WO2017133591A1 - 杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途 - Google Patents

杂环取代的n-磺酰基苯甲酰胺衍生物、其制法与医药上的用途 Download PDF

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WO2017133591A1
WO2017133591A1 PCT/CN2017/072470 CN2017072470W WO2017133591A1 WO 2017133591 A1 WO2017133591 A1 WO 2017133591A1 CN 2017072470 W CN2017072470 W CN 2017072470W WO 2017133591 A1 WO2017133591 A1 WO 2017133591A1
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alkyl
group
ring
compound
alkoxy
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PCT/CN2017/072470
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English (en)
French (fr)
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兰炯
周福生
赵金柱
黄栋
谢婧
胡毅
吕强
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN201780005514.8A priority Critical patent/CN108430969B/zh
Priority to AU2017215697A priority patent/AU2017215697A1/en
Priority to US16/068,627 priority patent/US10815197B2/en
Priority to KR1020187019155A priority patent/KR20180086259A/ko
Priority to JP2018534660A priority patent/JP2019505508A/ja
Priority to EP17746911.1A priority patent/EP3412653A1/en
Priority to CA3011169A priority patent/CA3011169A1/en
Publication of WO2017133591A1 publication Critical patent/WO2017133591A1/zh

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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates in particular to a heterocyclic substituted N-sulfonylbenzamide derivative, a process for its preparation and its use as a sodium ion channel (particularly Nav1.7) inhibitor, and a pharmaceutical combination prepared therefrom And pharmaceutical compositions.
  • Nav1.7 (PN1, SCN9A) VGSC is sensitive to the blocking of tetrodotoxin, which is mainly expressed in peripheral sympathetic neurons and sensory neurons.
  • the SCN9A gene has been replicated by a variety of species including humans, rats and rabbits and shows approximately 90% identity of amino acids between human and rat genes.
  • Nav1.7 plays an important role in a variety of pain states, including acute, chronic, inflammatory, and/or neuropathic pain.
  • Nav1.7 protein accumulates in neuromas, Especially the neuroma that causes pain.
  • Mutations in Nav1.7 function have been implicated in primary erythematous limb pain (a disease characterized by burning and inflammation of the extremities), and sudden extreme pain.
  • Reports on the use of non-selective sodium channel blockers lidocaine and mexiletine to alleviate the symptoms of hereditary erythematous limb pain, and the extent and severity of carbamazepine that effectively reduce the invasion of PEPD are consistent with the above observations. .
  • Nav1.7 is specifically expressed in DRG sensory neurons and not in other tissues such as cardiomyocytes and central nervous system, the development of its specific blockers for the treatment of chronic pain may not only improve the efficacy, but also greatly reduce the side effects. And selective inhibitors of the Nav1.7 ion channel are used in almost all types of pain treatment.
  • the Nav1.7 ion channel is an important target for the development of non-addictive analgesic drugs.
  • many patented Nav1.7 ion channel inhibitors have been reported in the patent literature, the development of highly active Nav1.7 ion channel inhibitors
  • the effect of human liver microsome stability indicators on liver tissue clearance is critical to drug development, so the development of highly metabolically selective Nav1.7 ion channel inhibitors is essential.
  • the object of the present invention is to provide an inhibitor which is highly selective for the Nav1.7 sodium ion channel and has stable stability of liver microsome metabolism based on the existing Nav1.7 inhibitor and its pharmaceutical application.
  • a first aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen, hydroxy, CN, NO 2 , halogen, -NR a R b , C 1-20 alkyl, C 3-20 cycloalkyl, C 3-20 cycloalkoxy, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, -CHO, -CO-(C 1-20 alkyl), -CO-( C 6-20 aryl), C 6-20 aryl, -CONR a R b , -C(O)O-(C 1-20 alkyl), -OC(O)-(C 1-20 alkyl ), -SO 2 -(C 1-20 alkyl) or -SO 2 -(C 6-20 aryl);
  • R 5 is hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl, halogenated C 1-20 alkyl;
  • R 6 is C 6-20 aryl, C 1-20 alkyl, C 3-20 cycloalkyl, C 3-8 heterocyclic, -NR a R b ; the C 3-8 heterocyclic group contains 1 a hetero atom selected from N, O, S, wherein R a and R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl or C 6-20 aryl;
  • L 1 , L 2 are attached at any different position on the ring, each independently being a bond, or -C(O)N(R y )-, -N(R y )C(O)-, -N( R y )SO 2 -, -SO 2 N(R y )-, -OC(O)-, -C(O)O-, -(CR y R x ) r1 (O) r2 (CR y R x ) R3 -, -S(O)-, -SO 2 -, -N(R y )-, -O-, -S-, -C(O)- or cyclopropylene; wherein R y , R x Each independently is hydrogen, halogen, hydroxy, CN, NO 2 , C 1-20 alkyl, halogenated C 1-20 alkyl, C 3-20 cycloalkyl, C 2-20 alkenyl, C 2-20 Alky
  • W 1 and W 2 are each independently C, N, O or S;
  • n, m are each independently 0, 1, 2 or 3, and n, m are not 0 at the same time; wherein, when n is 0 or m is 0, W 1 and W 2 are connected by a single bond;
  • R 0 ) p is a hydrogen at any position on the ring substituted by p R 0 , p is 0, 1, 2, 3, 4 or 5, and each R 0 is the same or different, and each independently is hydrogen, helium, C 1-20 alkyl, deuterated C 1-20 alkyl or halogenated C 1-20 alkyl; or any two R 0 are linked by a single bond or -(CH 2 ) p1 -, p1 is 1, 2 or 3;
  • A is a C 6-20 aryl group, a 3 to 7 membered monocyclic ring, an 8 to 10 membered bicyclic ring, a 3 to 7 membered monoheterocyclic ring, an 8 to 10 membered bicyclic heterocyclic ring, a 5 or 6 membered monocyclic heteroaryl ring, and 8 Up to 10 membered bicyclic heteroaryl ring, benzo 3 to 7 membered monocyclic ring, benzo 3 to 7 membered monoheterocyclic ring, 5 to 6 membered monocyclic heteroaryl ring and 3 to 7 membered monocyclic ring, 5 to 6 membered a monocyclic heteroaryl ring and a 3 to 7 membered monoheterocyclic ring;
  • the R 6 is a C 3-10 cycloalkyl group or a C 3-8 heterocyclic group.
  • the R 6 is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • R 1 , R 2 , R 3 , R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl, C 3-20 cycloalkoxy or C 1-20 alkoxy.
  • R 2 and R 4 are hydrogen, and R 1 and R 3 are each independently hydrogen, halogen, C 3-20 cycloalkyl, C 1-20 alkyl, C 3-20 naphthenic. Oxy or C 1-20 alkoxy.
  • R 5 is hydrogen
  • A is a C 6-20 aryl or a 5 or 6 membered monocyclic heteroaryl ring; the aryl or 5 or 6 membered monocyclic heteroaryl ring is substituted or unsubstituted
  • substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of halogen, C 1-20 alkyl, halogenated C 1-20 alkyl, C 1-20 Alkoxy, halogenated C 1-20 alkoxy, C 3-20 cycloalkyl, and C 3-20 cycloalkoxy.
  • the C 6-20 aryl group is a phenyl group; and the 5 or 6 membered monocyclic heteroaryl ring is a pyridyl group.
  • the phenyl group is wherein R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, nitro, hydroxy, cyano, C 6-20 aryl, C 1-20 alkyl, Halogenated C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, halo C 3-20 cycloalkyl, C 3-20 ring Alkoxy, halogenated C 3-20 cycloalkoxy, C 2-20 alkenyl, halogenated C 2-20 alkenyl, C 2-20 alkynyl, halogenated C 2-20 alkynyl, -NR a R b , -C(O)NR a R b , -N(R a )C(O)-(C 1-20 alkyl), -N(R a )SO 2 -(C 1-20 alkyl) ,
  • the pyridyl group is or Wherein R 21 , R 31 , R 41 , R 51 , R 12 , R 32 , R 42 , R 52 , R 13 , R 23 , R 43 , R 53 are each independently hydrogen, halogen, nitro, hydroxy, cyanide , C 6-20 aryl, C 1-20 alkyl, halo C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl Halogenated C 3-20 cycloalkyl, C 3-20 cycloalkoxy, halo C 3-20 cycloalkoxy, C 2-20 alkenyl, halogenated C 2-20 alkenyl, C 2 - 20 alkynyl, halogenated C 2-20 alkynyl, -NR a R b , -C(O)NR a R b , -N(R a )C(O)-(C 1-20 alkyl),
  • R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, C 1-20 alkyl, halo C 1-20 alkyl, Halogenated C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy.
  • R 21 , R 31 , R 41 , R 51 , R 12 , R 32 , R 42 , R 52 , R 13 , R 23 , R 43 , R 53 are each independently hydrogen, halogen, C 1-20 alkyl, halo C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy .
  • L 1 , and R 0 are as defined in the specification.
  • L 1 is -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y , R x are each independently hydrogen; r1, r3 are each independently Is 0, 1, 2 or 3; r2 is 0 or 1.
  • r2 is zero.
  • r1 is 1, 2 or 3; r2 is 1; r3 is 0;
  • r1 is 0; r2 is 1; r3 is 1, 2 or 3; or
  • W 2 is N, O, S or C, and when W 2 is O or S, L 2 is bonded to any carbon atom other than W 1 and W 2 on the ring, when W 2 is In the case of N or C, L 2 is bonded to any ring atom other than W 1 on the ring.
  • L 2 is linked to W 2 .
  • L 2 is a bond
  • A is bonded to any ring atom other than W 1 on the ring.
  • L 2 is a bond
  • W 2 is N, O, S or C
  • W 2 is O or S
  • A is bonded to any carbon atom other than W 1 and W 2 on the ring.
  • W 2 is N or C
  • A is bonded to any ring atom other than W 1 on the ring.
  • W 1 is N, O, S or C
  • W 1 is O or S
  • L 1 is bonded to any carbon atom other than W 1 and W 2 on the ring
  • W 1 is In the case of N or C
  • L 1 is bonded to any ring atom other than W 2 on the ring
  • L 1 is bonded to W 1 .
  • the compound is a compound of formula (II):
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, L 1 , W 1 , W 2 , n, p, m are as defined in claim 1.
  • each R 0 is the same or different and is each independently hydrogen.
  • A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring.
  • A is a phenyl or pyridyl group; said phenyl or pyridyl group is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are selected from Substituted by the following group of substituents: halogen, C 1-20 alkyl, halogenated C 1-20 alkyl, C 1-20 alkoxy, halogenated C 1-20 alkoxy, C 3-20 naphthenic a group, and a C 3-20 cycloalkoxy group.
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y , R x are each independently hydrogen; r1 R3 is each independently 0, 1, 2 or 3; r2 is 0 or 1.
  • the compound is a compound of formula (III):
  • W 1 is N, O, S or C, and when W 1 is O or S, (CR y R x ) r1 and W 1 and W 2 are removed from the ring. Any other carbon atom other than the connection, when W 1 is N or C, (CR y R x ) r1 is bonded to any ring atom other than W 2 on the ring, and r1 is as defined above.
  • W 2 is N.
  • W 1 is N, O, S or C.
  • A, L 1 and R 0 are defined as before.
  • A, L 1 and R 0 are defined as before.
  • A, L 1 and R 0 are defined as before.
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y , R x are each independently hydrogen; r1 and r3 are each independently 0 1, 2 or 3; r2 is 0 or 1; each R 0 is the same or different and each independently is hydrogen.
  • A is wherein R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are as defined in the specification.
  • A, L 1 and R 0 are defined as before. .
  • A, L 1 and R 0 are defined as before.
  • the compound is a compound of formula (IV):
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , R y , r1, r2, r3, A, W 2 , n, p, m are as defined above; W 1 is N or C.
  • r2 is zero.
  • r1 and r3 are 0; r2 is 1.
  • r1 is 1, 2 or 3; r2 is 1; r3 is 0.
  • r1, r2, and r3 are zero.
  • the compound is a compound of formula (V):
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , W 1 , W 2 , n, p, m are as defined above;
  • R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, nitro, hydroxy, cyano, C 6-20 aryl, C 1-20 alkyl, halo C 1-20 alkyl, Halogenated C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, halogenated C 3-20 cycloalkyl, C 3-20 cycloalkoxy, halogenated C 3- 20 cycloalkoxy, C 2-20 alkenyl, halogenated C 2-20 alkenyl, C 2-20 alkynyl, halogenated C 2-20 alkynyl, -NR a R b , -C(O)NR a R b ,
  • R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, C 1-20 alkyl, halo C 1-20 alkyl, Halogenated C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl.
