTCN2017095396-appb-000213
将化合物22-3(372mg，顺反异构体混合物)经prep-HPLC(分离条件15)得到化合物22-3a(18.2mg，出峰时间：16.4～17.1分钟，单一立体构型)和22-3b(19.2mg，出峰时间：17.2～17.9分钟，单一立体构型)，均为白色固体。Compound 22-3 (372 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 15) to give compound 22-3a (18.2 mg, peak time: 16.4 to 17.1 minutes, single stereo configuration) and 22- 3b (19.2 mg, peak time: 17.2 to 17.9 minutes, single stereo configuration), all white solids.
m/z:[M+H]+459；22-3a,1H NMR(400MHz,DMSO-d6):δ11.06(s,1H),8.56(d,J＝1.6Hz,1H),8.54(t,J＝2.8Hz,1H),8.45(d,J＝2.4Hz,1H),7.74-7.72(m,1H),7.45-7.43(m,1H),7.41-7.39(m,1H),7.34-7.32(m,1H),6.23(d,J＝1.6Hz,1H),3.29-3.27(m,1H),2.99(t,J＝6.4Hz,2H),2.72-2.66(m,1H),2.19(s,3H),1.87-1.85(m,4H),1.51-1.50(m,3H),1.87-1.85(m,2H)；22-3b,1H NMR(400MHz,DMSO-d6):δ11.06(s,1H),8.57(d,J＝1.6Hz,1H),8.55(t,J＝2.8Hz,1H),8.44(d,J＝2.4Hz,1H),7.48-7.46(m,1H),7.46-7.44(m,1H),7.43-7.40(m,1H),7.37-7.35(m,1H),6.21(d,J＝1.6Hz,1H),3.29-3.27(m,1H),3.16(t,J＝6.4Hz,2H),2.82-2.80(m,1H),2.18(s,3H),1.89-1.85(m,3H),1.51-1.23(m,6H)。m/z: [M+H] + 459; 22-3a, 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.06 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.54 (t, J = 2.8 Hz, 1H), 8.45 (d, J = 2.4 Hz, 1H), 7.74 - 7.72 (m, 1H), 7.45 - 7.43 (m, 1H), 7.41 - 7.39 (m, 1H), 7.34-7.32(m,1H), 6.23(d,J=1.6Hz,1H), 3.29-3.27(m,1H),2.99(t,J=6.4Hz,2H),2.72-2.66(m,1H) , 2.19 (s, 3H), 1.87-1.85 (m, 4H), 1.51-1.50 (m, 3H), 1.87-1.85 (m, 2H); 22-3b, 1 H NMR (400 MHz, DMSO-d 6 ) : δ11.06(s,1H), 8.57 (d, J=1.6Hz, 1H), 8.55 (t, J=2.8Hz, 1H), 8.44 (d, J=2.4Hz, 1H), 7.48-7.46 ( m,1H), 7.46-7.44 (m, 1H), 7.43-7.40 (m, 1H), 7.37-7.35 (m, 1H), 6.21 (d, J = 1.6 Hz, 1H), 3.29-3.27 (m, 1H), 3.16 (t, J = 6.4 Hz, 2H), 2.82-2.80 (m, 1H), 2.18 (s, 3H), 1.89-1.85 (m, 3H), 1.51-1.23 (m, 6H).
Figure PCTCN2017095396-appb-000214
Figure PCTCN2017095396-appb-000214
将化合物22-4(168mg，顺反异构体混合物)经prep-HPLC(分离条件17)得到化合物22-4a(11.5mg，出峰时间：14.2～15.0分钟，单一立体构型)和22-4b(16.4mg，出峰时间：15.1～16.0分钟，单一立体构型)，均为白色固体。Compound 22-4 (168 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 17) to give compound 22-4a (11.5 mg, peak time: 14.2 to 15.0 min, single stereo configuration) and 22- 4b (16.4 mg, peak time: 15.1 to 16.0 minutes, single stereo configuration), all white solids.
m/z:[M+H]+461；22-4a,1H NMR(400MHz,CDCl3):δ8.15(s,1H),7.62-7.59(m,1H),7.42-7.28(m,4H),7.10(s,1H),6.27-6.24(m,1H),5.57-5.49(m,1H),3.84(s,3H),3.15(t,J＝6.4Hz,2H),2.41-2.31(m,1H),2.30(s,3H),1.96-1.89(m,2H),1.71-1.63(m,2H),1.46-1.35(m,1H),1.25-1.17(m,2H),1.02-0.91(m,2H)；22-4b,1H NMR(400MHz,CDCl3):δ8.15(s,1H),7.61-7.57(m,1H),7.41-7.28(m,4H),7.12(s,1H),6.23(d,J＝2.0Hz,1H),5.51-5.43(m,1H),3.84(s,3H),3.21(t,J＝6.4Hz,2H),2.74-2.66(m,1H),2.30(s,3H),1.74-1.62(m,4H),1.51-1.41(m,2H),1.36-1.24(m,3H)。m/z: [M+H] + 461; 22-4a, 1 H NMR (400MHz, CDCl 3 ): δ 8.15 (s, 1H), 7.62-7.59 (m, 1H), 7.42-7.28 (m, 4H), 7.10 (s, 1H), 6.27-6.24 (m, 1H), 5.57-5.49 (m, 1H), 3.84 (s, 3H), 3.15 (t, J = 6.4 Hz, 2H), 2.41-2.31 (m, 1H), 2.30 (s, 3H), 1.96-1.89 (m, 2H), 1.71-1.63 (m, 2H), 1.46-1.35 (m, 1H), 1.25-1.17 (m, 2H), 1.02 -0.91 (m, 2H); 22-4b, 1 H NMR (400MHz, CDCl 3 ): δ 8.15 (s, 1H), 7.61 - 7.57 (m, 1H), 7.41 - 7.28 (m, 4H), 7.12 (s, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.51-5.43 (m, 1H), 3.84 (s, 3H), 3.21 (t, J = 6.4 Hz, 2H), 2.74 - 2.66 ( m, 1H), 2.30 (s, 3H), 1.74-1.62 (m, 4H), 1.51-1.41 (m, 2H), 1.36-1.24 (m, 3H).
实施例89：化合物23-1～23-4的合成Example 89: Synthesis of Compounds 23-1 to 23-4
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6、20.4和化合物6.3、6.4反应得到化合物23-1～23-4：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 20.6, 20.4 and compound 6.3, 6.4 to give compound 23-1 to 23-4:
Figure PCTCN2017095396-appb-000215
Figure PCTCN2017095396-appb-000215
将化合物23-1(198mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物23-1a(38mg，出峰时间：12.2～12.8分钟，单一立体构型)和23-1b(26mg，出峰时间：12.9～13.5分钟，单一立体构型)，均为白色固体。Compound 23-1 (198 mg, cis-trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give Compound 23-1a (38 mg, peak time: 12.2 to 12.8 minutes, single stereo configuration) and 23-1b (26 mg, peak time: 12.9 to 13.5 minutes, single stereo configuration), all white solids.
m/z:[M+H]+502；23-1a,1H NMR(400MHz,CD3OD):δ7.51(dd,J＝2.0,7.6Hz,1H),7.31-7.42(m,3H),7.27(s,2H),6.21(d,J＝0.8Hz,1H),3.10(d,J＝6.8Hz,2H),2.50(s,6H),2.46-2.48(m,1H),2.26(d,J＝0.8Hz,3H),1.83-1.88(m,4H),1.39-1.57(m,3H),1.02-1.12(m,2H)；23-1b,1H NMR(400MHz,CD3OD):δ7.51(dd,J＝1.6,7.2Hz,1H),7.29-7.42(m,5H),6.20(d,J＝0.8Hz,1H),3.32(d,J＝8.0Hz,2H),2.58-2.66(m,1H),2.50(s,6H),2.25(d,J＝0.8Hz,3H),1.57-1.92(m,9H)。m/z: [M+H] + 502; 23-1a, 1 H NMR (400 MHz, CD 3 OD): δ 7.51 (dd, J = 2.0, 7.6 Hz, 1H), 7.31-7.42 (m, 3H) ), 7.27 (s, 2H), 6.21 (d, J = 0.8 Hz, 1H), 3.10 (d, J = 6.8 Hz, 2H), 2.50 (s, 6H), 2.46-2.48 (m, 1H), 2.26 (d, J = 0.8 Hz, 3H), 1.83-1.88 (m, 4H), 1.39-1.57 (m, 3H), 1.02-1.12 (m, 2H); 23-1b, 1 H NMR (400 MHz, CD 3 OD): δ7.51 (dd, J=1.6, 7.2 Hz, 1H), 7.29-7.42 (m, 5H), 6.20 (d, J = 0.8 Hz, 1H), 3.32 (d, J = 8.0 Hz, 2H) ), 2.58-2.66 (m, 1H), 2.50 (s, 6H), 2.25 (d, J = 0.8 Hz, 3H), 1.57-1.92 (m, 9H).
Figure PCTCN2017095396-appb-000216
Figure PCTCN2017095396-appb-000216
将化合物23-2(121mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物23-2a(25mg，出峰时间：10.5～11.2分钟，单一立体构型)和23-2b(20mg，出峰时间：11.6～12.3分钟，单一立体构型)，均为白色固体。Compound 23-2 (121 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 23-2a (25 mg, peak time: 10.5 to 11.2 minutes, single stereo configuration) and 23-2b (20 mg, peak time: 11.6 to 12.3 minutes, single stereo configuration), all white solids.
m/z:[M+H]+448；23-2a,1H NMR(400MHz,CD3OD):δ7.26-7.38(m,4H),5.98-7.09(m,2H),6.17(d,J＝0.8Hz,1H),3.80(s,3H),3.07(d,J＝6.8Hz,2H),2.50(s,6H),2.41-2.48(m,1H),2.23(d,J＝0.8Hz,3H),1.82(d,J＝10.8Hz,2H),1.70(d,J＝13.2Hz,2H),1.34-1.45(m,3H),0.93-1.03(m,2H)；23-2b,1H NMR(400MHz,CD3OD):δ7.28-7.35(m,4H),6.94-7.06(m,2H),6.17(d,J＝0.8Hz,1H),3.78(s,3H),6.17(d,J＝2.4Hz,2H),2.55-2.71(m,1H),2.50(s,6H),2.23(d,J＝0.8Hz,3H),1.54-1.68(m,9H)。m/z: [M+H] + 448; 23-2a, 1 H NMR (400 MHz, CD 3 OD): δ 7.26-7.38 (m, 4H), 5.98-7.09 (m, 2H), 6.17 (d) , J = 0.8 Hz, 1H), 3.80 (s, 3H), 3.07 (d, J = 6.8 Hz, 2H), 2.50 (s, 6H), 2.41-2.48 (m, 1H), 2.23 (d, J = 0.8 Hz, 3H), 1.82 (d, J = 10.8 Hz, 2H), 1.70 (d, J = 13.2 Hz, 2H), 1.34-1.45 (m, 3H), 0.93-1.03 (m, 2H); 2b, 1 H NMR (400MHz, CD 3 OD): δ 7.28-7.35 (m, 4H), 6.94-7.06 (m, 2H), 6.17 (d, J = 0.8 Hz, 1H), 3.78 (s, 3H) ), 6.17 (d, J = 2.4 Hz, 2H), 2.55 - 2.71 (m, 1H), 2.50 (s, 6H), 2.23 (d, J = 0.8 Hz, 3H), 1.54-1.68 (m, 9H) .
Figure PCTCN2017095396-appb-000217
Figure PCTCN2017095396-appb-000217
将化合物23-3(74mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物23-3a(7mg，出峰时间：13.0～13.8分钟，单一立体构型)和23-3b(6mg，出峰时间：14.2～14.8分钟，单一立体构型)，均为白色固体。Compound 23-3 (74 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 23-3a (7 mg, peak time: 13.0 to 13.8 minutes, single stereo configuration) and 23-3b (6 mg, peak time: 14.2 to 14.8 minutes, single stereo configuration), all white solids.
m/z:[M+H]+434；23-3a,1H NMR(400MHz,CDCl3):δ8.42(s,1H),8.15(d,J＝4.0Hz,1H),7.48(d,J＝8.0Hz,1H),7.26-7.33(m,1H),6.95-7.05(m,4H),6.32(s,1H),5.72-5.73(m,1H),3.86(s,3H),3.15-3.18(m,2H),2.50(s,3H),2.37-2.38(m,1H),2.30(s,3H),1.83(d,J＝12.0Hz,2H),1.73(d,J＝8.0Hz,2H),1.26-1.32(m,3H),0.97-1.00(m,2H)；23-3b,1H NMR(400MHz,CDCl3):δ8.43(s,1H),8.14(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.26-7.32(m,1H),7.09(d,J＝4.0Hz,1H),6.97-7.01(m,3H),6.31(d,J＝4.0Hz,1H),5.64-5.65(m,1H),3.85(s,3H),3.33-3.36(m,2H),2.50-2.51(m,4H),2.30(s,3H),1.53-1.73(m,9H)。 m/z: [M+H] + 434; 23-3a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.42 (s, 1H), 8.15 (d, J = 4.0 Hz, 1H), 7.48 (d) , J=8.0 Hz, 1H), 7.26-7.33 (m, 1H), 6.95-7.05 (m, 4H), 6.32 (s, 1H), 5.72-5.73 (m, 1H), 3.86 (s, 3H), 3.15-3.18(m,2H), 2.50(s,3H), 2.37-2.38(m,1H), 2.30(s,3H),1.83(d,J=12.0Hz,2H),1.73(d,J= 8.0 Hz, 2H), 1.26-1.32 (m, 3H), 0.97-1.00 (m, 2H); 23-3b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.43 (s, 1H), 8.14 (d) , J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.26-7.32 (m, 1H), 7.09 (d, J = 4.0 Hz, 1H), 6.97-7.01 (m, 3H) , 6.31 (d, J = 4.0 Hz, 1H), 5.64 - 5.65 (m, 1H), 3.85 (s, 3H), 3.33 - 3.36 (m, 2H), 2.50 - 2.51 (m, 4H), 2.30 (s , 3H), 1.53-1.73 (m, 9H).
