WO2021052501A1 - 杂环酰胺类化合物、其可药用的盐及其制备方法和用途 - Google Patents

杂环酰胺类化合物、其可药用的盐及其制备方法和用途 Download PDF

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WO2021052501A1
WO2021052501A1 PCT/CN2020/116614 CN2020116614W WO2021052501A1 WO 2021052501 A1 WO2021052501 A1 WO 2021052501A1 CN 2020116614 W CN2020116614 W CN 2020116614W WO 2021052501 A1 WO2021052501 A1 WO 2021052501A1
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alkyl
substituted
hydrogen
halogen
group
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PCT/CN2020/116614
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French (fr)
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段文虎
耿美玉
张惠斌
谢作权
周金培
杨一飞
王玺渊
杨晓骏
张燕
胡兆雪
丁健
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中国科学院上海药物研究所
中国药科大学
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Priority to BR112022005182A priority Critical patent/BR112022005182A2/pt
Priority to EP20866743.6A priority patent/EP4032890A1/en
Priority to US17/761,252 priority patent/US20220389025A1/en
Priority to CN202080066382.1A priority patent/CN114981273B/zh
Priority to KR1020227012596A priority patent/KR20220097388A/ko
Priority to CA3151776A priority patent/CA3151776C/en
Priority to AU2020348825A priority patent/AU2020348825B2/en
Priority to MX2022003270A priority patent/MX2022003270A/es
Priority to JP2022543603A priority patent/JP2022549030A/ja
Publication of WO2021052501A1 publication Critical patent/WO2021052501A1/zh

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Definitions

  • the invention relates to heterocyclic amide compounds and their pharmaceutically acceptable salts, preparation methods and uses thereof.
  • immunostimulatory monoclonal antibodies for example, anti-OX40, an agonistic monoclonal antibody targeting the receptor OX40 or BB1, targeting CD74
  • STING pathway is a key sensor system that allows the innate immune system to respond to infection and tumor growth and coordinate the immune response.
  • cyclic GMP-AMP synthetase combines with dsDNA from damaged cells of the pathogen or host to produce a small molecule ligand, cyclic GMP-AMP (cGAMP).
  • cGAMP cyclic GMP-AMP
  • STING is phosphorylated by the SER/THR kinase--TANK-binding kinase 1 (TBK1).
  • Phosphorylated STING recruits a transcription factor, interferon regulatory factor 3 (IRF3), and promotes the phosphorylation of IRF3 by TBK1, leading to the dimerization of IRF3.
  • IRF3 dimer transfers to the nucleus and binds to the IFN- ⁇ promoter, leading to the production of IFN- ⁇ and other cytokines.
  • STING Since the discovery of STING, it has been found to play an important role in infectious diseases, cancer and autoimmune diseases. Therefore, STING has gradually developed into a potential immunotherapy target.
  • the direct activation of STING by bacterial CDN has been verified by X-ray crystallography (Burdette DL et al. Nature Immunolog, 2013(14): 19-26). It has been discovered that the new CDN signal transduction molecule cGAMP can activate STING, and its interaction with STING has also been verified by X-ray crystallography (Cai X et al. Molecular Cell, 2014(54): 289-296). Synthetic STING agonists with good druggability can be used as adjuvants, anti-tumor drugs or other immunotherapy preparations.
  • the objective of the present invention is to provide a heterocyclic amide compound with a novel structure and a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition.
  • Another object of the present invention is to provide a method for preparing the heterocyclic amide compound and the pharmaceutically acceptable salt thereof.
  • the last objective of the present invention is to provide the heterocyclic amide compound and its pharmaceutically useful use.
  • the first aspect of the present invention provides a heterocyclic amide compound and a pharmaceutically acceptable salt thereof,
  • R 4 and R 4' are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 and R 5' are each selected from hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 alkynyl group, C 3 ⁇ C 6 alkenyl group, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 6 and R 7 are independently selected from hydrogen, C 1 ⁇ C 6 alkyl, nitro, halogen, halogen substituted C 1 ⁇ C 6 alkyl, or R 6 , R 7 and the atom connected to R 6 , R 7 Cyclization between the three to form a saturated or unsaturated 4- to 6-membered carbocyclic or heterocyclic ring;
  • R 6'and R 7' are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl, nitro, halogen, halogen substituted C 1 ⁇ C 6 alkyl, or R 6' , R 7'and R 6' , cyclized saturated or unsaturated 4 to 6-membered carbocyclic or heterocyclic ring is connected to three atoms between R 7 ';
  • R 1, R 2, R 3 , R 2 ', R 3' are independently selected from hydrogen, -OR d, -NR d R e , halo, CN, C (O) OR d, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkyl substituted by halogen, -SO 2 NH 2 , -C(O)NR a R b ;
  • R a , R b , R d , and R e are selected from hydrogen, C 1 ⁇ C 6 alkyl, respectively;
  • R B is selected from hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 R h , -OR f , -NR f R g , -C(O)R f , -CO 2 R f ,- C(O)NR f R g , -NR f C(O)R g , -NR f C(O)R; R B , R 1 and the atoms connected to R B , R 1 are cyclized to saturation Or unsaturated 4-6 membered carbocyclic or heterocyclic ring;
  • R f and R g are each selected from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i, and 0 to 4 R i- substituted 3-6 membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , -NR j C (O) R k , is substituted with 0 to 4
  • R i is a substituted 3-6 membered cycloalkyl, substituted with 0 to 4 R i 3 to 6-membered heterocycloalkyl;
  • R i is selected from halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl, cyano;
  • R j and R k are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl
  • L is selected from substituted with 0 to 4 R n alkylene group of C 4 ⁇ C 6, R n 0-4 alkenyl substituted alkylene group of C 4 ⁇ C 6, substituted with 0 to 4 R n C 4 ⁇ C 6 alkynylene group; C 4 ⁇ C 6 alkylene group, C 4 ⁇ C 6 alkenylene group, C 4 ⁇ C 6 alkynylene group whose carbon atoms are -O-, -S -, -NR m -Replace;
  • R m is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • R n is selected from halogen, hydroxy, amino, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, and halogen substituted C 1 to C 6 alkyl.
  • heterocyclic amide compound of general formula (I) and its pharmaceutically acceptable salt have the following characteristics:
  • R 4 and R 4' are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 and R 5' are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 alkynyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl group, -(CH 2 ) s -L 3 ; wherein s is 1, 2 or 3, and L 3 is selected from: C 3 ⁇ C 6 cycloalkyl group, 3-6 membered heterocyclic group ;
  • R 6 and R 7 are independently selected from hydrogen, C 1 ⁇ C 6 alkyl, nitro, halogen, halogen substituted C 1 ⁇ C 6 alkyl, or R 6 , R 7 and the atom connected to R 6 , R 7 Cyclization between the three to form a saturated or unsaturated 4- to 6-membered carbocyclic or heterocyclic ring;
  • R 6'and R 7' are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl, nitro, halogen, halogen substituted C 1 ⁇ C 6 alkyl, or R 6' , R 7'and R 6' , cyclized saturated or unsaturated 4 to 6-membered carbocyclic or heterocyclic ring is connected to three atoms between R 7 ';
  • R 1, R 2, R 3 , R 2 ', R 3' are independently selected from hydrogen, -OR d, -NR d R e , halo, CN, C (O) OR d, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkyl substituted by halogen, -SO 2 NH 2 , -C(O)NR a R b , -L 1 -L 2 -C(O)NR a R b ;
  • R a , R b , R d , and R e are selected from hydrogen, C 1 ⁇ C 6 alkyl, respectively;
  • L 1 is selected from: -(CH 2 ) t -, -C(O)-, -SO 2 -, -C(O)-; where t is 0, 1, 2 or 3;
  • L 2 is selected from: C 1 ⁇ C 6 alkyl, C 2 ⁇ C 6 alkynyl, C 2 ⁇ C 6 alkenyl, C 3 ⁇ C 6 cycloalkyl, 3-6 membered heterocyclic group;
  • R B is selected from hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 R h , -OR f , -NR f R g , -C(O)R f , -CO 2 R f ,- C(O)NR f R g ; or R B , R 1 and the atoms connected to R B , R 1 are cyclized into a saturated or unsaturated 4- to 6-membered carbocyclic or heterocyclic ring;
  • R f and R g are each selected from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i, and 0 to 4 R i- substituted 3-6 membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , 3 substituted by 0 to 4 R i ⁇ 6-membered cycloalkyl, 3-6 membered heterocycloalkyl substituted with 0 to 4 R i;
  • R i is selected from halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl, cyano;
  • R j and R k are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl
  • L is selected from substituted with 0 to 4 R n alkylene group of C 4 ⁇ C 6, R n 0-4 alkenyl substituted alkylene group of C 4 ⁇ C 6, substituted with 0 to 4 R n
  • the C 4 ⁇ C 6 alkynylene group; the C 4 ⁇ C 6 alkylene group, the C 4 ⁇ C 6 alkenylene group, the C 4 ⁇ C 6 alkynylene group may have a carbon atom by -O- , -S-, -NR m -replacement;
  • R m is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • R n is selected from halogen, hydroxy, amino, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, and halogen substituted C 1 to C 6 alkyl.
  • R 5 and R 5' are each independently hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, -CH 2- C 3 ⁇ C 6 cycloalkyl, more preferably R 5 and R 5'are each independently methyl, ethyl, propyl, butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , allyl,
  • C is a saturated or unsaturated furanyl or tetrahydrofuranyl substituted with 0 to 4 R i , wherein R i is selected from the group consisting of halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 -C 6 alkyl substituted with halogen.
  • the heterocyclic amide compound of formula I and the pharmaceutically acceptable salt thereof wherein the A ring and the B ring are the same or different, and each is independently
  • Each R t is independently selected from: C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy; p is 0, 1, 2, 3 or 4;
  • R 5 The definition of R 5 is as described above.
  • heterocyclic amide compound of formula I and the pharmaceutically acceptable salt thereof wherein the A ring and the B ring are the same, and each is independently
  • R 5 is selected from: hydrogen, C 1 to C 6 alkyl, C 3 to C 6 alkenyl, and halogen substituted C 1 to C 6 alkyl.
  • the A ring and the B ring are the same, and each independently is Wherein, R 5 is selected from: methyl, ethyl, propyl, butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , allyl.
  • heterocyclic amide compound of formula I and a pharmaceutically acceptable salt thereof, wherein the Partly selected from:
  • y is 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • Each R x is independently selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl,
  • Each R t is independently selected from: C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy,
  • R 5 defined R 2 'is as described above.
  • y is 0, 1, 2, 3 or 4;
  • Each R x is independently selected from: halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • Each R t is independently selected from: C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 2' is independently selected from: hydrogen, -SO 2 NH 2 , -C(O)NR a R b ;
  • R a and R b are each independently selected from: hydrogen, C 1 -C 6 alkyl.
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, preferably methyl, ethyl, propyl, butyl Base, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , Allyl.
  • heterocyclic amide compound of formula I and a pharmaceutically acceptable salt thereof, wherein: Partly selected from: among them,
  • y is 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • Each R x is independently selected from: halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • Each R t is independently selected from: C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 2 is independently selected from: hydrogen, -SO 2 NH 2 , -C(O)NR a R b ;
  • R a and R b are each independently selected from: hydrogen, C 1 ⁇ C 6 alkyl;
  • R B is selected from: hydrogen, -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i 3 ⁇ 6 membered cycloalkyl, substituted with 0 to 4 R i 3 ⁇ 6 membered heterocycloalkyl group;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are each independently selected from hydrogen and C 1 to C 6 alkyl.
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 2 is independently selected from: hydrogen, -SO 2 NH 2 , -C(O)NR a R b ;
  • R a and R b are each independently selected from: hydrogen, C 1 ⁇ C 6 alkyl;
  • R B is selected from: hydrogen, -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i 3 ⁇ 6 membered cycloalkyl, substituted with 0 to 4 R i 3 ⁇ 6 membered heterocycloalkyl group;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are each independently selected from hydrogen and C 1 to C 6 alkyl.
  • R 2 is independently -C(O)NH 2 ;
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, preferably methyl, ethyl, propyl, butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , allyl base;
  • R B is selected from: hydrogen, -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i 3 ⁇ 6 membered cycloalkyl, substituted with 0 to 4 R i 3 ⁇ 6 membered heterocycloalkyl group;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are each independently selected from hydrogen and C 1 to C 6 alkyl.
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, preferably methyl, ethyl, propyl, butyl Base, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , Allyl.
  • L is selected from: substituted with 0 to 4 R n substituted C 4 ⁇ C 6 alkenylene group, substituted with 0 to 4 R n C 4 ⁇ C 6 alkylene group, wherein , R n is selected from: halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl.
  • heterocyclic amide compound having the general formula (I) and the pharmaceutically acceptable salt thereof, wherein R B is selected from hydrogen and -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i 3 ⁇ 6 membered cycloalkyl, substituted with 0 to 4 R i 3 ⁇ 6 membered heterocycloalkyl group;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are each independently selected from hydrogen and C 1 to C 6 alkyl.
  • R 4, R 4 ' are H.
  • R 1 , R 3 , R 1' , and R 3' are each hydrogen.
  • R 4 and R 4' are each hydrogen
  • R 5 and R 5' are each selected from hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 alkynyl group, C 3 ⁇ C 6 alkenyl group, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 6 and R 7 are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl, R 6 , R 7 and the atoms connected to R 6 , R 7 are cyclized into a saturated or unsaturated 4-6 membered carbocyclic ring Or heterocycle;
  • R 6 ', R 7' are independently selected from hydrogen, C 1 ⁇ C 6 alkyl group, R 6 ', R 7' and with R 6 ', R 7' is cyclized to three atoms between saturated or unsaturated attached 4 to 6-membered carbocyclic or heterocyclic ring;
  • R 1 , R 3 , and R 3' are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl, -OR d ;
  • R 2 and R 2' are respectively selected from hydrogen, -SO 2 NH 2 , and -C(O)NR a R b ;
  • R a and R b are each selected from hydrogen, C 1 ⁇ C 6 alkyl
  • R d is selected from hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 alkynyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • R B is selected from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , -NR j C (O) R k , is substituted with 0 to 4
  • R i is a substituted 3-6 membered cycloalkyl, substituted with 0 to 4 R i 3 to 6-membered heterocycloalkyl;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl
  • L is selected from C 4 to C 6 alkenylene and C 4 to C 6 alkylene.
  • R 6 and R 7 are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl
  • R 6'and R 7' are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl
  • R 1 , R 3 , and R 3' are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl;
  • R 2 and R 2' are each independently selected from hydrogen, -SO 2 NH 2 , and -C(O)NH 2 ;
  • R B is selected from hydrogen, -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , -NR j C (O) R k , is substituted with 0 to 4
  • R i is a substituted 3-6 membered cycloalkyl, substituted with 0 to 4 R i 3 to 6-membered heterocycloalkyl;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are each independently selected from hydrogen and C 1 to C 6 alkyl.
  • L is among them, Represents a single bond or a double bond.
  • A, B, C, L , R 1, R 2, R 3, R 4, R B, R 2 ', R 3', R 4 ' for the specific compounds in the examples correspond to The specific group.
  • heterocyclic amide compound and the pharmaceutically acceptable salt thereof are any one of the following:
  • the compound is the compound shown in the embodiment.
  • a pharmaceutical composition containing a therapeutically effective amount of one or more heterocyclic amide compounds with general formula (I) described in the first aspect, and pharmaceutically acceptable salts thereof, And a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides a pharmaceutical composition containing a therapeutically effective amount of one or more of the heterocyclic amide compounds of the general formula (I) described in the first aspect, and pharmaceutically acceptable salts thereof, And pharmaceutically acceptable excipients.
  • the fourth aspect of the present invention provides a method for preparing the heterocyclic amide compound having the general formula (I) as described in the first aspect and a pharmaceutically acceptable salt thereof, which comprises the following steps:
  • A, B, L, R 1 , R 2 , R 3 , R 4 , R B , R 2' , R 3' , and R 4' are defined as described above.
  • the fifth aspect of the present invention provides a use of the heterocyclic amide compound with the general formula (I) as described in the first aspect and a pharmaceutically acceptable salt thereof in the preparation of an immune adjuvant.
  • the heterocyclic amide compound with the general formula (I) and the pharmaceutically acceptable salt thereof as described in the first aspect in the preparation of a medicament for the treatment of diseases related to STIGN activity.
  • the diseases related to STIGN activity are one or more of diseases related to inflammatory, autoimmune diseases, infectious diseases, cancers, and precancerous syndromes.