  • L 1 is -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -, and r1, r2, and r3 are as defined above.
  • W 1 is N, O, S or C, and when W 1 is O or S, L 1 and any carbon other than W 1 and W 2 on the ring The atom is bonded.
  • W 1 is N or C, L 1 is bonded to any ring atom other than W 2 on the ring.
  • L 1 is bonded to W 1 .
  • W 2 is N.
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl;
  • R 5 is hydrogen
  • R 6 is C 1-20 alkyl, -NR a R b ;
  • R a and R b are each independently hydrogen or a C 1-20 alkyl group
  • W 1 , W 2 are each independently C, O, S or N;
  • L 2 is a key
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -, -O- or -C(O)-; wherein R y and R x are each independently Hydrogen; r1, r3 are each independently 0 or 1; r2 is 0 or 1;
  • n, m are each independently 1 or 2;
  • (R 0 ) p is a hydrogen at any position on the ring is replaced by p R 0 , p is 0;
  • A is a phenyl group
  • W 1 and/or W 2 is N or C
  • A is bonded to any ring atom other than W 1 on the ring
  • L 1 is bonded to any ring atom other than W 2 on the ring;
  • alkyl group, cycloalkyl group or phenyl group is substituted or unsubstituted; and the substitution means that 1 to 5 hydrogens in the group are substituted with a substituent selected from the group consisting of halogen, C 1-20 alkyl, halogenated C 1-20 alkyl, C 1-20 alkoxy, halogenated C 1-20 alkoxy.
  • R 2 and R 4 are hydrogen, and R 1 and R 3 are each independently halogen, C 3-6 cycloalkyl, C 1-3 alkyl, C 3-6 cycloalkoxy. Or C 1-3 alkoxy.
  • L 2 is a bond (indicating that A is attached to any ring atom other than W 1 on the ring), or is -(CH 2 ) r1 (O) r2 (CH 2 ) r3 -, - S-, -C(O)-, -S(O)-, -SO 2 - or -N(R y )-, wherein r1, r2, r3, R y are as defined above.
  • the compound is a compound of any one of the formulae (I) to (V), wherein R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1- 20 alkyl, C 3-20 cycloalkyl;
  • R 5 is hydrogen
  • R 6 is C 1-20 alkyl, -NR a R b ; wherein R a and R b are each independently hydrogen and C 1-20 alkyl.
  • A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring.
  • L 2 is a bond; or L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y , R x are each Independently hydrogen; r1, r3 are each independently 0, 1, 2 or 3; r2 is 0 or 1.
  • each R 0 is the same or different and is each independently hydrogen.
  • A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y and R x are each independently hydrogen; r1 and r3 are each independently 0. 1, 2 or 3; r2 is 0 or 1;
  • Each R 0 is the same or different and is each independently hydrogen
  • the alkyl, cycloalkyl, aryl, 5- or 6-membered monocyclic heteroaryl ring is substituted or unsubstituted; and the substitution means that 1 to 5 hydrogens in the group are selected from Substituted by a group of substituents: halogen, nitro, hydroxy, cyano, C 6-20 aryl, C 1-20 alkyl, halo C 1-20 alkyl, C 1-20 alkoxy, halogenated C 1-20 alkoxy, C 3-20 cycloalkyl, halogenated C 3-20 cycloalkyl, C 3-20 cycloalkoxy, halogenated C 3-20 cycloalkoxy, C 2-20 Alkenyl, halogenated C 2-20 alkenyl, C 2-20 alkynyl, halogenated C 2-20 alkynyl, C 1-20 alkylthio, halogenated C 1-20 alkylthio, C 1-20 An alkylamino group, a hal
  • A is a phenyl or pyridyl group; said phenyl or pyridyl group is substituted or unsubstituted; and said substitution means that 1 to 5 hydrogens in the group are selected from Substituted by the following group of substituents: halogen, C 1-20 alkyl, halogenated C 1-20 alkyl, C 1-20 alkoxy, halogenated C 1-20 alkoxy, C 3-20 naphthenic Base, C 3-20 cycloalkoxy.
  • the phenyl group is wherein R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are each independently hydrogen, halogen, C 1-20 alkyl, halo C 1-20 alkyl, halo C 1-20 Alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl.
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y and R x are each independently hydrogen; r1 and r3 are each independently 0. 1, 2 or 3; r2 is 0 or 1;
  • Each R 0 is the same or different and is each independently hydrogen.
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y and R x are each independently hydrogen; r1 and r3 are each independently 0. 1, 2 or 3; r2 is 0 or 1;
  • Each R 0 is the same or different and is each independently hydrogen.
  • r1 and r3 are 0; r2 is 1.
  • L 1 is a bond, or -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -; wherein R y and R x are each independently hydrogen; r1 and r3 are each independently 0. 1, 2 or 3; r2 is 0 or 1;
  • Each R 0 is the same or different and is each independently hydrogen.
  • r1 is 1, 2 or 3; r2 is 1; r3 is 0.
  • R 1 and R 3 are each independently hydrogen, halogen, C 1-20 alkyl or C 3-20 cycloalkyl; and R 2 and R 4 are hydrogen.
  • the C 1-20 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl.
  • the C 3-20 cycloalkyl group is a cyclopropyl group.
  • the halo C 1-20 alkyl group is a trifluoromethyl group.
  • the halo C 1-20 alkoxy group is a trifluoromethoxy group, a trifluoroethoxy group, or a difluoromethoxy group.
  • the C 1-20 alkoxy group is a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, or an isobutoxy group.
  • the C 3-20 cycloalkoxy group is a cyclopropoxy group.
  • the halogen is fluorine or chlorine.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , L 1 , R y , R x , W 1 , W 2 , n And m, R 0 , A and the like are each independently the corresponding group of each of the compounds of the specific formula II in the examples.
  • the compound of formula II of the present invention is each specific compound noted in the Examples section, especially any of Z-80 to Z-197.
  • the compound is a compound prepared in the examples of the present application.
  • a second aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; and pharmaceutically acceptable Acceptable carrier.
  • a third aspect of the invention provides a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention Use in the preparation of a medicament for treating a disease or condition.
  • the disease or condition is selected from the group consisting of pain, depression, cardiovascular disease, respiratory disease, mental illness, or a combination thereof.
  • the disease or condition is selected from the group consisting of HIV-related pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, intestinal tract Jain syndrome, Crohn's disease, pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, bone and joint Inflammation, atherosclerosis, sudden dystonia, myasthenia gravis syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudohyperaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety , schizophrenia, sodium channel toxin-related disorders, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain, cancer, epilepsy, local and generalized tonic seizures, restless legs syndrome, Arrhythmia
  • the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-operative pain, production pain, labor pain, toothache, chronic pain, Persistent pain, peripheral-mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, trigeminal neuralgia, post-herpetic neuralgia, acute Pain, familial erythematous limb pain, primary erythematous limb pain, familial rectal pain or fibromyalgia or a combination thereof.
  • a fourth aspect of the invention provides a method of treating a disease or condition in a mammal, the method comprising administering to a subject in need thereof, such as a mammal, a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutical thereof An acceptable salt, solvate, stereoisomer or prodrug, or a pharmaceutical composition of the second aspect of the invention.
  • Figure 1 shows the baseline of rat cold pain test in compound Z-164 in a rat model of spinal nerve ligation.
  • Figure 2 shows that Compound Z-164 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
  • heterocyclic-substituted N-sulfonylbenzamide derivative of the present invention is highly selective to the Nav1.7 sodium ion channel and has stable liver microsomal metabolism. stability.
  • a significant analgesic effect is also shown in the pain model test, and thus the series of compounds of the present invention can be developed into drugs for the treatment of a wide range of pain.
  • the inventors completed the present invention.
  • C 1-20 alkyl refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing from 1 to 20 carbon atoms, as defined below; more preferably C 1-10 alkyl, non-limiting Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylp
  • alkenyl refers to an aliphatic hydrocarbon group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • C 2-20 alkenyl means having from 2 to 20 carbon atoms.
  • the linear and branched alkenyl groups are similarly defined as follows; more preferably C 2-10 alkenyl; more preferably C 2-6 alkenyl; most preferably C 2-4 alkenyl, such as vinyl, 1-propenyl , 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • alkynyl refers to an aliphatic hydrocarbon radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C 2-20 alkynyl is meant to contain from 2 to 20 carbon atoms.
  • the straight-chain and branched alkynyl groups are similarly defined as follows; more preferably C 2-10 alkynyl; more preferably C 2-6 alkynyl; more preferably C 2-4 alkynyl; for example ethynyl, 1-propenyl Alkynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group
  • C 3-20 cycloalkyl refers to a cyclic hydrocarbon group containing from 3 to 20 carbon atoms, as defined below; More preferably, it is a C 3-10 cycloalkyl group; more preferably a C 3-8 cycloalkyl group; most preferably a C 3-6 cycloalkyl group.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
  • the alkenyl group, the cyclooctyl group, the adamantyl group and the like are preferably a cyclopropyl group, a cyclopentyl group or a cyclohexenyl group.
  • Non-limiting examples of polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • heterocycloalkyl and “heterocyclyl” are used interchangeably and mean a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, preferably a 3 to 20 membered heterocycloalkyl group.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
  • Non-limiting examples of polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • partially unsaturated refers to a pi-electron system that contains one or more unsaturated bonds but does not have a complete conjugation.
  • C 1-20 alkoxy refers to -O-(C 1-20 alkyl), wherein alkyl is as defined above.
  • a C 1-10 alkoxy group is preferred, a C 1-6 alkoxy group is more preferred, and a C 1-3 alkoxy group is most preferred.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy and the like.
  • C 3-20 cycloalkoxy refers to -O-(C 3-20 cycloalkyl), wherein cycloalkyl is as defined above.
  • a C 3-10 cycloalkoxy group is preferred, preferably a C 3-8 cycloalkoxy group, more preferably a C 3-6 cycloalkoxy group.
  • Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • C 6-20 aryl refers to an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, meaning 6 to 20 An aryl group of a carbon atom; more preferably a C 6-12 aryl group, more preferably a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • a bond refers to the attachment of two groups attached thereto through a covalent bond.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • halo means that one or more (eg 1, 2, 3, 4 or 5) hydrogens in the group are replaced by a halogen.
  • halo C 1-20 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) halogens, wherein alkyl is as defined above. It is preferably a halogenated C 1-10 alkyl group, more preferably a halogenated C 1-6 alkyl group, and most preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-20 alkyl groups include, but are not limited to, monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, monofluoroethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, and the like.
  • halo C 1-20 alkoxy means that the alkoxy group is substituted by one or more (eg 1, 2, 3, 4 or 5) halogens, wherein the alkoxy group is as defined above. It is preferably a halogenated C 1-10 alkoxy group, more preferably a halogenated C 1-6 alkoxy group, and most preferably a halogenated C 1-3 alkoxy group. These include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • halo C 3-20 cycloalkyl refers to a cycloalkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halo, wherein cycloalkyl is as defined above.
  • Preferred is a halogenated C 3-10 cycloalkyl group, more preferably a halogenated C 3-8 cycloalkyl group, and most preferably a halogenated C 3-6 cycloalkyl group.
  • halogenated C 3-10 cycloalkyl group more preferably a halogenated C 3-8 cycloalkyl group, and most preferably a halogenated C 3-6 cycloalkyl group.
  • These include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • deuterated C 1-20 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) deuterium atoms, wherein alkyl is as defined above. It is preferably a deuterated C 1-10 alkyl group, more preferably a deuterated C 1-6 alkyl group, and most preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, didecanoethyl, triterpene methyl, triterpenoid Base.
  • C 1-20 hydroxyalkyl refers to a C 1-20 alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. It is preferably a C 1-10 hydroxyalkyl group, more preferably a C 1-6 hydroxyalkyl group, and most preferably a C 1-3 hydroxyalkyl group.
  • amino means -NH 2
  • cyano refers to -CN
  • Niro refers to -NO 2
  • benzyl refers to -CH 2 - phenyl
  • Carboxy means -C(O)OH
  • thiol means -SH
  • cyclopropylene structure is:
  • Carboxylate group refers to -C(O)O-( C1-20 alkyl) or ( C3-20 cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • C 1-20 alkylthio refers to -S-(C 1-20 alkyl), wherein alkyl is as defined above. It is preferably a C 1-10 alkylthio group, more preferably a C 1-6 alkylthio group, and most preferably a C 1-3 alkylthio group.