Figure PCTCN2017095396-appb-000218
Figure PCTCN2017095396-appb-000218
将化合物23-4(74mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物23-4a(7mg，出峰时间：16.0～16.7分钟，单一立体构型)。Compound 23-4 (74 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 5) to give compound 23-4a (7 mg, peak time: 16.0 to 16.7 minutes, single stereo configuration).
m/z:[M+H]+488；23-4a，1H NMR(400MHz,CDCl3):δ8.14(d,J＝4.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.26-7.39(m,5H),7.09(s,1H),6.99-7.00(m,1H),6.24(s,1H),5.50-5.51(m,1H),3.34-3.38(m,2H),2.50-2.51(m,4H),2.30(s,3H),1.57-1.65(m,8H)。m/z: [M+H] + 488; 23-4a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.14 (d, J = 4.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H) ), 7.26-7.39 (m, 5H), 7.09 (s, 1H), 6.99-7.00 (m, 1H), 6.24 (s, 1H), 5.50-5.51 (m, 1H), 3.34-3.38 (m, 2H) ), 2.50-2.51 (m, 4H), 2.30 (s, 3H), 1.57-1.65 (m, 8H).
实施例90：化合物23-5a～23-6a的合成Example 90: Synthesis of compounds 23-5a to 23-6a
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.6、20.5和化合物6.5a反应得到化合物23-5a～23-6a：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid is replaced by compound 20.6, 20.5 and compound 6.5a to give compound 23-5a-23-6a:
Figure PCTCN2017095396-appb-000219
Figure PCTCN2017095396-appb-000219
Figure PCTCN2017095396-appb-000220
Figure PCTCN2017095396-appb-000220
实施例91：化合物24-1、24-2a和24-2b的合成Example 91: Synthesis of Compounds 24-1, 24-2a and 24-2b
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.17和化合物4.8、4.21a、4.21b反应得到化合物24-1、24-2a和24-2b：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid was replaced with compound 20.17 and compound 4.8, 4.21a, 4.21b to give compounds 24-1, 24-2a and 24-. 2b:
Figure PCTCN2017095396-appb-000221
Figure PCTCN2017095396-appb-000221
将化合物24-1(199mg，顺反异构体混合物)经prep-HPLC(分离条件5)得到化合物24-1a(35mg，出峰时间：20.0～20.6分钟，单一立体构型)和24-1b(26mg，出峰时间：20.9～21.5分钟，单一立体构型)，均为白色固体。Compound 24-1 (199 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 24-1a (35 mg, peak time: 20.0 to 20.6 minutes, single stereo configuration) and 24-1b. (26 mg, peak time: 20.9 to 21.5 minutes, single stereo configuration), all white solids.
m/z:[M+H]+554；24-1a,1H NMR(400MHz,CD3OD):δ8.64(d,J＝4.8Hz,1H),7.97(dd,J＝5.6,J＝9.2Hz,1H),7.76(dd,J＝2.8,J＝10.8Hz,1H),7.23-7.51(m,6H),6.18(s,1H),3.12-3.15(m,1H),3.08(d,J＝6.8Hz,2H),2.80-2.86(m,1H),1.89(d,J＝12.4Hz,2H),1.81(d,J＝11.2Hz,2H),1.45-1.59(m,3H),1.12-1.22(m,8H)；24-1b,1H NMR(400MHz,CD3OD):δ8.64(d,J＝4.8Hz,1H),7.97(dd,J＝5.6,9.2Hz,1H),7.76(dd,J＝2.4,10.4Hz,1H),7.21- 7.50(m,6H),6.18(d,J＝0.8Hz,1H),3.32(d,J＝8.0Hz,2H),3.21-3.23(m,1H),2.79-2.86(m,1H),1.94(s,1H),1.64-1.76(m,8H),1.19(s,3H),1.17(s,3H)。m/z: [M+H] + 554; 24-1a, 1 H NMR (400 MHz, CD 3 OD): δ 8.64 (d, J = 4.8 Hz, 1H), 7.97 (dd, J = 5.6, J = 9.2 Hz, 1H), 7.76 (dd, J = 2.8, J = 10.8 Hz, 1H), 7.23 - 7.51 (m, 6H), 6.18 (s, 1H), 3.12-3.15 (m, 1H), 3.08 ( d, J = 6.8 Hz, 2H), 2.80-2.86 (m, 1H), 1.89 (d, J = 12.4 Hz, 2H), 1.81 (d, J = 11.2 Hz, 2H), 1.45-1.59 (m, 3H) ), 1.12-1.22 (m, 8H); 24-1b, 1 H NMR (400 MHz, CD 3 OD): δ 8.64 (d, J = 4.8 Hz, 1H), 7.97 (dd, J = 5.6, 9.2 Hz) , 1H), 7.76 (dd, J = 2.4, 10.4 Hz, 1H), 7.21 - 7.50 (m, 6H), 6.18 (d, J = 0.8 Hz, 1H), 3.32 (d, J = 8.0 Hz, 2H) , 3.21-3.23 (m, 1H), 2.79-2.86 (m, 1H), 1.94 (s, 1H), 1.64-1.76 (m, 8H), 1.19 (s, 3H), 1.17 (s, 3H).
Figure PCTCN2017095396-appb-000222
Figure PCTCN2017095396-appb-000222
m/z:[M+H]+568；24-2a,1H NMR(400MHz,CD3OD):δ7.98-8.01(m,1H),7.80(d,J＝2.8Hz,1H),7.52-7.57(m,2H),7.34-7.46(m,4H),6.30(s,1H),3.45(d,J＝7.6Hz,2H),2.94-2.97(m,1H),2.69(s,3H),2.02-2.09(m,1H),1.75-1.88(m,8H),1.31(d,J＝7.2Hz,7H)；24-2b,1H NMR(400MHz,CD3OD):δ7.98-8.02(m,1H),7.80(d,J＝2.8Hz,1H),7.52-7.58(m,2H),7.36-7.47(m,4H),6.30(s,1H),3.15-3.26(m,3H),2.94-2.97(m,1H),2.70(s,3H),1.97(dd,J＝12.0,10.4Hz,4H),1.57-1.69(m,3H),1.28-1.35(m,8H)。m/z: [M+H] + 568; 24-2a, 1 H NMR (400 MHz, CD 3 OD): δ 7.98-8.01 (m, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.34-7.46 (m, 4H), 6.30 (s, 1H), 3.45 (d, J = 7.6 Hz, 2H), 2.94 - 2.97 (m, 1H), 2.69 (s, 3H), 2.02-2.09 (m, 1H), 1.75-1.88 (m, 8H), 1.31 (d, J = 7.2 Hz, 7H); 24-2b, 1 H NMR (400 MHz, CD 3 OD): δ 7. 98-8.02 (m, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.52-7.58 (m, 2H), 7.36-7.47 (m, 4H), 6.30 (s, 1H), 3.15-3.26 ( m, 3H), 2.94-2.97 (m, 1H), 2.70 (s, 3H), 1.97 (dd, J = 12.0, 10.4 Hz, 4H), 1.57-1.69 (m, 3H), 1.28-1.35 (m, 8H).
实施例92：化合物24-3～24-4的合成Example 92: Synthesis of compounds 24-3 to 24-4
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.18、20.17和化合物4.9反应得到化合物24-3～24-4：By the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid was replaced with compound 20.18, 20.17 and compound 4.9 to give compound 24-3 to 24-4:
Figure PCTCN2017095396-appb-000223
Figure PCTCN2017095396-appb-000223
将化合物24-3(270mg，顺反异构体混合物)经prep-HPLC(分离条件7)得到化合物24-3a(11.3mg，出峰时间：23.0～23.5分钟，单一立体构型)和24-3b(5.5mg，出峰时间：22.0～23.0分钟，单一立体构型)，均为白色固体。Compound 24-3 (270 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 7) to give compound 24-3a (11.3 mg, peak time: 23.0 to 23.5 minutes, single stereo configuration) and 24- 3b (5.5 mg, peak time: 22.0 to 23.0 minutes, single stereo configuration), all white solid.
m/z:[M+H]+441；24-3a,1H NMR(400MHz,CDCl3):δ10.55(s,1H),8.38(d,J＝5.2Hz,1H),7.92(d,J＝8.0Hz,1H),7.52-7.56(m,1H),7.45-7.47(m,1H),7.36-7.40(m,1H),6.96(s,1H),6.91(d,J＝4.8Hz,1H),6.22(d,J＝2.4Hz,1H),6.01-6.02(m,1H),3.32(t,J＝6.4Hz,2H),2.89-2.94(m,1H),2.52(s,3H),2.38-2.44(m,1H),1.81-1.91(m,4H),1.68-1.70(m,1H),1.35-1.46(m,2H),1.29(d,J＝7.2Hz,6H),1.06-1.15(m,2H)；24-3b,1H NMR(400MHz,CDCl3):δ10.56(s,1H),8.40(d,J＝5.2Hz,1H),7.91(d,J＝7.6Hz,1H),7.52-7.56(m,1H),7.43-7.45(m,1H),7.35-7.39(m,1H),7.02(s,1H),6.98(d,J＝4.8Hz,1H),6.21(d,J＝2.4Hz,1H),5.95-5.97(m,1H),3.45-3.49(m,2H),2.83-2.88(m,1H),2.55-2.61(m,4H),1.87-1.90(m,1H),1.65-1.75(m,4H),1.53-1.59(m,4H),1.25(d,J＝6.8Hz,6H)。m/z: [M+H] + 441; 24-3a, 1 H NMR (400MHz, CDCl 3 ): δ 10.55 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.92 (d , J=8.0Hz, 1H), 7.52-7.56(m,1H), 7.45-7.47(m,1H), 7.36-7.40(m,1H),6.96(s,1H),6.91(d,J=4.8 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 6.01-6.02 (m, 1H), 3.32 (t, J = 6.4 Hz, 2H), 2.89-2.94 (m, 1H), 2.52 (s) , 3H), 2.38-2.44 (m, 1H), 1.81-1.91 (m, 4H), 1.68-1.70 (m, 1H), 1.35-1.46 (m, 2H), 1.29 (d, J = 7.2 Hz, 6H ), 1.06-1.15 (m, 2H); 24-3b, 1 H NMR (400MHz, CDCl 3 ): δ 10.56 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.52-7.56 (m, 1H), 7.43-7.45 (m, 1H), 7.35-7.39 (m, 1H), 7.02 (s, 1H), 6.98 (d, J = 4.8 Hz) , 1H), 6.21 (d, J = 2.4 Hz, 1H), 5.95 - 5.97 (m, 1H), 3.45-3.49 (m, 2H), 2.83 - 2.88 (m, 1H), 2.55 - 2.61 (m, 4H) ), 1.87-1.90 (m, 1H), 1.65-1.75 (m, 4H), 1.53-1.59 (m, 4H), 1.25 (d, J = 6.8 Hz, 6H).
Figure PCTCN2017095396-appb-000224
Figure PCTCN2017095396-appb-000224
将化合物24-4(330mg，顺反异构体混合物)经prep-HPLC(分离条件9)得到化合物24-4a(67.3mg，出峰时间：19.2～20.0分钟，单一立体构型)和24-4b(12.4mg，出峰时间：20.0～21.0分钟，单一立体构型)，均为白色固体。Compound 24-4 (330 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 9) to give compound 24-4a (67.3 mg, peak time: 19.2 to 20.0 minutes, single stereo configuration) and 24- 4b (12.4 mg, peak time: 20.0 to 21.0 minutes, single stereo configuration), all white solids.
m/z:[M+H]+500；24-4a,1H NMR(400MHz,CD3OD):δ8.26(d,J＝8.0Hz,1H),7.54-7.52 (m,1H),7.46-7.37(m,2H),7.35-7.33(m,1H),7.15(s,1H),7.09(d,J＝4.0Hz,1H),6.26(s,1H),3.13-3.10(m,2H),2.96-2.89(m,1H),2.51-2.45(m,4H),1.83-1.81(m,4H),1.57-1.55(m,1H),1.51-1.41(m,2H),1.28(d,J＝8.0Hz,6H),1.13–1.03(m,2H)；24-4b,1H NMR(400MHz,CD3OD):δ8.14(d,J＝4.0Hz,1H),7.43-7.41(m,1H),7.35-7.21(m,4H),7.10(s,1H),7.03(d,J＝8.0Hz,1H),6.16(s,1H),2.87-2.77(m,1H),2.52-2.47(m,1H),2.51-2.38(m,4H),1.82-1.80(m,1H),1.72-1.60(m,2H),1.54-1.51(m,6H),1.19-1.17(m,6H)。m/z: [M+H]+500; 24-4a, 1 H NMR (400 MHz, CD 3 OD): δ 8.26 (d, J = 8.0 Hz, 1H), 7.54 - 7.52 (m, 1H), 7.46-7.37 (m, 2H), 7.35-7.33 (m, 1H), 7.15 (s, 1H), 7.09 (d, J = 4.0 Hz, 1H), 6.26 (s, 1H), 3.13-3.10 (m, 2H), 2.96-2.89 (m, 1H), 2.51-2.45 (m, 4H), 1.83-1.81 (m, 4H), 1.57-1.55 (m, 1H), 1.51-1.41 (m, 2H), 1.28 ( d, J = 8.0 Hz, 6H), 1.13 - 1.03 (m, 2H); 24-4b, 1 H NMR (400 MHz, CD 3 OD): δ 8.14 (d, J = 4.0 Hz, 1H), 7.43 7.41 (m, 1H), 7.35-7.21 (m, 4H), 7.10 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.16 (s, 1H), 2.87-2.77 (m, 1H) , 2.52-2.47 (m, 1H), 2.51-2.38 (m, 4H), 1.82-1.80 (m, 1H), 1.72-1.60 (m, 2H), 1.54-1.51 (m, 6H), 1.19-1.17 ( m, 6H).