  • diseases related to STING activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.
  • the cancer is selected from the group consisting of colon cancer, breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), lung cancer (e.g., non-small cell lung cancer, small Cell lung cancer, malignant mesothelioma) and ovarian cancer (eg, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant potential tumor), brain cancer, fibrosarcoma and squamous cell carcinoma, melanoma, and other cancers.
  • breast cancer e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer
  • lung cancer e.g., non-small cell lung cancer, small Cell lung cancer, malignant mesothelioma
  • ovarian cancer eg, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low-grade malignant potential tumor
  • brain cancer fibrosarcoma and squamous cell carcinoma,
  • the inflammatory disease is selected from: acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis , Sarcoidosis, vasculitis, airway inflammation and interstitial cystitis caused by house dust mites.
  • the infectious disease is an infectious disease caused by a virus, wherein the virus is selected from the group consisting of hepatitis B virus, human papilloma virus, and nasopharyngeal carcinoma-related Epstein-Barr virus.
  • the inflammatory disease is asthma.
  • the eighth aspect of the present invention provides a method for inducing an immune response in a subject, the method comprising administering a therapeutically effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect to the subject The subject.
  • the subject is a mammal, preferably a human.
  • the ninth aspect of the present invention provides a method for activating STING activity, including the step of contacting the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof with somatic cells (or tissues), thereby activating STING activity.
  • somatic cells are derived from rodents (such as mice, rats) or primates (such as humans).
  • the tenth aspect of the present invention provides a method for treating diseases related to STING activity, comprising administering a therapeutically effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect to a subject in need thereof .
  • the disease related to STING activity defined in the present invention is a disease in which STING plays a role in the pathogenesis of the disease.
  • Diseases related to STING activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.
  • Figure 1 shows the in vivo anti-tumor activity of compound 19 in a CT26 colon cancer model.
  • Figure 2 shows the in vivo anti-tumor activity of compound 19 in an EMT6 breast cancer orthotopic xenograft model.
  • the present inventors unexpectedly developed a heterocyclic amide compound with a novel structure for the first time, and the experimental results showed that the compound of the present invention has a good activation effect on STING, and can be used for preparation of treatment and activation. STING or drugs for diseases related to STING activity.
  • the present invention has been completed on this basis.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-C6 means containing 1, 2, 3, 4, 5 or 6 Carbon atoms).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and similar alkyl groups.
  • an alkyl group is also intended to include a substituted alkyl group, that is, one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkenyl means a straight or branched hydrocarbon group containing one or more double bonds and usually having a length of 2 to 20 carbon atoms (or C2-C8).
  • C2-C6 alkenyl contains 2, 3, 4, 5, or 6 carbon atoms alkenyl, "C3-C6 alkenyl”.
  • Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.
  • the alkenyl group includes a substituted alkenyl group.
  • alkynyl means a straight or branched hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms (or C2-C8).
  • C2-6 alkynyl refers to a linear or branched alkynyl group having 2, 3, 4, 5 or 6 carbon atoms, including but not limited to ethynyl, propynyl or similar groups .
  • alkynyl groups also include substituted alkynyl groups, and the substituents can be halogenated, hydroxy, cyano, nitro and the like.
  • alkylamino refers to an alkyl group connected to the rest of the molecule through an amino group.
  • C 1 -C 6 alkylamino has the formula C 1 -C 6 alkyl-NH-.
  • alkylene by itself or as part of another substituent refers to a divalent group derived from an alkane, such as -CH 2 CH 2 CH 2 CH 2 -.
  • Alkyl groups or alkylene groups
  • Alkyl groups generally have 1 to 24 carbon atoms, of which those groups having 10 or less carbon atoms (such as C 4 to C 6 alkylene groups) are preferred in the present invention.
  • alkenylene or “alkynylene” refers to an unsaturated form of “alkylene” having a double bond or a triple bond, respectively. Examples of “alkenylene” or “alkynylene” include but are not limited to: vinylene, alkenylene, Wait.
  • C1-C6 alkoxy refers to a linear or branched or cyclic alkoxy group having 1 to 6 carbon atoms (such as C3-C6 cycloalkoxy).
  • Representative examples include ( But not limited to): methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.
  • it is a C1-C3 alkoxy group.
  • cycloalkyl refers to a cyclic alkyl group that includes saturated monocyclic or bicyclic (eg, fused bicyclic or spiro bicyclic) or polycyclic rings.
  • 3- to 6-membered cycloalkyl group refers to a cyclic alkyl group including 3, 4, 5, and 6 carbon atoms.
  • Representative cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • substituted or unsubstituted cycloalkyl groups such as branched cycloalkyl groups (such as 1-methylcyclopropyl and 2-methylcyclopropyl), are included in the definition of "cycloalkyl".
  • heterocycloalkyl refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • the heterocycloalkyl group can be a monocyclic, bicyclic or polycyclic ring system.
  • “3- to 6-membered heterocycloalkyl” refers to a group in which one or two ring C atoms in a C3 to 6 cycloalkyl group are substituted with heteroatoms selected from N, O and S.
  • Heterocycloalkane examples include but are not limited to: pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine , 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3- Pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc.
  • the heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom.
  • heterocyclic group refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O, which may be a monocyclic ring or a bicyclic ring, such as a bridged ring or a spiro ring.
  • the heterocyclic group is preferably a 3-8 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, and more preferably a 5-6 membered heterocyclic group.
  • heterocyclic groups include but are not limited to: oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, etc. .
  • heteroaryl refers to a cyclic aromatic group having 1 to 3 atoms as heteroatoms selected from the group consisting of N, S, and O, which may be a monocyclic ring or a condensed ring form.
  • the heteroaryl group is preferably a 5-6 membered heteroaryl group.
  • heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • carbocyclic or heterocyclic ring alone or as part of another group refers to a monocyclic or bicyclic saturated, partially saturated or aromatic carbocyclic ring (for example, the above-mentioned cycloalkyl, ring Alkenyl, phenyl, etc.), or monocyclic or bicyclic saturated, partially saturated or aromatic heterocycle (for example, heteroalkyl, heterocyclyl, heteroaryl, etc. as described above), wherein , 4-6 membered carbocyclic or heterocyclic ring refers to a carbocyclic or heterocyclic ring containing 4-6 ring atoms, preferably 5-6 membered carbocyclic or heterocyclic ring.
  • carbocyclic or heterocyclic rings include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, Oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, Pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thiophene Group, isoxazolyl, thiazolyl, oxazolyl
  • amino means having the structure -N(R)(R'), and R and R'can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Aryl or substituted aryl, heterocycle or substituted heterocycle are as defined above. R and R'may be the same or different in the dialkylamine segment.
  • alkyl, alkoxy, cycloalkyl, heteroaryl, heterocycloalkyl, alkenyl, alkyne, heterocyclic, carbocyclic, heterocyclic, etc. groups may be substituted Or unsubstituted.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, carbocyclic or heterocyclic groups may be optionally substituted.
  • the substituents such as (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1 -C6 urea group and so on.
  • halo or halogen includes fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to -OH.
  • cyclization in “R 6 , R 7 and the atoms connected to R 6 and R 7 are cyclized into a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring” means R 6, R 7 with its attached C atoms fused to form a ring and, similarly, R 6 'and R 7', R B and cyclization of R 1 have the same meaning.
  • the 4- to 6-membered carbocyclic or heterocyclic ring is defined above and is intended to include a substituted or unsubstituted 4- to 6-membered carbocyclic or heterocyclic ring.
  • substitution refers to one or Multiple (1, 2, 3, 4) substituent substitutions: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 to C 6 alkyl, cyano.
  • the compound of the present invention refers to the compound represented by Formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs, or solvates related to the compound of Formula I.
  • the compound of formula I of the present invention has the following structure
  • R 4 and R 4' are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 and R 5' are each selected from hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 alkynyl group, C 3 ⁇ C 6 alkenyl group, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 6 and R 7 are each selected from hydrogen, C 1 ⁇ C 6 alkyl, nitro, halogen, halogen substituted C 1 ⁇ C 6 alkyl, or R 6 , R 7 and those connected to R 6 , R 7 Cyclization between the three atoms into a saturated or unsaturated 4- to 6-membered carbocyclic or heterocyclic ring;
  • R 6'and R 7' are independently selected from hydrogen, C 1 ⁇ C 6 alkyl, nitro, halogen, halogen substituted C 1 ⁇ C 6 alkyl, or R 6' , R 7'and R 6' , cyclized saturated or unsaturated 4 to 6-membered carbocyclic or heterocyclic ring is connected to three atoms between R 7 ';
  • R 1, R 2, R 3 , R 2 ', R 3' are independently selected from hydrogen, -OR d, -NR d R e , halo, CN, C (O) OR d, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkyl substituted by halogen, -SO 2 NH 2 , -C(O)NR a R b ;
  • R a , R b , R d , and R e are selected from hydrogen, C 1 ⁇ C 6 alkyl, respectively;
  • R B is selected from hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 R h , -OR f , -NR f R g , -C(O)R f , -CO 2 R f ,- C(O)NR f R g , -NR f C(O)R g ; or R B , R 1 and the atoms connected to R B , R 1 are cyclized into saturated or unsaturated 4-6 members Carbocyclic or heterocyclic ring;
  • R f and R g are each selected from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i, and 0 to 4 R i- substituted 3-6 membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i 3 ⁇ 6 membered cycloalkyl, substituted with 0 to 4 R i 3 ⁇ 6 membered heterocycloalkyl group;
  • R i is selected from halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl, cyano;
  • R j and R k are respectively selected from hydrogen, C 1 ⁇ C 6 alkyl
  • L is selected from substituted with 0 to 4 R n alkylene group of C 4 ⁇ C 6, R n 0-4 alkenyl substituted alkylene group of C 4 ⁇ C 6, substituted with 0 to 4 R n
  • the C 4 ⁇ C 6 alkynylene group; the C 4 ⁇ C 6 alkylene group, the C 4 ⁇ C 6 alkenylene group, the C 4 ⁇ C 6 alkynylene group may have a carbon atom by -O- , -S-, -NR m -replacement;
  • R m is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • R n is selected from halogen, hydroxy, amino, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, and halogen substituted C 1 to C 6 alkyl.
  • the compound of formula I may also have the following structure:
  • Ring B is selected from
  • R 1, R 2, R 3 , R 2 ', R 3' are independently selected from hydrogen, -OR d, -NR d R e , halo, CN, C (O) OR d, C 1 ⁇ C 6 alkyl group, C 1 ⁇ C 6 alkyl substituted by halogen, -SO 2 NH 2 , -C(O)NR a R b , -L 1 -L 2 -C(O)NR a R b (the new compound 15 is not in the original scope Inside);
  • R a , R b , R d , and R e are selected from hydrogen, C 1 ⁇ C 6 alkyl, respectively;
  • L 1 is selected from: -(CH 2 ) t -, -C(O)-, -SO 2 -, -C(O)-; where t is 0, 1, 2 or 3;
  • L 2 is selected from: C 1 ⁇ C 6 alkyl, C 2 ⁇ C 6 alkynyl, C 2 ⁇ C 6 alkenyl, C 3 ⁇ C 6 cycloalkyl, 3-6 membered heterocyclic group;
  • R 5 and R 5' are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 alkynyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl group, -(CH 2 ) s -L 3 ; wherein s is 1, 2 or 3, and L 3 is selected from: C 3 ⁇ C 6 cycloalkyl group, 3-6 membered heterocyclic group ;
  • R 5 and R 5' are each independently hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, -CH 2 -C 3 ⁇ C 6 cycloalkyl, more preferably R 5 and R 5'are each independently methyl, ethyl, propyl, butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2
  • R 7 A, B, C, L, R 4, R B, R 4 ', R 6, R 6', R 7, the definition of R 7 'described above.
  • -L 1 -L 2 -C(O)NR a R b is
  • C is a saturated or unsaturated furanyl or tetrahydrofuranyl substituted with 0 to 4 R i , wherein R i is selected from the group consisting of halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, halogen substituted C 1 to C 6 alkyl.
  • ring A and ring B are the same or different, each independently being
  • Each R t is independently selected from: C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy; p is 0, 1, 2, 3 or 4;
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 alkynyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl .
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, preferably, R 5 is selected from: methyl, ethyl , Propyl, butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , allyl.
  • y is 0, 1, 2, 3 or 4;
  • p is 0, 1, 2, 3 or 4;
  • Each R x is independently selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl,
  • Each R t is independently selected from: C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy,
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 2 ' are independently selected from: hydrogen, -SO 2 NH 2, -C ( O) NR a R b; wherein, R a, R b are each independently selected from: hydrogen, C 1 ⁇ C 6 alkyl group.
  • R a, R b are each independently selected from: hydrogen, C 1 ⁇ C 6 alkyl group.
  • y is 0, 1, 2, 3 or 4;
  • Each R x is independently selected from: halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • Each R t is independently selected from: C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • R 2' is independently selected from: hydrogen, -SO 2 NH 2 , -C(O)NR a R b ;
  • R a and R b are each independently selected from: hydrogen, C 1 -C 6 alkyl.
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, preferably methyl, ethyl, propyl, butyl Base, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , Allyl.
  • y is 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • Each R x is independently selected from: halogen, hydroxy, amino, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl;
  • Each R t is independently selected from: C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl; preferably methyl, ethyl, propyl, butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , allyl base;
  • R 2 is independently selected from: hydrogen, -SO 2 NH 2 , -C(O)NR a R b , preferably -C(O)NH 2 ;
  • R a and R b are each independently selected from: hydrogen, C 1 ⁇ C 6 alkyl;
  • R B is selected from: hydrogen, -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i 3 ⁇ 6 membered cycloalkyl, substituted with 0 to 4 R i 3 ⁇ 6 membered heterocycloalkyl group;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are each independently selected from hydrogen and C 1 to C 6 alkyl.
  • Partly with Some are the same or different.
  • R 5 is selected from: hydrogen, C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 alkenyl, halogen substituted C 1 ⁇ C 6 alkyl, preferably methyl, ethyl, propyl, butyl Base, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CHF 2 , CH 2 CH 2 CF 3 , Allyl.
  • L is selected from: substituted with 0 to 4 R n alkenylene substituted C 4 ⁇ C 6, and substituted with 0 to 4 R n substituted C 4 ⁇ C 6 alkylene group, where, R n is selected from From: halogen, hydroxy, amino, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 alkylamino, halogen substituted C 1 to C 6 alkyl.
  • R B is selected from hydrogen and -OR f ;
  • R f is from hydrogen, C 1 to C 6 alkyl substituted with 0 to 4 R h , 3 to 6 membered cycloalkyl substituted with 0 to 4 R i , 3 to 6 substituted with 0 to 4 R i 6-membered heterocycloalkyl;
  • R h is selected from halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i 3 ⁇ 6 membered cycloalkyl, substituted with 0 to 4 R i 3 ⁇ 6 membered heterocycloalkyl group;
  • R i is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl
  • R j and R k are each independently selected from hydrogen, C 1 -C 6 alkyl; more preferably, R B is selected from: H, methoxy,
  • Salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts.
  • the term "salt” as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion (“internal salt") that may be formed is contained in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the compound I can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or by freeze-drying in an aqueous solution.
  • the basic fragments contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate.
  • Benzene sulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g.
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
  • the acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed by organic bases (such as organic amines), such as benzathine and bicyclohexylamine.
  • Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl) And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
  • alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates E.g., dimethyl sulfate, diethyl, dibutyl
  • prodrugs and solvates of the compounds of the present invention are also within the scope of coverage.
  • prodrug herein refers to a compound that undergoes metabolic or chemical transformation to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
  • All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention.
  • the independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them.
  • the chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.
  • the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed.
  • very pure compounds of the invention are also part of the invention.
  • All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures.
  • the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
  • the ratio of the mixture of isomers containing isomers can be varied.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, which are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention.
  • Certain isotope-labeled compounds of the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion.
  • substituents or functional groups Generally, whether the term “substituted” appears before or after the term “optional”, the general formula including substituents in the formula of the present invention means that the substituents of the specified structure are substituted for hydrogen radicals. When a plurality of positions in a specific structure are substituted by a plurality of specific substituents, each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds.
  • the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds.
  • stable here refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • the compound of formula I of the present invention can be prepared by the following steps
  • A, B, L, R 1 , R 2 , R 3 , R 4 , R B , R 2' , R 3' , and R 4' are defined as described above.
  • the compound of the present invention can be obtained by the following steps:
  • L Represents a single bond or a double bond
  • R 4 ' is as described above.