  • C 1-20 alkylamino refers to -(C 1-20 alkyl)-NH 2 or -NH 2 -(C 1-20 alkyl), wherein alkyl is as defined above. It is preferably a C 1-10 alkylamino group, more preferably a C 1-6 alkylamino group, and most preferably a C 1-3 alkylamino group.
  • C 3-20 cycloalkylthio refers to -S-(C 3-20 cycloalkyl), wherein cycloalkyl is as defined above. It is preferably a C 3-10 cycloalkylthio group, more preferably a C 3-8 cycloalkylthio group, and most preferably a C 3-6 cycloalkylthio group.
  • 3-membered to 20-membered heterocycloalkylthio refers to -S-(3- to 20-membered heterocycloalkyl), wherein heterocycloalkyl is as defined above. It is preferably a 3- to 10-membered heterocycloalkylthio group.
  • 3-membered to 20-membered heterocycloalkyloxy refers to -O- (3- to 20-membered heterocycloalkyl), wherein heterocycloalkyl is as defined above. It is preferably a 3- to 10-membered heterocycloalkyloxy group.
  • heteroaryl ring and “heteroaryl” are used interchangeably and mean having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl.
  • the ring array shares 6, 10 or 14 ⁇ electrons; and has a group of 1 to 5 hetero atoms in addition to carbon atoms.
  • Hetero atom means nitrogen, oxygen or sulfur.
  • 3- to 7-membered monocyclic refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing from 3 to 7 ring atoms. It is preferably 5 to 6 yuan.
  • monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, rings A pentenyl ring, a cyclohexyl ring, a cyclohexenyl ring, a cyclohexadienyl ring, a cycloheptyl ring, a cycloheptatrienyl ring, a cyclooctyl ring or the like.
  • 3 to 7 membered monoheterocycle means that 1, 2 or 3 carbon atoms in a 3 to 7 membered monocyclic ring are substituted with a heteroatom selected from nitrogen, oxygen or sulfur. It is preferably 5 to 6 yuan.
  • monoheterocycles include, but are not limited to, tetrahydrofuran ring, tetrahydrothiophene ring, pyrrolidinyl ring, piperidine ring, pyrroline ring, oxazolidine ring, piperazine ring, dioxolane, morpholine ring, Thiomorpholine ring, homopiperazine ring, pyran ring and the like.
  • 8- to 10-membered bicyclic refers to a saturated all-carbon bicyclic or partially unsaturated, all-carbon bicyclic ring containing from 8 to 10 ring atoms, examples of which include, but are not limited to:
  • 8- to 10-membered bicyclic heterocycle means that 1, 2, 3, 4 or 5 carbon atoms in the 8- to 10-membered bicyclic ring are replaced by a heteroatom selected from nitrogen, oxygen or sulfur.
  • bicyclic heterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.
  • a "5- to 6-membered monocyclic heteroaryl ring” refers to a monoheteroaryl ring containing from 5 to 6 ring atoms, including, for example, but not limited to, a thiophene ring, an N-alkylpyrrole ring, Furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, Pyrimidine ring, pyrazine ring and the like.
  • 8- to 10-membered bicyclic heteroaryl ring refers to a biheteroaryl ring containing from 8 to 10 ring atoms, and includes, for example, but not limited to: benzofuran ring, benzothiophene ring, hydrazine Anthracene ring, isoindole ring, quinoline ring, isoquinoline ring, indazole ring, benzothiazole ring, benzimidazole ring, quinazoline ring, quinoxaline ring, porphyrin ring, pyridazine ring.
  • benzo 3 to 7 membered monocyclic or benzo 3 to 7 membered monoheterocyclic ring means a bicyclic structure formed by condensing a monocyclic or monoheterocyclic ring having 3 to 7 ring atoms to a benzene ring.
  • the benzo is a 5- to 6-membered monocyclic or benzo 5- to 6-membered monoheterocyclic ring.
  • Non-limiting examples include:
  • 5 to 6 membered monocyclic heteroaryl ring and 3 to 7 membered monocyclic or 5 to 6 membered monocyclic heteroaryl ring and 3 to 7 membered monoheterocyclic ring means a 3 to 7 membered single ring. Or a 3 to 7 membered monoheterocyclic ring fused to a bicyclic structure formed on a 5 to 6 membered monocyclic heteroaryl ring, non-limiting examples comprising:
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with each other by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other. The ground is replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • alkyl may be substituted or unsubstituted
  • alkenyl may be substituted or unsubstituted
  • alkynyl may be substituted or unsubstituted
  • cycloalkyl may be substituted or unsubstituted
  • hetero The cyclo group may be substituted or unsubstituted
  • the alkoxy group may be optionally substituted or unsubstituted
  • the cycloalkoxy group may be optionally substituted or unsubstituted
  • the aryl group may be substituted or unsubstituted.
  • the 3 to 7 membered monocyclic ring may be substituted or unsubstituted
  • the 3 to 7 membered monocyclic heterocyclic ring may be substituted or unsubstituted
  • the 8 to 10 membered bicyclic ring may be substituted or unsubstituted, 8 to 10 membered.
  • the bicyclic heterocycle may be substituted or unsubstituted, and the benzo 3 to 7 membered monocyclic or benzo 3 to 7 membered monoheterocyclic ring may be substituted or unsubstituted, 5 to 6 membered monocyclic heteroaryl ring and
  • the 3- to 7-membered monocyclic or 5- to 6-membered monocyclic heteroaryl ring and the 3- to 7-membered monoheterocyclic ring may be substituted or unsubstituted, and when the above group is substituted, the substituent is preferably 1 to 5 or less.
  • the present invention provides a process for the preparation of a compound of formula (I), which compounds can be readily prepared by a variety of synthetic procedures which are well known to those skilled in the art. Exemplary methods of preparation of these compounds can include, but are not limited to, the procedures described below.
  • the compound of the formula (I) of the present invention can be prepared by referring to the following synthetic route, and in the specific operation, it can be The steps in the method need to be extended or merged.
  • Step 1 The carboxyl group in the compound of formula (Ia) can be activated first by a reagent such as oxalyl chloride, carbonyldiimidazole (CDI), propylphosphonic anhydride, urea-based amide coupling agent or carbodiimide, followed by affinity Alkaloids such as 4-dimethylaminopyridine, N,N-dimethylaminopropyl-N'-ethylcarbodiimide, 4-dimethylaminopyridine/N,N-diisopropylethylamine
  • a reagent such as oxalyl chloride, carbonyldiimidazole (CDI), propylphosphonic anhydride, urea-based amide coupling agent or carbodiimide
  • affinity Alkaloids such as 4-dimethylaminopyridine, N,N-dimethylaminopropyl-N'-ethylcarbodiimide, 4-dimethylamin
  • Step 2 a compound of the formula (Ic) and a compound of the formula (Id) are produced in the presence of a base system by a substitution reaction (for example, an affinity substitution reaction or the like) or a coupling reaction (such as a Suzuki coupling or the like) to form a compound of the formula (Ie).
  • a substitution reaction for example, an affinity substitution reaction or the like
  • a coupling reaction such as a Suzuki coupling or the like
  • Suitable base systems include potassium t-butoxide present in DMSO, sodium hydride present in DMF, potassium carbonate present in DMF, and the like.
  • Step 3 A compound of the formula (Ie) can be substituted with a compound of the formula (If) to form a compound of the formula (I), and Lev in the formula (If) is a leaving group including, but not limited to, a triflate. Chlorine, bromine, iodine; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy, such as acetoxy, trifluoroacetoxy Base.
  • the compound of formula (Id) may be first substituted with a compound of formula (If) to form a compound of formula (Ig), followed by reaction with a compound of formula (Ic) to form a compound of formula (I), the reaction conditions being the same as step 3 and step in Scheme 1, respectively. 2.
  • a series of novel heterocyclic substituted N-sulfonylbenzamide derivatives are provided which are highly selective for the Nav1.7 sodium ion channel and have stable stability of liver microsome metabolism and can be used as a wide range of pain Therapeutic drugs.
  • DMF is dimethylformamide
  • DMSO is dimethyl sulfoxide
  • THF is tetrahydrofuran
  • DIPEA is N,N-diisopropylethylamine
  • EA is ethyl acetate
  • PE is petroleum ether
  • BINAP is (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl
  • LiHMDS is lithium bistrimethylsilylamine
  • THF is tetrahydrofuran
  • HATU 2-(7-azo Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • n-BuLi is n-butyllithium
  • DCM is dichloromethane
  • DME ethylene glycol dimethyl ether
  • NBS is N-bromosuccinimide
  • Pd2(dba)3 is tris(dibenzy
  • Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • DIAD is diisopropyl azodicarboxylate
  • EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DMAP is 4-dimethylaminopyridine
  • LDA is lithium diisopropylamide.
  • room temperature means about 25 °C.
  • EtOAc EtOAc
  • Step a To a solution of compound 17-a-1 (4.5 g, 28.8 mmol), p-toluenesulfonic acid (499 mg, 2.9 mmol) in dichloromethane (100 ml) The imide (4 g, 30.3 mmol) was stirred for 2 hours and stirred at room temperature overnight. After completion of the reaction, the mixture was poured into EtOAc EtOAc m. MS m/z (ESI): 189 [MH] - .
  • Step b Concentrated sulfuric acid (7 ml, 1 mmol) was added dropwise to a solution of Compound 17-a-2 (5 g, 26.3 mmol After the reaction was completed, it was cooled to room temperature, poured into water, EtOAc EtOAcjjjjjjjjj ). MS m/z (ESI): 203 [MH] - .
  • Step a Refer to the preparation method of Step 3 in Example 57 using the compound 17-a (2 g) as a starting material, except that the reaction conditions were changed to room temperature and stirred overnight to obtain Compound 22-a-2 (552 mg), purity 96.57%. Yield 14%, MS m/z (ESI): 3221. [M+H-56] + .
  • Step b Using the compound 22-a-2 (552 mg) as a starting material, the title compound of Step 4 of Example 4 gave Compound 22-a (409 mg), purity 100%, yield 41%, MS m/z (ESI) ): 288 [M+H] + .
  • Step 1 Add compound 36-a-1 (500 mg, 2.23 mmol), compound 36-a-2 (671 mg, 3.35 mmol), Pd 2 (dba) 3 (tris(dibenzylideneacetone)) to a 50 ml sealed tube.
  • Di-palladium) 41 mg, 0.045 mmol
  • BI NAP (( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl) (56 mg, 0.089 mmol)
  • potassium tert-butoxide (644 mg, 6.7 mmol), 7 ml of 1,4-dioxane, stirred at 90 ° C for 2 h.
  • Step 2 A methanol solution of hydrogen chloride (1.5 ml, 5.53 mmol) was added to a solution of Compound 36-a-3 (475 mg) in methanol, and the mixture was stirred at room temperature for 4 hr. Used directly without purification.
  • Step 1 Compound 42-a-1 (200 mg, 0.966 mmol), N-Boc-piperazine (270 mg, 1.449 mmol), Pd 2 (dba) 3 (44 mg, 0.097 mmol), Johnphos (30 mg, 0.193 mmol), A mixed solution of sodium tert-butoxide (280 mg, 2.988 mmol) in dioxane was stirred at 40 ° C under argon overnight. The reaction mixture was cooled to room temperature, filtered with EtOAc (EtOAc)EtOAc. The rate was 50%, MS m/z (ESI): 257.2 [M+H-56] + .
  • Step 2 A yellow solid compound 42-a (212 mg) was obtained by the procedure of step 2 in Intermediate 36-a.
  • the intermediate compound is represented by the formula (I), and the substituted aromatic ring group Ar is shown in the following table.
  • Step a slowly add DIAD to a solution of compound 61-a-1 (2.01 g, 0.01 mol), compound 25-a (2.49 g, 0.01 mol), triphenylphosphine (5.24 g, 0.02 mol) in tetrahydrofuran. (4.04 g, 0.02 mol), the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with saturated brine, dried and evaporated, then evaporated,462462462462462462462462462462462462462462462462462462462462462462462462462462462 -56] + .
  • Step b To a solution of Compound 61-a-2 (2.08 g, 4. The reaction solution was concentrated under reduced pressure to give 61-a (1.6g), purity 100%, yield 98%, MS m / z ( ESI): 370 [M + H] +.