实施例93：化合物24-5的合成Example 93: Synthesis of Compound 24-5
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.17得到化合物24-5：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 20.17 to obtain compound 24-5 by the synthesis of compound 1-1:
Figure PCTCN2017095396-appb-000225
Figure PCTCN2017095396-appb-000225
将化合物24-5(272mg，顺反异构体混合物)经prep-HPLC(分离条件9)得到化合物24-5a(22.8mg，出峰时间：21.0～21.8分钟，单一立体构型)和24-5b(51.4mg，出峰时间：21.9～22.7分钟，单一立体构型)，均为白色固体。Compound 24-5 (272 mg, cis and trans isomer mixture) was subjected to prep-HPLC (separation condition 9) to give compound 24-5a (22.8 mg, peak time: 21.0 to 21.8 minutes, single stereo configuration) and 24- 5b (51.4 mg, peak time: 21.9 to 22.7 minutes, single stereo configuration), all white solids.
m/z:[M+H]+485；24-5a,1HNMR(400MHz,CD3OD):δ7.44-7.41(m,1H),7.32-7.27(m,2H),7.23-7.21(m,2H),7.14-7.11(m,3H),7.03-7.02(m,1H),6.16(s,1H)3.26-3.24(m,2H),2.84-2.81(m,1H),2.44(m,1H),1.80(m,1H),1.65-1.49(m,8H),1.19(s,3H),1.17(s,3H)；24-5b,1H NMR(400MHz,CD3OD):δ7.45-7.42(m,1H),7.36-7.29(m,2H),7.27-7.23(m,1H),7.16-7.12(m,2H),7.09-7.07(m,2H),7.04-7.00(m,1H),6.17(s,1H),3.09-3.06(m,2H),2.86-2.79(m,1H),2.36-2.30(m,1H),1.77-1.69(m,4H),1.45-1.43(m,1H),1.40-1.31(m,2H),1.19(s,3H),1.17(s,3H),0.98-0.94(m,2H)。m/z: [M+H] + 485; 24-5a, 1 H NMR (400 MHz, CD 3 OD): δ 7.44-7.41 (m, 1H), 7.32-7.27 (m, 2H), 7.23-7.21 ( m,2H),7.14-7.11(m,3H),7.03-7.02(m,1H),6.16(s,1H)3.26-3.24(m,2H),2.84-2.81(m,1H),2.44(m , 1H), 1.80 (m, 1H), 1.65-1.49 (m, 8H), 1.19 (s, 3H), 1.17 (s, 3H); 24-5b, 1 H NMR (400 MHz, CD 3 OD): δ 7 .45-7.42 (m, 1H), 7.36-7.29 (m, 2H), 7.27-7.23 (m, 1H), 7.16-7.12 (m, 2H), 7.09-7.07 (m, 2H), 7.04-7.00 ( m,1H), 6.17 (s, 1H), 3.09-3.06 (m, 2H), 2.86-2.79 (m, 1H), 2.36-2.30 (m, 1H), 1.77-1.69 (m, 4H), 1.45- 1.43 (m, 1H), 1.40-1.31 (m, 2H), 1.19 (s, 3H), 1.17 (s, 3H), 0.98-0.94 (m, 2H).
实施例94：化合物25-1～25-2的合成Example 94: Synthesis of Compounds 25-1 to 25-2
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物20.4、20.6和化合物7.3反应得到化合物25-1～25-2：In the synthesis of compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid was replaced with compound 20.4, 20.6 and compound 7.3 to give compound 25-1 to 25-2:
Figure PCTCN2017095396-appb-000226
Figure PCTCN2017095396-appb-000226
Figure PCTCN2017095396-appb-000227
Figure PCTCN2017095396-appb-000227
实施例95：化合物16-1～16-2的合成Example 95: Synthesis of Compounds 16-1 to 16-2
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸替换为化合物21.3和化合物1.6或 4.9反应得到化合物16-1～16-2：Substituting 4-phenyl-1H-pyrazole-3-carboxylic acid with compound 21.3 and compound 1.6 or by the synthesis of compound 1-1 The reaction of 4.9 gives compounds 16-1 to 16-2:
Figure PCTCN2017095396-appb-000228
Figure PCTCN2017095396-appb-000228
将化合物16-1(120mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1～1/1)得到极性较小的化合物16-1a(37mg，单一立体构型)和极性较大的化合物16-1b(8mg，单一立体构型)，均为白色固体。The compound 16-1 (120 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to give the compound 16-1a (37 mg, The stereo configuration) and the more polar compound 16-1b (8 mg, single stereo configuration) were both white solids.
m/z:[M+H]+404；16-1a,1H NMR(400MHz,CDCl3):δ7.41-7.54(m,2H),7.29-7.33(m,2H),7.18-7.23(m,3H),7.04-7.12(m,2H),5.80-5.82(m,1H),3.88(s,3H),3.16-3.19(m,2H),2.61(s,3H),2.35-2.44(m,1H),1.85-1.88(m,1H),1.32-1.66(m,6H),0.89-1.00(m,2H)；16-1b,1H NMR(400MHz,CDCl3):δ7.42-7.52(m,2H),7.28-7.33(m,2H),7.18-7.23(m,3H),7.04-7.11(m,2H),5.74-5.76(m,1H),3.88(s,3H),3.36-3.39(m,2H),2.61(s,3H),2.52-2.57(m,1H),1.42-1.71(m,9H)。m/z: [M+H] + 404; 16-1a, 1 H NMR (400MHz, CDCl 3 ): δ 7.41 - 7.54 (m, 2H), 7.29-7.33 (m, 2H), 7.18-7.23 ( m, 3H), 7.04-7.12 (m, 2H), 5.80-5.82 (m, 1H), 3.88 (s, 3H), 3.16-3.19 (m, 2H), 2.61 (s, 3H), 2.35-2.44 ( m, 1H), 1.85-1.88 (m, 1H), 1.32-1.66 (m, 6H), 0.89-1.00 (m, 2H); 16-1b, 1 H NMR (400 MHz, CDCl 3 ): δ 7.42 7.52 (m, 2H), 7.28-7.33 (m, 2H), 7.18-7.23 (m, 3H), 7.04-7.11 (m, 2H), 5.74-5.76 (m, 1H), 3.88 (s, 3H), 3.36-3.39 (m, 2H), 2.61 (s, 3H), 2.52-2.57 (m, 1H), 1.42-1.71 (m, 9H).
Figure PCTCN2017095396-appb-000229
Figure PCTCN2017095396-appb-000229
将化合物16-2(150mg，顺反异构体混合物)经硅胶柱色谱分离(石油醚/乙酸乙酯＝3/1～1/1)得到极性较小的化合物16-2a(40mg，单一立体构型)和极性较大的化合物16-2b(40mg，单一立体构型)，均为白色固体。The compound 16-2 (150 mg, cis-trans isomer mixture) was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 3/1 to 1/1) to give the compound 16-2a (40 mg, single The stereo configuration) and the more polar compound 16-2b (40 mg, single stereo configuration) were both white solids.
m/z:[M+H]+419；16-2a,1H NMR(400MHz,CDCl3):δ8.68-8.69(m,1H),7.28-7.52(m,5H),7.04-7.10(m,2H),5.81-5.83(m,1H),3.86(s,3H),3.35-3.38(m,2H),2.82(s,3H),2.71-2.76(m,1H),2.58(s,3H),1.54-1.72(m,9H)；16-2b,1H NMR(400MHz,CDCl3):δ8.70-8.72(m,1H),7.31-7.53(m,5H),7.06-7.12(m,2H),5.85-5.88(m,1H),3.88(s,3H),3.15-3.20(m,2H),2.82(s,3H),2.59(s,3H),1.90-1.93(m,2H),1.70-1.73(m,2H),1.16-1.43(m,4H),0.98-1.04(m,2H)。m/z: [M+H] + 419; 16-2a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.68-8.69 (m, 1H), 7.28-7.52 (m, 5H), 7.04-7. m, 2H), 5.81-5.83 (m, 1H), 3.86 (s, 3H), 3.35-3.38 (m, 2H), 2.82 (s, 3H), 2.71-2.76 (m, 1H), 2.58 (s, 3H), 1.54-1.72 (m, 9H); 16-2b, 1 H NMR (400MHz, CDCl 3 ): δ 8.70-8.72 (m, 1H), 7.31-7.53 (m, 5H), 7.06-7.12 ( m, 2H), 5.85-5.88 (m, 1H), 3.88 (s, 3H), 3.15-3.20 (m, 2H), 2.82 (s, 3H), 2.59 (s, 3H), 1.90 to 1.93 (m, 2H), 1.70-1.73 (m, 2H), 1.16-1.43 (m, 4H), 0.98-1.04 (m, 2H).
实施例96：化合物17-1的合成Example 96: Synthesis of Compound 17-1
Figure PCTCN2017095396-appb-000230
Figure PCTCN2017095396-appb-000230
冰浴冷却下，向化合物22.2(180mg，0.83mmol)和化合物1.6(157mg，0.83mmol)的甲苯(10mL)溶液中，滴加三甲基铝的甲苯溶液(0.52mL，1.25mmol，1.6M)，反应体系80℃加热搅拌3小时。反应液用水淬灭，乙酸乙酯(3×20mL)萃取，分离出有机相。有机相用饱和食盐水洗涤一次，过滤，滤液减压浓缩得到化合物17-1。将17-1用Flash柱层析纯化(二氯甲烷/甲醇＝95/5)得到极性较大的化合物17-1a(2.1mg，产率：1％)和极性较小的化合物17-1b(1.3mg，产率：1％)，均为白色固体。To a solution of the compound 22.2 (180 mg, 0.83 mmol) and compound 1.6 (157 mg, 0.83 mmol) in toluene (10 mL), EtOAc (3 mL) The reaction system was heated and stirred at 80 ° C for 3 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The organic phase was washed once with saturated brine, filtered, and the filtrate was evaporated. Purification of 17-1 by flash column chromatography (dichloromethane/methanol = 95/5) afforded the compound of compound 17-1a (2.1 mg, yield: 1%) and the less polar compound 17- 1b (1.3 mg, yield: 1%), both as white solid.
m/z:[M+H]+361；17-1a,1H NMR(400MHz,CDCl3):δ8.59-8.60(m,1H),7.85-7.90(m,2H),7.52-7.61(m,3H),7.29-7.34(m,2H),7.20-7.26(m,3H),5.81-5.88(m,1H),3.27- 3.31(m,2H),2.44-2.51(m,1H),1.92-1.96(m,2H),1.80-1.86(m,2H),1.71-1.76(m,1H),1.41-1.52(m,2H),1.06-1.16(m,2H)；17-1b,1H NMR(400MHz,CDCl3):δ8.59(s,1H),7.85-7.88(m,2H),7.52-7.58(m,3H),7.30-7.34(m,2H),7.20-7.26(m,3H),5.36-5.38(m,1H),3.49(d,J＝7.6Hz,2H),2.60-2.64(m,1H),1.86-1.90(m,1H),1.70-1.76(m,4H),1.61-1.68(m,4H)。m/z: [M+H] + 361; 17-1a, 1 H NMR (400MHz, CDCl 3 ): δ 8.59-8.60 (m, 1H), 7.85-7.90 (m, 2H), 7.52-7.61 ( m, 3H), 7.29-7.34 (m, 2H), 7.20-7.26 (m, 3H), 5.81-5.88 (m, 1H), 3.27- 3.31 (m, 2H), 2.44-2.51 (m, 1H), 1.92-1.96 (m, 2H), 1.80 - 1.86 (m, 2H), 1.71-1.76 (m, 1H), 1.41-1.52 (m, 2H), 1.06-1.16 (m, 2H); 17-1b, 1 H NMR (400MHz, CDCl 3 ): δ 8.59 (s, 1H), 7.85-7.88 (m, 2H), 7.52-7.58 (m, 3H), 7.30-7.34 (m, 2H), 7.20-7.26 (m) , 3H), 5.36-5.38 (m, 1H), 3.49 (d, J = 7.6 Hz, 2H), 2.60-2.64 (m, 1H), 1.86-1.90 (m, 1H), 1.70-1.76 (m, 4H) ), 1.61-1.68 (m, 4H).
实施例97：化合物18-1～18-2的合成Example 97: Synthesis of Compounds 18-1 to 18-2
用化合物1-1的合成方法，将4-苯基-1H-吡唑-3-羧酸和化合物17.4或18.2得到化合物18-1～18-2：Using the synthesis of Compound 1-1, 4-phenyl-1H-pyrazole-3-carboxylic acid and Compound 17.4 or 18.2 are obtained as Compounds 18-1 to 18-2:
Figure PCTCN2017095396-appb-000231
Figure PCTCN2017095396-appb-000231
m/z:[M+H]+359；1HNMR(400MHz,DMSO-d6):δ11.6(s,1H),7.81-7.84(m,1H),7.64(d,J＝8.0Hz,2H),7.17-7.42(m,8H),6.93-6.94(m,1H),3.34(t,J＝7.6Hz,1H),3.11(t,J＝6.8Hz,1H),1.41-2.01(m,10H)。m / z: [M + H ] + 359; 1 HNMR (400MHz, DMSO-d 6): δ11.6 (s, 1H), 7.81-7.84 (m, 1H), 7.64 (d, J = 8.0Hz, 2H), 7.17-7.42 (m, 8H), 6.93-6.94 (m, 1H), 3.34 (t, J = 7.6 Hz, 1H), 3.11 (t, J = 6.8 Hz, 1H), 1.41-2.01 (m , 10H).
Figure PCTCN2017095396-appb-000232
Figure PCTCN2017095396-appb-000232
m/z:[M+H]+359；1H NMR(400MHz,DMSO-d6):δ11.60(s,1H),8.05-8.08(m,1H),7.55(s,1H),7.53(s,1H),7.13-7.35(m,10H),3.36-3.39(m,1H),3.15(t,J＝6.4Hz,1H),2.50-2.51(m,1H),1.59-1.89(m,7H),1.43-1.46(m,1H),1.06-1.16(m,1H)。m/z: [M+H] + 359; 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.60 (s, 1H), 8.05-8.08 (m, 1H), 7.55 (s, 1H), 7. (s, 1H), 7.13-7.35 (m, 10H), 3.36-3.39 (m, 1H), 3.15 (t, J = 6.4 Hz, 1H), 2.50-2.51 (m, 1H), 1.59-1.89 (m , 7H), 1.43-1.46 (m, 1H), 1.06-1.16 (m, 1H).