  • the compound of the present invention has excellent STING kinase agonistic activity
  • the compound of the present invention or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, and containing the compound of the present invention are the main activities.
  • the pharmaceutical composition of the components can be used to prevent and/or treat (stabilize, reduce or cure) STING kinase-related diseases such as inflammatory diseases (acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel Disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation caused by house dust mites and interstitial cystitis), autoimmune diseases, infectious diseases (such as hepatitis B) Infectious diseases caused by viruses, human papillomavirus, nasopharyngeal carcinoma-related Epstein-Barr virus, etc.), cancers (such as colon cancer, brain cancer, breast cancer, fibrosarcoma and squamous cell carcinoma, melanoma, breast cancer, colon cancer) , Lung cancer and ovarian cancer), diseases related to precancerous syndrome.
  • inflammatory diseases acne vulgaris
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-200 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as STING agonists).
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (such as STING agonists).
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used for the prevention and/or treatment of STING simultaneously, separately or sequentially with the compound of the present invention Diseases related to kinase activity or expression.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the compound of the present invention has a novel structure and excellent STING kinase activation effect
  • the compounds of the present invention can be used to prepare STING agonists, which have better pharmacodynamics and pharmacokinetic properties.
  • the compound prepared by the present invention has a better activation effect on STING than the positive control (ADU-S100, GSK compound 3, GSK compound 1). Good or equivalent, it provides a new option for clinical screening and/or preparation of drugs for diseases related to STING activity.
  • the structure of the compound was determined by nuclear magnetic resonance ( 1 H-NMR) or mass spectrometry (MS).
  • the NMR measurement was carried out by BrukerAV-300 nuclear magnetic resonance instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-D 6 ) or deuterated chloroform (CDCl 3 ), and TMS was the internal standard.
  • DMSO-D 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • Ethyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (1 g, 5.49 mmol) was dissolved in a mixed solution of methanol (10 mL) and water (5 mL). After stirring for ten minutes at room temperature, lithium hydroxide (0.263 g, 10.98 mmol) was added to the above reaction solution. Continue to react at room temperature for 3 hours, remove methanol by distillation under reduced pressure, adjust the pH to 5-6 with dilute hydrochloric acid, and obtain a white solid by suction filtration. Without purification, it was directly used in the next reaction.
  • Step a Synthesis of (4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)butyl) tert-butyl carbamate
  • Step b Synthesis of 4-((4-aminobutyl)amino)-3-methoxy-5-nitrobenzamide hydrochloride
  • Step c 4-((4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)butyl)amino)-2,2-dimethyl-5-nitro Synthesis of -2,3-dihydrobenzofuran-7-carboxamide
  • Step d 5-amino-4-((4-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)butyl)amino)-2,2-dimethyl-2 Synthesis of ,3-Dihydrobenzofuran-7-carboxamide
  • Step e 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo [d]Imidazol-1-yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,7-dimethyl-7,8- Synthesis of dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxamide
  • step c The operation process and reaction conditions are the same as in Example 1, except that the raw material in step c is 4-chloro-2-methyl-5-nitrobenzofuran-7-carboxamide, a pale yellow solid, and the yield is 68%.
  • Step b Synthesis of (E)-4-((4-aminobut-2-en-1-yl)amino)-2-methyl-5-nitrobenzofuran-7-carboxamide hydrochloride
  • Step c (E)-4-((4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)amino)-2 Synthesis of -methyl-5-nitrobenzofuran-7-carboxamide
  • Step e (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy- 1H-Benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7 Synthesis of -Methyl-1H-benzofuro[4,5-d]imidazole-5-carboxamide
  • Step a (E)-4-((4-((2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoyl-6-nitrobenzene (Yl)amino)but-2-en-1-yl)amino)-2-methyl-5-nitrobenzofuran-7-carboxamide
  • Step b (E)-5-amino-4-((4-((2-amino-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-amino Synthesis of formylphenyl)amino)but-2-en-1-yl)amino)-2-methylbenzofuran-7-carboxamide
  • Step c ((E)-1-(4-(7-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5-carbamoyl-2-(1-ethyl 3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl Synthesis of -3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuro[4,5-d]imidazole-5-carboxamide
  • Step d (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxy Propoxy)-1H-benzo(d)imidazopiperazin-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5 -Carboxamido)-7-methyl-1H-benzofuro[4,5-d]imidazole-5-carboxamide
  • step c The operation process and reaction conditions are the same as in Example 3, except that the raw material in step c is 4-chloro-2-methyl-5-nitrobenzofuran-7-carboxamide, an off-white solid, and the yield is 61%.
  • Example 8 The operation process and reaction conditions are the same as in Example 8.
  • the different raw material is 1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate, pale yellow solid , The yield is 78%.
  • Example 23 The effect of the compound on the activation of type I interferon pathway (ISG) produced by human peripheral blood mononuclear cell line PBMC cells
  • the function of STING agonist was evaluated by detecting the changes of type I interferon IFN ⁇ produced by the compound stimulated human peripheral blood mononuclear cell line PBMC cells (AllCells, Cat#: PB005F).
  • PBMC cells AllCells, Cat#: PB005F.
  • the test compound was dissolved in DMSO to prepare a mother liquor with a concentration of 10 mM.
  • the compound was diluted to 100 times the working concentration (working concentrations were 30, 10, 3.33, 1.11, 0.370, 0.123, 0.0412, 0.0137uM). Collect PBMCs and adjust to a cell concentration of 5x10 ⁇ 5/ml.
  • the experimental results indicate that the compound prepared by the present invention has an activating effect on STING, and can be used to prepare drugs for activating STING or diseases related to STING activity.
  • Example 24 The effect of the compound on the activation of type I interferon pathway (ISG) in human THP1-Dual cells
  • THP1-Dual cells were purchased from InvivoGen company.
  • the compound was dissolved into 10 mM compound with DMSO.
  • Each well of a 96-well cell culture plate was added with 20 ⁇ L of the compound diluted with DMSO/physiological saline, the concentration of the compound was 100 ⁇ M, and the concentration of the positive control ADU-S100 was 100 ⁇ M.
  • the untreated control group was added with 20 ⁇ l of physiological saline containing 1% DMSO. Set 3 repeating holes for each.
  • the THP1-Dual cells adjust the cell concentration to 1 ⁇ 10 6 /ml, add 180 ⁇ l of cells to each well for incubation. Therefore, the final volume of each test well is 200 ⁇ l, the content of DMSO is 0.1%, and the test concentration of the compound is 10 ⁇ M.
  • the final concentration of the positive control ADU-S100 was 10 ⁇ M and incubated for 24 hours; the other blank group was added with 200 ⁇ l culture medium. After 24 hours, take 20 ⁇ l of culture medium from each well to a new bottom-transmissive 96-well plate, add 50 ⁇ l of luciferase detection reagent QUANTI-Luc TM , and immediately measure the fluorescence value.
  • the experimental results show that the compound prepared by the present invention has a better or equivalent activating effect on STING than the positive control (ADU-S100, GSK compound 3, GSK compound 1), especially the compounds 16, 18, and 20.
  • the positive control ADU-S100 has an activating effect on STING 2-3 times or more than that of the positive control.
  • GSK compound 3 its activating effect on STING is more than twice that of the positive control. Therefore, the compound of the present invention can It is used to prepare medicines for activating STING or diseases related to STING activity.
  • Example 25 Pharmacodynamic study of the compound of the present invention in CT26 colon cancer subcutaneous transplantation tumor model
  • mice 4-6 weeks old Balb/C female mice were used, and each mouse was injected with CT26 cells (2.5*10 5 ) under the axillary skin. Observe the tumor growth in mice.
  • the tumor volume grows to 50-100mm 3
  • the compound 19 of the present invention and the negative control are administered.
  • the dosage of each group was 0.1 mg/kg and 0.3 mg/kg, respectively.
  • the experimental results are evaluated in the form of tumor volume growth curve, and the experimental results are shown in Figure 1.
  • the compound 19 of the present invention has a significant anti-tumor effect.
  • Example 26 Pharmacodynamic study of the compound of the present invention in EMT6 breast cancer orthotopic xenograft model
  • mice 4-6 weeks old Balb/C female mice were used, and each mouse was injected with EMT6 cells (2.5*10 5 ) under the axillary skin. Observe the tumor growth of the mice , and start grouping when the tumor volume grows to 50-100 mm3 , and give compound 19 of the present invention and a negative control on the first, fourth, and ninth days.
  • the dosage of compound 19 of the present invention is 1 mg/kg.
  • the experimental results are evaluated in the form of tumor volume growth curve, and the experimental results are shown in Figure 2.
  • the compound 19 of the present invention has a significant anti-tumor effect.

Abstract

一种通式(I)的杂环酰胺类化合物、其可药用盐及其制备方法，以及所述化合物在制备治疗与STING活性相关的疾病的药物中的用途、在制备免疫佐剂中的用途、在制备激活STING药物中的用途。

Description

杂环酰胺类化合物、其可药用的盐及其制备方法和用途 技术领域
本发明涉及杂环酰胺类化合物及其可药用的盐、其制备方法和用途。
背景技术
近年来，免疫疗法的出现显示出改变癌症治疗方法的潜力。通过免疫检查点阻断释放抗肿瘤T细胞反应，在无法治疗的肿瘤中产生了显著的反应。扩大免疫治疗方法有效性的主要领域之一是要找到能够免疫免疫地转变“冷”到肿瘤“热”的方法，并因此克服局部免疫抑制机制，增加免疫检查等方法的有效性。这些类型的方法包括使用免疫刺激性单克隆抗体(例如抗-OX40，一种激动性单克隆抗体针对受体OX40或BB1，靶向CD74)直接刺激T细胞活性和溶瘤病毒，它可以选择性地和特异性地裂解肿瘤细胞，建立炎症微环境。局部免疫刺激的一个策略是激活STING通路，这是一个关键的传感***，它允许先天免疫***对感染和肿瘤生长做出反应，协调免疫反应。
在细胞质中，环GMP-AMP合成酶(cGAS)与来自病原体or宿主受损细胞的dsDNA结合，产生小分子配体，环GMP-AMP(cGAMP)。cGAMP与内质网(ER)上的STING二聚体结合后，STING被SER/THR激酶--TANK-binding kinase 1(TBK1)磷酸化。磷酸化的STING招募了一个转录因子，干扰素调节因子3(IRF3)，并促进TBK1磷酸化IRF3，导致IRF3二聚化。IRF3二聚体后转移到细胞核，与IFN-β启动子结合,导致IFN-β和其他细胞因子的产生。
自STING被发现以来，其被发现在感染疾病，癌症以及自身免疫性疾病中扮演重要角色。因此，STING逐步发展成为一个潜在的免疫疗法靶点。细菌CDN直接激活STING已通过X射线晶体学进行验证(Burdette DL et al.Nature Immunolog,2013(14):19-26)。已发现新的CDN信号转导分子cGAMP可激活STING，其与STING的相互作用也已经通过X射线晶体学进行验证(Cai X et al.Molecular Cell,2014(54):289-296)。合成具有良好成药性的STING激动剂可以用来作为佐剂，抗肿瘤药物或者其他免疫疗法制剂。
发明内容
发明目的：本发明目的是提供一种结构新颖的杂环酰胺类化合物及其可药用的盐。
本发明另一目的是提供一种药物组合物。
本发明另一目的是提供所述杂环酰胺类化合物及其可药用的盐的制备方法。
本发明最后一目的是提供所述杂环酰胺类化合物及其可药用的用途。
本发明第一方面，提供一种杂环酰胺类化合物、其可药用的盐，
Figure PCTCN2020116614-appb-000001
其中，
A环选自
Figure PCTCN2020116614-appb-000002
B环选自
Figure PCTCN2020116614-appb-000003
C选自被0～4个R i任选取代的饱和或不饱和的4～6元碳环或杂环；
R 4、R 4’分别选自氢、C 1～C 6烷基、卤素；
R 5、R 5’分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 6、R 7分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6、R 7及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 6’、R 7’分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6’、R 7’及与R 6’、R 7’连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 1、R 2、R 3、R 2’、R 3’分别选自氢、-OR d、-NR dR e、卤素、CN、C(O)OR d、C 1～C 6烷基、卤素取代的C 1～C 6烷基、-SO 2NH 2、-C(O)NR aR b；