  • Step 1 Compound 62-a-1 (1.0 g, 5.85 mmol), N-Boc-piperazine (1.3 g, 7.02 mmol), HATU (2.22 g, 5.85 mmol) and DIPEA (1.51 g, 11.7 mmol)
  • the methyl chloride mixed solution was stirred at room temperature for 16 h.
  • the reaction mixture was diluted with methylene chloride, washed with EtOAc EtOAc EtOAc (EtOAc m. %, yield 76%, MS m/z (ESI): 283.0 [M+H] + .
  • Step 2 Using compound 62-a-2 as a starting material, refer to the preparation method of Step 2 in 36-a to give compound 62-a (1.21 g), purity 96%, yield 99%, MS m/z (ESI) :239.0[M+H] + .
  • the compound 63-a was obtained by referring to the preparation method of the compound 62-a.
  • Step 1 Compound 80-a (9.0 g, 40 mmol), compound 7-a (6.08 g, 60 mmol), (L)-valine (920 mg, 8 mmol), cuprous iodide (764 mg, 4 mmol), potassium carbonate A mixed solution of (16.56 g, 120 mmol) in dimethyl sulfoxide (50 ml) was stirred at 100 ° C for 16 h under argon.
  • Step 2 To a mixed solution of compound 80-b (956 mg, 3.9 mmol), compound 17-a (800 mg, 3.9 mmol), triphenylphosphine (2.04 g, 7.8 mmol) in tetrahydrofuran (10 ml) was added dropwise DIAD ( 1.58 g, 7.8 mmol), stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjj :432.2[M+H] + .
  • Step 3 To a solution of the compound 80-c (1.1 g, 2.55 mmol) in methanol (20 ml) was added 2M sodium hydroxide solution (5 ml), and the mixture was stirred at 60 ° C for 2 h. The solvent was removed under reduced pressure. The residue was evaporated to dryness. 0.84 g), purity 96%, yield 79%, MS m/z (ESI): 418.1 [M+H] + .
  • Step 4 Compound 80-d (100 mg, 0.239 mmol), cyclopropylsulfonamide (58 mg, 0.478 mmol), HATU (100 mg, 0.263 mmol), DIPEA (62 mg, 0.478 mmol), DMAP (3 mg, 0.024 mmol)
  • the mixture was mixed with dichloromethane and stirred at room temperature for 16 h.
  • the reaction mixture was diluted with EtOAc (2 mL). Yield 10%, MS m/z (ESI): 521.2 [M+H] + .
  • Step 1 Compound 119-a (1.13 g, 5 mmol), Compound 7-a (1.01 g, 10 mmol) After the reaction mixture was cooled to room temperature, the mixture was poured into EtOAc EtOAc (EtOAc m. 420 mg), purity 100%, yield 34%, MS m/z (ESI): 247.1 [M+H] + .
  • Step 2 Compound 119-b (318 mg) was obtained from compound 119-b, m.p. M+H] + .
  • Step 3 Compound 119-c was used as the starting material.
  • Compound 119-d (409 mg) was obtained as a white solid, m.p. 95%, yield 52%, MS m/z (ESI): 419.1 M+H] + .
  • Step 4 Compound #119-d was used as the starting material. mp. mp. M+H] + .
  • Step 1 Compound 22-a (6.87 g, 0.02 mol), compound 2-fluoro-5-(trifluoromethyl)pyridine (3.5 g, 0.02 mol), potassium carbonate (8.29 g, 0.06 mmol) in acetonitrile Stir at 80 ° C overnight. After the reaction mixture was cooled to room temperature, water was added, EtOAc was evaporated,jjjjjjjjjjj %, yield 75%, MS m/z (ESI): 433.1 [M+H] + .
  • Step 2 Compound #150-a was used as a starting material, and the title compound was obtained by the procedure of Step 3 in Example 80 to give white compound 150-b (6.422), purity 99%, yield 92%, MS m/z (ESI): 419.1 [ M+H] + .
  • Step 3 Starting from compound 150-b, mp. [M+H] + .
  • Step 1 4-Bromo-trifluoromethylbenzene (20 g, 0.089 mol), compound 7-a (13.486 g, 0.133 mol), (L)-valine (2.047 g, 0.017 mol), cuprous iodide (1.693 g, 0.009 mol) and a mixed solution of potassium carbonate (30.854 g, 0.267 mol) in dimethyl sulfoxide were stirred under argon at 90 ° C overnight, the reaction solution was cooled to room temperature, poured into water, and extracted with ethyl acetate.
  • Step 2 To a solution of compound 125-b (1.48 g, 6.02 mmol), compound 25-a (1.5 g, 6.02 mmol), triphenylphosphine (3.15 g, 12.04 mmol) in tetrahydrofuran, DIAD (2.43 g) , 12.04 mmol), after completion of the dropwise addition, the reaction mixture was further stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjj 98%, yield 43%, MS m/z (ESI): 478.1 [M+H] + .
  • Step 3 Compound 125-c (1.13 g, 2.6 mmol), cyclopropylboronic acid (0.45 g, 5.2 mmol), Pd (dppf) Cl 2 (0.19 g, 0.26 mmol), cesium carbonate (1.7 g, 5.2 mmol)
  • the dioxane solution was stirred at 90 ° C for 24 h under argon.
  • the reaction mixture was cooled to room temperature and filtered, and the filtered cake was washed with EtOAc. %, yield 99%, MS m/z (ESI): 438.2 [M+H] + .
  • Step 4 To a solution of the compound 125-d (1.053 g, 2.407 mmol) in methanol, 1M sodium hydroxide solution (10 ml), and the mixture was stirred at 60 ° C for 2 h. The reaction solution was concentrated under reduced pressure to remove methanol, water was added, and the mixture was adjusted to pH 2-3 with 1M hydrochloric acid solution, filtered, and the filter cake was washed with water and dried to give a white solid 125-e (1.16 g), purity 100%, yield 100% MS m/z (ESI): 424.1 [M+H] + .
  • Step 5 Compound 125-e (200 mg, 0.472 mmol), EtOAc (EtOAc: EtOAc: EtOAc: EtOAc The dichloromethane mixed solution was stirred at room temperature overnight. Reaction mixture was washed with water, dried and concentrated, the crude product was purified by Pre-HPLC purification as a white solid compound Z-125 (72mg), purity 100%, yield 29%, MS m / z ( ESI): 527 [M + H] +.
  • Step 1 Compound 61-a (1.6 g, 4.34 mmol), 2-fluoro-5-trifluoromethylpyridine (0.72 g, 4.34 mmol), potassium carbonate (1.8 g, 13.02 mmol) in acetonitrile 20h.
  • the reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Step 2 Compound 142-a (1.0 g, 2.1 mmol) was used as a starting material.
  • Step 3 Compound 142-b (0.8 g) was obtained from compound 142-b (0.9 g, 2.05 mmol). /z (ESI): 425.2 [M + H] + .
  • Step 1 The compound 13-a-3 (300 mg) was used as a starting material to give the compound 89-c (456 mg), MS m/z (ESI): 290 [MH] - .
  • Step 2 Compound 89-c (452 mg) was used as a starting material. ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ RTIgt; .
  • Step 3 A mixed solution of the compound 89-d (109 mg), Compound 10-a, and potassium carbonate in acetonitrile was stirred at 80 ° C for 3 h. The reaction solution was cooled to room temperature, added with water, EtOAc EtOAc. :520.1[M+H] + .
  • Step 1 4-bromo-1,2-dichlorobenzene (200 g, 0.885 mol), compound 117-a (224 g, 2.218 mol), (L)-valine (10.2 g, 0.089 mol), iodide
  • a mixed solution of copper (34.2 g, 0.180 mol) and potassium carbonate (366 g, 2.652 mol) in dimethyl sulfoxide (1.0 L) was stirred under argon at 100 ° C for 16 h.
  • the reaction mixture was cooled to room temperature, 2.0 L of ethyl acetate was added, and the insoluble material was removed by filtration, and the cake was washed with ethyl acetate.
  • the filtrate was washed with brine, and dried and evaporated to give a crude compound 117-b (175 g).
  • Step 2 To a solution of compound 117-b (4.7 g, 16.26 mmol), compound 17-a (3.34 g, 16.26 mmol), triphenylphosphine (8.52 g, 32.52 mmol) in tetrahydrofuran (20 ml) DIAD (6.5 g, 32.52 mmol) was added dropwise, and the reaction mixture was stirred at room temperature under nitrogen for 12 h. The reaction mixture was poured into water and extracted with EtOAc. EtOAc (EtOAc m. +H] + .
  • Step 3 To a solution of Compound 117-c (6.7 g, 15.5 mmol The THF was concentrated under reduced pressure, and the mixture was evaporated to dryness eluted with EtOAc EtOAc EtOAc (EtOAc) MS m/z (ESI): 419 [M+H] + .
  • Step 4 Compound 117-d (100 mg, 0.239 mmol), cyclopropylsulfonamide (58 mg, 0.478 mmol), HATU (100 mg, 0.263 mmol), triethylamine (48 mg, 0.478 mmol), DMAP (3 mg, 0.024 mmol)
  • the dichloromethane solution was stirred at room temperature for 12 h.
  • the reaction solution was diluted with 20 ml of dichloromethane, washed with 2N hydrochloric acid, and the organic phase was dried and concentrated, and the crude was purified by Pre-HPLC to yield compound Z-117 (15 mg), purity 100%, yield 12%, MS m/z (ESI) ): 523.1 [M+H] + .
  • Step 1 Using the compound 87-b as a starting material, the method of the preparation of the step 1 in Example 89 was carried out to obtain the compound 189-a.
  • Step 2 The compound 189-a was used as a starting material, and the preparation method of the step 2 in Example 89 was carried out to obtain the compound 189-b.
  • Step 3 Using the compound 189-b as a starting material, the title compound was obtained by the procedure of Step 3 in Example 89 to give Compound 189-c.
  • Step 4 Compound 189-c, potassium trifluoroborate, Pd(dppf)Cl 2 and triethylamine in ethanol were stirred under argon at 90 ° C for 6 h. The reaction solution was cooled to room temperature, filtered over Celite, and then filtered and evaporated.
  • Step 5 To a methanol solution of the compound 189-d, palladium on charcoal was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj +H] + .
  • the compound Z-190 to Z-193 is prepared by using the compound 189-b as the starting material, and the preparation method of the step 3-5 in the embodiment 189 is carried out, except that the palladium carbon in the step 5 is replaced in the preparation of the Z-191 to Z-193. Formed into platinum dioxide.
  • Step 1 Using the compound 57-a as a starting material, the procedure of Step 3 in Example 189 was used to give Compound 194-a.
  • Step 2 Using Compound 194-a as a starting material, the title compound was obtained by the procedure of Step 4 in Example 189.
  • Step 3 using compound 194-b as a starting material, referring to the preparation method of the step 5 in Example 189, to obtain the compound Z-194.
  • Step 1 The compound 142-a (520 mg, 1.09 mmol) was used as the starting material, and the preparation method of the step 3 in Example 125 was used, except that the cyclopropylboronic acid was replaced with methylboronic acid to obtain a white solid compound 195-b (440 mg). The purity was 100%, the yield was 98%, MS m/z (ESI): 413.2 [M+H] + .
  • Step 2 Compound 195-b (440 mg, 1.07 mmol) was used as a starting material to give a white solid compound 195-c (420 mg), purity 92%, yield 98%, MS m/z. (ESI): 399.2 [M+H] + .
  • Step 3 Compound 195-c (100 mg, 0.25 mmol) was used as a starting material.
  • Step 1 Using the compound 189-b as a starting material, the procedure of the step 3 in Example 89 was carried out to give the compound 196-a.
  • Step 2 Using Compound 196-a as a starting material, the title compound was obtained by the procedure of Step 3 in Example 125 to give Compound Z-196.
  • Step 1 Using Compound 189-b as a starting material, the procedure of Step 3 in Example 89 was followed, except that Compound 10-a was replaced with Compound 59-a to give Compound 197-a.
  • Step 2 using compound 197-a as a starting material, referring to the preparation method of the step 3 in Example 125, to obtain the compound Z-197
  • Step 1 Compound 1-1 (1.96 g, 10.0 mmol), N-Boc-piperazine (1.95 g, 10.5 mmol), potassium carbonate (2.76 g, 20.0 mmol) in acetonitrile (20 ml) .
  • the reaction mixture was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated.
  • -2 (3.5 g), purity 90.26%, yield 100%.