实施例98：化合物19-3的合成Example 98: Synthesis of Compound 19-3
Figure PCTCN2017095396-appb-000233
Figure PCTCN2017095396-appb-000233
步骤1：化合物19-1的合成Step 1: Synthesis of Compound 19-1
向化合物14.1(600mg，2.43mmol)和化合物1.6(459mg，2.43mmol)的甲苯(15mL)溶液中加入三甲基铝的甲苯溶液(2.91mL，1.0M，2.91mmol)。将反应体系在室温下搅拌48小时。然后将反应体系冷却至0℃，加入水(100mL)淬灭反应，混合物用乙酸乙酯萃取(100mL×2)，有机相合并，无水硫酸钠干燥、过滤、浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝2/1)得到产物19-1(250mg，产率：25％)为白色固体。To a solution of the compound 14.1 (600 mg, 2.43 mmol) and compound 1.6 (459 mg, 2.43 mmol) in toluene (15 mL) was added to a toluene solution (2.91 mL, 1.0 M, 2.91 mmol). The reaction system was stirred at room temperature for 48 hours. The reaction system was then cooled to 0 ° C, and then the mixture was evaporated. EtOAc (EtOAc) Purification (petroleum ether / ethyl acetate = 2 / 1) gave product 19-1 (250 mg, yield: 25%) as white solid.
步骤2：化合物19-2的合成Step 2: Synthesis of Compound 19-2
化合物19-1(250mg,0.62mmol)，Pd/C(25mg，10％)和甲醇(15mL)的混合物在氢气氛(氢气球)下室温搅拌18小时。然后将反应液过滤除去Pd/C，滤液浓缩，残留物用用硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得到化合物19-2(175mg，产率：76％)为黄色固体。 A mixture of Compound 19-1 (250 mg, 0.62 mmol), Pd / C (25 mg, 10%) and methanol (15 mL) was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon) for 18 hours. Then, the reaction mixture was filtered to remove Pd / C, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate = 1 / 1) to afford compound 19-2 (175 mg, yield: 76%) solid.
m/z:[M+H]+375m/z: [M+H] + 375
步骤3：化合物19-3的合成Step 3: Synthesis of Compound 19-3
将化合物19-2(175mg，0.47mmol)和亚硝酸异丁酯(219mg，1.87mmol)的N,N-二甲基甲酰胺(15mL)溶液在80℃下搅拌16小时。然后将反应体系冷却至室温，用水(100mL)淬灭反应，用乙酸乙酯萃取(50mL×2)，有机相合并，并用无水硫酸钠干燥、过滤、浓缩，得到化合物19-3粗品，经过硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到极性较小的化合物19-3a(5.7mg，产率：3％)和极性较大的化合物19-3b(8.3mg，产率：5％)，均为白色固体。A solution of compound 19-2 (175 mg, 0.47 mmol) and EtOAc (EtOAc, EtOAc, EtOAc) After the reaction was cooled to room temperature, the mixture was crystallised eluted with EtOAc (EtOAc) Purification by silica gel column chromatography (petrole ether / ethyl acetate = 3 / 1) afforded the compound 19-3a (5.7 mg, yield: 3%) and the more polar compound 19-3b (8.3 mg) , Yield: 5%), both as a white solid.
m/z:[M+H]+360；19-3a,1H NMR(400MHz,CDCl3):7.15-7.56(m,12H),3.20-3.31(m,2H),2.45-2.52(m,1H),1.93-1.96(m,4H),1.15-1.69(m,6H)；19-3b,1H NMR(400MHz,CDCl3):7.16-7.60(m,12H),3.24-3.47(m,2H),2.41-2.60(m,1H),1.57-2.03(m,3H),1.67-1.75(m,3H),1.12-1.52(m,4H)。m/z: [M+H] + 360; 19-3a, 1 H NMR (400MHz, CDCl 3 ): 7.15-7.56 (m, 12H), 3.20-3.31 (m, 2H), 2.45-2.52 (m, 1H), 1.93-1.96 (m, 4H), 1.15-1.69 (m, 6H); 19-3b, 1 H NMR (400MHz, CDCl 3 ): 7.16-7.60 (m, 12H), 3.24 - 3.47 (m, 2H), 2.41-2.60 (m, 1H), 1.57-2.03 (m, 3H), 1.67-1.75 (m, 3H), 1.12-1.52 (m, 4H).
实施例99：化合物20-1的合成Example 99: Synthesis of Compound 20-1
Figure PCTCN2017095396-appb-000234
Figure PCTCN2017095396-appb-000234
步骤1：化合物30.1的合成Step 1: Synthesis of Compound 30.1
将β-苯乙烯磺酰氯(203mg，1.0mmol)和化合物1.6(226mg，1.0mmol)加入到二氯甲烷(20mL)中，然后分别加入吡啶(790mg，10.0mmol)和4-二甲氨基吡啶(12mg，0.1mmol)。反应体系室温搅拌过夜，减压浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物30.1(280mg，产率：79％)为淡黄色固体。Add β-styrenesulfonyl chloride (203 mg, 1.0 mmol) and compound 1.6 (226 mg, 1.0 mmol) to dichloromethane (20 mL), then add pyridine (790 mg, 10.0 mmol) and 4-dimethylaminopyridine, respectively. 12 mg, 0.1 mmol). The reaction mixture was stirred at room temperature EtOAc (EtOAc m.)
m/z:[M+H]+356m/z: [M+H] + 356
步骤2：化合物20-1的合成Step 2: Synthesis of Compound 20-1
将对甲基苯磺酰甲基异腈(231mg，1.18mmol)溶解在二甲亚砜(5mL)和四氢呋喃(10mL)中，加入钠氢(48mg，1.18mmol)，室温搅拌30分钟。将化合物30.1(280mg，0.79mmol)溶解在四氢呋喃(5mL)中，缓慢滴加到上述反应液中，反应体系在80℃下搅拌过夜。然后将反应混合物冷却至室温，用冰水淬灭反应，乙酸乙酯(2×30mL)萃取，合并有机相后减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝50/1)纯化得到化合物20-1(55mg，产率：18％)为淡黄色固体。p-Methylbenzenesulfonylmethyl isocyanide (231 mg, 1.18 mmol) was dissolved in dimethyl sulfoxide (5 mL) and tetrahydrofuran (10 mL), and sodium hydrogen (48 mg, 1.18 mmol) was added and stirred at room temperature for 30 min. Compound 30.1 (280 mg, 0.79 mmol) was dissolved in tetrahydrofuran (5 mL), and slowly added dropwise to the above reaction mixture, and the reaction mixture was stirred at 80 ° C overnight. After the reaction mixture was cooled to room temperature, the mixture was evaporated, evaporated,jjjjjjjjjjjjjjjj Purification gave Compound 20-1 (55 mg, yield: 18%) as pale yellow solid.
m/z:[M+H]+395；1H NMR(400MHz,DMSO-d6):δ11.63(s,1H),7.64-7.67(m,2H),7.01-7.38(m,11H),2.79(t,J＝7.2Hz,1H),2.59(t,J＝6.4Hz,1H),2.33-2.47(m,1H),1.64-1.72(m,2H),1.16-1.53(m,6H),0.78-0.88(m,1H)。m/z: [M+H] + 395; 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.63 (s, 1H), 7.64 - 7.67 (m, 2H), 7.01 - 7.38 (m, 11H) , 2.79 (t, J = 7.2 Hz, 1H), 2.59 (t, J = 6.4 Hz, 1H), 2.33 - 2.47 (m, 1H), 1.64-1.72 (m, 2H), 1.16-1.53 (m, 6H) ), 0.78-0.88 (m, 1H).
实施例100：化合物26-1的合成Example 100: Synthesis of Compound 26-1
Figure PCTCN2017095396-appb-000235
Figure PCTCN2017095396-appb-000235
步骤1：化合物30.1的合成Step 1: Synthesis of Compound 30.1
将3-溴-2-呋喃甲酸(206mg，1.08mmol)和化合物4.9(200mg，0.98mmol)溶解在二 氯甲烷(10mL)中，然后加入EDCI(282mg，1.47mmol)，4-二甲氨基吡啶(12mg，0.098mmol)和DIPEA(380mg，2.94mmol)，该反应体系在室温下搅拌过夜。该反应液用冰水(20mL)淬灭，有机相分离出来，水相用二氯甲烷(20mL×2)萃取。合并有机相后用饱和食盐水(20mL×2)洗涤。无水硫酸钠干燥，过滤后，滤液减压浓缩，残渣用Flash柱层析(石油醚/乙酸乙酯＝3/2)纯化得到化合物30.1(120mg，产率：29％)为黄色的油状物。3-Bromo-2-furancarboxylic acid (206 mg, 1.08 mmol) and compound 4.9 (200 mg, 0.98 mmol) were dissolved in two In chloroform (10 mL), EDCI (282 mg, 1.47 mmol), 4-dimethylaminopyridine (12 mg, 0.098 mmol) and DIPEA (380 mg, 2. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The organic phases were combined and washed with brine (20 mL×2). After drying over anhydrous sodium sulfate, the filtrate was evaporated to dryness crystals crystals crystals crystals crystals .
m/z:[M+H]+377m/z: [M+H] + 377
步骤2：化合物26-1的合成Step 2: Synthesis of Compound 26-1
氮气保护下，将化合物30.1(90mg，0.24mmol)，2-(三氟甲氧基)苯硼酸(60mg，0.29mmol)，Pd(dppf)2Cl2 .CH2Cl2(9.9mg，0.012mmol)和碳酸钠(75mg，0.72mmol)悬浮在1.4-二氧六环(6mL)和H2O(1mL)中，得到的混合物80℃搅拌3小时。反应混合物冷却至室温，过滤，固体用乙酸乙酯洗涤，滤液减压浓缩的化合物26-1(立体异构体混合物)，将化合物26-1用prep-HPLC(分离条件13)得到化合物26-1a(20.8mg，出峰时间：20.3～21.0分钟，单一立体构型)和26-1b(20.6mg，出峰时间：21.1～21.8分钟，单一立体构型)，均为白色固体。Compound 30.1 (90 mg, 0.24 mmol), 2-(trifluoromethoxy)benzeneboronic acid (60 mg, 0.29 mmol), Pd (dppf) 2 Cl 2 . CH 2 Cl 2 (9.9 mg, 0.012 mmol) And sodium carbonate (75 mg, 0.72 mmol) was suspended in 1.4-dioxane (6 mL) and H 2 O (1 mL), and the mixture was stirred at 80 ° C for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure of compound 26-1 (stereoisomer mixture), and compound 26-1 was obtained by prep-HPLC (isolation condition 13) to give compound 26- 1a (20.8 mg, peak time: 20.3 to 21.0 minutes, single stereo configuration) and 26-1b (20.6 mg, peak time: 21.1 to 21.8 minutes, single stereo configuration) were white solids.
m/z:[M+H]+459；26-1a,1HNMR(400MHz,CDCl3):δ8.35(d,J＝4.8Hz,1H),7.62-7.55(m,1H),7.48(d,J＝2.0Hz,1H),7.43-7.31(m,3H),6.96(s,1H),6.90(d,J＝5.2Hz,1H),6.59(d,J＝1.6Hz,1H),6.41(t,J＝5.6Hz,1H),3.27(t,J＝6.4Hz,2H),2.52(s,3H),2.46-2.37(m,1H),1.93-1.86(m,4H),1.68-1.54(m,1H),1.50-1.37(m,2H),1.18-1.04(m,2H)；26-1b,1H NMR(400MHz,CDCl3):δ8.35(d,J＝5.2Hz,1H),7.60-7.56(m,1H),7.47(d,J＝2.0Hz,1H),7.43-7.30(m,3H),7.00(s,1H),6.93(d,J＝5.2Hz,1H),6.59(d,J＝1.6Hz,1H),6.34-6.27(m,1H),3.49-3.41(m,2H),2.58-2.52(m,1H),2.52(s,3H),1.96-1.90(m,1H),1.77-1.61(m,8H)。m/z: [M+H] + 459; 26-1a, 1 H NMR (400 MHz, CDCl 3 ): δ 8.35 (d, J = 4.8 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.48 ( d, J = 2.0 Hz, 1H), 7.43 - 7.31 (m, 3H), 6.96 (s, 1H), 6.90 (d, J = 5.2 Hz, 1H), 6.59 (d, J = 1.6 Hz, 1H), 6.41 (t, J = 5.6 Hz, 1H), 3.27 (t, J = 6.4 Hz, 2H), 2.52 (s, 3H), 2.46-2.37 (m, 1H), 1.93-1.86 (m, 4H), 1.68 -1.54 (m, 1H), 1.50-1.37 (m, 2H), 1.18-1.04 (m, 2H); 26-1b, 1 H NMR (400 MHz, CDCl 3 ): δ 8.35 (d, J = 5.2 Hz) , 1H), 7.60-7.56 (m, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.43-7.30 (m, 3H), 7.00 (s, 1H), 6.93 (d, J = 5.2 Hz, 1H), 6.59 (d, J = 1.6 Hz, 1H), 6.34-6.27 (m, 1H), 3.49-3.41 (m, 2H), 2.58-2.52 (m, 1H), 2.52 (s, 3H), 1.96 -1.90 (m, 1H), 1.77-1.61 (m, 8H).