R a、R b、R d、R e分别选自氢、C 1～C 6烷基；
R B选自氢、卤素、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g、-NR fC(O)R g、-NR fC(O)R；R B、R 1以及与R B、R 1连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R f、R g分别选自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基；
R j、R k分别选自氢、C 1～C 6烷基；
L选自被0～4个R n取代的C 4～C 6的亚烷基、被0-4个R n取代的C 4～C 6的亚烯基、被0～4个R n取代的C 4～C 6的亚炔基；C 4～C 6的亚烷基、C 4～C 6的亚烯基、C 4～C 6的亚炔基中的碳原子被-O-、-S-、-NR m-取代；
R m选自氢、C 1～C 6烷基；
R n选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基。
在另一优选例中，通式(I)的杂环酰胺类化合物、其可药用的盐具有如下特征：
Figure PCTCN2020116614-appb-000004
其中，
A环选自
Figure PCTCN2020116614-appb-000005
B环选自
Figure PCTCN2020116614-appb-000006
C选自被0～4个R i取代的饱和或不饱和的4～6元碳环或杂环；
R 4、R 4’分别选自氢、C 1～C 6烷基、卤素；
R 5、R 5’各自独立地为分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基、-(CH 2) s-L 3；其中，s为1、2或3，L 3选自：C 3～C 6环烷基、3-6元杂环基；
R 6、R 7分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6、R 7及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 6’、R 7’分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6’、R 7’及与R 6’、R 7’连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 1、R 2、R 3、R 2’、R 3’分别选自氢、-OR d、-NR dR e、卤素、CN、C(O)OR d、C 1～C 6烷基、卤素取代的C 1～C 6烷基、-SO 2NH 2、-C(O)NR aR b、-L 1-L 2-C(O)NR aR b；
R a、R b、R d、R e分别选自氢、C 1～C 6烷基；
L 1选自：-(CH 2) t-、-C(O)-、-SO 2-、-C(O)-；其中，t为0、1、2或3；
L 2选自：C 1～C 6烷基、C 2～C 6炔烃基、C 2～C 6烯烃基、C 3～C 6环烷基、3-6元杂环基；
R B选自氢、卤素、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、- CO 2R f、-C(O)NR fR g；或者R B、R 1以及与R B、R 1连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R f、R g分别选自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基；
R j、R k分别选自氢、C 1～C 6烷基；
L选自被0～4个R n取代的C 4～C 6的亚烷基、被0-4个R n取代的C 4～C 6的亚烯基、被0～4个R n取代的C 4～C 6的亚炔基；所述C 4～C 6的亚烷基、C 4～C 6的亚烯基、C 4～C 6的亚炔基中的碳原子可以被-O-、-S-、-NR m-取代；
R m选自氢、C 1～C 6烷基；
R n选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基。
在另一优选例中，R 5、R 5’各自独立地为氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基、-CH 2-C 3～C 6环烷基，更佳地R 5、R 5’各自独立地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基、
Figure PCTCN2020116614-appb-000007
在另一优选例中，C为被0～4个R i取代的饱和或不饱和的呋喃基或四氢呋喃基，其中，R i选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基。
在另一优选例中，所述的式I杂环酰胺类化合物、其可药用的盐，其中，A环与B环相同或不同，各自独立地为
Figure PCTCN2020116614-appb-000008
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；p为0、1、2、3或4；
R 5的定义如上所述。
在另一优选例中，所述的式I杂环酰胺类化合物、其可药用的盐，其中，A环与B环相同，各自独立地为
Figure PCTCN2020116614-appb-000009
其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基。
在另一优选例中，A环与B环相同，各自独立地为
Figure PCTCN2020116614-appb-000010
其中，R 5选自：甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基。
在另一优选例中，所述的式I杂环酰胺类化合物、其可药用的盐，其中，所述的
Figure PCTCN2020116614-appb-000011
部分选自：
Figure PCTCN2020116614-appb-000012
Figure PCTCN2020116614-appb-000013
其中，y为0、1、2、3或4；
p为0、1、2、3或4；
各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基，
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基，
R 5、R 2'的定义如上所述。
在另一优选例中，
Figure PCTCN2020116614-appb-000014
部分为
Figure PCTCN2020116614-appb-000015
Figure PCTCN2020116614-appb-000016
其中，
y为0、1、2、3或4；
各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基；
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；
R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 2’独立地选自：氢、-SO 2NH 2、-C(O)NR aR b；
其中，R a、R b各自独立地选自：氢、C 1～C 6烷基。
在另一优选例中，
Figure PCTCN2020116614-appb-000017
部分为
Figure PCTCN2020116614-appb-000018
其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基，较佳地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基。
在另一优选例中，所述的式I杂环酰胺类化合物、其可药用的盐，其中，
Figure PCTCN2020116614-appb-000019
部分选自：
Figure PCTCN2020116614-appb-000020
Figure PCTCN2020116614-appb-000021
Figure PCTCN2020116614-appb-000022
其中，
y为0、1、2、3或4；
p为0、1、2、3或4；
各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基；
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；
R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 2独立地选自：氢、-SO 2NH 2、-C(O)NR aR b；
其中，R a、R b各自独立地选自：氢、C 1～C 6烷基；
R B选自：氢、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别独立地选自氢、C 1～C 6烷基。
在另一优选例中，
Figure PCTCN2020116614-appb-000023
部分为
Figure PCTCN2020116614-appb-000024
其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 2独立地选自：氢、-SO 2NH 2、-C(O)NR aR b；
其中，R a、R b各自独立地选自：氢、C 1～C 6烷基；
R B选自：氢、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别独立地选自氢、C 1～C 6烷基。
在另一优选例中，
Figure PCTCN2020116614-appb-000025
部分为
Figure PCTCN2020116614-appb-000026
其中，R 2独立地为-C(O)NH 2；
R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基，较佳地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基；
R B选自：氢、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别独立地选自氢、C 1～C 6烷基。
在另一优选例中，
Figure PCTCN2020116614-appb-000027
部分与
Figure PCTCN2020116614-appb-000028
部分相同或不同。
在另一优选例中，
Figure PCTCN2020116614-appb-000029
部分与
Figure PCTCN2020116614-appb-000030
部分相同，各自独立地为
Figure PCTCN2020116614-appb-000031
其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基，较佳地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基。
在另一优选例中，L选自：被0～4个R n取代的C 4～C 6的亚烯基、被0～4个R n取代的C 4～C 6的亚烷基，其中，R n选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基。
在另一优选例中，所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐，其中，R B选自氢、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别独立地选自氢、C 1～C 6烷基。
在另一优选例中，所述的式I杂环酰胺类化合物、其可药用的盐，其中，R B选自：H、甲氧基、
Figure PCTCN2020116614-appb-000032
Figure PCTCN2020116614-appb-000033
在另一优选例中，R 4、R 4’分别为H。
在另一优选例中，R 1、R 3、R 1’、R 3’分别为氢。
在另一优选例中，R 4、R 4’分别为氢；
R 5、R 5’分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 6、R 7分别选自氢、C 1～C 6烷基，R 6、R 7及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 6’、R 7’分别选自氢、C 1～C 6烷基，R 6’、R 7’及与R 6’、R 7’连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 1、R 3、R 3’分别选自氢、C 1～C 6烷基、-OR d；
R 2、R 2’分别选自氢、-SO 2NH 2、-C(O)NR aR b；
R a、R b分别选自氢、C 1～C 6烷基；
R d选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R B选自氢、被0～4个R h取代的C 1～C 6烷基、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别选自氢、C 1～C 6烷基；
L选自C 4～C 6的亚烯基、C 4～C 6的亚烷基。
在另一优选例中，R 6、R 7分别独立地选自氢、C 1～C 6烷基；
R 6’、R 7’分别独立地选自氢、C 1～C 6烷基；
R 1、R 3、R 3’分别独立地选自氢、C 1～C 6烷基；
R 2、R 2’分别独立地选自氢、-SO 2NH 2、-C(O)NH 2；
R B选自氢、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别独立地选自氢、C 1～C 6烷基。
在另一优选例中，L为
Figure PCTCN2020116614-appb-000034
其中，
Figure PCTCN2020116614-appb-000035
表示单键或双键。
在另一优选例中，A、B、C、L、R 1、R 2、R 3、R 4、R B、R 2'、R 3'、R 4'为实施例中各具体化合物相对应的具体基团。
在另一优选例中，所述的杂环酰胺类化合物、其可药用的盐，为如下任一种：
Figure PCTCN2020116614-appb-000036
在另一优选例中，所述化合物为实施例中所示化合物。
本发明第二方面，提供一种药物组合物，其含有治疗有效量的一种或多种第一方 面所述具有通式(I)的的杂环酰胺类化合物、其可药用的盐，及药学上可接受的载体。
本发明第三方面，提供一种药物组合物，其含有治疗有效量的一种或多种第一方面所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐，及药学上可接受的辅料。
本发明第四方面，提供一种第一方面所述具有通式(I)的杂环酰胺类化合物、其可药用的盐的制备方法，其中：包括如下步骤：
Figure PCTCN2020116614-appb-000037
(i)在惰性溶剂中，碱存在下，原料1a与单Boc保护的二胺
Figure PCTCN2020116614-appb-000038
发生亲核取代反应，生成化合物1b；
(ii)在惰性溶剂中，酸存在下，化合物1b脱去Boc保护，生成中间体1c；
(iii)在惰性溶剂中，碱存在下，中间体1c与
Figure PCTCN2020116614-appb-000039
发生取代反应，生成中间体1d；
(iv)在惰性溶剂中，在还原剂存在下，中间体1d生成化合物1e；
(v)在惰性溶剂中，催化剂存在下，化合物1e与
Figure PCTCN2020116614-appb-000040
反应，获得目标化合物I；
式中，A、B、L、R 1、R 2、R 3、R 4、R B、R 2'、R 3'、R 4'的定义如上所述。
本发明第五方面，提供一种第一方面所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐在制备免疫佐剂中的用途。
本发明第六方面，提供一种第一方面所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐在制备激活STIGN药物中的用途。
本发明第七方面，提供一种第一方面所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐在制备治疗与STIGN活性相关的疾病的药物中的用途，所述与STIGN活 性相关的疾病是与炎性、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
在另一优选例中，STING活性相关的疾病包括炎性、变应性和自身免疫性疾病、感染性疾病、癌症、癌前期综合征。
在另一优选例中，所述癌症选自下组：结肠癌、乳腺癌(如，浸润性导管癌、非浸润性导管癌、炎性乳腺癌)、肺癌(如，非小细胞肺癌、小细胞肺癌、恶性间皮瘤)和卵巢癌(如，卵巢上皮癌、卵巢生殖细胞瘤、卵巢低度恶性潜能肿瘤)、脑癌、纤维肉瘤和鳞状细胞癌、黑素瘤、等癌症。
在另一优选例中，所述炎性疾病选自：寻常性痤疮、哮喘、腹腔疾病、慢性***炎、肾小球肾炎、炎症性肠病、***、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症和间质性膀胱炎。
在另一优选例中，所述感染性疾病是由病毒引起的感染性疾病，其中，所述病毒选自：乙肝病毒、人***瘤病毒、鼻咽癌相关EB病毒。
在另一优选例中，所述炎性疾病与所述自身免疫性疾病之间存在显著重叠。
在另一优选例中，所述炎性疾病为哮喘。
本发明第八方面，提供一种诱导受试者中的免疫反应的方法，所述方法包括将治疗有效量的第一方面所述的化合物或第二方面所述的药物组合物给药至所述受试者。
在另一优选例中，所述的受试者为为哺乳动物，较佳地为人。
本发明第九方面，提供一种激活STING活性的方法，包括步骤：将本发明第一方面所述的化合物或其药学可接受的盐与体细胞(或组织)接触，从而激活STING活性。
在另一优选例中，所述的体细胞(或组织)来自啮齿动物(如小鼠、大鼠)、或灵长动物(如人)。
本发明第十方面，提供一种治疗STING活性相关的疾病的方法，包括向对其有需要的受试者施用治疗有效量的第一方面所述的化合物或第二方面所述的药物组合物。
本发明所定义的STING活性相关的疾病是STING在该疾病的病理发生中起作用的疾病。STING活性相关的疾病包括炎性、变应性和自身免疫性疾病、感染性疾病、癌症、癌前期综合征等。
附图说明
图1示出了化合物19在CT26结肠癌模型中的体内抗肿瘤活性。
图2示出了化合物19在EMT6乳腺癌原位移植瘤模型中的体内抗肿瘤活性。
具体实施方式
本发明人经过广泛而深入的研究，首次意外地开发了一种结构新颖的杂环酰胺类化合物，并且实验结果表明，本发明化合物对STING具有较好的激活作用，能够用于 制备治疗与激活STING或与STING活性相关的疾病的药物。在此基础上完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
术语“烷基”本身或作为另一取代基的一部分，是指具有指定的碳原子数的直链或支链烃基(即，C1-C6是指包含1、2、3、4、5或6个碳原子)。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。本申请中，烷基还意在包含取代烷基，即烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子(或C2-C8)的直链或支链的烃基。例如，本发明中，“C2-C6烯基”含有2、3、4、5或6个碳原子的烯基，“C3-C6烯基”。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明中，烯基包括取代的烯基。
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子(或C2-C8)的直链或支链的烃基。本发明中，“C2-6炔基”是指具有2、3、4、5或6个碳原子的直链或支链的炔基，包括但不限于乙炔基、丙炔基或类似基团。本发明中，炔基还包括取代炔基，取代基可以为卤代、羟基、氰基、硝基等。
术语"烷氨基"指通过氨基连接于分子的其余部分的烷基，本发明中，“C 1～C 6烷氨基”具有式C 1～C 6烷基-NH-。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团，例如-CH 2CH 2CH 2CH 2-。烷基(或亚烷基)通常具有1-24个碳原子，其中本发明优选具有10个或更少碳原子的那些基团(如C 4～C 6亚烷基)。类似地，“亚烯基”或“亚炔基”分别指具有双键或三键的不饱和形式的“亚烷基”。“亚烯基”或“亚炔基”的实例包括但不限于：亚乙烯基、亚并烯基、
Figure PCTCN2020116614-appb-000041
Figure PCTCN2020116614-appb-000042
等。
本发明中，“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链或环状烷氧基(如C3-C6环烷氧基)，代表性的例子包括(但并不限于)：甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C3烷氧基。
术语“环烷基”是指包括饱和单环或双环(如，稠合双环或螺双环)或多环的环状烷基。本发明中，“3～6元环烷基”指包括3、4、5、6个碳原子的环状烷基。本发明的代表性的环烷基包括但不限于：环丙基、环丁基、环戊基、环己基等。应理解，取代或未取代的环烷基，例如支化环烷基(如1-甲基环丙基和2-甲基环丙基)，均包括 在“环烷基”的定义中。
术语“杂环烷基”是指是指含有一至五个选自N、O和S的杂原子的环烷基，其中氮和硫原子任选被氧化，且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。本发明中，“3～6元杂环烷基”是指C3～6环烷基中的1或2个环C原子被选自N、O和S的杂原子取代的基团，杂环烷基的例子包括但不限于：吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、苯邻二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以经环碳或杂原子连接于分子的其余部分。
术语“杂环基”是指具有选自N、S和O的杂原子的饱和或部分饱和的环状基团，其可以是单环，也可以是双环形式，例如桥环或螺环形式。杂环基优选3-8元杂环基，更优选地为4-6元杂环基，更优选地为5-6元杂环基。杂环基的实例包括但不限于：氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基和吡咯烷基等。
术语“杂芳基”指具有1-3个原子为选自下组N、S和O的杂原子的环状芳香基，其可以是单环，也可以是稠环形式。本发明中，杂芳基优选地为5-6元杂芳基。杂芳基的实例包括但不限于：吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-***基以及(1,2,4)-***基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明中“碳环或杂环”单独或作为其他基团的一部分是指单环的或双环的饱和的、部分饱和的或芳族的碳环(例如，如上所述的环烷基、环烯基、苯基等)，或者单环的或双环的的饱和的、部分饱和的或芳族的杂环(例如，如上所述的杂烷基、杂环基、杂芳基等)，其中，4～6元碳环或杂环是指包含4-6个环原子的碳环或杂环，优选地为5-6元碳环或杂环。碳环或杂环的实例包括，但不限于：环丙基、环丁基、环戊基、环己基、环戊烯基、环己烯基、环戊二烯基、环己二烯基、氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基、吡咯烷基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-***基以及(1,2,4)-***基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
在本发明中，“氨基”是指具有-N(R)(R')结构，R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
在本发明中，上述的烷基、烷氧基、环烷基、杂芳基、杂环烷基、烯基、炔烃、杂环、碳环、杂环基等中各基团可以是取代的或未取代的。
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所 取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、氰基、硝基、氧代(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e，P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e、NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中，R a可以独立表示氢、氘、烷基、环烷基、烯基、炔基、碳环或杂环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、碳环或杂环，或者R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、碳环或杂环可以任选取代。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。
术语“卤代”或“卤素”包括氟、氯、溴和碘。
术语“羟基”指-OH。
本发明中，“R 6、R 7以及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环”中的“环化”是指R 6、R 7与其连接的C原子稠合形成并环，同理，R 6'和R 7'、R B和R 1中的环化具有相同含义。其中，所述的4～6元碳环或杂环上述定义，且意在包含取代或未取代的4～6元碳环或杂环，所述的取代是指被选自下组的一个或多个(1、2、3、4)取代基取代：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基。