  • Step 2 A solution of the compound 1-2 in MeOH (50 mL) was evaporated. %, yield 100%. MS m / z (ESI): 245.0 [M + H] +.
  • Step 3 Compound 1-3 (2.9 g, 10.28 mmol), Compound 1-4 (3.35 g, 10.28 mmol), EtOAc (EtOAc) The reaction mixture was cooled to room temperature, and the solvent was evaporated. EtOAcjjjjjjjjj to give a yellow oil was purified compound 1-5 (2.6g), purity 100%, yield 51.7%, MS m / z ( ESI): 491.0 [m + H] +.
  • Step 4 Compound 1-5 (1.0 g, 2.04 mmol), cyclopropylboronic acid (0.35 g, 4.08 mmol), Pd (dppf) Cl 2 (149 mg, 0.204 mmol), cesium carbonate (1.33 g, 4.08 mmol)
  • a solution of dioxane (10 ml) was stirred at 80 ° C for 16 h under argon. The reaction mixture was cooled to room temperature, and the solid was filtered. Yield 14.1%, MS m / z ( ESI): 451.0 [M + H] +.
  • Step 5 To a solution of compound 1-6 (130 mg, 0.265 mmol) in MeOH (10 mL) The solvent was removed under reduced pressure. The residue was evaporated to dryness eluted eluted eluted eluted eluted Colorless oily compound 1-7 (110 mg), purity 97.7%, yield 94.8%, MS m/z (ESI): 437.0 [M+H] + .
  • Step 6 Compound 1-7 (110 mg, 0.252 mmol), cyclopropyl sulfonamide (46 mg, 0.378 mmol), EDCI (97 mg, 0.504 mmol), DMAP (31 mg, 0.252 mmol), DIPEA (98 mg, 0.756 mmol)
  • the mixed solution of dichloromethane (5 ml) was stirred at room temperature for 20 h.
  • the reaction mixture was diluted with methylene chloride.
  • EtOAc EtOAc m. ): 540.1 [M+H] + .
  • Compound C2 was prepared by using 3,4-dichlorobenzyl bromide as a starting material, and the preparation method of Comparative Example 1, except that the cyclopropylsulfonamide in Step 6 was replaced with methylsulfonamide.
  • Compound C11 was prepared by referring to the preparation method of Comparative Example 1, except that the cyclopropylsulfonamide in Step 6 was replaced with methylsulfonamide.
  • Step 1 To a solution of the compound 3-1 (1 g, 5.85 mmol) in THF, br. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAcjjjjjjjj %, MS m/z (ESI): N/A.
  • EtOAc EtOAcjjjjjjjjj %, MS m/z (ESI): N/A.
  • Step 2 To a mixed solution of compound 4-1 (650 mg, 4.14 mmol) and DIPEA (1.07 g, 8.28 mmol) in dichloromethane, methylenesulfonyl chloride (524 mg, 4.55 mmol) in dichloromethane The solution was stirred at room temperature for 16 h. The reaction mixture was washed with EtOAc (EtOAc m.
  • Step 3 Compound 4-2 was used as a starting material, and Compound 4-3 (950 mg) was obtained as a yellow oil, with a purity of 100%, yield of 88%, MS m/z (ESI): 325.0 [ M+H] + .
  • Step 4 Compound 4-3 was used as a starting material, and Compound 4-4 (750 mg) was obtained as a white solid, with a yield of 100%, yield 95%, MS m/z (ESI): 225.0. M+H] + .
  • Step 5 Compound 4-4 was used as the starting material, and the white solid compound C4 (140 mg) was obtained by the procedure of Step 3 of Comparative Example 1, purity 100%, yield 70%, MS m/z (ESI): 513.8 [M+ H] + .
  • Compound C6 was prepared by using 4-chlorobenzoic acid as a starting material and referring to the preparation method of Comparative Example 4.
  • Step 1 Compound 22-a (75 mg, 0.463 mmol), Compound 7-1 (150 mg, 0.463 mmol), EtOAc. After the reaction mixture was cooled to room temperature, the reaction mixture was poured into EtOAc. EtOAcjjjjjjjjjjjjjjjjjjjj : 412.2 [M+H] + .
  • Step 2 A solution of the compound 7-2 in methanol (2M, EtOAc) The reaction mixture was concentrated under reduced pressure. The residue was purified eluting with EtOAc EtOAc EtOAc EtOAc. MS m/z (ESI): 398.1 [M+H] + .
  • Step 3 compound 7-3 as a starting material, prepared with reference to Comparative Example 6, step 2 to give a white solid compound C7 (19mg), MS m / z (ESI): 500.9 [M + H] +.
  • Step 1 A solution of compound 9-1 (100 mg, 0.639 mmol) in dichloromethane (2 mL). The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL). The reaction mixture was washed with EtOAc EtOAc EtOAc (EtOAc m. + .
  • Step 2 Compound 9-2 (228 mg, 0.535 mmol) was used as a material. ] + .
  • Step 3 Compound 9-3 (100mg, 0.242mmol) as the starting material, reference to method step 6 in Comparative Example 2 was prepared as a white solid compound C9 (23mg), MS m / z (ESI): 515.0 [M + H] + .
  • Test Example 1 Manual patch clamp experiment of sodium ions (hNav1.7, hNav1.5, and hNaV1.8) and calcium ion (hCav3.2) channels
  • Diaphragm voltage clamp electrophysiology can directly measure and quantify current blockade of voltage-gated sodium channels (various Nav) and can determine the time and voltage dependence of blockade, which has been interpreted as resting, open and sodium channels The difference in binding in the inactive state reflects the inhibitory or activating effect of the compound (Hille, B., Journal of General Physiology (1977), 69: 497-515).
  • Representative compounds of the invention were tested using a manual patch clamp experiment.
  • the purpose of this study was to test the effect of compounds on the ion channel current on a stable cell line transfected with a particular ion channel using a manual patch clamp method.
  • the stable cell lines CHO-hNav1.7 and HEK-hNav1.5 used were from Genionics and WuXi Apptec (Shanghai), respectively.
  • the manual patch clamp experimental protocol is as follows:
  • the positive control drug and the test compound were first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and stored in a certain concentration (100 nM, 1000 nM) stock solution.
  • DMSO Sigma-Aldrich, D2650
  • the above stock solution was serially diluted with DMSO before the experiment, and then used outside the cell.
  • the solution is further diluted to give the test solution at the desired concentration.
  • the final concentration of DMSO in the extracellular fluid does not exceed 0.30%.
  • This stimulation procedure can also be referred to as a channel state dependent voltage stimulation procedure.
  • the other is a non-inactivation stimulation program that maintains the clamp potential at -120 mV, gives a voltage stimulus to -10 mV, continues for 20 ms to draw sodium current, and finally returns to the clamp potential. That is to say, under the conditions of the stimulation program, all the channels have not experienced the inactivation state, but are directly activated from the resting state.
  • the time interval of the above two voltage stimulation programs is 10s.
  • the inhibitory effect of the compound was calculated by the change in current before and after dosing, and the IC 50 value was fitted by the Hill equation.
  • a compound is state dependent on the channel if it exhibits a multiple of the channel effect under the two different voltage stimuli described above. The results are shown in Table 1.
  • the recombinant HEK293 cell line stably expressed the human voltage-gated sodium channel subtype 1.8 (hNaV1.8).
  • the cDNA strictly followed the GenBank serial number: NM_014191.2.
  • the HEK293 or CHO cell line stably expressing the sodium channel was cultured in an F12/DMEM medium containing 10% fetal calf serum and 0.8 mg/mL G418 at a culture temperature of 37 ° C and a carbon dioxide concentration of 5%.
  • Pipette solution 145CsCl, 0.1CaCl 2, 2MgCl 2 , 10NaCl, 0.5Na2-GTP ( guanosine triphosphate disodium salt), 2Mg-ATP (adenosine nucleoside triphosphates magnesium), 1.1EGTA (ethylene glycol bis (2-Aminoethylether)tetraacetic acid), 10 HEPES (4-hydroxyethylpiperazineethanesulfonic acid), pH 7.2 with CsOH.
  • a capillary glass tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode using a microelectrode puller (P97, Sutter Instruments).
  • the microelectrode manipulator (MP285, Sutter Instruments) was operated under an inverted microscope (IX71, Olympus) to contact the recording electrode to the cells, and vacuum suction was applied to form a G ⁇ seal. After the G ⁇ seal is formed, rapid capacitance compensation is performed, and then the negative pressure is continued, and the cell membrane is sucked to form a whole cell recording mode. Then compensate for the slow capacitance and record the film capacitance and series resistance. No leakage compensation is given.
  • the sodium current was recorded and the data was collected by an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.
  • each drug is tested at 5-6 concentrations. Each drug concentration is applied to 5 minutes or the steady state is reached, and the next concentration is detected. Each cell is controlled by itself. . At least 3 cells were independently tested at each concentration. All electrophysiological experiments were performed at room temperature.
  • the sodium current voltage stimulation protocol is as follows: when the whole cell sealing is formed, the cell membrane voltage is clamped at -90 mV, the depolarization voltage step is maintained from -90 mV depolarization to -10 mV for 40 ms, and data is repeatedly collected every 10 seconds to observe the drug versus sodium. The role of current.
  • the stable cell line HEK-hCav3.2 for manual patch clamp experiments was obtained from WuXi Apptec (Shanghai) Co., Ltd.
  • the positive control drug and the compound to be tested were first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and configured to a certain concentration of the stock solution.
  • DMSO Sigma-Aldrich, D2650, and configured to a certain concentration of the stock solution.
  • the above stock solution was serially diluted with DMSO before the experiment, and then further diluted with the extracellular solution.
  • the test solution at the desired concentration.
  • the final concentration of DMSO in the extracellular fluid does not exceed 0.30%.
  • the following voltage stimulation program was applied to the hCav 3.2 manual patch clamp test, that is, the clamp potential was set at -110 mV, the pulse voltage of -85 mV was given for 500 ms, and then depolarized to -40 mV for 50 ms to induce the hCav3.2 calcium channel current. Finally return to the clamping potential. The stimulation procedure was repeated every 15 seconds and continued to be recorded. The inhibitory effect of the compound was calculated by the change in current before and after dosing, and the IC 50 value was fitted by the Hill equation.
  • the representative compounds of the present invention have a high inhibitory activity against Nav1.7.
  • the nitrogen atoms on the five-membered (pyrrole ring) and six-membered (piperazine ring) nitrogen-containing heterocycles are directly linked to the carbon atoms on the benzene or pyridine ring compared to the comparative compounds (eg, C1-C11). It has a significant effect on the inhibitory activity of Nav1.7.
  • a benzene ring or a pyridine ring is bonded to a nitrogen atom through a group such as a methylene group or a carbonyl group, and R 6 is a methyl group
  • the inhibitory activity against Nav1.7 is remarkably lowered (for example, C2 and Z-196, C11 and Z-197).
  • the compound Z-164 also showed selective inhibitory activity against other ion channels, particularly Nav1.5, Nav1.8 sodium ion channels and calcium ion channels.
  • Test Example 2 Effect on hERG potassium channel
  • the cells used in this assay were CHO cell lines transfected with hERG cDNA and stably expressing the hERG channel (supplied by Sophion Bioscience, Denmark) with a cell number of P15.
  • the cells were cultured in medium containing the following components (all from Invitrogen): Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 ⁇ l/ml hygromycin B, 100 ⁇ l/ml Geneticin.
  • CHO hERG cells were grown in culture dishes containing the above culture medium and cultured in an incubator containing 5% CO 2 at 37 °C. CHO hERG cells were transferred to circular glass slides in petri dishes 24 to 48 hours prior to electrophysiological experiments and grown under the same culture and culture conditions as above. The density of CHO hERG cells on each round glass piece needs to be achieved by the vast majority of cells being independent, individual requirements.
  • HEPES 10 10 EGTA - 5 Na-ATP - 4 PH 7.4 (adjusted with NaOH) 7.25 (adjusted with KOH) Osmotic pressure Osmotic pressure ⁇ 305mOsm Osmotic pressure ⁇ 295mOsm
  • This experiment used a manual patch clamp system (HEKA EPC-10 signal amplification and digital conversion system, purchased from HEKA Electronic, Germany) for the recording of whole cell currents.
  • a round glass slide with CHO hERG cells grown on it was placed in an electrophysiological recording cell under an inverted microscope.
  • the extracellular fluid was continuously perfused in the recording tank (about 1 ml per minute).