实施例101：化合物27-1的合成Example 101: Synthesis of Compound 27-1
用化合物1-1的合成方法，用化合物24.2和化合物4.9反应得到化合物27-1：Compound 27-1 is obtained by the synthesis of compound 1-1 using compound 24.2 and compound 4.9:
Figure PCTCN2017095396-appb-000236
Figure PCTCN2017095396-appb-000236
将化合物27-1(259mg，顺反异构体混合物)经prep-HPLC(分离条件8)得到化合物27-1a(20mg，出峰时间：19.3～20.0分钟，单一立体构型)和27-1b(27mg，出峰时间：20.1～20.9分钟，单一立体构型)，均为白色固体。Compound 27-1 (259 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 8) to give compound 27-1a (20 mg, peak time: 19.3 to 20.0 min, single stereo configuration) and 27-1b (27 mg, peak time: 20.1 to 20.9 minutes, single stereo configuration), all white solids.
m/z:[M+H]+475；27-1a,1H NMR(400MHz,CD3OD)δ8.28(d,J＝5.6Hz,1H),7.91(d,J＝3.2Hz,1H),7.52(dd,J＝2.0Hz,1H),7.41-7.47(m,3H),7.33-7.35(m,1H),7.18(s,1H),7.11(d,J＝5.2Hz,1H),3.14(d,J＝6.8Hz,2H),2.48-2.55(m,4H),1.87-1.91(m,4H),1.56-1.64(m,1H),1.43-1.55(m,2H),1.07-1.17(m,2H)；27-1b,1H NMR(400MHz,CD3OD)δ8.28(d,J＝5.2Hz,1H),7.91(d,J＝2.8Hz,1H),7.51(dd,J＝2.0,7.2Hz,1H),7.43-7.47(m,2H),7.38-7.42(m,1H),7.31-7.33(m,1H),7.22(s,1H),7.14(d,J＝4.8Hz,1H),3.36(d,J＝7.6Hz,2H),2.60-2.66(m,1H),2.50(s,3H),1.94-1.98(m,1H),1.62-1.82(m,8H)。m/z: [M+H] + 475; 27-1a, 1 H NMR (400 MHz, CD 3 OD) δ 8.28 (d, J = 5.6 Hz, 1H), 7.91 (d, J = 3.2 Hz, 1H) ), 7.52 (dd, J = 2.0 Hz, 1H), 7.41 - 7.47 (m, 3H), 7.33 - 7.35 (m, 1H), 7.18 (s, 1H), 7.11 (d, J = 5.2 Hz, 1H) , 3.14 (d, J = 6.8 Hz, 2H), 2.48-2.55 (m, 4H), 1.87-1.91 (m, 4H), 1.56-1.64 (m, 1H), 1.43-1.55 (m, 2H), 1.07 - 1.17 (m, 2H); 27-1b, 1 H NMR (400 MHz, CD 3 OD) δ 8.28 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 2.8 Hz, 1H), 7.51 ( Dd, J=2.0, 7.2 Hz, 1H), 7.43-7.47 (m, 2H), 7.38-7.42 (m, 1H), 7.31-7.33 (m, 1H), 7.22 (s, 1H), 7.14 (d, J=4.8 Hz, 1H), 3.36 (d, J=7.6 Hz, 2H), 2.60-2.66 (m, 1H), 2.50 (s, 3H), 1.94-1.98 (m, 1H), 1.62-1.82 (m) , 8H).
实施例102：化合物28-1的合成Example 102: Synthesis of Compound 28-1
用化合物1-1的合成方法，用化合物24.3和化合物4.9反应得到化合物28-1： Compound 28-1 is obtained by the synthesis of compound 1-1 using compound 24.3 and compound 4.9:
Figure PCTCN2017095396-appb-000237
Figure PCTCN2017095396-appb-000237
将化合物28-1(411mg，顺反异构体混合物)经prep-HPLC(分离条件10)得到化合物28-1a(65mg，出峰时间：18.0～19.0分钟，单一立体构型)和28-1b(32mg，出峰时间：19.5～21.0分钟，单一立体构型)，均为白色固体。Compound 28-1 (411 mg, cis and trans isomer mixture) was subjected to prep-HPLC (separation condition 10) to give compound 28-1a (65 mg, peak time: 18.0 to 19.0 min, single stereo configuration) and 28-1b (32 mg, peak time: 19.5 to 21.0 minutes, single stereo configuration), all white solids.
m/z:[M+H]+475；28-1a,1H NMR(400MHz,CD3OD):δ8.55(d,J＝8.0Hz,1H),7.81(s,1H),7.76(d,J＝4.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.55-7.41(m,4H),7.11(d,J＝8.0Hz,1H),3.16-3.13(m,2H),2.81-2.76(m,4H),1.95(d,J＝12.0Hz,2H),1.80(d,J＝8.0Hz,2H),1.58-1.48(m,3H),1.14-1.04(m,2H)；28-1b,1H NMR(400MHz,CD3OD):δ8.50(d,J＝8.0Hz,1H),7.75(s,1H),7.69(d,J＝8.0Hz,1H),7.66(d,J＝4.0Hz,1H),7.54-7.38(m,4H),7.10(d,J＝4.0Hz,1H),3.40-3.36(m,2H),2.88-2.83(m,1H),2.72(s,3H),1.89-1.62(m,9H)。m/z: [M+H] + 475; 28-1a, 1 H NMR (400 MHz, CD 3 OD): δ 8.55 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.76 ( d, J=4.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.55-7.41 (m, 4H), 7.11 (d, J=8.0 Hz, 1H), 3.16-3.13 (m, 2H) ), 2.81-2.76 (m, 4H), 1.95 (d, J = 12.0 Hz, 2H), 1.80 (d, J = 8.0 Hz, 2H), 1.58-1.48 (m, 3H), 1.14-1.04 (m, 2H); 28-1b, 1 H NMR (400MHz, CD 3 OD): δ 8.50 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H) , 7.66 (d, J = 4.0 Hz, 1H), 7.54 - 7.38 (m, 4H), 7.10 (d, J = 4.0 Hz, 1H), 3.40-3.36 (m, 2H), 2.88-2.83 (m, 1H) ), 2.72 (s, 3H), 1.89-1.62 (m, 9H).
生物测试实施例：IDO生物活性的测定Biological test examples: Determination of IDO biological activity
实施例1：基于HeLa细胞的IDO抑制活性测试(IC50)Example 1: HeLa cell-based IDO inhibitory activity test (IC 50 )
HeLa细胞株来源：ATCC，用MEM/EBSS液体培养基培养，另外加入牛胎儿血清(10％FBS)、青霉素-链霉素(100,000U/L)，非必须氨基酸(0.1mM)，丙酮酸钠(Na-pyruvate)(1.0mM)。细胞在培养器中保持37℃、95％的湿度和5％的二氧化碳。与γ-干扰素(IFNγ)共孵育使其表达IDO，使其在培养基中可以将色氨酸代谢为N-甲酰犬尿氨酸。具体实验方法如下：HeLa cell line source: ATCC, cultured in MEM/EBSS liquid medium, plus bovine fetal serum (10% FBS), penicillin-streptomycin (100,000 U/L), non-essential amino acids (0.1 mM), sodium pyruvate (Na-pyruvate) (1.0 mM). The cells were maintained at 37 ° C, 95% humidity and 5% carbon dioxide in the incubator. Co-incubation with gamma-interferon (IFNy) allows expression of IDO, which allows the metabolism of tryptophan to N-formyl kynurenine in the medium. The specific experimental methods are as follows:
将HeLa细胞以25,000个细胞/孔的量种植在96孔板内，每孔含有100μl的培养基，接下来用IFNγ和特定浓度的测试化合物(浓度范围10μM到1nM，是其在常规培养基中的最后体积为200μL)诱导细胞过夜，使其表达人重组IDO。接下来进行孵育，将上层清液(140μL)转移到96孔板内，加入6.1N TCA(10μL)后继续在50℃下孵育30分钟，使IDO产生的N-甲酰犬尿氨酸充分水解为犬尿氨酸。之后将反应液在2500rpm转速下离心10分钟，除去固体沉淀物，之后将上清液以100μL/孔转移到另一个96孔板内，并加入100μL的2％(w/v)4-(N,N-二甲基氨基)苯甲醛的醋酸溶液。在室温下孵育10分钟，犬尿氨酸产生黄色的溶液可以用用酶标仪(TECAN Infinite M1000Pro)记录其在480nm处有的吸光度。HeLa cells were seeded in 96-well plates at 25,000 cells/well, each well containing 100 μl of medium, followed by IFNγ and specific concentrations of test compound (concentration range 10 μM to 1 nM, which is in conventional medium) The final volume of 200 μL) induced cells overnight to express human recombinant IDO. Next, incubate, transfer the supernatant (140 μL) to a 96-well plate, add 6.1N TCA (10 μL) and continue incubation at 50 ° C for 30 minutes to fully hydrolyze the N-formyl kynurenine produced by IDO. For kynurenine. The reaction solution was then centrifuged at 2500 rpm for 10 minutes to remove the solid precipitate, after which the supernatant was transferred to another 96-well plate at 100 μL/well, and 100 μL of 2% (w/v) 4-(N was added. , N-dimethylamino) benzaldehyde in acetic acid solution. After incubating for 10 minutes at room temperature, the yellow solution of kynurenine can be recorded for absorbance at 480 nm using a microplate reader (TECAN Infinite M1000Pro).
待测化合物各个浓度的抑制百分数以0.1％的DMSO空白溶液作参考对比评估待测化合物体系中犬尿氨酸的减少量来确定，数据用Graph Pad
Figure PCTCN2017095396-appb-000238
4通过非线性回归得到IC50值。The percentage inhibition of each concentration of the test compound was determined by using 0.1% DMSO blank solution as a reference to evaluate the reduction of kynurenine in the test compound system. The data was determined by Graph Pad.
Figure PCTCN2017095396-appb-000238
4 IC 50 values were obtained by nonlinear regression.
本发明所述多环化合物活性测试结果，IC50值报告的范围为：+表示﹥1μM，++表示1-0.25μM，+++表示0.25-0.05μM，++++表示<0.05μM。As a result of the polycyclic compound activity test of the present invention, the range of the IC 50 value report is: + means >1 μM, ++ means 1-0.25 μM, +++ means 0.25-0.05 μM, and ++++ means <0.05 μM.
化合物编号Compound number Hela细胞IC50Hela cell IC50 化合物编号Compound number Hela细胞IC50Hela cell IC50
1-11-1 ++++++ 2-12-1 ++
3-1a3-1a ++++++++ 3-1b3-1b ++++
3-2a3-2a ++++++++ 3-2b3-2b ++++
4-1a4-1a ++++++ 4-1b4-1b ++++++++
4-2a4-2a ++ 4-2b4-2b ++++++
5-1a5-1a ++++++++ 5-1b5-1b ++++++
6-1a6-1a ++++++++ 6-1b6-1b ++++++++
6-2a6-2a ++++++++ 6-2b6-2b ++++++
6-3a6-3a ++++++++ 6-3b6-3b ++++
6-4a6-4a ++++++++ 6-4b6-4b ++++
6-5a6-5a ++++++++ 6-5b6-5b ++++++
6-6a6-6a ++++++++ 6-6b6-6b ++++
6-7a6-7a ++++++++ 6-7b6-7b ++++
6-8a6-8a ++++++++ 6-8b6-8b ++++++++
6-9a6-9a ++++ 6-9b6-9b ++++++++
6-106-10 ++++++++ 6-116-11 ++++++++
6-11a6-11a ++++++++ 6-11b6-11b ++
6-126-12 ++++ 6-136-13 ++
6-146-14 ++++ 6-15a6-15a ++++++++
6-15b6-15b ++++++ 6-16a6-16a ++++++++
6-16b6-16b ++++++ 6-17a6-17a ++
6-17b6-17b ++++++++ 6-19a6-19a ++++++
6-19b6-19b ++++++++ 6-20a6-20a ++++
6-20b6-20b ++++++++ 6-21a6-21a ++++++++
6-22a6-22a ++++++ 6-22b6-22b ++++++++
6-23b6-23b ++++++++ 6-24b6-24b ++++++++
6-25b6-25b ++++++++ 6-26b6-26b ++++++++
6-28b6-28b ++++++++ 6-29b6-29b ++++++++
6-30b6-30b ++++++++ 6-31a6-31a ++++++++
6-32a6-32a ++++++++ 6-33a6-33a ++++++++
6-34a6-34a ++++++++ 6-35a6-35a ++++++++
6-36a6-36a ++++++++ 6-38b6-38b ++++++++
6-38a6-38a ++++++ 6-40a6-40a ++++++++
6-39b6-39b ++++++++ 6-41b6-41b ++++
6-41a6-41a ++++++++ 6-42b6-42b ++++++
6-42a6-42a ++ 6-43b6-43b ++++++++
6-43a6-43a ++++++ 6-47b6-47b ++++++
6-44b6-44b ++++++ 6-49a6-49a ++++++++
6-48b6-48b ++++++++ 7-1a7-1a ++++++
7-1b7-1b ++ 7-2a7-2a ++++++
7-2b7-2b ++++++++ 7-3a7-3a ++
7-3b7-3b ++++++++ 7-4a7-4a ++
7-4b7-4b ++++ 7-5a7-5a ++
7-5b7-5b ++++++++ 7-6a7-6a ++
7-6b7-6b ++++++++ 7-7a7-7a ++
7-7b7-7b ++++ 7-87-8 ++
7-97-9 ++ 8-1a8-1a ++
8-1b8-1b ++++++++ 8-2a8-2a ++
8-2b8-2b ++++++++ 8-3a8-3a ++++++++
8-3b8-3b ++++++ 8-4b8-4b ++++++++
8-5a8-5a ++++++++ 8-6b8-6b ++++++++
8-7a8-7a ++++++++ 8-10a8-10a ++++++++
8-11a8-11a ++++++++ 8-12a8-12a ++++++++
8-13a8-13a ++++++++ 8-19a8-19a ++++++++
8-20a8-20a ++++++++ 8-21a8-21a ++++++++
8-22a8-22a ++++++++ 9-1a9-1a ++
9-1b9-1b ++++++++ 9-2a9-2a ++
9-2b9-2b ++++++++ 9-3a9-3a ++
9-3b9-3b ++++++++ 9-49-4 ++
9-5a9-5a ++++++++ 9-5b9-5b ++++++++
9-6b9-6b ++++++++ 9-7b9-7b ++++++++
10-110-1 ++ 11-1a11-1a ++++++
11-1b11-1b ++ 12-1a12-1a ++++++++
12-1b12-1b ++++++++ 13-1a13-1a ++++++
13-1b13-1b ++++++++ 13-2a13-2a ++++++++
13-2b13-2b ++++++++ 13-3a13-3a ++++++++
13-3b13-3b ++++++ 13-4a13-4a ++++
13-4b13-4b ++++++++ 13-5a13-5a ++++++++
13-7a13-7a ++++++++ 13-8a13-8a ++++++++
13-10a13-10a ++++ 13-10b13-10b ++++++++
13-11a13-11a ++++++++ 13-11b13-11b ++++++
13-1213-12 ++++ 13-1313-13 ++++++
14-1a14-1a ++ 14-1b14-1b ++++++
14-2a14-2a ++++ 14-2b14-2b ++++++++
14-3a14-3a ++++ 14-3b14-3b ++++++++
14-4a14-4a ++++++++ 14-5b14-5b ++++++++
14-6b14-6b ++++++ 14-7b14-7b ++++++++
14-11b14-11b ++++++++ 14-12b14-12b ++++++++
14-13a14-13a ++++++++ 16-1a16-1a ++++++
16-1b16-1b ++++++++ 16-2a16-2a ++++++
16-2b16-2b ++ 17-117-1 ++
18-118-1 ++++++++ 18-218-2 ++++++++
19-319-3 ++ 20-120-1 ++
21-1a21-1a ++++++ 21-1b21-1b ++++++++
21-2b21-2b ++++++++ 21-321-3 ++++++++
21-4a21-4a ++++++ 21-4b21-4b ++++++++
21-11a21-11a ++++++++ 21-12a21-12a ++++++++
22-2b22-2b ++++++ 22-3b22-3b ++++++
22-4b22-4b ++++++++ 23-1b23-1b ++++++++
23-2b23-2b ++++++++ 23-3b23-3b ++++++
23-4a23-4a ++++++++ 23-5a23-5a ++++++++
23-6a23-6a ++++++++ 24-1b24-1b ++++++++
24-2a24-2a ++++++++ 24-2b24-2b ++++++
24-3b24-3b ++++++ 24-4b24-4b ++++++++
24-5a24-5a ++++++++ 26-1b26-1b ++++++
27-1a27-1a ++++ 27-1b27-1b ++++++++
其中，化合物3-2a、5-1a、6-1a、6-2a、6-5a、6-7a、6-8a、6-9b、6-11a、6-15a、6-16a、6-19b、6-20b、6-21b、6-22b、6-24b、6-25b、6-26b、6-29b、6-31a、6-33a、6-34a、6-36a、6-38b、6-39b、6-43b、7-2b、7-5b、8-1b、8-2b、8-3a、8-4b、8-5a、8-6b、8-7a、8-10a、8-11a、8-12a、8-13a、8-21a、9-1b、9-3b、9-6b、9-7b、12-1a、13-1b、13-2b、13-4b、13-5a、13-7a、13-8a、14-2b、14-3b、14-4a、14-11a、14-13a、21-1b、21-2b、21-3、21-4b、21-10a、21-11a、21-12a、23-5a、24-1b、24-2a、24-4b、24-5a、27-1b的IC50值均<0.01μM。Wherein, compounds 3-2a, 5-1a, 6-1a, 6-2a, 6-5a, 6-7a, 6-8a, 6-9b, 6-11a, 6-15a, 6-16a, 6-19b , 6-20b, 6-21b, 6-22b, 6-24b, 6-25b, 6-26b, 6-29b, 6-31a, 6-33a, 6-34a, 6-36a, 6-38b, 6 -39b, 6-43b, 7-2b, 7-5b, 8-1b, 8-2b, 8-3a, 8-4b, 8-5a, 8-6b, 8-7a, 8-10a, 8-11a , 8-12a, 8-13a, 8-21a, 9-1b, 9-3b, 9-6b, 9-7b, 12-1a, 13-1b, 13-2b, 13-4b, 13-5a, 13 -7a, 13-8a, 14-2b, 14-3b, 14-4a, 14-11a, 14-13a, 21-1b, 21-2b, 21-3, 21-4b, 21-10a, 21-11a The IC 50 values of 21-12a, 23-5a, 24-1b, 24-2a, 24-4b, 24-5a, and 27-1b were all <0.01 μM.