本发明中的-C(O)NR aR b、-C(O)OR、-C(O)R、-NRC(O)R的-C(O)-表示由碳和氧两种原子通过双键链接而成的羰基(-C＝O-)。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括涉及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
本发明的式I化合物具有如下结构
Figure PCTCN2020116614-appb-000043
其中，
A环选自
Figure PCTCN2020116614-appb-000044
B环选自
Figure PCTCN2020116614-appb-000045
C选自被0～4个R i取代的饱和或不饱和的4～6元碳环或杂环；
R 4、R 4’分别选自氢、C 1～C 6烷基、卤素；
R 5、R 5’分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 6、R 7分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者，R 6、R 7及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 6’、R 7’分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者，R 6’、R 7’及与R 6’、R 7’连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R 1、R 2、R 3、R 2’、R 3’分别选自氢、-OR d、-NR dR e、卤素、CN、C(O)OR d、C 1～C 6烷基、卤素取代的C 1～C 6烷基、-SO 2NH 2、-C(O)NR aR b；
R a、R b、R d、R e分别选自氢、C 1～C 6烷基；
R B选自氢、卤素、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g、-NR fC(O)R g；或者R B、R 1以及与R B、R 1连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
R f、R g分别选自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基；
R j、R k分别选自氢、C 1～C 6烷基；
L选自被0～4个R n取代的C 4～C 6的亚烷基、被0-4个R n取代的C 4～C 6的亚烯基、被0～4个R n取代的C 4～C 6的亚炔基；所述C 4～C 6的亚烷基、C 4～C 6的亚烯基、C 4～C 6的亚炔基中的碳原子可以被-O-、-S-、-NR m-取代；
R m选自氢、C 1～C 6烷基；
R n选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基。
本发明中，所述的式I化合物还可以具有如下结构：
Figure PCTCN2020116614-appb-000046
其中，
A环选自
Figure PCTCN2020116614-appb-000047
B环选自
Figure PCTCN2020116614-appb-000048
R 1、R 2、R 3、R 2’、R 3’分别选自氢、-OR d、-NR dR e、卤素、CN、C(O)OR d、C 1～C 6烷基、卤素取代的C 1～C 6烷基、-SO 2NH 2、-C(O)NR aR b、-L 1-L 2-C(O)NR aR b(新增化合物15不在原来范围内)；
R a、R b、R d、R e分别选自氢、C 1～C 6烷基；
L 1选自：-(CH 2) t-、-C(O)-、-SO 2-、-C(O)-；其中，t为0、1、2或3；
L 2选自：C 1～C 6烷基、C 2～C 6炔烃基、C 2～C 6烯烃基、C 3～C 6环烷基、3-6元杂环基；
R 5、R 5’各自独立地为分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基、-(CH 2) s-L 3；其中，s为1、2或3，L 3选自：C 3～C 6环烷基、3-6元杂环基；较佳地，R 5、R 5’各自独立地为氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基、-CH 2-C 3～C 6环烷基，更佳地R 5、R 5’各自独立地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基、
Figure PCTCN2020116614-appb-000049
A、B、C、L、R 4、R B、R 4'、R 6、R 6’、R 7、R 7’的定义如上所述。
优选地，-L 1-L 2-C(O)NR aR b为
Figure PCTCN2020116614-appb-000050
优选地，C为被0～4个R i取代的饱和或不饱和的呋喃基或四氢呋喃基，其中，R i选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基。
优选地，A环与B环相同或不同，各自独立地为
Figure PCTCN2020116614-appb-000051
Figure PCTCN2020116614-appb-000052
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；p为0、1、2、3或4；
R 5选自：氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基。
优选地，上述化合物中，A环与B环相同，各自独立地为
Figure PCTCN2020116614-appb-000053
其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基，较佳地，R 5选自：甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基。
优选地，上述化合物中，
Figure PCTCN2020116614-appb-000054
部分选自：
Figure PCTCN2020116614-appb-000055
其中，y为0、1、2、3或4；p为0、1、2、3或4；
各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基，
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基，
R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 2’独立地选自：氢、-SO 2NH 2、-C(O)NR aR b；其中，R a、R b各自独立地选自：氢、C 1～C 6烷基。优选地，上述化合物中，
Figure PCTCN2020116614-appb-000056
部分为
Figure PCTCN2020116614-appb-000057
其中，
y为0、1、2、3或4；
各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基；
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；
R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
R 2’独立地选自：氢、-SO 2NH 2、-C(O)NR aR b；
其中，R a、R b各自独立地选自：氢、C 1～C 6烷基。
优选地，上述化合物中，
Figure PCTCN2020116614-appb-000058
部分为
Figure PCTCN2020116614-appb-000059
其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基，较佳地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基。
优选地，上述化合物中，
Figure PCTCN2020116614-appb-000060
部分选自：
Figure PCTCN2020116614-appb-000061
Figure PCTCN2020116614-appb-000062
较佳地为
Figure PCTCN2020116614-appb-000063
其中，
y为0、1、2、3或4；
p为0、1、2、3或4；
各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基；
各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；
R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；较佳地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基；
R 2独立地选自：氢、-SO 2NH 2、-C(O)NR aR b，较佳地为-C(O)NH 2；
其中，R a、R b各自独立地选自：氢、C 1～C 6烷基；
R B选自：氢、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别独立地选自氢、C 1～C 6烷基。
优选地，
Figure PCTCN2020116614-appb-000064
部分与
Figure PCTCN2020116614-appb-000065
部分相同或不同。
优选地，
Figure PCTCN2020116614-appb-000066
部分与
Figure PCTCN2020116614-appb-000067
部分相同，各自独立地为
Figure PCTCN2020116614-appb-000068
其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基，较佳地为甲基、乙基、丙基、丁基、CH 2F、CHF 2、CF 3、CH 2CH 2F、CH 2CHF 2、CH 2CF 3、CH 2CH 2CH 2F、CH 2CH 2CHF 2、CH 2CH 2CF 3、烯丙基。
优选地，L选自：被0～4个R n取代的C 4～C 6的亚烯基、被0～4个R n取代的C 4～C 6的亚烷基，其中，R n选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基。
优选地，上述化合物中，R B选自氢、-OR f；
R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
R i选自卤素、羟基、氨基、C 1～C 6烷基；
R j、R k分别独立地选自氢、C 1～C 6烷基；更优选地，R B选自：H、甲氧基、
Figure PCTCN2020116614-appb-000069
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N- 二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements，CAS version，Handbook of Chemistry and Physics，75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito:1999，也有说明，其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷 基。所有异构体以及它们的混合物，都包涵在本发明中。
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为 本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
化合物的制备方法
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～150℃，优选10℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
优选地，本发明式I化合物可用如下步骤制得
Figure PCTCN2020116614-appb-000070
(i)在惰性溶剂(如正丁醇)中，碱(N，N-二异丙基乙胺)存在下，原料1a与单Boc保护的二胺
Figure PCTCN2020116614-appb-000071
发生亲核取代反应，生成化合物1b；
(ii)在惰性溶剂(如乙酸乙酯)中，酸(盐酸)存在下，化合物1b脱去Boc保护，生成中间体1c；
(iii)在惰性溶剂(正丁醇)中，碱(N，N-二异丙基乙胺)存在下，中间体1c与
Figure PCTCN2020116614-appb-000072
发生取代反应，生成中间体1d；
(iv)在惰性溶剂(甲醇)中，在还原剂(连二亚硫酸钠)存在下，中间体1d生成化合物1e；
(v)在惰性溶剂(如N,N-二甲基甲酰胺和/或二氧六环)中，催化剂(如EDCI)存在下，化合物1e与
Figure PCTCN2020116614-appb-000073
反应，获得目标化合物I；
式中，A、B、L、R 1、R 2、R 3、R 4、R B、R 2'、R 3'、R 4'的定义如上所述。
优选地，本发明化合物可通过如下步骤获得：
Figure PCTCN2020116614-appb-000074
原料1a与单Boc保护的丁二胺或反式丁烯-1,4-二胺在正丁醇中N，N-二异丙基乙胺存在下，发生亲核取代反应生成化合物1b，在乙酸乙酯的盐酸溶液中脱去Boc保护生成中间体1c，后在正丁醇中N，N-二异丙基乙胺存在下与
Figure PCTCN2020116614-appb-000075
发生取代反应生成中间体1d，中间体1d在甲醇中经连二亚硫酸钠还原生成化合物1e，然后与不同的异硫氰酸酯
Figure PCTCN2020116614-appb-000076
在EDCI条件下缩合获得目标化合物；
式中，L为
Figure PCTCN2020116614-appb-000077
其中，
Figure PCTCN2020116614-appb-000078
表示单键或双键；
A、B、R 1、R 2、R 3、R 4、R B、C、R 2'、R 3'、R 4'的定义如上所述。
药物组合物和施用方法
由于本发明化合物具有优异的STING激酶的激动活性，因此本发明化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)STING激酶相关疾病例如，炎性疾病(寻常性痤疮、哮喘、腹腔疾病、慢性***炎、肾小球肾炎、炎症性肠病、***、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症和间质性膀胱炎)、自身免疫性疾病、感染性疾病(如由乙肝病毒、人***瘤病毒、鼻咽癌相关EB病毒等引起的感染性疾病)、癌症(如结肠癌、脑癌、乳腺癌、纤维肉瘤和鳞状细胞癌、黑素瘤、乳腺癌、结肠癌、肺癌和卵巢癌等癌症)、癌前期综合征相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的 赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2020116614-appb-000079
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙 烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如STING激动剂)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如STING激动剂)。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗STING激酶的活性或表达量相关的疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点在于：
1.本发明的化合物结构新颖且具有优异的STING激酶激活作用；
2.本发明的化合物可以制备STING激动剂，其具有较好的药效及药代动力学特性。
3.在巨噬细胞，如THP1-Dual细胞、Raw-lucia细胞等中，本发明制备的化合物对STING的激活作用，相较于阳性对照(ADU-S100、GSK compound 3、GSK compound 1)更好或相当，为临床上筛选和/或制备与STING活性相关的疾病的药物提供了一种新的选择。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例
化合物的结构通过核磁共振( 1H-NMR)或质谱(MS)来确定。NMR测定是用BrukerAV-300型核磁共振仪，测定溶剂为氘代二甲亚砜(DMSO-D 6)或氘代氯仿(CDCl 3),TMS为内标。
本发明化合物的制备
中间体化合物1：1-乙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的合成
Figure PCTCN2020116614-appb-000080
将1-乙基-3-甲基-1H-吡唑-5-羧酸乙酯(1g，5.49mmol)溶于甲醇(10mL)和水(5mL)的混合溶液中。室温搅拌十分钟后，向上述反应液中加入氢氧化锂(0.263g,10.98mmol)。继续室温反应3小时，减压蒸馏除去甲醇，稀盐酸调PH至5-6，抽滤获得白色固体。未经纯化，直接用于下一步反应。
将1-乙基-3-甲基-1H-吡唑-5-羧酸(0.8g，5.19mmol)溶于二氯甲烷(5mL)溶液中，滴入3滴N,N-二甲基甲酰胺，冰浴下搅拌十分钟后，向上述反应液中缓慢滴入二氯甲烷(5mL)稀释的草酰氯(0.527mL,6.23mmol)。冰浴下继续搅拌十分钟后，移除冰浴，室温反应两个小时。TLC监测反应完全后，减压蒸馏浓缩，残留物用于下一步反应。将硫氰酸钾(0.61g，6.26mmol)冰浴下溶于丙酮(10mL)溶液中，冰浴下搅拌十分钟，缓慢向上述反应液中滴入丙酮(5mL)稀释的残留物，冰浴下继续反应30分钟。TLC监测反应完成后，向上述反应液中加入正己烷(15mL)，减压蒸馏浓缩溶液体积至1/2，再加入正己烷(15mL)，减压蒸馏浓缩溶液体积至1/2，减压抽滤，收集滤液制砂，经柱层析分离纯化(石油醚：乙酸乙酯＝6:1)获得无色透明油状化合物为中间体化合物1。MS(ESI)m/z＝196[M+H] +； 1H NMR(300MHz,CDCl 3)δ6.76(s,1H),4.52(s,2H),2.32(s,3H),1.42(s,3H).
中间体化合物2：1-炔丙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的合成
Figure PCTCN2020116614-appb-000081
操作过程和反应条件同中间体化合物1,不同的原料是1-炔丙基-3-甲基-1H-吡唑-5-羧酸乙酯，MS(ESI)m/z＝206[M+H] +。
中间体化合物3：1-烯丙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的合成
Figure PCTCN2020116614-appb-000082
操作过程和反应条件同中间体化合物1,不同的原料是1-烯丙基-3-甲基-1H-吡唑-5-羧酸乙酯，MS(ESI)m/z＝208[M+H] +。
中间体化合物4：1-(环丙基甲基)-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的合成
Figure PCTCN2020116614-appb-000083
操作过程和反应条件同中间体化合物1,不同的原料是1-(环丙基甲基)-3-甲基-1H-吡唑-5-羧酸乙酯，MS(ESI)m/z＝222[M+H] +。
中间体化合物5：3-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-5-羰基异硫氰酸酯的合成
Figure PCTCN2020116614-appb-000084
操作过程和反应条件同中间体化合物1,不同的原料是3-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-5-羧酸乙酯，MS(ESI)m/z＝250[M+H] +。
中间体化合物6：1-(2-氟乙基)-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的合成
Figure PCTCN2020116614-appb-000085
操作过程和反应条件同中间体化合物1,不同的原料是1-(2-氟乙基)-3-甲基-1H-吡唑-5-羧酸乙酯，MS(ESI)m/z＝214[M+H] +。
中间体化合物7：4-氯-3-甲氧基-5-硝基苯甲酰胺的合成
Figure PCTCN2020116614-appb-000086
将4-氯-3-甲氧基-5-硝基苯甲酸甲酯(4g，16.3mmol)分散于氨水(20mL)溶液中，升温至50℃，反应过夜。次日TLC监测反应完全后，抽滤，纯净水(10ml)洗涤，获得淡黄色固体为中间体化合物7。 1H NMR(300MHz,DMSO-d 6)δ8.31(s,1H),8.05(d,J＝2.1Hz,1H),7.85(d,J＝21.0Hz,2H),4.02(d,J＝2.1Hz,3H).
中间体化合物8：4-氯-3-羟基-5-硝基苯甲酰胺的合成
Figure PCTCN2020116614-appb-000087
将4-氯-3-甲氧基-5-硝基苯甲酰胺(4g，8.67mmol)分散于二氯甲烷(30mL)溶液中，室温搅拌十分钟，缓慢向上述反应液中滴入1M/L的三溴化硼二氯甲烷溶液(52mL,52mmol)，继续室温搅拌过夜。TLC监测反应完成后，将上述反应液缓慢滴入冰水(100mL)中，滴完后，继续搅拌两个小时，抽滤获得灰白色固体为中间体化合物8。 1H NMR(300MHz,DMSO-d 6)δ11.51(s,1H),8.16(s,1H),7.92(s,1H),7.72(s, 1H),7.65(s,1H).
中间体化合物9：3-(3-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-氯-5-硝基苯甲酰胺的合成
Figure PCTCN2020116614-appb-000088
将4-氯-3-羟基-5-硝基苯甲酰胺(1g,4.62mmol)溶于N.N-二甲基甲酰胺(10mL)溶液中，然后向上述溶液中分别加入(3-溴丙氧基)(叔丁基)二甲基硅烷(1.29mL,5.54mmol)和碳酸钾(0.83g,6.0mmol)，室温搅拌十分钟后，转移至油浴升温至80℃，反应过夜。TLC监测反应完成后，将上述反应液滴入水(20mL)中，加入乙酸乙酯(20mL)，分离有机相，再次使用乙酸乙酯(20mL)萃取两次合并有机相，无水硫酸钠干燥。减压蒸馏浓缩制砂，经柱层析(石油醚：乙酸乙酯＝8:1-3:1)分离纯化，获得白色固体为中间体化合物9。 1H NMR(400MHz,DMSO)δ8.30(s,1H),8.09–7.98(m,1H),7.88(t,J＝9.0Hz,1H),7.79(s,1H),4.30(t,J＝5.9Hz,2H),3.80(dd,J＝7.8,4.2Hz,2H),1.97(dd,J＝12.0,6.0Hz,2H),0.84(s,9H),0.07–0.04(m,6H).
中间体化合物10：4-氯-3-硝基-5-(氧杂环丁烷-3-基氧基)苯甲酰胺的合成
Figure PCTCN2020116614-appb-000089
将4-氯-3-羟基-5-硝基苯甲酰胺(1g,4.62mmol)溶于N.N-二甲基甲酰胺(10mL)溶液中，然后向上述溶液中分别加入3-碘氧杂环丁烷(0.48mL,5.54mmol)和碳酸钾(1.28g,9.23mmol)，室温搅拌十分钟后，转移至油浴升温至80℃，反应过夜。TLC监测反应完成后，将上述反应液滴入水(20mL)中，加入乙酸乙酯(20mL)，分离有机相，再次使用乙酸乙酯(20mL)萃取两次合并有机相，无水硫酸钠干燥。减压蒸馏浓缩制砂，经柱层析(石油醚：乙酸乙酯＝8:1-3:1)分离纯化，获得黄色固体为中间体化合物10。 1H NMR(400MHz,DMSO)δ8.29(s,1H),8.11(d,J＝1.7Hz,1H),7.89–7.78(m,1H),7.45(d,J＝1.6Hz,1H),5.56(dt,J＝10.3,5.2Hz,1H),5.00(dd,J＝13.4,7.4Hz,2H),4.63(dd,J＝7.4,4.6Hz,2H).
中间体化合物11：4-氯-2-羟基-5-硝基苯甲酰胺的合成
Figure PCTCN2020116614-appb-000090
将4-氯-2-甲氧基-5-硝基苯甲酰胺(4g，8.67mmol)分散于二氯甲烷(30mL)溶液中，室温搅拌十分钟，缓慢向上述反应液中滴入1M/L的三溴化硼二氯甲烷溶液(52mL,52mmol)，继续室温搅拌过夜。TLC监测反应完成后，将上述反应液缓慢滴 入冰水(100mL)中，滴完后，继续搅拌两个小时，抽滤获得灰白色固体为中间体化合物11。 1H NMR(400MHz,DMSO)δ14.11(s,1H),8.77(s,1H),8.69(s,1H),8.33(s,1H),7.27(s,1H).
中间体化合物12：4-氯-2-甲基-5-硝基苯并呋喃-7-甲酰胺的合成
Figure PCTCN2020116614-appb-000091
将4-氯-2-羟基-5-硝基苯甲酰胺(2.4g,11.08mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中，室温搅拌，然后向上述反应液中加入3-溴丙炔(1.04mL,13.3mmol)和碳酸钾(3.06g,22.16mmol)，转移至油浴，升温至80℃，反应过夜。TLC监测反应完全后，将反应液冷却至室温，加入水(50mL)中，室温搅拌，抽滤获得淡黄色固体，用于下一步反应。 1H NMR(400MHz,DMSO)δ8.42(s,1H),7.91(s,1H),7.76(s,1H),7.57(s,1H),5.16(s,2H),3.79(d,J＝2.1Hz,1H).
将2-(炔丙氧基)-4-氯-5-硝基苯甲酰胺(0.7g,2.75mmol)溶于N,N-二乙基苯胺(10mL)溶液中，加入氟化铯(0.63g,4.12mmol)，室温搅拌十分钟后，转移至油浴升温至220℃。反应4小时，TLC监测反应完全后，将反应液冷却至室温，加入乙酸乙酯(30mL)稀释反应液，然后用1M的稀盐酸溶液多次洗涤，无水硫酸钠干燥。减压蒸馏，浓缩制砂，经柱层析(石油醚：乙酸乙酯＝5:1–1:1)获得淡黄色固体为中间体化合物12。 1H NMR(400MHz,DMSO)δ8.29(s,1H),8.07(s,1H),7.95(s,1H),6.97(s,1H),2.57(s,3H).