  • the experimental procedure uses conventional whole-cell patch clamp current recording techniques. Unless otherwise stated, the experiments were carried out at regular room temperature ( ⁇ 25 ° C). The cells were clamped at a voltage of -80 mV.
  • the cell clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and after 5 seconds it was clamped to -50 mV to eliminate inactivation and generate tail current.
  • the tail current peak is used as the value of the hERG current magnitude.
  • Cisapride ( ⁇ , purchased from Sigma) was used in the experiment as a positive control to ensure that the cells used were of normal quality.
  • test data was analyzed by HEKA Patchmaster (V2x73.2), Microsoft Excel and data analysis software provided by Graphpad Prism 5.0.
  • the experimental results are shown in Table 4.
  • the representative compound of the present invention has little inhibitory activity on the hERG potassium ion channel, and thus has selective inhibition of the potassium ion channel.
  • the experimental animals were male Sprague-Dawley rats with a body weight of 140-150 g at the start of the experiment.
  • the experimental animals were purchased from Slack Company. After purchase, the food and water supply were carried out in a free-feeding manner. They were kept in cages, 4 cages, and the animals were labeled with animal tail marking.
  • the solvent components of the positive control and the test drug were 5% dimethylacetamide, 5% solutol and 90% physiological saline.
  • the positive control and the test substance inhibited the cold pain hypersensitivity caused by spinal nerve ligation in rats after oral administration for 2 hours at a dose of 30 mg/kg, respectively, as shown in Table 5.
  • pregabalin 30 mg/kg pregabalin: Weigh 129.48 mg of pregabalin, add 1.08mL of dimethylacetamide, add 1.08mL of solutol after complete dissolution, mix well by shaking and add 90% physiological saline to 21.58mL, fully mixed Oral administration
  • the rats were subjected to a cold hyperalgesia hypersensitivity baseline test, and 100 ⁇ l of acetone was applied to the hind paw skin of the animal side using a pipette. Record the time the animal patted, retracted, lifted, and licked the foot in one minute. The acetone test was performed twice in total, 10 minutes apart. The sum of the two times was recorded as the time of cold allodynia hypersensitivity in rats. Animals were randomized according to the results of the cold allodynia hypersensitivity test one day prior to dosing.
  • acetone was applied to the skin of the toes of the animal side using a pipette. Record the time the animal pats, shrinks, lifts, and affects the affected foot in one minute. The acetone test was performed twice in total, 10 minutes apart. The sum of the two times was recorded as the time of cold allodynia hypersensitivity in rats.
  • the cold stimulating pain test was orally administered 2 hours before.
  • the results of the experiment are shown in Fig. 1 and Fig. 2.
  • the results show that after 2 hours of oral administration, the compound Z-164 of the present invention has a cold allodynia-induced hypersensitivity effect induced by rat spinal nerve ligation in a rat model of spinal nerve ligation, in rats. There is a statistically significant inhibitory effect in the neuralgia model.
  • Buffer A 1 L of a 1 mM EDTA (Sigma, V900157-100G), 100 mM potassium dihydrogen phosphate solution was prepared.
  • Buffer B 1 L of a solution of 1 mM EDTA, 100 mM dipotassium hydrogen phosphate was prepared.
  • Buffer C Take 700 mL of Buffer B, titrate with Buffer A, and adjust to pH 7.4.
  • liver microsome solution 2.2 20 uL (20 mg/mL) human liver microsomes (Corning Lot. NO. 4133007) stock solution was added to 513.4 uL of buffer C and operated on wet ice. A 0.75 mg/mL liver microsome solution was prepared.
  • the mixture of the test compound and the ketochrome mixture were separately dispensed onto the reaction plate and operated on wet ice.
  • reaction plate was preheated in a 37-degree water bath incubator for 5 min.
  • 15 uL of reduced coenzyme II solution was added to each well to start the reaction and timed.
  • 135 uL of ice-acetonitrile containing an internal standard was added to each well to terminate the reaction.
  • reaction plate was sealed with an aluminum film and placed on a shaking mixer at 500 rpm for 5 min. The plate was then centrifuged in a centrifuge for 15 min at 3750 rpm.
  • the K value and the scale factor are calculated by those skilled in the art according to the methods described in the prior art and the liver microsome product specification.
  • the compound of the present invention has excellent metabolic stability, and it has been found that the change of the substituent R 6 has a significant influence on the metabolic stability, in particular, when it is changed from a cyclopropyl group to a methyl group.
  • the stability is significantly reduced (eg C12 and Z-173, C13 and Z-164).

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Abstract

本发明公开了一种杂环取代的N-磺酰基苯甲酰胺衍生物、其制法与医药上的用途。具体地，本发明公开了式(II)化合物或其药学上可接受的盐、立体异构体、溶剂化合物或前药，及其制备方法和应用，式中各基团的定义详见说明书。

Description

杂环取代的N-磺酰基苯甲酰胺衍生物、其制法与医药上的用途 技术领域
本发明属于医药技术领域。具体地，本发明特别涉及一种杂环取代的N-磺酰基苯甲酰胺衍生物及其制备方法和作为钠离子通道(特别是Nav1.7)抑制剂的应用，以及由其制备的药物组合物和药用组合物。
背景技术
最近，英国的Cox等在Nature上首次报道了编码电压门控Nav1.7通道的SCN9A基因突变导致遗传个体无痛症的出人意料研究结果。该遗传突变的个体先天失去痛觉，但机体的其它功能完全正常，此外最近的研究表明，表达在DRG神经元的电压门控Nav1.7通道参与痛信号的产生并发挥控制痛觉信号传入的闸门功能。该研究提示Nav1.7通道可能会成为选择性治疗疼痛并无副作用的药物靶点。
Nav1.7(PN1，SCN9A)VGSC对河豚毒素的阻断敏感，其主要表达于末梢交感神经元和感觉神经元。SCN9A基因已由多种物种(包括人类、大鼠及兔)复制，并且显示人与大鼠基因之间的氨基酸有约90％的一致性。
越来越多的身体证据表明Nav1.7在多种疼痛状态(包括急性、慢性、炎性和/或神经性疼痛)中扮演重要的角色，在人类中，Nav1.7蛋白质积累于神经瘤，特别是引起疼痛的神经瘤。Nav1.7功能增加的突变(不论是遗传性或偶发性)已被认为涉及原发性红斑性肢痛(一种特征为四肢的灼痛和发炎的疾病)，和突发性极度疼痛症。有关非选择性钠通道阻断剂利多卡因和美西律可缓和遗传性红斑性肢痛的症状，以及卡马西平可有效地减低PEPD的侵袭的次数和严重度的报道结果与上述观察相一致。Nav1.7在疼痛中扮演的角色的其他证据可见于SCN9A基因的功能丧失的突变的显型。后续的研究已显示会导致SCN9A基因的功能丧失与CIP显型的许多不同的突变。
由于Nav1.7特异地在DRG感觉神经元表达而不在心肌细胞和中枢神经系统等其它组织表达，因此研发其特异阻断剂用于治疗慢性痛，不仅可能提高疗效，且副作用也会大大减少，并且Nav1.7离子通道的选择性抑制剂几乎可用于各种疼痛的治疗。
由于患急性或慢性疼痛疾病的许多患者对目前疼痛疗法响应较差，并且通常对阿片制剂产生抗性和不敏感性。此外，目前使用的钠通道阻断剂对于上述疾病状况的功效在很大程度上受许多副作用的限制。这些副作用包括各种CNS紊乱，比如视力模糊、眩晕、恶心和镇静，以及更潜在地威胁生命的心律失常和心力衰竭。
因此，鉴于目前可用药剂有限的效力和不可接受的副作用，迫切需要开发更加安全有效的镇痛药，使其具有较高功效和较少副作用。而Nav1.7离子通道是开发无成瘾性镇痛药物的重要靶标，目前虽已有专利文献报道了多类Nav1.7离子通道抑制剂，然而在开发高活性Nav1.7离子通道抑制剂的同时还应关注其对其他离子通道，如钾离子通道以及人肝微粒体稳定性的影响，由于与HERG钾离子通道相关的心脏毒性以及预测化 合物在肝组织清除率的人肝微粒体稳定性指标对药物开发的影响至关重要，因此开发代谢好的高选择性Nav1.7离子通道抑制剂十分必要。
发明内容
本发明的目的是在现有Nav1.7抑制剂基础上提供一种对Nav1.7钠离子通道具有高度选择性，并具有稳定的肝微粒体代谢稳定性的抑制剂及其在医药上应用。
本发明的第一方面提供了一种式(I)所示的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药：
Figure PCTCN2017072470-appb-000001
式中，R1、R2、R3、R4各自独立地为氢、羟基、CN、NO2、卤素、-NRaRb、C1-20烷基、C3-20环烷基、C3-20环烷氧基、C2-20烯基、C2-20炔基、C1-20烷氧基、-CHO、-CO-(C1-20烷基)、-CO-(C6-20芳基)、C6-20芳基、-CONRaRb、-C(O)O-(C1-20烷基)、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)或-SO2-(C6-20芳基)；
R5为氢、C1-20烷基、C3-20环烷基、卤代C1-20烷基；
R6为C6-20芳基、C1-20烷基、C3-20环烷基、C3-8杂环基、-NRaRb；所述C3-8杂环基含1-3个选自N、O、S的杂原子，其中，Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基；
L1、L2连接在环上的任意不同的位置，各自独立地为一个键、或-C(O)N(Ry)-、-N(Ry)C(O)-、-N(Ry)SO2-、-SO2N(Ry)-、-OC(O)-、-C(O)O-、-(CRyRx)r1(O)r2(CRyRx)r3-、-S(O)-、-SO2-、-N(Ry)-、-O-、-S-、-C(O)-或亚环丙基；其中，Ry、Rx各自独立地为氢、卤素、羟基、CN、NO2、C1-20烷基、卤代C1-20烷基、C3-20环烷基、C2-20烯基、C2-20炔基或C6-20芳基；r1、r3各自独立地为0、1、2或3；r2为0或1；
W1、W2各自独立地为C、N、O或S；
n、m各自独立地为0、1、2或3，且n、m不同时为0；其中，当n为0时或m为0时，W1和W2之间通过单键相连；
(R0)p为环上的任意位置的氢被p个R0取代，p为0、1、2、3、4或5，每个R0相同或不同，各自独立地为氢、氘、C1-20烷基、氘代C1-20烷基或卤代C1-20烷基；或任意两个R0通过单键或-(CH2)p1-连接，p1为1、2或3；
A为C6-20芳基、3至7元单环、8至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、5至6元单环杂芳基环并3至7元单杂环；