实施例2：化合物14-3b的药代动力学测试Example 2: Pharmacokinetic test of compound 14-3b
药物及试剂：化合物14-3b用20％丙二醇+80％(20％羟丙基-β-环糊精)配成溶液，其它试剂均为分析纯。Drugs and Reagents: Compound 14-3b was formulated with 20% propylene glycol + 80% (20% hydroxypropyl-β-cyclodextrin) and the other reagents were of analytical grade.
测试用动物：雄性SPF级别SD大鼠(6只)，购于上海西普尔-必凯实验动物有限公司，所有动物给药前禁食10-14小时，给药后4小时恢复给食。Test animals: Male SPF grade SD rats (6 rats) were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., and all animals were fasted for 10-14 hours before administration and returned to food 4 hours after administration.
给药剂量：口服(PO)10mg/Kg，10mL/kg；静脉注射(IV)：2.5mg/Kg，5mL/Kg。Dosage: Oral (PO) 10 mg/Kg, 10 mL/kg; intravenous (IV): 2.5 mg/Kg, 5 mL/Kg.
药代动力学测试：将待测化合物14-3b，分别通过口服和静脉给药方式给予SD雄性大鼠，血样经颈静脉穿刺采血，每个样品采集约0.20mL，肝素钠抗凝，采血时间点如下：静脉给药组采血时间：给药前，给药后0.083h，0.25h，0.5h，1h，2h，4h，6h，8h，12h，24h。口服给药组采血时间：给药前，给药后0.25h，0.5h，1h，2h，4h，6h，8h，12h，24h。血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)。收集的血浆分析前存放于-80℃。血浆样品采用LC-MS/MS进行分析，根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数 AUC0-∞、Cmax、Tmax、T1/2、Vd、CL和F等参数及其平均值和标准差。测试结果见下表：Pharmacokinetic test: The test compound 14-3b was administered to SD male rats by oral and intravenous administration respectively. The blood samples were collected by jugular vein puncture, and each sample was collected about 0.20 mL. Heparin sodium anticoagulation and blood collection time. The points are as follows: blood collection time in the intravenous administration group: before administration, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h after administration. Blood collection time in the oral administration group: before administration, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h after administration. Blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C). The collected plasma was stored at -80 °C prior to analysis. Plasma samples were analyzed by LC-MS/MS. According to the plasma concentration data of the drug, the pharmacokinetic parameters of the test samples were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2. AUC 0-∞ , C Parameters such as max , T max , T 1/2 , Vd, CL, and F and their mean and standard deviation. The test results are shown in the table below:
Figure PCTCN2017095396-appb-000239
Figure PCTCN2017095396-appb-000239
实施例3：细胞色素氧化酶P450抑制作用测试Example 3: Cytochrome oxidase P450 inhibition test
采用LC-MS/MS方法来评估发明化合物对5种CYP亚型的抑制作用(1A2，2C9，2C19，2D6，3A4)。该方法将测试化合物与含有CYP模型底物的人肝微粒体的溶液混合，在加入NADPH的条件下共同孵育，通过测定反应液中模型底物的代谢物的量来计算化合物对CYP的抑制IC50。具体实验方法如下：The LC-MS/MS method was used to evaluate the inhibitory effects of the inventive compounds on five CYP subtypes (1A2, 2C9, 2C19, 2D6, 3A4). The method mixes the test compound with a solution of human liver microsomes containing the CYP model substrate, and co-incubates under the condition of adding NADPH, and calculates the inhibition of the compound on the CYP by measuring the amount of the metabolite of the model substrate in the reaction solution. . The specific experimental methods are as follows:
待测化合物用DMSO配制为10mM浓度的贮存液，随后用乙腈溶液将其稀释为4mM。同时针对不同CYP亚型配制相应的参考抑制物溶液，其中对于CYP1A2，CYP2C9，CYP2D6使用参考抑制物的混合液，依照下述比例配制：12μL of 1mMα-Naphthoflavon(CYP1A2抑制物)+10μL of 40mMSulfaphenazole(CYP2C9抑制物)+10μL of 10mM Quinidine(CYP2D6)+8μL of DMSO。CYP2C19的参考抑制物为Omeprazole，CYP3A4的参考抑为Ketoconazole，两者分别单独配制(8uL抑制物DMSO储存液+12uL乙腈)，上述条件下配制的样品为400X浓度。随后将上述溶液用DMSO：乙腈的混合液(v/v:40:60)进行3倍梯度稀释配制为最终测试用溶液，每个测试化合物设7个浓度点，起始测试终浓度为10uM。用预热磷酸钾缓冲液(0.1M，pH7.4)分别将NADPH，CYP酶模型底物以及人肝微粒体溶液稀释到合适的浓度。其中人肝微粒体溶液购于BD Gentest(20mg/mL，Corning，货号#452161)。The test compound was prepared in DMSO as a 10 mM stock solution, which was then diluted to 4 mM with an acetonitrile solution. At the same time, corresponding reference inhibitor solutions were prepared for different CYP subtypes, wherein CYP1A2, CYP2C9, and CYP2D6 were prepared using a mixture of reference inhibitors according to the following ratios: 12 μL of 1 mM α-Naphthoflavon (CYP1A2 inhibitor) + 10 μL of 40 ml MSulfaphenazole ( CYP2C9 inhibitor) + 10 μL of 10 mM Quinidine (CYP2D6) + 8 μL of DMSO. The reference inhibitor of CYP2C19 was Omeprazole, and the reference of CYP3A4 was Ketoconazole, which were separately prepared (8 uL inhibitor DMSO stock solution + 12 uL acetonitrile), and the sample prepared under the above conditions was 400X concentration. Subsequently, the above solution was diluted with a mixture of DMSO:acetonitrile (v/v: 40:60) in a 3-fold gradient to prepare a final test solution, and each test compound was set at 7 concentration points, and the initial test final concentration was 10 uM. The NADPH, CYP enzyme model substrate and human liver microsome solution were diluted to a suitable concentration with preheated potassium phosphate buffer (0.1 M, pH 7.4). The human liver microsome solution was purchased from BD Gentest (20 mg/mL, Corning, Cat. #452161).
向96孔板中的测试化合物各孔中加入400uL的人肝微粒体溶液(0.2mg/mL)，之后加入2ul前述经过梯度稀释配制的测试化合物最终测试用样品；对于参考抑制物对应各孔，加入200uL的人肝微粒体溶液(0.2mg/mL)以及1uL的最终测试用样品。混匀后取30uL的测试化合物/参考抑制物-人肝微粒体混合液并转移到另一块96孔板中，加入15uL对应的模型底物溶液后混匀并在37℃下孵育5分钟，之后加入15uL在37℃下预热的8mM NADPH溶液开始反应。每个测试设有复孔对照，同时设有无测试物质加入的空白对照。将含有总体积为60uL反应液的96孔板在37℃下进行孵育，孵育结束后，向各孔内加入120μL含有内标的乙腈溶液终止反应，随后将96孔板在微孔板振荡器上振荡10分钟(600rpm/min)，离心15分钟。之后从各孔中取50μL上清液转移至另一96孔板中，再向各孔中加入50μL超纯水，然后进行LC-MS/MS检测。通过比较各测试浓度下和无测试物质加入情况下的模型底物代谢物的量来确定抑制率，在GraphPad Prism 5.0软件中，以测试浓度的对数为横坐标，抑制率为纵坐标进行非线性回归(Sigmoidal(non-linear)dose-response model)分析，得出测试化合物的IC50值。400 uL of human liver microsome solution (0.2 mg/mL) was added to each well of the test compound in a 96-well plate, followed by the addition of 2 ul of the test compound prepared by the above gradient dilution to the final test sample; for the reference inhibitor corresponding to each well, 200 uL of human liver microsome solution (0.2 mg/mL) and 1 uL of final test sample were added. After mixing, take 30 uL of test compound/reference inhibitor-human liver microsome mixture and transfer to another 96-well plate, add 15 uL of the corresponding model substrate solution, mix and incubate at 37 ° C for 5 minutes, then The reaction was started by adding 15 uL of a 8 mM NADPH solution preheated at 37 °C. Each test was provided with a duplicate well control and a blank control with no test substance added. A 96-well plate containing a total volume of 60 uL of the reaction solution was incubated at 37 ° C. After the incubation, 120 μL of an acetonitrile solution containing an internal standard was added to each well to terminate the reaction, and then the 96-well plate was shaken on a microplate shaker. Centrifuge for 15 minutes at 10 minutes (600 rpm). Thereafter, 50 μL of the supernatant was transferred from each well to another 96-well plate, and 50 μL of ultrapure water was added to each well, followed by LC-MS/MS detection. The inhibition rate was determined by comparing the amount of model substrate metabolites at each test concentration and without test substance addition. In GraphPad Prism 5.0 software, the logarithm of the test concentration was plotted on the abscissa and the inhibition rate was on the ordinate. Linear regression (Sigmoidal (non-linear) dose-response model) analysis, the IC50 value of the test compound was obtained.