中间体化合物13：4-氯-2-甲基-5-硝基苯并呋喃-7-甲酰胺的合成
Figure PCTCN2020116614-appb-000092
将4-氯-2-羟基-5-硝基苯甲酰胺(2.4g,11.08mmol)溶于N,N-二甲基甲酰胺(10mL)溶液中，室温搅拌，然后向上述反应液中加入3-溴-2-甲基丙烯(1.34mL,13.3mmol)和碳酸钾(3.06g,22.16mmol)，转移至油浴，升温至80℃，反应过夜。TLC监测反应完全后，将反应液冷却至室温，加入水(50mL)中，室温搅拌，抽滤获得淡黄色固体，用于下一步反应。 1H NMR(300MHz,DMSO-d 6)δ8.53(s,1H),7.83(s,2H),6.53(s,1H),5.20(s,1H),5.00(s,1H),4.50(s,2H),3.76(s,3H),1.81(s,3H).
将4-氯-2-((2-甲基烯丙基)氧基)-5-硝基苯甲酰胺(0.7g,2.59mmol)溶于N,N-二乙基苯胺(10mL)溶液中，加入氟化铯(0.59g,3.88mmol)，室温搅拌十分钟后，转移至油浴升温至220℃。反应4小时，TLC监测反应完全后，将反应液冷却至室温，加入乙酸乙酯(30mL)稀释反应液，然后用1M的稀盐酸溶液多次洗涤，无 水硫酸钠干燥。减压蒸馏，浓缩制砂，经柱层析(石油醚：乙酸乙酯＝5:1–1:1)获得淡黄色固体为中间体化合物13。 1H NMR(300MHz,DMSO-d 6)δ8.52(s,1H),7.48(s,2H),3.81–3.72(m,3H),2.89(s,2H),1.49(d,J＝1.8Hz,6H).
实施例1
Figure PCTCN2020116614-appb-000093
步骤a:(4-((4-氨基甲酰基-2-甲氧基-6-硝基苯基)氨基)丁基)氨基甲酸叔丁酯的合成
将4-氯-3-甲氧基-5-硝基苯甲酰胺(1g,4.34mmol)溶于正丁醇(10mL)溶液中，室温搅拌，然后向上述反应液中加入N-(叔丁氧羰基)-1,4-二氨基丁烷(1.1mL,5.64mmol)和N，N-二异丙基乙胺(2.15mL,13.0mmol)，封管中升温至110℃，反应12小时，次日抽滤，适量乙酸乙酯洗涤获得(4-((4-氨基甲酰基-2-甲氧基-6-硝基苯基)氨基)丁基)氨基甲酸叔丁酯(化合物1A)，淡黄色固体，收率89％。 1H NMR(300MHz,DMSO-d 6)δ8.23–8.17(m,1H),8.02(s,1H),7.72(d,J＝5.9Hz,1H),7.55(s,1H),7.33(s,1H),6.81(s,1H),3.92–3.86(m,3H),3.46(d,J＝6.3Hz,2H),2.89(d,J＝6.4Hz,2H),1.49(s,4H),1.37–1.32(m,9H).
步骤b:4-((4-氨基丁基)氨基)-3-甲氧基-5-硝基苯甲酰胺盐酸盐的合成
将化合物1A(2g，5.23mmol)分散于乙酸乙酯(20mL)溶液中，置于冰浴下搅拌十分钟，向上述溶液中通入新制的HCl气体至饱和。继续冰浴反应10分钟后，移除冰浴，室温反应两个小时。TLC监测反应完全后，减压蒸馏除去乙酸乙酯，向残留物中加入***(15mL)，室温搅拌两个小时，抽滤获得4-((4-氨基丁基)氨基)-3-甲氧基-5-硝基苯甲酰胺盐酸盐(化合物1B)，红褐色固体，收率93％。 1H NMR (300MHz,DMSO-d 6)δ8.21(dd,J＝3.9,2.0Hz,1H),8.04(s,1H),7.73(s,1H),7.57(d,J＝3.0Hz,1H),7.34(s,1H),3.89(d,J＝4.0Hz,3H),3.50(s,2H),2.78(s,2H),1.61–1.51(m,4H).
步骤c:4-((4-((4-氨基甲酰基-2-甲氧基-6-硝基苯基)氨基)丁基)氨基)-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-7-甲酰胺的合成
将化合物4-((4-氨基丁基)氨基)-3-甲氧基-5-硝基苯甲酰胺盐酸盐(1g,3.14mmol)溶于正丁醇(10mL)溶液中，室温搅拌，然后向上述反应液中加入4-氯-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-7-甲酰胺(1.02g,3.76mmol)和N，N-二异丙基乙胺(1.56mL,9.41mmol)，封管中升温至110℃，反应12小时，次日抽滤，适量乙酸乙酯洗涤获得4-((4-((4-氨基甲酰基-2-甲氧基-6-硝基苯基)氨基)丁基)氨基)-2,2-二甲基-5-硝基-2,3-二氢苯并呋喃-7-甲酰胺(化合物1C)，红褐色固体，收率81％。 1H NMR(300MHz,DMSO-d 6)δ8.56(s,1H),8.35(s,1H),8.17(s,1H),8.02(s,1H),7.78(s,1H),7.61(s,1H),7.53(s,1H),7.33(s,1H),7.14(s,1H),3.87(s,3H),3.53(s,4H),3.31(s,2H),1.58(d,J＝7.2Hz,4H),1.50(s,6H).
步骤d:5-氨基-4-((4-((2-氨基-4-氨基甲酰基-6-甲氧基苯基)氨基)丁基)氨基)-2,2-二甲基-2,3-二氢苯并呋喃-7-甲酰胺的合成
将化合物1C(1g,1.94mmol)分散于甲醇(30mL)溶液中，向上述反应液中分别加入连二亚硫酸钠(3.37g,19.36mmol)和氨水(2mL)，室温搅拌十分钟后，转移至油浴升温至60℃，反应4个小时。TLC监测反应完全后，抽滤，甲醇洗涤滤饼，合并收集滤液，减压蒸馏浓缩制砂，经柱层析(二氯甲烷：甲醇＝30:1–7:1)分离纯化，获得5-氨基-4-((4-((2-氨基-4-氨基甲酰基-6-甲氧基苯基)氨基)丁基)氨基)-2,2-二甲基-2,3-二氢苯并呋喃-7-甲酰胺(化合物1D)，淡黄色固体，收率63％。 1H NMR(300MHz,DMSO-d 6)δ7.61(s,1H),6.97(d,J＝15.0Hz,4H),6.85(s,1H),6.78(s,1H),4.64(s,2H),4.05(s,2H),3.73(s,3H),3.20(s,2H),3.05(s,2H),2.94(s,2H),1.49(s,4H),1.39(d,J＝6.0Hz,6H).
步骤e:1-(4-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰氨基)-7-甲氧基-1H-苯并[d]咪唑-1-基)丁基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7,7-二甲基-7,8-二氢-1H-苯并呋喃并[4,5-d]咪唑-5-甲酰胺的合成
将化合物1D(0.55g,1.2mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中，加入0.4M的1-乙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的二氧六环溶液(4mL,1.6mmol)，冰浴下搅拌十分钟后，加入另一份0.4M的1-乙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的二氧六环溶液(1mL,0.4mmol)，冰浴下搅拌十五分钟后，加入最后一份0.4M的1-乙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯的二氧六环溶液(1mL,0.4mmol)，继续冰浴反应半个小时后，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(0.58mg,3.01mmol)和三乙胺(1mL,7.23mmol)，继续冰浴下搅拌十分钟后，转 移至室温反应过夜。TLC监测反应完成后，将反应液缓慢滴入到水(20mL)中，有白色不溶物析出，抽滤，收集滤饼干燥，经柱层析(二氯甲烷：甲醇＝20:1–5:1)分离纯化得1-(4-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰氨基)-7-甲氧基-1H-苯并[d]咪唑-1-基)丁基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7,7-二甲基-7,8-二氢-1H-苯并呋喃并[4,5-d]咪唑-5-甲酰胺(实施例化合物1)，灰白色固体，收率78％。ESI-MS(m/z):779.37[M+H] +； 1H NMR(300MHz,DMSO-d 6)δ12.84(s,1H),12.66(s,1H),8.01(s,1H),7.81(s,1H),7.63(s,2H),7.36(s,3H),6.59(s,2H),4.57(s,4H),4.39(s,2H),4.18(s,2H),3.89(s,3H),3.27(s,2H),2.09(s,6H),1.89(s,2H),1.77(s,2H),1.45(s,6H),1.30(s,6H)
实施例2
Figure PCTCN2020116614-appb-000094
操作过程和反应条件同实施例1相同，不同的是步骤c中原料为4-氯-2-甲基-5-硝基苯并呋喃-7-甲酰胺,淡黄色固体，收率68％。ESI-MS(m/z):763.34[M+H] +； 1H NMR(300MHz,DMSO-d 6)δ12.85(s,1H),12.70(s,1H),7.98(d,J＝18.0Hz,2H),7.82(s,2H),7.65(s,1H),7.54(s,1H),7.39(s,1H),7.30(s,1H),6.90(s,1H),6.61(s,1H),6.54(s,1H),4.56(s,4H),4.39(s,2H),4.31(s,2H),3.81(s,3H),2.10(d,J＝10.4Hz,6H),1.88(s,4H),1.30(d,J＝8.0Hz,6H).
实施例3
Figure PCTCN2020116614-appb-000095
Figure PCTCN2020116614-appb-000096
步骤a:(E)-(4-((7-氨基甲酰基-2-甲基-5-硝基苯并呋喃-4-基)氨基)丁-2-烯-1-基)氨基甲酸叔丁酯的合成
将化合物4-氯-2-甲基-5-硝基苯并呋喃-7-甲酰胺(1g,3.93mmol)溶于正丁醇(10mL)溶液中，室温搅拌，然后向上述反应液中加入(E)-(4-氨基丁-2-烯-1-基)氨基甲酸叔丁酯(0.88g,4.71mmol)和N，N-二异丙基乙胺(2.06mL,11.78mmol)，封管中升温至110℃，反应12小时，次日抽滤，适量乙酸乙酯洗涤获得(E)-(4-((7-氨基甲酰基-2-甲基-5-硝基苯并呋喃-4-基)氨基)丁-2-烯-1-基)氨基甲酸叔丁酯(化合物3A)，红褐色固体，收率69％。 1H NMR(300MHz,DMSO)δ9.08(s,1H),8.53(s,1H),7.63(d,J＝52.0Hz,2H),7.04(s,2H),5.83–5.62(m,2H),4.36(s,2H),4.11(s,2H),2.48(s,3H),1.37(s,9H).
步骤b:(E)-4-((4-氨基丁-2-烯-1-基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺盐酸盐的合成
将化合物1A(1.6g，3.93mmol)分散于乙酸乙酯(20mL)溶液中，置于冰浴下搅拌十分钟，向上述溶液中通入新制的HCl气体至饱和。继续冰浴反应10分钟后，移除冰浴，室温反应两个小时。TLC监测反应完全后，减压蒸馏除去乙酸乙酯，向残留物中加入***(15mL)，室温搅拌两个小时，抽滤获得E)-4-((4-氨基丁-2-烯-1-基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺盐酸盐(化合物1B)，红褐色固体，收率93％。 1H NMR(300MHz,DMSO)δ9.13(s,1H),8.54(s,1H),7.95(s,3H),7.66(d,J＝53.1Hz,2H),7.02(s,1H),6.09(d,J＝15.5Hz,1H),5.82–5.64(m,1H),4.43(s,2H),3.18(s,2H),2.49(s,3H).
步骤c:(E)-4-((4-((4-氨基甲酰基-2-甲氧基-6-硝基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺的合成
将化合物3B(1g,2.93mmol)溶于正丁醇(10mL)溶液中，室温搅拌，然后向上述反应液中加入4-氯-3-甲氧基-5-硝基苯甲酰胺(0.812g,3.52mmol)和N，N-二异丙基乙胺(1.54mL,8.8mmol)，封管中升温至110℃，反应12小时，次日抽滤，适量乙酸乙酯洗涤获得(E)-4-((4-((4-氨基甲酰基-2-甲氧基-6-硝基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺(化合物3C)，红褐色固体， 收率69％。 1H NMR(400MHz,DMSO)δ9.06(t,J＝5.9Hz,1H),8.51(s,1H),8.15(s,1H),8.03(s,1H),7.76(t,J＝5.8Hz,1H),7.70(s,1H),7.51(s,2H),7.34(s,1H),6.91(s,1H),5.81–5.73(m,2H),4.32(s,2H),4.13(s,2H),3.81(s,3H),2.41(s,3H).
步骤d:(E)-5-氨基-4-((4-((2-氨基-4-氨基甲酰基-6-甲氧基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基苯并呋喃-7-甲酰胺的合成
将化合物3C(1g,2.01mmol)分散于甲醇(30mL)溶液中，向上述反应液中分别加入连二亚硫酸钠(3.49g,20.06mmol)和氨水(2mL)，室温搅拌十分钟后，转移至油浴升温至60℃，反应4个小时。TLC监测反应完全后，抽滤，甲醇洗涤滤饼，合并收集滤液，减压蒸馏浓缩制砂，经柱层析(二氯甲烷：甲醇＝30:1–7:1)分离纯化，获得(E)-5-氨基-4-((4-((2-氨基-4-氨基甲酰基-6-甲氧基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基苯并呋喃-7-甲酰胺(化合物3D)，淡黄色固体，收率62％。 1H NMR(400MHz,DMSO)δ7.62(s,1H),7.28(s,1H),7.15(s,1H),7.10(s,1H),6.97(s,1H),6.86(d,J＝1.8Hz,1H),6.78(d,J＝1.8Hz,1H),6.61(d,J＝1.0Hz,1H),5.76(s,2H),5.08(t,J＝5.9Hz,1H),4.65(s,2H),4.56(s,1H),4.10(d,J＝5.2Hz,1H),3.98(s,2H),3.71(s,3H),3.55(s,2H),3.37(s,1H),2.38(s,3H).
步骤e:(E)-1-(4-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲基-1H-苯并呋喃并[4,5-d]咪唑-5-甲酰胺的合成
操作过程和反应条件同实施例1步骤e相同,不同的是原料为化合物3D,淡黄色固体，收率70％。ESI-MS(m/z):761.32[M+H] +； 1H NMR(300MHz,DMSO-d 6)δ12.91(s,1H),12.82(s,1H),8.00(s,1H),7.88(s,1H),7.81(s,1H),7.64(s,1H),7.53(s,1H),7.38(s,1H),7.24(s,1H),6.67(s,1H),6.58(s,1H),6.44(s,1H),5.83(s,2H),4.97(s,2H),4.85(s,2H),4.52(s,4H),3.60(s,3H),2.29(s,3H),2.11(d,J＝13.0Hz,6H),1.26(s,6H).
实施例4
Figure PCTCN2020116614-appb-000097
操作过程和反应条件同实施例3相同,不同的原料是1-烯丙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯,淡黄色固体，收率66％。ESI-MS(m/z):785.4[M+H] +； 1H NMR(400 MHz,DMSO)δ12.84(d,J＝37.3Hz,2H),7.99(s,1H),7.90(s,1H),7.79(s,1H),7.65(s,1H),7.53(s,1H),7.35(s,1H),7.25(s,1H),6.66(d,J＝16.1Hz,2H),6.50(s,1H),6.04–5.89(m,3H),5.85(d,J＝2.6Hz,2H),5.17(dd,J＝25.3,4.2Hz,4H),5.01(dd,J＝10.5,1.4Hz,4H),4.88(s,4H),3.61(s,3H),2.31(s,3H),2.15(s,3H),2.11(s,3H).
实施例5
Figure PCTCN2020116614-appb-000098
操作过程和反应条件同实施例3相同,不同的原料是1-(环丙基甲基)-3-甲基-1H-吡唑-5-羰基异硫氰酸酯,淡黄色固体，收率55％。ESI-MS(m/z):813.5[M+H] +； 1H NMR(400MHz,DMSO)δ12.84(d,J＝37.5Hz,2H),7.97(s,1H),7.89(s,1H),7.78(s,1H),7.64(s,1H),7.51(s,1H),7.34(s,1H),7.24(s,1H),6.67(s,1H),6.62(s,1H),6.47(s,1H),5.85(d,J＝4.1Hz,2H),5.00(s,2H),4.87(s,2H),4.44(d,J＝6.8Hz,2H),4.37(d,J＝6.7Hz,2H),3.59(s,3H),2.29(s,3H),2.14(s,3H),2.10(s,3H),1.31(dd,J＝15.0,6.7Hz,2H),0.38(t,J＝8.1Hz,4H),0.30(dd,J＝13.9,4.1Hz,4H).