其中，所述烷基、环烷基、环烷氧基、烯基、炔基、烷氧基、芳基、3至7元单环、8 至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、或5至6元单环杂芳基环并3至7元单杂环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、C1-20烷硫基、卤代C1-20烷硫基、C1-20烷基氨基、卤代C1-20烷基氨基、硫醇、3元至20元的杂环烷基、3元至20元的杂环烷基氧基、C3-20环烷硫基、卤代C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、C1-20羟烷基、羧基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C6-20芳基)；Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基。
在另一优选例中，所述R6为C3-10环烷基、C3-8杂环基。
在另一优选例中，所述R6为环丙基、环丁基、环戊基、环己基。
在另一优选例中，R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基、C3-20环烷氧基或C1-20烷氧基。
在另一优选例中，R2和R4为氢，且R1、R3各自独立地为氢、卤素、C3-20环烷基、C1-20烷基、C3-20环烷氧基或C1-20烷氧基。
在另一优选例中，R5为氢。
在另一优选例中，A为C6-20芳基或5或6元单环杂芳基环；所述的芳基或5或6元单环杂芳基环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、和C3-20环烷氧基。
在另一优选例中，所述C6-20芳基为苯基；所述5或6元单环杂芳基环为吡啶基。
在另一优选例中，所述苯基为
Figure PCTCN2017072470-appb-000002
其中R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；和/或
所述吡啶基为
Figure PCTCN2017072470-appb-000003
或
Figure PCTCN2017072470-appb-000004
其中R21、R31、R41、R51、R12、R32、R42、R52、R13、R23、R43、R53各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；Ra、Rb如上所定义。
在另一优选例中，R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
在另一优选例中，R21、R31、R41、R51、R12、R32、R42、R52、R13、R23、R43、R53各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
在另一优选例中，
Figure PCTCN2017072470-appb-000005
选自：
Figure PCTCN2017072470-appb-000006
Figure PCTCN2017072470-appb-000007
或
Figure PCTCN2017072470-appb-000008
A、L1、R0如说明书中所定义。
在另一优选例中，L1为-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1。
在另一优选例中，r2为0。
在另一优选例中，
(i)r1、r3为0；r2为1；
(ii)r1为1、2或3；r2为1；r3为0；
(iii)r1为0；r2为1；r3为1、2或3；或
(iv)r1、r2、r3为0。
在另一优选例中，W2为N、O、S或C，当W2为O或S时，L2与环上除W1和W2以外的其它任意碳原子连接，当W2为N或C时，L2与环上除W1以外的其它任意环原子连接。较佳地，L2与W2连接。
在另一优选例中，L2为一个键，A与环上除W1以外的其它任意环原子连接。
在另一优选例中，L2为一个键，W2为N、O、S或C，当W2为O或S时，A与环上除W1和W2以外的其它任意碳原子连接，当W2为N或C时，A与环上除W1以外的其它任意 环原子连接。
在另一优选例中，W1为N、O、S或C，当W1为O或S时，L1与环上除W1和W2以外的其它任意碳原子连接，当W1为N或C时，L1与环上除W2以外的其它任意环原子连接，较佳地，L1与W1连接。
在另一优选例中，所述化合物为式(II)所示化合物：
Figure PCTCN2017072470-appb-000009
式中，R0、R1、R2、R3、R4、R5、R6、A、L1、W1、W2、n、p、m如权利要求1所定义。
在另一优选例中，每个R0相同或不同，各自独立地为氢。
在另一优选例中，A为C6-20芳基或5或6元单环杂芳基环。
在另一优选例中，A为苯基或吡啶基；所述的苯基或吡啶基为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、和C3-20环烷氧基。
在另一优选例中，L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1。
在另一优选例中，所述化合物为式(III)所示化合物：
Figure PCTCN2017072470-appb-000010
式中，R0、R1、R2、R3、R4、R5、R6、Rx、Ry、r1、r2、r3、A、W1、W2、n、p、m如权利要求1所定义。
在另一优选例中，式(III)化合物中，W1为N、O、S或C，当W1为O或S时，(CRyRx)r1与环上除W1和W2以外的其它任意碳原子连接，当W1为N或C时，(CRyRx)r1与环上除W2以外的其它任意环原子连接，r1如上所定义。
在另一优选例中，
Figure PCTCN2017072470-appb-000011
选自：
Figure PCTCN2017072470-appb-000012
Figure PCTCN2017072470-appb-000013
Figure PCTCN2017072470-appb-000014
在另一优选例中，W2为N。
在另一优选例中，W1为N、O、S或C。
在另一优选例中，
Figure PCTCN2017072470-appb-000015
选自：
Figure PCTCN2017072470-appb-000016
Figure PCTCN2017072470-appb-000017
在另一优选例中，
Figure PCTCN2017072470-appb-000018
选自：
Figure PCTCN2017072470-appb-000019
Figure PCTCN2017072470-appb-000020
Figure PCTCN2017072470-appb-000021
其中，A、L1、R0定义同前。
在另一优选例中，
Figure PCTCN2017072470-appb-000022
选自：
Figure PCTCN2017072470-appb-000023
和
Figure PCTCN2017072470-appb-000024
其中，A、L1、R0定义同前。
在另一优选例中，
Figure PCTCN2017072470-appb-000025
选自：
Figure PCTCN2017072470-appb-000026
其中，A、L1、R0定义同前。
在另一优选例中，
Figure PCTCN2017072470-appb-000027
选自：
Figure PCTCN2017072470-appb-000028
且L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；每个R0相同或不同，各自独立地为氢。
在另一优选例中，A为
Figure PCTCN2017072470-appb-000029
其中R1’、R2’、R3’、R4’、R5’如说明书中所定义。
在另一优选例中，
Figure PCTCN2017072470-appb-000030
选自：
Figure PCTCN2017072470-appb-000031
和
Figure PCTCN2017072470-appb-000032
其中，A、L1、R0定义同前。。
在另一优选例中，
Figure PCTCN2017072470-appb-000033
选自：
Figure PCTCN2017072470-appb-000034
和
Figure PCTCN2017072470-appb-000035
其中，A、L1、R0定义同前。
在另一优选例中，所述化合物为式(IV)所示化合物：
Figure PCTCN2017072470-appb-000036
式中，R0、R1、R2、R3、R4、R5、R6、Rx、Ry、r1、r2、r3、A、W2、n、p、m定义如前；W1为N或C。
在另一优选例中，r2为0。
在另一优选例中，r1、r3为0；r2为1。
在另一优选例中，r1为1、2或3；r2为1；r3为0。
在另一优选例中，r1为0；r2为1；r3为1、2或3。
在另一优选例中，r1、r2、r3为0。
在另一优选例中，所述化合物为式(V)所示化合物：
Figure PCTCN2017072470-appb-000037
式中，R0、R1、R2、R3、R4、R5、R6、L1、W1、W2、n、p、m定义如前；R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；Ra、Rb如上所定义。
在另一优选例中，R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基。
在另一优选例中，式(V)化合物中，L1为-(CRyRx)r1(O)r2(CRyRx)r3-，r1、r2、r3如上所定义。
在另一优选例中，式(V)化合物中，W1为N、O、S或C，当W1为O或S时，L1与环上除W1和W2以外的其它任意碳原子连接，当W1为N或C时，L1与环上除W2以外的其它任意环原子连接，较佳地，L1与W1连接。
在另一优选例中，式(V)化合物中，W2为N。
在另一优选例中，R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；
R5为氢；
R6为C1-20烷基、-NRaRb；
其中，Ra、Rb各自独立地为氢、或C1-20烷基；
W1、W2各自独立地为C、O、S或N；
L2为一个键；
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-、-O-或-C(O)-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0或1；r2为0或1；
n、m各自独立地为1或2；
(R0)p为环上的任意位置的氢被p个R0取代，p为0；
A为苯基；
且当W1和/或W2为O或S时，L1和A分别与环上除W1和W2以外的其它任意碳原子连接；
当W1和/或W2为N或C时，A与环上除W1以外的其它任意环原子连接，L1与环上除W2以外的其它任意环原子连接；
其中，所述烷基、环烷基或苯基为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基。
在另一优选例中，R2和R4为氢，且R1、R3各自独立地为卤素、C3-6环烷基、C1-3烷基、C3-6环烷氧基或C1-3烷氧基。
在另一优选例中，L2为一个键(表示A与环上除W1以外的其它任意环原子连接)，或为-(CH2)r1(O)r2(CH2)r3-、-S-、-C(O)-、-S(O)-、-SO2-或-N(Ry)-，其中r1、r2、r3、Ry的定义如上所述。
在另一优选例中，所述化合物为式(I)～(V)中任一所示化合物，其中，R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；
R5为氢；
R6为C1-20烷基、-NRaRb；其中，Ra、Rb各自独立地为氢、C1-20烷基。
在另一优选例中，A为C6-20芳基或5或6元单环杂芳基环。
在另一优选例中，L2为一个键；或L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1。
在另一优选例中，每个R0相同或不同，各自独立地为氢。
在另一优选例中，
Figure PCTCN2017072470-appb-000038
选自：
Figure PCTCN2017072470-appb-000039
Figure PCTCN2017072470-appb-000040
或
Figure PCTCN2017072470-appb-000041
A为C6-20芳基或5或6元单环杂芳基环；
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；
每个R0相同或不同，各自独立地为氢；
所述烷基、环烷基、芳基、5或6元单环杂芳基环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、 C1-20烷硫基、卤代C1-20烷硫基、C1-20烷基氨基、卤代C1-20烷基氨基、硫醇、3元至20元的杂环烷基、3元至20元的杂环烷基氧基、C3-20环烷硫基、卤代C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、C1-20羟烷基、羧基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C6-20芳基)；Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基。
在另一优选例中，A为苯基或吡啶基；所述的苯基或吡啶基为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
在另一优选例中，所述苯基为
Figure PCTCN2017072470-appb-000042
其中R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基。
在另一优选例中，
Figure PCTCN2017072470-appb-000043
选自：
Figure PCTCN2017072470-appb-000044
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；
每个R0相同或不同，各自独立地为氢。
在另一优选例中，r1为0；r3为1；r2为0。
在另一优选例中，
Figure PCTCN2017072470-appb-000045
选自：
Figure PCTCN2017072470-appb-000046
或
Figure PCTCN2017072470-appb-000047
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；
每个R0相同或不同，各自独立地为氢。
在另一优选例中，r1、r3为0；r2为1。
在另一优选例中，
Figure PCTCN2017072470-appb-000048
选自：
Figure PCTCN2017072470-appb-000049
或
Figure PCTCN2017072470-appb-000050
L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1；
每个R0相同或不同，各自独立地为氢。
在另一优选例中，r1为1、2或3；r2为1；r3为0。
在另一优选例中，r1为1；r2为1；r3为0。
在另一优选例中，R1、R3各自独立地为氢、卤素、C1-20烷基或C3-20环烷基；R2和R4为氢。
在另一优选例中，C1-20烷基为甲基、乙基、正丙基、异丙基、正丁基。
在另一优选例中，C3-20环烷基为环丙基。
在另一优选例中，卤代C1-20烷基为三氟甲基。
在另一优选例中，卤代C1-20烷氧基为三氟甲氧基、三氟乙氧基、二氟甲氧基。
在另一优选例中，C1-20烷氧基为甲氧基、乙氧基、异丙氧基、叔丁氧基、异丁氧基。
在另一优选例中，C3-20环烷氧基为环丙氧基。
在另一优选例中，卤素为氟或氯。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2017072470-appb-000051
在另一优选例中，所述化合物选自下组：
Figure PCTCN2017072470-appb-000052
Figure PCTCN2017072470-appb-000053
在另一优选例中，所述的R1、R2、R3、R4、R5、R6、Ra、Rb、L1、Ry、Rx、W1、W2、n、m、R0、A等各自独立地为实施例中各具体式II化合物中相应的基团。
在另一优选例中，本发明的式II化合物为实施例部分中所注备的各具体化合物，尤其是Z-80至Z-197中任一化合物。
在另一优选例中，所述化合物为本申请实施例所制备的化合物。
本发明第二方面提供了一种药物组合物，所述组合物包括本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体。
本发明第三方面提供了如本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或本发明第二方面所述药物组合物在制备治疗疾病或病症的药物中的应用。