由下表可知，化合物6-2a对测试的细胞色素氧化酶P450各亚型均无抑制作用：As can be seen from the table below, Compound 6-2a did not inhibit the subtypes of the tested cytochrome oxidase P450:
  IC50(μM)IC50 (μM)
编号/亚型Number / subtype 1A21A2 2C92C9 2C192C19 2D62D6 3A43A4
6-2a6-2a ﹥10>10 ﹥10>10 ﹥10>10 ﹥10>10 ﹥10>10

Claims (23)

  1. 一种多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐；a polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt;
    Figure PCTCN2017095396-appb-100001
    Figure PCTCN2017095396-appb-100001
    其中，A环为苯、或5-6元杂芳环；Wherein the ring A is a benzene or a 5-6 membered heteroaryl ring;
    B环为5元杂芳环，并且A1、A2、A3和A4为如下任一组合；The B ring is a 5-membered heteroaryl ring, and A 1 , A 2 , A 3 and A 4 are any combination of the following;
    1)A1为C、A2为NR4、O或S、A3为CR5、A4为CH或N；1) A 1 is C, A 2 is NR 4 , O or S, A 3 is CR 5 , and A 4 is CH or N;
    2)A1为C、A2为CR5或N、A3为NR4、O或S、A4为CR5a或N；2) A 1 is C, A 2 is CR 5 or N, A 3 is NR 4 , O or S, and A 4 is CR 5a or N;
    3)A1为C、A2为CH或N、A3为CR5、A4为NR4、O或S；3) A 1 is C, A 2 is CH or N, A 3 is CR 5 , and A 4 is NR 4 , O or S;
    4)A1为N、A2为CR5或N、A3为CR5a或N、A4为N或CR5b；4) A 1 is N, A 2 is CR 5 or N, A 3 is CR 5a or N, and A 4 is N or CR 5b ;
    5)A1为CR5、A2为C、A3为NR4、O或S、A4为NR4或CR5a；5) A 1 is CR 5 , A 2 is C, A 3 is NR 4 , O or S, and A 4 is NR 4 or CR 5a ;
    6)A1为CR5、A2为C、A3为CR5a、A4为NR4、O或S；6) A 1 is CR 5 , A 2 is C, A 3 is CR 5a , and A 4 is NR 4 , O or S;
    X1为连接键、-O-、-NR4-或-CR6R6a-；X 1 is a linkage, -O-, -NR 4 - or -CR 6 R 6a -;
    X2为-C(O)-或-S(O)1-2-；X 2 is -C(O)- or -S(O) 1-2 -;
    X3为连接键、-NR4-或-CR6R6a-；并且，当X1为-NR4-，X2为-C(O)-时，X3为-NR4-；X 3 is a linkage, -NR 4 - or -CR 6 R 6a -; and, when X 1 is -NR 4 -, X 2 is -C(O)-, X 3 is -NR 4 -;
    Y为连接键或-(CR6R6a)p-；Y is a bond or -(CR 6 R 6a ) p -;
    U和V分别独立地选自N或CR3；U and V are each independently selected from N or CR 3 ;
    Z和W分别独立地选自CHR3、NR3、O、C(O)或S(O)2；Z and W are each independently selected from CHR 3 , NR 3 , O, C(O) or S(O) 2 ;
    L为连接键、C2-6亚烯基、C2-6亚炔基或-(CR6R6a)m-；L is a linkage, C 2-6 alkenylene, C 2-6 alkynylene or -(CR 6 R 6a ) m -;
    R1选自氢、卤素、羟基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C2-6炔基、C2-6烯基、-SH、-CN、-NO2、-ORb、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-NRbC(O)Ra、-N(Rb)C(O)ORb、-N(Rb)C(O)N(Rb)2、-NRbS(O)2Ra、-S(O)0-2Ra、-S(O)2N(Rb)2、芳基、环烷基、杂环烷基和杂芳基中的一种或多种；R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl, -SH, -CN, -NO 2 , -OR b , -OC(O)R a , -OC(O)OR b , -OC(O)N(R b ) 2 , -C(O)OR b , -C(O)R a , -C(O)N(R b ) 2 , -NR b C(O)R a , -N(R b )C(O)OR b , -N(R b )C(O)N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 0-2 R a , -S(O) 2 N(R b ) 2 , aryl, cycloalkyl, heterocycloalkyl and hetero One or more of aryl groups;
    R2或R3分别独立地选自氢、-NO2、-CN、-OH、-NH2、-SH、-OR8、-OC(O)R8、-OC(O)NR7R8、-OC(O)OR8、-OP(O)(O-R7)2、-OS(O)2(OH)、-OS(O)1-2R8、-S(O)1-2OR8、-S(O)2NR7R8、-S(O)0-2R8、-S(O)2N(R7)C(O)NR7R8、-C(O)OR8、-C(O)R8、-C(O)N(OH)R8、-C(O)NR7R8、-NR7R8、-N(R7)C(O)OR8、-N(R7)C(O)N(R7)S(O)2R8、-N(R7)C(O)NR7R8、-N(R7)S(O)1-2R8、-N(R7)C(O)R8、-N(R7)S(O)1-2NR7R8、-N(R7)C(O)R8、-N(R7)OR8、-N(R7)C(O)NR7R8、取代或未取代的烷基、取代或未取代的杂芳基、取代或未取代的环烷基、取代或未取代的杂环烷基或取代或未取代的芳基；当所述的R2或R3为取代的烷基、取代的环烷基、取代的杂环烷基、取代的芳基或取代的杂芳基时可被如下1～3个RA基团取代在任意位置：-OH、-SH、-CN、-NO2、-NH2、卤素、烷硫基、-C(O)N(Rb)2、-OC(O)Ra、-OC(O)ORb、-OC(O)N(Rb)2、-C(O)ORb、-C(O)Ra、-C(O)N(Rb)2、-N(Rb)2、-NRbC(O)Ra、-NRbC(O)Ra、-NRbC(O)ORa、-NRbC(O)N(Rb)2、-NRbC(O)N(Rb)2、-NRbS(O)2Ra、-NRbS(O)2N(Rb)2、-S(O)0-2Ra、-S(O)2N(Rb)2、取代或未取代的 烷基、取代或未取代的烷氧基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的杂环烷基或取代或未取代的杂芳基；RA中，所述烷基、烷氧基、芳基、杂芳基、环烷基或杂环烷基被取代时，可进一步被1～3个选自卤素、羟基、氨基、C1-4烷基或卤代C1-3烷氧基的取代基取代在任意位置；R 2 or R 3 are each independently selected from the group consisting of hydrogen, -NO 2 , -CN, -OH, -NH 2 , -SH, -OR 8 , -OC(O)R 8 , -OC(O)NR 7 R 8 , -OC(O)OR 8 , -OP(O)(OR 7 ) 2 , -OS(O) 2 (OH), -OS(O) 1-2 R 8 , -S(O) 1-2 OR 8 , -S(O) 2 NR 7 R 8 , -S(O) 0-2 R 8 , -S(O) 2 N(R 7 )C(O)NR 7 R 8 , -C(O)OR 8 , -C(O)R 8 , -C(O)N(OH)R 8 , -C(O)NR 7 R 8 , -NR 7 R 8 , -N(R 7 )C(O)OR 8 , -N(R 7 )C(O)N(R 7 )S(O) 2 R 8 , -N(R 7 )C(O)NR 7 R 8 , -N(R 7 )S(O) 1 -2 R 8 , -N(R 7 )C(O)R 8 , -N(R 7 )S(O) 1-2 NR 7 R 8 , -N(R 7 )C(O)R 8 ,- N(R 7 )OR 8 , -N(R 7 )C(O)NR 7 R 8 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted heterocycloalkyl group or a substituted or unsubstituted aryl group; when said R 2 or R 3 is a substituted alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group or The substituted heteroaryl group may be substituted at any position by the following 1 to 3 R A groups: -OH, -SH, -CN, -NO 2 , -NH 2 , halogen, alkylthio, -C(O) N(R b ) 2 , -OC(O)R a , -OC(O)OR b , -OC(O)N(R b 2 , -C(O)OR b , -C(O)R a , -C(O)N(R b ) 2 , -N(R b ) 2 , -NR b C(O)R a ,- NR b C(O)R a , -NR b C(O)OR a , -NR b C(O)N(R b ) 2 , -NR b C(O)N(R b ) 2 , -NR b S(O) 2 R a , -NR b S(O) 2 N(R b ) 2 , -S(O) 0-2 R a , -S(O) 2 N(R b ) 2 , substituted or not a substituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group or a substituted or unsubstituted heteroaryl group; In R A , when the alkyl group, alkoxy group, aryl group, heteroaryl group, cycloalkyl group or heterocycloalkyl group is substituted, it may be further selected from 1 to 3 selected from the group consisting of halogen, hydroxyl group, amino group, and C 1- a substituent of a 4- alkyl or halogenated C 1-3 alkoxy group at any position;
    R4为H、C1-6烷基或C3-8环烷基；R 4 is H, C 1-6 alkyl or C 3-8 cycloalkyl;
    R5、R5a和R5b分别独立地选自H或C1-6烷基；R 5 , R 5a and R 5b are each independently selected from H or C 1-6 alkyl;
    R6为氢、氘、卤素、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基，或取代或未取代的烷氧基；所述取代的烷基、取代的环烷基、取代的杂环烷基，或取代的烷氧基被如下一个或多个基团取代在任意位置：卤素、羟基、烷基、杂环烷基、环烷基、烷氧基、氨基、芳基、杂芳基、-SRa、-N(Rb)2、-S(O)2N(Rb)2、-NRbC(O)N(Rb)2、-NRbC(O)Ra、-C(O)Ra、-S(O)0-2Ra、-C(O)ORb、-(CH2)mOH或-(CH2)mN(Rb)2；R 6 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted alkoxy; substituted An alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, or a substituted alkoxy group is substituted at any position by one or more of the following groups: halogen, hydroxy, alkyl, heterocycloalkyl, cycloalkyl , alkoxy, amino, aryl, heteroaryl, -SR a , -N(R b ) 2 , -S(O) 2 N(R b ) 2 , -NR b C(O)N(R b 2 , -NR b C(O)R a , -C(O)R a , -S(O) 0-2 R a , -C(O)OR b , -(CH 2 ) m OH or -( CH 2 ) m N(R b ) 2 ;
    R6a为氢、氘、卤素、羟基、氨基、烷基、-SRa、-ORb、-N(Rb)2、-NRbS(O)2Ra、-S(O)2N(Rb)2、-(CH2)mS(O)0-2CH3、-OS(O)3H、-OP(O)(O-Rb)2、-OC(O)Ra、-OC(O)N(Rb)2、-C(O)N(Rb)2、-(CH2)mC(O)OH、-(CH2)mOH、-(CH2)mN(Rb)2或-(CH2)mC(O)N(Rb)2；R 6a is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, -SR a , -OR b , -N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 2 N (R b ) 2 , -(CH 2 ) m S(O) 0-2 CH 3 , -OS(O) 3 H, -OP(O)(OR b ) 2 , -OC(O)R a ,- OC(O)N(R b ) 2 , -C(O)N(R b ) 2 , -(CH 2 ) m C(O)OH, -(CH 2 ) m OH, -(CH 2 ) m N (R b ) 2 or -(CH 2 ) m C(O)N(R b ) 2 ;
    或者，R6和R6a与它们共同连接的C原子一起形成3-8元单环环烷基；Alternatively, R 6 and R 6a together with the C atom to which they are attached form a 3-8 membered monocyclic cycloalkyl group;
    R7或R8分别独立地选自氢、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、或取代或未取代的杂芳基烷基；当所述烷基、芳基、杂芳基、环烷基、杂环烷基、芳基烷基、杂芳基烷基、环烷基烷基或杂环烷基烷基被取代时，可进一步被1～3个选自卤素、羟基、氨基、C1-4烷基、或卤代C1-3烷氧基的取代基取代在任意位置；或者，R7和R8与它们共同连接的N原子一起形成3-8元的单杂环烷基；R 7 or R 8 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl When the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl group is substituted, It may be further substituted at any position by 1 to 3 substituents selected from a halogen, a hydroxyl group, an amino group, a C 1-4 alkyl group, or a halogenated C 1-3 alkoxy group; or, R 7 and R 8 are common thereto The linked N atoms together form a 3-8 membered monoheterocycloalkyl group;
    Ra和Rb各自独立地选自氢、烷基、卤代烷基、环烷基、杂环烷基、芳基、杂芳基、杂环烷基烷基、环烷基烷基、芳基烷基、或杂芳基烷基，或者，两个Rb与它们共同连接的N原子一起形成3-8元的单环杂环烷基；R a and R b are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkylalkyl, cycloalkylalkyl, arylalkane Or a heteroarylalkyl group, or two R b together with the N atom to which they are attached together form a 3-8 membered monocyclic heterocycloalkyl group;
    n、m和p分别独立地为1、2或3；n, m and p are independently 1, 2 or 3;
    q和t分别独立地为0、1或2。q and t are independently 0, 1, or 2, respectively.
  2. 如权利要求1所述的多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其特征在于：A环为苯基、吡啶基、或嘧啶基。The polycyclic compound (I), an isomer, a prodrug, a solvate, a hydrate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the ring A is a phenyl group. , pyridyl, or pyrimidinyl.
  3. 如权利要求1所述的多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其特征在于：B环为如下任一结构：The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the ring B is as follows A structure:
    Figure PCTCN2017095396-appb-100002
    Figure PCTCN2017095396-appb-100002
    Figure PCTCN2017095396-appb-100003
    Figure PCTCN2017095396-appb-100003
    R5、R5a和R5b的定义如权利要求1所述。R 5 , R 5a and R 5b are as defined in claim 1.
  4. 如权利要求1所述的多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其特征在于：R1为氢、卤素、羟基、巯基、氰基、C1-3烷氧基、C1-3烷硫基、C1-4烷基、卤代C1-3烷基、卤代C1-3烷氧基、-C(O)OH、-C(O)NH2和-S(O)2CH3中的一种或多种。The polycyclic compound (I), an isomer, a prodrug, a solvate, a hydrate thereof, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is hydrogen, Halogen, hydroxy, decyl, cyano, C 1-3 alkoxy, C 1-3 alkylthio, C 1-4 alkyl, halo C 1-3 alkyl, halo C 1-3 alkoxy One or more of -C(O)OH, -C(O)NH 2 and -S(O) 2 CH 3 .
  5. 如权利要求1所述的多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其特征在于：所述Y为连接键、-CH2-、-CH2CH2-、-CH(CH3)-、-CH(CH2CH3)-、-C(CH3)2-、-CHF-或-CF2-。The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the Y is a linkage A bond, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -CHF- or -CF 2 -.
  6. 如权利要求1所述的多环化合物(I)、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐，其特征在于：L为连接键或-O-；The polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is a linkage or -O-;
    和/或，R2为取代或未取代的C1-3烷基、取代或未取代的C6-10芳基、取代或未取代的6-10元杂芳基、取代或未取代的C3-8环烷基或取代或未取代的3-8元杂环烷基；当所述C1-3烷基、C6-10芳基、6-10元杂芳基、C3-8环烷基或3-8元杂环烷基被取代时可被1～3个RA基团取代在任意位置；RA基团的定义如权利要求1所述。And/or R 2 is a substituted or unsubstituted C 1-3 alkyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted 6-10 membered heteroaryl group, a substituted or unsubstituted C 3-8 cycloalkyl or substituted or unsubstituted 3-8 membered heterocycloalkyl; when said C 1-3 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 3-8 The cycloalkyl or 3-8 membered heterocycloalkyl group may be substituted at any position by 1 to 3 R A groups when substituted; the R A group is as defined in claim 1.
  7. 如权利要求1、2、4、5、6任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：其结构通式为：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4, 5 or 6, which is characterized in that: Its structural formula is:
    Figure PCTCN2017095396-appb-100004
    Figure PCTCN2017095396-appb-100004
    其中，among them,
    1)A1为C、A2为NR4、O或S、A3为CR5、A4为CH或N；1) A 1 is C, A 2 is NR 4 , O or S, A 3 is CR 5 , and A 4 is CH or N;
    2)A1为C、A2为CR5或N、A3为NR4、O或S、A4为CR5a或N；2) A 1 is C, A 2 is CR 5 or N, A 3 is NR 4 , O or S, and A 4 is CR 5a or N;
    3)A1为C、A2为CH或N、A3为CR5、A4为NR4、O或S；3) A 1 is C, A 2 is CH or N, A 3 is CR 5 , and A 4 is NR 4 , O or S;
    A环、R1、R2、R4、R5、R5a、L、X1、X2、X3、Y、U、W、Z、V、t、q和n的定义如权利要求1、2、4、5、6任一项所述。A ring, R 1 , R 2 , R 4 , R 5 , R 5a , L, X 1 , X 2 , X 3 , Y, U, W, Z, V, t, q and n are defined as claim 1 , any of 2, 4, 5, and 6.