实施例6
Figure PCTCN2020116614-appb-000099
操作过程和反应条件同实施例3相同,不同的原料是3-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-5-羰基异硫氰酸酯，灰白色固体，收率72％。ESI-MS(m/z):867.3[M-H] -； 1H NMR(400MHz,DMSO)δ12.93(s,1H),12.83(s,1H),7.99(s,1H),7.90(s,1H),7.81(s,1H),7.67(d,J＝1.0Hz,1H),7.53(s,1H),7.37(s,1H),7.26(s,1H),6.77(s,1H),6.66(s,1H),6.57(s,1H), 5.88(s,2H),5.60(dd,J＝17.8,8.8Hz,2H),5.56–5.48(m,2H),5.02(s,2H),4.89(s,3H),3.60(s,3H),2.28(s,3H),2.18(s,3H),2.12(s,3H).
实施例7
Figure PCTCN2020116614-appb-000100
操作过程和反应条件同实施例3相同,不同的原料是1-炔丙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯，灰白色固体，收率71％。ESI-MS(m/z):782.4[M+H] +； 1H NMR(300MHz,DMSO)δ12.92(d,J＝27.5Hz,1H),8.04(s,1H),7.92(s,1H),7.84(s,1H),7.68(s,1H),7.56(s,1H),7.41(s,1H),7.25(s,1H),6.69(s,2H),6.53(s,1H),5.91(s,2H),5.43(d,J＝21.7Hz,4H),4.99(d,J＝36.9Hz,4H),3.60(s,3H),3.27(d,J＝7.2Hz,2H),2.30(s,3H),2.19(s,3H),2.14(s,3H).
实施例8
Figure PCTCN2020116614-appb-000101
步骤a:(E)-4-((4-((2-(3-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-氨基甲酰基-6-硝基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺的合成
将化合物3B(1g,2.93mmol)溶于正丁醇(10mL)溶液中，室温搅拌，然后向上述反应液中加入3-(3-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-氯-5-硝基苯甲酰胺(1.37g,3.52mmol)和N，N-二异丙基乙胺(1.46mL,8.8mmol)，封管中升温至110℃，反应12小时，次日抽滤，适量乙酸乙酯洗涤获得(E)-4-((4-((2-(3-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-氨基甲酰基-6-硝基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺(化合物8A)，红褐色固体，收率66％。MS(ESI)m/z＝657[M+H] +。
步骤b:(E)-5-氨基-4-((4-((2-氨基-6-(3-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-氨基甲酰基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基苯并呋喃-7-甲酰胺的合成
将化合物8A(1g,1.52mmol)分散于甲醇(30mL)溶液中，向上述反应液中分别加入连二亚硫酸钠(2.65g,15.2mmol)和氨水(2mL)，室温搅拌十分钟后，转移至油浴升温至60℃，反应4个小时。TLC监测反应完全后，抽滤，甲醇洗涤滤饼，合并收集滤液，减压蒸馏浓缩制砂，经柱层析(二氯甲烷：甲醇＝30:1–7:1)分离纯化，获得(E)-5-氨基-4-((4-((2-氨基-6-(3-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-氨基甲酰基苯基)氨基)丁-2-烯-1-基)氨基)-2-甲基苯并呋喃-7-甲酰胺(化合物8B)，淡黄色固体，收率61％。MS(ESI)m/z＝597[M+H] +。
步骤c:((E)-1-(4-(7-(3-((叔丁基二甲基硅烷基)氧基)丙氧基)-5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1H-苯并[d]咪唑-1-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲基-1H-苯并呋喃并[4,5-d]咪唑-5-甲酰胺的合成
操作过程和反应条件同实施例1步骤e相同,不同的原料是化合物8B,淡黄色固体，收率58％。MS(ESI)m/z＝919[M+H] +
步骤d:(E)-1-(4-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰氨基)-7-(3-羟基丙氧基)-1H-苯并[d]咪唑哌嗪-1-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲基-1H-苯并呋喃并[4,5-d]咪唑-5-甲酰胺的合成
将化合物8C(0.5g,0.54mmol)分散于4M HCL的二氧六环(5mL)溶液中，室温搅拌30分钟，TLC监测反应完成后，减压蒸馏除去溶剂，加入***(5mL)室温搅拌30分钟后，抽滤，收集滤饼，干燥得(E)-1-(4-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰氨基)-7-(3-羟基丙氧基)-1H-苯并[d]咪唑哌嗪-1-基)丁-2-烯-1-基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲基-1H-苯并呋喃并[4,5-d]咪唑-5-甲酰胺(实施例化合物8)，灰白色固体，收率89％。ESI-MS(m/z):805.4[M+H] +； 1H  NMR(400MHz,DMSO)δ8.02(s,1H),7.90(s,1H),7.81(s,1H),7.66(s,1H),7.53(s,1H),7.34(s,1H),7.26(s,1H),6.68(s,1H),6.62(s,1H),6.46(s,1H),5.86(s,2H),5.00(s,2H),4.91(s,2H),4.61–4.46(m,6H),3.89(t,J＝6.1Hz,2H),3.58(s,1H),2.30(s,3H),2.15(s,3H),2.11(s,3H),1.59–1.54(m,2H),1.33–1.28(m,6H).
实施例9
Figure PCTCN2020116614-appb-000102
操作过程和反应条件同实施例8相同,不同的原料是1-烯丙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯，灰白色固体，收率88％。ESI-MS(m/z):829.5[M+H] +； 1H NMR(400MHz,DMSO)δ8.02(s,1H),7.90(s,1H),7.81(s,1H),7.66(s,1H),7.53(s,1H),7.38(d,J＝10.0Hz,1H),7.27(s,1H),6.67(d,J＝3.6Hz,2H),6.50(s,1H),6.02–5.93(m,2H),5.85(s,2H),5.19(d,J＝3.9Hz,2H),5.12(d,J＝3.8Hz,2H),5.06–4.98(m,5H),4.90(d,J＝10.4Hz,5H),3.89(s,2H),3.80(s,1H),3.38(d,J＝8.6Hz,5H),2.29(s,3H),2.15(s,3H),2.11(s,3H),1.59–1.52(m,2H).
实施例10
Figure PCTCN2020116614-appb-000103
操作过程和反应条件同实施例8相同,不同的原料是1-炔丙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯，灰白色固体，收率84％。ESI-MS(m/z):825.4[M+H] +； 1H NMR(400MHz,DMSO)δ8.09–7.97(m,1H),7.90(s,1H),7.81(s,1H),7.66(s,1H),7.52(s,1H),7.34(s,1H),7.24(s,1H),6.66(d,J＝9.1Hz,2H),6.51(s,1H),5.88(s,2H),5.42(s,2H),5.36(s,2H),5.03(s,2H),4.93(s,2H),3.86(d,J＝6.0Hz,2H),3.57(s,1H),3.37(d,J＝5.9Hz,2H),3.24(d,J＝2.0Hz,2H),2.27(s,3H),2.16(s,3H),2.12(s,3H),1.55–1.51(m,2H).
实施例11
Figure PCTCN2020116614-appb-000104
操作过程和反应条件同实施例8相同,不同的原料是3-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-5-羰基异硫氰酸酯，灰白色固体，收率84％。ESI-MS(m/z):911.3[M-H] -； 1H NMR(400MHz,DMSO)δ12.85(d,J＝41.7Hz,2H),8.02(s,1H),7.89(s,1H),7.79(s,1H),7.65(s,1H),7.53(s,1H),7.34(s,1H),7.23(s,1H),6.75(s,1H),6.61(s,1H),6.55(s,1H),5.85(s,2H),5.63–5.46(m,4H),4.99(s,2H),4.89(s,2H),4.58(t,J＝5.1Hz,1H),3.85(t,J＝6.4Hz,2H),3.51(d,J＝0.8Hz,2H),2.26(s,3H),2.17(s,3H),2.12(s,3H),1.58–1.48(m,2H).
实施例12
Figure PCTCN2020116614-appb-000105
操作过程和反应条件同实施例8相同,不同的原料是1-(环丙基甲基)-3-甲基-1H-吡唑-5-羰基异硫氰酸酯，灰白色固体，收率82％。ESI-MS(m/z):855.4[M-H] -； 1H NMR(400MHz,DMSO)δ12.83(d,J＝33.7Hz,2H),8.01(s,1H),7.90(s,1H),7.79(s,1H),7.65(s,1H),7.51(d,J＝6.3Hz,1H),7.33(s,1H),7.24(s,1H),6.64(d,J＝12.9Hz,2H),6.49(s,1H),5.85(s,2H),5.00(s,2H),4.89(s,2H),4.52(d,J＝21.5Hz,1H),4.44(d,J＝6.6Hz,2H),4.38(d,J＝6.9Hz,2H),3.86(s,4H),2.29(s,3H),2.15(s,3H),2.11(s,3H),1.59–1.47(m,2H),1.30(dd,J＝12.2,7.3Hz,2H),0.39(s,4H),0.31(dd,J＝9.6,4.3Hz,4H).
实施例13
Figure PCTCN2020116614-appb-000106
操作过程和反应条件同实施例3相同,不同的是步骤c中原料为4-氯-2-甲基-5-硝基苯并呋喃-7-甲酰胺，灰白色固体，收率61％。ESI-MS(m/z):785.4[M+H] +； 1H NMR(400MHz,DMSO)δ12.91(s,2H),7.91(s,2H),7.79(s,2H),7.53(s,2H),6.56(d,J＝3.3Hz,4H),5.92(s,2H),4.95(s,4H),4.56(d,J＝7.0Hz,4H),2.21(s,6H),2.15(s,6H),1.31(t,J＝7.0Hz,7H).
实施例14
Figure PCTCN2020116614-appb-000107
操作过程和反应条件同实施例8相同,不同的原料是1-(2-氟乙基)-3-甲基-1H-吡唑-5-羰基异硫氰酸酯，灰白色固体，收率76％。ESI-MS(m/z):839.4[M-H] -； 1H NMR(300MHz,DMSO)δ8.01(s,1H),7.90(s,1H),7.80(s,1H),7.65(s,1H),7.52(s,1H),7.34(s,1H),7.24(s,1H),6.66(d,J＝4.7Hz,2H),6.51(s,1H),5.84(s,2H),4.99(s,2H),4.85(dd,J＝13.3,9.0Hz,10H),4.70–4.63(m,2H),3.39–3.34(m,2H),2.28(s,3H),2.13(d,J＝12.2Hz,6H),1.53(s,2H).
实施例15
Figure PCTCN2020116614-appb-000108
操作过程和反应条件同实施例2相同,不同的原料是1-(4-氯-3-硝基苯甲酰基)哌啶-4-甲酰胺，白色固体，收率78％。ESI-MS(m/z):842.5[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ12.76(s,2H),7.88(s,1H),7.79(s,1H),7.52(d,J＝9.1Hz,2H),7.42–7.32(m,2H),7.09(d,J＝8.1Hz,1H),6.84(s,1H),6.75(s,1H),6.61(d,J＝9.6Hz,1H),6.48(s,1H),6.04(d,J＝16.1Hz,1H),5.80(d,J＝21.4Hz,1H),5.01(s,2H),4.88–4.73(m,2H),4.62–4.43(m,4H),2.90(s,4H),2.38(d,J＝16.7Hz,3H),2.14(t,J＝11.7Hz,6H),1.91(s,1H),1.73(s,2H),1.56–1.42(m,2H),1.23(d,J＝10.5Hz,6H).
实施例16
Figure PCTCN2020116614-appb-000109
操作过程和反应条件同实施例3相同,不同的是步骤c中原料为4-氯-3-硝基-5-(氧杂环丁烷-3-基氧基)苯甲酰胺，灰白色固体，收率69％。ESI-MS(m/z):803.5[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ12.88(d,J＝16.9Hz,2H),8.06–7.85(m,2H),7.80(s,1H),7.69(d,J＝7.2Hz,1H),7.54(s,1H),7.38(s,1H),6.82(d,J＝7.7Hz,1H),6.73(d,J＝8.2Hz,1H),6.59(d,J＝7.7Hz,1H),6.48(d,J＝7.6Hz,1H),5.90(s,2H),5.00(t,J＝21.9Hz,4H),4.77–4.63(m,2H),4.53(dq,J＝14.6,7.3Hz,4H),4.44–4.31(m,2H),3.08(d,J＝7.5Hz,1H),2.30(d,J＝7.1Hz,3H),2.24–2.06(m,6H),1.31–1.24(m,6H).
实施例17
Figure PCTCN2020116614-appb-000110
操作过程和反应条件同实施例16相同,不同的原料是3-甲基-1-(丙-2-炔-1-基)-1H-吡唑-5-羰基异硫氰酸酯，淡黄色固体，收率82％。ESI-MS(m/z):823.5[M+H] +； 1H NMR(400MHz,DMSO)δ12.90(s,2H),7.93(d,J＝17.4Hz,2H),7.73(d,J＝29.6Hz,2H),7.35(s,1H),7.19(s,1H),6.81(s,1H),6.68(s,1H),6.64(s,1H),6.52(s,1H),5.93(s,2H),5.40(d,J＝20.5Hz,4H),5.01(d,J＝14.1Hz,5H),4.67(s,2H),4.35(s,2H),3.21(s,2H),2.27(s,3H),2.18–2.10(m,6H).
实施例18
Figure PCTCN2020116614-appb-000111
操作过程和反应条件同实施例16相同,不同的原料是1-烯丙基-3-甲基-1H-吡唑-5-羰基异硫氰酸酯，淡黄色固体，收率78％。ESI-MS(m/z):849.5[M+Na] +； 1H NMR(400MHz,DMSO)δ12.87(d,J＝16.5Hz,2H),7.93(d,J＝19.0Hz,2H),7.80(s,1H),7.69(s,1H),7.53(s,1H),7.38(s,1H),6.81(s,1H),6.71(s,1H),6.63(s,1H),6.52(s,1H),5.93(d,J＝20.1Hz,4H),5.18(d,J＝18.0Hz,4H),5.02(d,J＝15.5Hz,5H),4.91(dd,J＝25.2,14.8Hz,4H),4.69(s,2H),4.36(s,2H),2.29(s,3H),2.13(d,J＝9.7Hz,6H).
实施例19
Figure PCTCN2020116614-appb-000112
操作过程和反应条件同实施例2相同,不同的原料是4-氯-3-(3-吗啉丙氧基)-5-硝基苯甲酰胺，白色固体，收率78％。ESI-MS(m/z):874.3450[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ12.90(d,J＝29.2Hz,2H),7.99(s,1H),7.91(s,1H),7.82(s,1H),7.67(s,1H),7.56(s,1H),7.36(s,1H),7.16(s,1H),6.64(s,1H),6.59(d,J＝9.7Hz,1H),6.52(s,1H),5.80(d,J＝22.4Hz,2H),4.96(d,J＝13.1Hz,2H),4.89(s,2H),4.56(p,J＝7.8,7.3Hz,4H),3.71(s,4H),3.61–3.49(m,2H),3.07(dt,J＝13.3,5.9Hz,4H),2.26(s,2H),2.15(d,J＝5.1Hz,9H),1.31(q,J＝6.5Hz,8H).
实施例20
Figure PCTCN2020116614-appb-000113
操作过程和反应条件同实施例19相同,不同的原料是3-甲基-1-(2,2,2-三氟乙基)-1H-吡唑-5-羰基异硫氰酸酯，白色固体，收率78％。ESI-MS(m/z):982.3543[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ12.93(d,J＝32.4Hz,2H),8.00(s,1H),7.91(s,1H),7.84(s,1H),7.69(s,1H),7.58(s,1H),7.39(s,1H),7.21(s,1H),6.83–6.72(m,1H),6.62(s,2H),5.99(s,2H),5.65–5.51(m,4H),5.00(s,2H),4.91(s,2H),4.12(s,2H),3.75(s,4H),3.12–3.06(m,4H),2.39–1.92(m,11H),1.77(s,2H).
实施例21
Figure PCTCN2020116614-appb-000114
操作过程和反应条件同实施例2相同,不同的原料是4-氯-3-(3-甲氧基丙氧基)-5-硝基苯甲酰胺，白色固体，收率78％。ESI-MS(m/z):819.5[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ12.87(d,J＝34.2Hz,2H),8.00(s,1H),7.90(s,1H),7.81(s,1H),7.65(s,1H),7.55(d,J＝15.0Hz,1H),7.35(d,J＝10.1Hz,2H),6.68(d,J＝10.7Hz,1H),6.58(s,1H),6.47(d,J＝16.6Hz,1H),5.83(s,2H),4.91(dd,J＝43.4,19.8Hz,4H),4.54(dq,J＝14.8,7.7,7.0Hz,4H),3.80(d,J＝6.7Hz,2H),3.20(d,J＝6.4Hz,2H),3.12(s,3H),2.29(s,3H),2.13(d,J＝8.0Hz,6H),1.71–1.53(m,2H),1.29(q,J＝9.7,8.1Hz,6H).
实施例22
Figure PCTCN2020116614-appb-000115
操作过程和反应条件同实施例8相同,不同的原料是1-(2,2-二氟乙基)-3-甲基-1H-吡唑-5-羰基异硫氰酸酯，淡黄色固体，收率78％。
实施例23：化合物对人外周血单核细胞系PBMC细胞产生I型干扰素通路(ISG)的激活影响
本实验通过检测化合物刺激人外周血单核细胞系PBMC细胞(AllCells,Cat#:PB005F)产生的Ⅰ型干扰素IFNβ变化来评价STING激动剂的功能。使用前将低温保存的PBMCs在RPMI1640培养基中解冻复苏过夜后。将测试化合物溶解到DMSO中配制为浓度为10mM的母液。测试前，将化合物稀释至工作浓度的100倍(工作浓度分别为30、10、3.33、1.11、0.370、0.123、0.0412、0.0137uM)。采集PBMCs，调整至细胞浓度为5x10^5/ml浓度。将LPS添加到PBMCs中，最终浓度为10ng/ml。96孔细胞培养板中，每孔加入200ul PBMCs(每孔1x10^5个细胞)。然后每孔加入2ul稀释后的化合物(复孔，每孔中DMSO最终浓度为1％)。然后用移液管小心地将细胞和化合物混合均匀。阴性对照，加入2ul DMSO(1％终浓度)。细胞在37℃培养箱中培养过夜。收集细胞培养上清液检测Ⅰ型干扰素IFNβ浓度。通过固相抗体R&D-MAB8144-100和检测抗体R&D-MAB8143-100(Biotinylated)的ELISA试剂盒来测定IFNβ的浓度，根据标准曲线换算成IP10浓度，并用GraphPad 5.0拟合剂校曲线计算EC 50值。本发明实施例化合物能强烈地刺激人PBMCs细胞释放IFNβ，EC50值小于10μM.实验结果见表1。
表1细胞实验结果一览表
实施例 EC 50(μM)
1 0.3615
2 0.1033
3 0.004919
实验结果说明，本发明制备的化合物对STING具有激活作用，能够用于制备激活STING或与STING活性相关的疾病的药物。
实施例24：化合物对人源THP1-Dual细胞中I型干扰素通路(ISG)的激活影响
本实验通过检测化合物刺激人外周血单核细胞系THP1-Dual细胞产生ΙFΝ-β的能力来评估其激活STING的能力。实验中THP1-Dual细胞购自InvivoGen公司。化合物用DMSO溶解成10mM的化合物。96孔细胞培养板中的每孔加入20μL用DMSO/生理盐水稀释的化合物，化合物的浓度为100μM，阳性对照ADU-S100浓度为100μM。不加药对照组加20μl含1％DMSO的生理盐水。各设3个重复孔。THP1-Dual细胞计数，调整细胞浓度至1×10 6/ml，每孔加入180μl的细胞进行孵育。因此，每个测试孔的终体积为200μl，DMSO的含量为0.1％，化合物的测试浓度为10μM。阳性对照ADU-S100的终浓度为10μM，孵育24小时；另空白组加200μl培养液。24小时后，每孔取20μl的培养液至新的底部透光96孔板中，加入荧光素酶检测试剂QUANTI-Luc TM50μl，立即测定荧光值。使用(Nature.2018Dec；564(7736):439-443)中报道的compound 3(WO2019069275)中报道的compound 1作为阳性参考化合物。数据采用化合物LUM与空白对照组LUM的比值描述。实验结果见表2。
Figure PCTCN2020116614-appb-000116
表2细胞实验结果一览表
实施例 Fold change(Ratio to control)
2 53.15
3 62.82
5 66.65
6 86.31
9 148.64
10 13.14
16 147.24
17 4.30
18 175.49
19 90.48
20 159.71
ADU-S100 49.93
GSK compound 3 70.83
GSK compound 1 80.54
实验结果说明，本发明制备的化合物对STING的激活作用，相较于阳性对照(ADU-S100、GSK compound 3、GSK compound 1)更好或相当，尤其是化合物16、18、20，相较于阳性对照ADU-S100，其对STING的激活作用是阳性对照的2-3倍或以上，相较于GSK compound 3，其对STING的激活作用是阳性对照的2倍以上，因此，本发明化合物能够用于制备激活STING或与STING活性相关的疾病的药物。
实施例25：本发明的化合物在CT26结肠癌皮下移植瘤模型中的药效研究
1、实验方法
本实验使用4-6周龄Balb/C雌性小鼠，每只小鼠腋皮下各注射CT26细胞(2.5*10 5)。观察小鼠肿瘤生长情况，待肿瘤体积长到50-100mm 3时开始分组给予本发明的化合物19和阴性对照，分组后第1,4,7天给药本发明的化合物19和阴性对照，化合物19每组的给药剂量分别为0.1mg/kg和0.3mg/kg。实验结果以瘤体积(Tumor volume)生长曲线的形式评价，实验结果如图1所示。
2、实验结果
在Balb/C品系的CT26结肠癌肿瘤模型中，相较于阴性对照，本发明的化合物19具有显著的抗肿瘤效果。
实施例26：本发明的化合物在EMT6乳腺癌原位移植瘤模型中的药效研究
1、实验方法
本实验使用4-6周龄Balb/C雌性小鼠，每只小鼠腋皮下各注射EMT6细胞(2.5*10 5)。观察小鼠肿瘤生长情况，待肿瘤体积长到50-100mm 3时开始分组，并于第1、4、9天给予本发明的化合物19和阴性对照。本发明的化合物19给药剂量为1mg/kg。实验结果以瘤体积(Tumor volume)生长曲线的形式评价，实验结果如图2所示
2、实验结果
在Balb/C品系的EMT6乳腺癌原位移植瘤模型中，相较于阴性对照，本发明的化合物19具有显著的抗肿瘤效果。

Claims (16)

  1. 具有通式(I)的杂环酰胺类化合物、其可药用的盐：
    Figure PCTCN2020116614-appb-100001
    其中，
    A环选自
    Figure PCTCN2020116614-appb-100002
    B环选自
    Figure PCTCN2020116614-appb-100003
    C选自被0～4个R i取代的饱和或不饱和的4～6元碳环或杂环；
    R 4、R 4’分别选自氢、C 1～C 6烷基、卤素；
    R 5、R 5’分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
    R 6、R 7分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6、R 7及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
    R 6’、R 7’分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6’、R 7’及与R 6’、R 7’连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
    R 1、R 2、R 3、R 2’、R 3’分别选自氢、-OR d、-NR dR e、卤素、CN、C(O)OR d、C 1～C 6烷基、卤素取代的C 1～C 6烷基、-SO 2NH 2、-C(O)NR aR b；
    R a、R b、R d、R e分别选自氢、C 1～C 6烷基；
    R B选自氢、卤素、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g、-NR fC(O)R g、-NR fC(O)R；或者R B、R 1以及与R B、R 1连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；R f、R g分别选自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、- NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R i选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基；
    R j、R k分别选自氢、C 1～C 6烷基；
    L选自被0～4个R n取代的C 4～C 6的亚烷基、被0-4个R n取代的C 4～C 6的亚烯基、被0～4个R n取代的C 4～C 6的亚炔基；所述C 4～C 6的亚烷基、C 4～C 6的亚烯基、C 4～C 6的亚炔基中的碳原子可以被-O-、-S-、-NR m-取代；
    R m选自氢、C 1～C 6烷基；
    R n选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基。
  2. 具有通式(I)的杂环酰胺类化合物、其可药用的盐：
    Figure PCTCN2020116614-appb-100004
    其中，
    A环选自
    Figure PCTCN2020116614-appb-100005
    B环选自
    Figure PCTCN2020116614-appb-100006
    C选自被0～4个R i取代的饱和或不饱和的4～6元碳环或杂环；
    R 4、R 4’分别选自氢、C 1～C 6烷基、卤素；
    R 5、R 5’各自独立地为分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基、-(CH 2) s-L 3；其中，s为1、2或3，L 3选自：C 3～C 6环烷基、3-6元杂环基；
    R 6、R 7分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6、R 7及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
    R 6’、R 7’分别选自氢、C 1～C 6烷基、硝基、卤素、卤素取代的C 1～C 6烷基，或者R 6’、R 7’及与R 6’、R 7’连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
    R 1、R 2、R 3、R 2’、R 3’分别选自氢、-OR d、-NR dR e、卤素、CN、C(O)OR d、C 1～C 6烷基、卤素取代的C 1～C 6烷基、-SO 2NH 2、-C(O)NR aR b、-L 1-L 2-C(O)NR aR b；
    R a、R b、R d、R e分别选自氢、C 1～C 6烷基；
    L 1选自：-(CH 2) t-、-C(O)-、-SO 2-、-C(O)-；其中，t为0、1、2或3；
    L 2选自：C 1～C 6烷基、C 2～C 6炔烃基、C 2～C 6烯烃基、C 3～C 6环烷基、3-6元杂环基；
    R B选自氢、卤素、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g；或者R B、R 1以及与R B、R 1连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
    R f、R g分别选自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R i选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基；
    R j、R k分别选自氢、C 1～C 6烷基；
    L选自被0～4个R n取代的C 4～C 6的亚烷基、被0-4个R n取代的C 4～C 6的亚烯基、被0～4个R n取代的C 4～C 6的亚炔基；所述C 4～C 6的亚烷基、C 4～C 6的亚烯基、C 4～C 6的亚炔基中的碳原子可以被-O-、-S-、-NR m-取代；
    R m选自氢、C 1～C 6烷基；
    R n选自卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基。
  3. 如权利要求1或2所述的式I杂环酰胺类化合物、其可药用的盐，其特征在于，A环与B环相同或不同，各自独立地为
    Figure PCTCN2020116614-appb-100007
    各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；p为0、1、2、3或4；
    R 5的定义如权利要求1所述。
  4. 如权利要求1或2所述的式I杂环酰胺类化合物、其可药用的盐，其特征在于，A环与B环相同，各自独立地为
    Figure PCTCN2020116614-appb-100008
    其中，R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基。
  5. 如权利要求1或2所述的式I杂环酰胺类化合物、其可药用的盐，其特征在 于，所述的
    Figure PCTCN2020116614-appb-100009
    部分选自：
    Figure PCTCN2020116614-appb-100010
    Figure PCTCN2020116614-appb-100011
    其中，y为0、1、2、3或4；
    p为0、1、2、3或4；
    各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基，
    各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基，
    R 5、R 2'的定义如权利要求1所述。
  6. 如权利要求1或2所述的式I杂环酰胺类化合物、其可药用的盐，其特征在于，
    Figure PCTCN2020116614-appb-100012
    部分选自：
    Figure PCTCN2020116614-appb-100013
    Figure PCTCN2020116614-appb-100014
    Figure PCTCN2020116614-appb-100015
    Figure PCTCN2020116614-appb-100016
    其中，
    y为0、1、2、3或4；
    p为0、1、2、3或4；
    各R x独立地选自：卤素、羟基、氨基、C 1～C 6烷基、卤素取代的C 1～C 6烷基；
    各R t独立地选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基、C 1～C 6烷氧基；
    R 5选自：氢、C 1～C 6烷基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
    R 2独立地选自：氢、-SO 2NH 2、-C(O)NR aR b；
    其中，R a、R b各自独立地选自：氢、C 1～C 6烷基；
    R B选自：氢、-OR f；
    R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R i选自卤素、羟基、氨基、C 1～C 6烷基；
    R j、R k分别独立地选自氢、C 1～C 6烷基。
  7. 如权利要求1或2所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐，其特征在于，R B选自氢、-OR f；
    R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R i选自卤素、羟基、氨基、C 1～C 6烷基；
    R j、R k分别独立地选自氢、C 1～C 6烷基。
  8. 如权利要求1或2所述的式I杂环酰胺类化合物、其可药用的盐，其特征在于，R B选自：H、甲氧基、
    Figure PCTCN2020116614-appb-100017
    Figure PCTCN2020116614-appb-100018
  9. 如权利要求1或2所述的杂环酰胺类化合物、其可药用的盐，其特征在于，
    R 4、R 4’分别为氢；
    R 5、R 5’分别选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
    R 6、R 7分别选自氢、C 1～C 6烷基，R 6、R 7及与R 6、R 7连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
    R 6’、R 7’分别选自氢、C 1～C 6烷基，R 6’、R 7’及与R 6’、R 7’连接的原子三者之间环化成饱和或不饱和的4～6元碳环或杂环；
    R 1、R 3、R 3’分别选自氢、C 1～C 6烷基、-OR d；
    R 2、R 2’分别选自氢、-SO 2NH 2、-C(O)NR aR b；
    R a、R b分别选自氢、C 1～C 6烷基；
    R d选自氢、C 1～C 6烷基、C 3～C 6环烷基、C 3～C 6炔烃基、C 3～C 6烯烃基、卤素取代的C 1～C 6烷基；
    R B选自氢、被0～4个R h取代的C 1～C 6烷基、-OR f；
    R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R i选自卤素、羟基、氨基、C 1～C 6烷基；
    R j、R k分别选自氢、C 1～C 6烷基；
    L选自C 4～C 6的亚烯基、C 4～C 6的亚烷基。
  10. 如权利要求1或2所述的杂环酰胺类化合物、其可药用的盐，其特征在于，
    R 6、R 7分别独立地选自氢、C 1～C 6烷基；
    R 6’、R 7’分别独立地选自氢、C 1～C 6烷基；
    R 1、R 3、R 3’分别独立地选自氢、C 1～C 6烷基；
    R 2、R 2’分别独立地选自氢、-SO 2NH 2、-C(O)NH 2；
    R B选自氢、-OR f；
    R f自氢、被0～4个R h取代的C 1～C 6烷基、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R h选自卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基、被0～4个R i取代的3～6元杂环烷基；
    R i选自卤素、羟基、氨基、C 1～C 6烷基；
    R j、R k分别独立地选自氢、C 1～C 6烷基。
  11. 如权利要求1或2所述的杂环酰胺类化合物、其可药用的盐，为如下任一 种：
    Figure PCTCN2020116614-appb-100019
  12. 一种药物组合物，其含有治疗有效量的一种或多种如权利要求1-11中任一项所述的具有通式(I)的的杂环酰胺类化合物、其可药用的盐，及药学上可接受的载体。
  13. 一种药物组合物，其含有治疗有效量的一种或多种如权利要求1-11中任一项 所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐，及药学上可接受的辅料。
  14. 如权利要求1所述具有通式(I)的杂环酰胺类化合物、其可药用的盐的制备方法，其特征在于：包括如下步骤：
    Figure PCTCN2020116614-appb-100020
    (i)在惰性溶剂中，碱存在下，原料1a与单Boc保护的二胺
    Figure PCTCN2020116614-appb-100021
    发生亲核取代反应，生成化合物1b；
    (ii)在惰性溶剂中，酸存在下，化合物1b脱去Boc保护，生成中间体1c；
    (iii)在惰性溶剂中，碱存在下，中间体1c与
    Figure PCTCN2020116614-appb-100022
    发生取代反应，生成中间体1d；
    (iv)在惰性溶剂中，在还原剂存在下，中间体1d生成化合物1e；
    (v)在惰性溶剂中，催化剂存在下，化合物1e与
    Figure PCTCN2020116614-appb-100023
    反应，获得目标化合物I；
    式中，A、B、L、R 1、R 2、R 3、R 4、R B、R 2'、R 3'、R 4'的定义如权利要求1所述。
  15. 权利要求1-11所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐在制备免疫佐剂或激活STIGN药物中的用途。
  16. 权利要求1-11所述的具有通式(I)的杂环酰胺类化合物、其可药用的盐在制备治疗与STING活性相关的疾病的药物中的用途，所述与STING活性相关的疾病是与炎性、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
PCT/CN2020/116614 2019-09-19 2020-09-21 杂环酰胺类化合物、其可药用的盐及其制备方法和用途 WO2021052501A1 (zh)

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