  8. 如权利要求1、2、4、5、6任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：其结构通式为： The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4, 5 or 6, which is characterized in that: Its structural formula is:
    Figure PCTCN2017095396-appb-100005
    Figure PCTCN2017095396-appb-100005
    其中，W为N或CH；Where W is N or CH;
    A2、A3和A4为以下组合：A 2 , A 3 and A 4 are the following combinations:
    1)A2为CR5，A3为NR4，A4为N；1) A 2 is CR 5 , A 3 is NR 4 , and A 4 is N;
    2)A2为N，A3为NR4，A4为CR5a；2) A 2 is N, A 3 is NR 4 , and A 4 is CR 5a ;
    3)A2为CR5，A3为NR4，A4为CR5a；3) A 2 is CR 5 , A 3 is NR 4 , and A 4 is CR 5a ;
    4)A2为N，A3为NR4，A4为N；4) A 2 is N, A 3 is NR 4 , and A 4 is N;
    或5)A2为N，A3为O或S，A4为CH；Or 5) A 2 is N, A 3 is O or S, and A 4 is CH;
    R1、R2、R4、R5、R5a、L、X1、X2、X3、Y、U、V、n和q的定义如权利要求1、2、4、5、6任一项所述。R 1 , R 2 , R 4 , R 5 , R 5a , L, X 1 , X 2 , X 3 , Y, U, V, n and q are as defined in claims 1 , 2 , 4 , 5 , 6 One mentioned.
  9. 如权利要求1、2、4、5、6任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：其结构通式为：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4, 5 or 6, which is characterized in that: Its structural formula is:
    Figure PCTCN2017095396-appb-100006
    Figure PCTCN2017095396-appb-100006
    其中，W为N或CH；R4为H或-CH3；Wherein W is N or CH; R 4 is H or -CH 3 ;
    R1、R2、R3、R5、R5a、L和Y的定义如权利要求1、2、4、5、6任一项所述。 R 1, R 2, R 3 , definition of R 5, R 5a, L and Y are as claimed in any one of the claims 1,2,4,5,6.
  10. 如权利要求9所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：Y为-CH2-、-CH(CH3)-或-C(CH3)2-；The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to claim 9, wherein Y is -CH 2 -, -CH(CH) 3 )- or -C(CH 3 ) 2 -;
    和/或，R5为H、甲基、乙基或异丙基；And/or, R 5 is H, methyl, ethyl or isopropyl;
    和/或，R5a为H、甲基、乙基或异丙基；And/or R 5a is H, methyl, ethyl or isopropyl;
    和/或，R3为H或羟基；And/or, R 3 is H or a hydroxyl group;
    和/或，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基、C1-3烷氧基、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3。And/or R 2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted N-oxidized pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted isoquine group. a phenyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyrazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrrolyl group; R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl, C 1-3 alkoxy, F, Cl, Br, I, -OH, -NH 2 , -CN And -S(O) 2 CH 3 .
  11. 如权利要求1、2、4、5、6任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：其结构通式为：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4, 5 or 6, which is characterized in that: Its structural formula is:
    Figure PCTCN2017095396-appb-100007
    Figure PCTCN2017095396-appb-100007
    其中，A2、A3和A4为以下组合：Among them, A 2 , A 3 and A 4 are the following combinations:
    1)A2为NR4，A3为CR5，A4为CH；1) A 2 is NR 4 , A 3 is CR 5 , and A 4 is CH;
    2)A2为NR4，A3为N，A4为CH；2) A 2 is NR 4 , A 3 is N, and A 4 is CH;
    3)A2为S，A3为CH，A4为N；3) A 2 is S, A 3 is CH, and A 4 is N;
    或4)A2为O，A3为CH，A4为N；Or 4) A 2 is O, A 3 is CH, and A 4 is N;
    R1、R2、R4、R5、L、X1、X2、X3、Y、U、V、q和n的定义如权利要求1、2、4、5、6任一项所述。R 1 , R 2 , R 4 , R 5 , L, X 1 , X 2 , X 3 , Y, U, V, q and n are as defined in any one of claims 1 , 2 , 4 , 5 and 6. Said.
  12. 如权利要求1、2、4、5、6任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：其结构通式为：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4, 5 or 6, which is characterized in that: Its structural formula is:
    Figure PCTCN2017095396-appb-100008
    Figure PCTCN2017095396-appb-100008
    其中，W为N或CH；Where W is N or CH;
    R1、R2、R3、R5、L、Y和n的定义如权利要求1、2、4、5、6任一项所述。R 1 , R 2 , R 3 , R 5 , L, Y and n are as defined in any one of claims 1 , 2 , 4 , 5 and 6.
  13. 如权利要求12所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：Y为-CH2-、-CH(CH3)-或-C(CH3)2-；The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to claim 12, wherein Y is -CH 2 -, -CH(CH) 3 )- or -C(CH 3 ) 2 -;
    和/或，R5为H、甲基、乙基或异丙基；And/or, R 5 is H, methyl, ethyl or isopropyl;
    和/或，R3为H或羟基；And/or, R 3 is H or a hydroxyl group;
    和/或，R2为取代或未取代的苯基、取代或未取代的吡啶基、取代或未取代的N-氧化吡啶基、取代或未取代的喹啉基、取代或未取代的异喹啉基、取代或未取代的哒嗪基、取代或未取代的嘧啶基、取代或未取代的吡嗪基、取代或未取代的吡唑基、取代或未取代的吡咯基；所述取代的R2可被如下1～3个RA基团取代在任意位置：C1-3烷基、C1-3烷氧基、F、Cl、Br、I、-OH、-NH2、-CN和-S(O)2CH3。And/or R 2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted N-oxidized pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted isoquine group. a phenyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyrazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrrolyl group; R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl, C 1-3 alkoxy, F, Cl, Br, I, -OH, -NH 2 , -CN And -S(O) 2 CH 3 .
  14. 如权利要求1、2、4、5、6任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：其结构通式为：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4, 5 or 6, which is characterized in that: Its structural formula is:
    Figure PCTCN2017095396-appb-100009
    Figure PCTCN2017095396-appb-100009
    其中，A2、A3和A4为以下组合：Among them, A 2 , A 3 and A 4 are the following combinations:
    1)A2为CH，A3为CH，A4为NR4；1) A 2 is CH, A 3 is CH, and A 4 is NR 4 ;
    2)A2为CH，A3为N，A4为CH；2) A 2 is CH, A 3 is N, and A 4 is CH;
    3)A2为N，A3为CH，A4为CH；3) A 2 is N, A 3 is CH, and A 4 is CH;
    4)A2为N，A3为N，A4为CH；4) A 2 is N, A 3 is N, and A 4 is CH;
    或5)A2为N，A3为N，A4为NR4；Or 5) A 2 is N, A 3 is N, and A 4 is NR 4 ;
    R1、R2、R4、R5、L、X1、X2、X3、Y、U和V的定义如权利要求1、2、4、5、6任一 项所述。R 1 , R 2 , R 4 , R 5 , L, X 1 , X 2 , X 3 , Y, U and V are as defined in any one of claims 1 , 2 , 4 , 5 and 6.
  15. 如权利要求1～6任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：其结构通式为如下任一一种：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which has the following structural formula: Either one:
    Figure PCTCN2017095396-appb-100010
    Figure PCTCN2017095396-appb-100010
    其中，A环、R1、R2、L、X1、X2、X3、Y、A1、A2、A3、A4和n的定义如权利要求1～6任一项所述。Wherein A ring, R 1 , R 2 , L, X 1 , X 2 , X 3 , Y, A 1 , A 2 , A 3 , A 4 and n are as defined in any one of claims 1 to 6. .
  16. 如权利要求1所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：如式(I)所示的化合物为如下任一结构：The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by the formula (I) is as follows Any structure:
    Figure PCTCN2017095396-appb-100011
    Figure PCTCN2017095396-appb-100011
    Figure PCTCN2017095396-appb-100012
    Figure PCTCN2017095396-appb-100012
    Figure PCTCN2017095396-appb-100013
    Figure PCTCN2017095396-appb-100013
    Figure PCTCN2017095396-appb-100014
    Figure PCTCN2017095396-appb-100014
    Figure PCTCN2017095396-appb-100015
    Figure PCTCN2017095396-appb-100015
    Figure PCTCN2017095396-appb-100016
    Figure PCTCN2017095396-appb-100016
    Figure PCTCN2017095396-appb-100017
    Figure PCTCN2017095396-appb-100017
    Figure PCTCN2017095396-appb-100018
    Figure PCTCN2017095396-appb-100018
    Figure PCTCN2017095396-appb-100019
    Figure PCTCN2017095396-appb-100019
    Figure PCTCN2017095396-appb-100020
    Figure PCTCN2017095396-appb-100020
    Figure PCTCN2017095396-appb-100021
    Figure PCTCN2017095396-appb-100021
    Figure PCTCN2017095396-appb-100022
    Figure PCTCN2017095396-appb-100022
    Figure PCTCN2017095396-appb-100023
    Figure PCTCN2017095396-appb-100023
    Figure PCTCN2017095396-appb-100024
    Figure PCTCN2017095396-appb-100024
    Figure PCTCN2017095396-appb-100025
    Figure PCTCN2017095396-appb-100025
  17. 一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括如权利要求1～16任一项所述的多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐。A pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprising the polycyclic compound (I) according to any one of claims 1 to 16, which is different A construct, prodrug, stable isotope derivative or pharmaceutically acceptable salt.
  18. 如权利要求17所述的药物组合物，其特征在于：所述药物组合物中，所述活性组分还包括癌症、病毒感染或自身免疫疾病的其它治疗剂；The pharmaceutical composition according to claim 17, wherein said active ingredient further comprises a therapeutic agent for cancer, viral infection or autoimmune disease;
    和/或，所述药物组合物中，所述药学上可接受的辅料包括药学上可接受的载体、稀释剂和/或赋形剂。And/or, in the pharmaceutical composition, the pharmaceutically acceptable excipient comprises a pharmaceutically acceptable carrier, diluent and/or excipient.
  19. 如权利要求1～16任一项所述多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求17或18所述药物组合物在制备吲哚胺2,3-双加氧酶抑制剂中的应用。The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17 or 18. The use of the substance in the preparation of a guanamine 2,3-dioxygenase inhibitor.
  20. 如权利要求1～16任一项所述多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求17或18所述药物组合物在制备刺激T细胞增殖药物中的应用。The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17 or 18. The use of the substance in the preparation of a medicament for stimulating T cell proliferation.
  21. 如权利要求1～16任一项所述多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求17或18所述药物组合物在制备治疗、缓解和/或预防由吲哚胺2，3-双加氧酶介导的相关疾病的药物中的应用；所述的2，3-双加氧酶介导的相关 疾病包括：病毒或其它感染、癌症、或自身免疫性疾病。The polycyclic compound (I), an isomer thereof, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17 or 18. Use in the preparation of a medicament for the treatment, alleviation and/or prevention of a disease mediated by indoleamine 2,3-dioxygenase; said 2,3-dioxygenase mediated correlation Diseases include: viruses or other infections, cancer, or autoimmune diseases.
  22. 如权利要求21所述的应用，其特征在于：所述多环化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物和一种或多种其它种类的用于治疗癌症的治疗剂和/或治疗方法联合使用；所述其它种类的用于治疗癌症的治疗剂和/或治疗方法为微管蛋白抑制剂、烷化剂、拓扑酶I/II抑制剂、铂类化合物、抗代谢类药物、激素和激素类似物、信号转导通路抑制剂、血管生成抑制剂、靶向治疗、免疫治疗剂、促凋亡剂、细胞周期信号通路抑制剂和放疗中的一种或多种。The use according to claim 21, wherein said polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or said pharmaceutical composition and One or more other types of therapeutic agents and/or therapeutic methods for treating cancer; the other types of therapeutic agents and/or therapeutic methods for treating cancer are tubulin inhibitors, alkylating agents , Topois I/II inhibitors, platinum compounds, antimetabolites, hormones and hormone analogues, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies, immunotherapeutics, pro-apoptotic agents, cells One or more of a periodic signaling pathway inhibitor and radiation therapy.
  23. 如权利要求21所述的应用，其特征在于：所述的病毒或其它感染为皮肤感染、胃肠道感染、泌尿生殖系统感染和/或系统性感染；所述的癌症为骨癌、肺癌、胃癌、结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、膀胱癌、子宫颈癌、睾丸癌、肾癌、头颈癌、淋巴癌、白血病和皮肤癌中的一种或多种；所述的自身免疫性疾病为类风湿性关节炎、全身性红斑狼疮、混合性结缔组织病、系统硬皮病、皮肌炎、结节性脉管炎、肾病、内分泌相关疾病、肝病、银屑病和由于感染引起的自身免疫反应中的一种或多种；所述病毒感染为由流感、丙型肝炎病毒、人类乳头状瘤病毒、巨细胞病毒、爱泼斯坦-巴尔病毒、脊髓灰质炎病毒、水痘-带状疱疹病毒、柯萨奇病毒和人类免疫缺陷病毒中的一种或多种引起的感染。 The use according to claim 21, wherein the virus or other infection is a skin infection, a gastrointestinal infection, a genitourinary infection, and/or a systemic infection; the cancer is bone cancer, lung cancer, One of gastric cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and skin cancer. Various; the autoimmune diseases are rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, systemic scleroderma, dermatomyositis, nodular vasculitis, nephropathy, endocrine-related diseases, One or more of liver disease, psoriasis, and autoimmune reactions due to infection; the virus infection is caused by influenza, hepatitis C virus, human papilloma virus, cytomegalovirus, Epstein-Barr virus An infection caused by one or more of poliovirus, varicella-zoster virus, coxsackie virus, and human immunodeficiency virus.
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