在另一优选例中，所述疾病或病症选自疼痛、抑郁症、心血管疾病、呼吸系统疾病、精神疾病或其组合。
在另一优选例中，所述疾病或病症选自与HIV相关的疼痛、HIV治疗诱导的神经病变、三叉神经痛、带状疱疹后神经痛、急性疼痛、热敏感、结节病、肠易激综合征、克罗恩病、与多发性硬化(MS)有关的疼痛、肌萎缩性侧索硬化(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿性关节炎、骨关节炎、动脉粥样硬化、突发性张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退、双相抑郁症、焦虑症、精神分裂症、钠通道毒素相关病症、家族性红斑性肢痛症、原发性红斑性肢痛症，家族性直肠疼痛、癌症、癫痫、局部和全身强直性发作、不宁腿综合征、心律失常、纤维肌痛、在由中风或神经损伤导致的缺血性疾病状态下的神经保护、快速性心律失常、心房颤动和心室颤动。
在另一优选例中，所述疼痛选自神经性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、手术后疼痛、生产疼痛、分娩疼痛、牙痛、慢性疼痛、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢痛、周围神经损伤、三叉神经痛、带状疱疹后神经痛、急性疼痛、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛或纤维肌痛或其组合。
本发明第四方面提供了一种治疗哺乳动物疾病或病症的方法，所述方法包括给需要的对象(如哺乳动物)施用治疗有效量的本发明第一方面所述的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药，或本发明第二方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了化合物Z-164在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。
图2显示了化合物Z-164在脊神经结扎大鼠模型中抑制冷刺激痛觉超敏效果。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了本发明的杂环取代的N-磺酰基苯甲酰胺衍生物对Nav1.7钠离子通道具有高度选择性，并具有稳定的肝微粒体代谢稳定性。同时在疼痛模型测试中还显示出明显的镇痛效果，因此本发明的系列化合物可开发成用于广泛疼痛的治疗的药物。在此基础上，发明人完成了本发明。
术语定义
如本文所用，“C1-20烷基”指包含1至20个碳原子的直链和支链的饱和的脂族烃基，如下定义类似；更优选为C1-10烷基，非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等；更优选为C1-6烷基，最优选为C1-3烷基。
如本文所用，“烯基”指至少由两个碳原子和至少一个碳-碳双键组成的如上定义的脂族烃基，“C2-20烯基”是指包含2至20个碳原子的直链和支链的烯基，如下定义类似；更优选为C2-10烯基；更优选为C2-6烯基；最优选C2-4烯基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。
如本文所用，“炔基”指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义 的脂族烃基，“C2-20炔基”指包含2至20个碳原子的直链和支链的炔基，如下定义类似；更优选为C2-10炔基；更优选为C2-6炔基；更优选为C2-4炔基；例如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。
如本文所用，“环烷基”指饱和或部分不饱和单环或多环环状烃基，“C3-20环烷基”是指包含3至20个碳原子的环烃基，如下定义类似；更优选为C3-10环烷基；更优选为C3-8环烷基；最优选为C3-6环烷基。单环环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基、金刚烷基等，优选环丙基、环戊基、环己烯基。多环环烷基的非限制性实施例包括螺环、稠环和桥环的环烷基。
如本文所用，“杂环烷基”和“杂环基”可互换使用，指饱和或部分不饱和单环或多环环状烃基，优选为3元至20元的杂环烷基(是指杂环烷基包含3至20个环原子，且其中一个或多个环原子选自氮、氧或S(O)t(其中t是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳)；更优选为3元至10元的杂环烷基，其中1～3个环原子是杂原子；更优选为3元至6元的杂环烷基；更优选为5元至6元的杂环烷基。单环杂环基的非限制性实施例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、四氢呋喃基等。多环杂环基的非限制性实施例包括螺环、稠环和桥环的杂环基。
如本文所用，“部分不饱和”是指含有一个或多个不饱和键但不具有完全共轭的π电子系统。
如本文所用，“C1-20烷氧基”指-O-(C1-20烷基)，其中烷基的定义如上所述。优选C1-10烷氧基，更优选C1-6烷氧基，最优选C1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C3-20环烷氧基”指-O-(C3-20环烷基)，其中环烷基的定义如上所述。优选C3-10环烷氧基，优选C3-8环烷氧基，更优选C3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“C6-20芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至20个碳原子的芳基；更优选为C6-12芳基，更优选苯基和萘基，最优选苯基。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C1-20烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。优选为卤代C1-10烷基，更优选为卤代C1-6烷基，最优选为卤代C1-3烷基。卤代C1-20烷基的例子包括(但不限于)一氯乙基、二氯甲基、1,2-二氯乙基、一溴乙基、一氟乙基、一氟甲基、二氟甲基、三氟甲基等。
又例如，“卤代C1-20烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C1-10烷氧基，更优选为卤代C1-6烷氧基，最优选为卤代C1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
又例如，“卤代C3-20环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C3-10环烷基，更优选为卤代C3-8环烷基，最优选为卤代C3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文所用，“氘代C1-20烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C1-10烷基，更优选为氘代C1-6烷基，最优选为氘代C1-3烷基。氘代C1-20烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。
如本文所用，“C1-20羟烷基”指被羟基取代的C1-20烷基，其中烷基的定义如上所述。优选为C1-10羟烷基，更优选为C1-6羟烷基，最优选为C1-3羟烷基。
如本文所用，“氨基”指-NH2，“氰基”指-CN，“硝基”指-NO2，“苄基”指-CH2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“硫醇”指-SH，“亚环丙基”结构为：
Figure PCTCN2017072470-appb-000054
如本文所用，“羧酸酯基”指-C(O)O-(C1-20烷基)或(C3-20环烷基)，其中烷基、环烷基的定义如上所述。
如本文所用，“C1-20烷硫基”指-S-(C1-20烷基)，其中烷基的定义如上所述。优选为C1-10烷硫基，更优选为C1-6烷硫基，最优选为C1-3烷硫基。
如本文所用，“C1-20烷基氨基”指-(C1-20烷基)-NH2或-NH2-(C1-20烷基)，其中烷基的定义如上所述。优选为C1-10烷基氨基，更优选为C1-6烷基氨基，最优选为C1-3烷基氨基。
如本文所用，“C3-20环烷硫基”指-S-(C3-20环烷基)，其中环烷基的定义如上所述。优选为C3-10环烷硫基，更优选为C3-8环烷硫基，最优选为C3-6环烷硫基。
如本文所用，“3元至20元的杂环烷基硫基”指-S-(3元至20元的杂环烷基)，其中杂环烷基的定义如上所述。优选为3元至10元的杂环烷基硫基。
如本文所用，“3元至20元的杂环烷基氧基”指-O-(3元至20元的杂环烷基)，其中杂环烷基的定义如上所述。优选为3元至10元的杂环烷基氧基。
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。
如本文所用，“3至7元单环”是指含3至7个环原子的饱和或部分不饱和的全碳单环。优选5至6元。单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环 戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环辛基环等。
如本文所用，“3至7元单杂环”是指3至7元单环中的1、2或3个碳原子被选自氮、氧或硫的杂原子所取代。优选5至6元。单杂环的实例包括(但不限于)四氢呋喃环、四氢噻吩环、吡咯烷基环、哌啶环、吡咯啉环、噁唑烷环、哌嗪环、二氧戊环、吗啉环、硫代吗啉环、高哌嗪环、吡喃环等。
如本文所用，“8至10元双环”是指含8至10个环原子的饱和的全碳双环或部分不饱和的全碳双环，双环的实例包括(但不限于)：
Figure PCTCN2017072470-appb-000055
如本文所用，“8至10元双杂环”是指8至10元双环中的1、2、3、4或5个碳原子被选自氮、氧或硫的杂原子所取代。双杂环的实例包括(但不限于)四氢喹啉环、四氢异喹啉环、十氢喹啉环等。
如本文所用，“5至6元单环杂芳基环”是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃环、苯并噻吩环、吲哚环、异吲哚环、喹啉环、异喹啉环、吲唑环、苯并噻唑环、苯并咪唑环、喹唑啉环、喹喔啉环、噌啉环、酞嗪环。
如本文所用，“苯并3至7元单环或苯并3至7元单杂环”是指含3至7个环原子的单环或单杂环稠合于苯环上形成的双环结构，优选苯并5至6元单环或苯并5至6元单杂环。非限制性实施例包含：
Figure PCTCN2017072470-appb-000056
Figure PCTCN2017072470-appb-000057
如本文所用，“5至6元单环杂芳基环并3至7元单环或5至6元单环杂芳基环并3至7元单杂环”是指3至7元单环或3至7元单杂环稠合于5至6元单环杂芳基环上形成的双环结构，非限制性实施例包含：
Figure PCTCN2017072470-appb-000058
Figure PCTCN2017072470-appb-000059
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
如本文所用，烷基可以是取代的或未取代的，烯基可以是取代的或非取代的，炔基可以是取代的或非取代的，环烷基可以是取代的或未取代的，杂环基可以是取代的或未取代的，烷氧基可以是任选取代的或未取代的，环烷氧基可以是任选取代的或未取代的，芳基可以是取代的或未取代的，3至7元单环可以是取代的或未取代的，3至7元单杂环可以是取代的或未取代的，8至10元双环可以是取代的或未取代的，8至10元双杂环可以是取代的或未取代的，苯并3至7元单环或苯并3至7元单杂环可以是取代的或未取代的，5至6元单环杂芳基环并3至7元单环或5至6元单环杂芳基环并3至7元单杂环可以是取代的或未取代的，上述基团为取代时，取代基优选为1至5个以下基团，独立地选自C1-20烷基、卤代C1-20烷基、C2-20烯基、C2-20炔基、C1-20烷氧基、C1-20烷硫基、C1-20烷基氨基、卤素、硫醇、羟基、硝基、氰基、C3-20环烷基、3元至20元的杂环基、C6-20芳基、5或6元单环杂芳基或8至10元双环杂芳基、C3-20环烷氧基、3元至20元的杂环烷基氧基、C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、氨基、C1-20羟烷基、羧基或羧酸酯基。
制备方法
本发明提供了式(I)化合物的制备方法，本发明中的化合物可以通过多种合成操作容易地制备，这些操作是所属领域技术人员熟练掌握的。这些化合物的示例性制备方法可以包括(但不限于)下文所述的流程。
本发明式(I)化合物可以参照下述合成路线进行制备，在具体操作过程中，可以根据 需要对方法中的步骤进行扩展或合并。
路线1
Figure PCTCN2017072470-appb-000060
步骤1：可先通过例如草酰氯、羰基二咪唑(CDI)、丙基膦酸酐、基于脲的酰胺偶联剂或碳二亚胺等试剂激活式(I-a)化合物中的羧基，随后在亲和性碱，例如4-二甲氨基吡啶、N,N-二甲基氨基丙基-N’-乙基碳二亚胺、4-二甲氨基吡啶/N,N-二异丙基乙胺的存在下与式(I-b)化合物中的磺酰胺基团发生置换反应，生成式(I-c)化合物。
步骤2：式(I-c)化合物与式(I-d)化合物在碱体系的存在下，通过取代反应(例如亲和取代反应等)或偶联反应(如Suzuki偶联等)生成式(I-e)化合物，合适的碱体系包括存在于DMSO的叔丁醇钾、存在于DMF中的氢化钠、存在于DMF的碳酸钾等。
步骤3：式(I-e)化合物可与式(I-f)化合物发生取代反应生成式(I)化合物，式(I-f)中的Lev为离去基团，包括(但不限于)三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等。
路线2
Figure PCTCN2017072470-appb-000061
式(I-d)化合物可先与式(I-f)化合物发生取代反应生成式(I-g)化合物，随后与式(I-c)化合物反应生成式(I)化合物，反应条件分别同路线1中的步骤3和步骤2。
以上各步骤中的反应均是本领域技术人员已知的常规反应。如无特殊说明，合成路线中所使用的试剂和原料化合物均可市购得到，或本领域技术人员根据所设计的不同化合物结构参考已知方法制备得到。
与现有技术相比，本发明的主要优点在于：
提供了一系列结构新颖的杂环取代的N-磺酰基苯甲酰胺衍生物，其对Nav1.7钠离子通道具有高度选择性，并具有稳定的肝微粒体代谢稳定性，可用作广泛疼痛治疗的药物。
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，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
如本文所用，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，THF为四氢呋喃，DIPEA为N,N-二异丙基乙胺，EA为乙酸乙酯，PE为石油醚，BINAP为(2R,3S)-2,2’-双二苯膦基-1,1’-联萘，LiHMDS为双三甲基硅基胺基锂，THF为四氢呋喃，HATU为2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯，n-BuLi为正丁基锂，DCM为二氯甲烷，DME乙二醇二甲醚，NBS为N-溴代丁二酰亚胺，Pd2(dba)3为三(二亚苄基丙酮)二钯，CDI为N,N’-羰基二咪唑，DBU为1,5-二氮杂二环[5.4.0]十一-5-烯，Pd(dppf)Cl2为[1,1’-双(二苯基膦基)二茂铁]二氯化钯，DIAD为偶氮二甲酸二异丙酯，EDCI为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，DMAP为4-二甲氨基吡啶，LDA为二异丙基氨基锂。
如本文所用，室温是指约为25℃。
化合物13-a的制备方法：
Figure PCTCN2017072470-appb-000062
步骤a：将化合物13-a-1(50g,0.40mol)加入到浓盐酸(400ml)中，混合物冷却到0℃，滴加亚硝酸钠(28.6g,0.44mol)的水(100ml)溶液。混合物在0℃反应0.5h后，加入氯化亚铜(91.68g,0.48mol)。混合物在室温搅拌0.5h后，加热到100℃搅拌1h。冷却后过滤，滤液用石油醚(500ml x 2)萃取，有机相用饱和食盐水洗涤(500ml)，无水硫酸钠干燥，过滤，滤液减压蒸干，所得粗品通过柱层析提纯(eluent/PE:EA＝10:1)，得到无色油状化合物13-a-2(24.1g，产率：41％)。
步骤b：将化合物13-a-2(18.72g,130mmol)溶解在无水THF(200ml)中，冷却至-78℃,氮气保护下，滴加n-BuLi(62.4ml,2.4M/L,248mmol)。混合物在-78℃搅拌1h，然后倒到干冰上。混合物在-78℃搅拌1h，然后在室温下搅拌1h。混合物倒入2N盐酸水溶液(200ml)中，用乙酸乙酯(250ml)萃取。分出有机相用食盐水(200ml)洗涤。无水硫酸钠干燥，过滤。滤液用旋转蒸发仪旋干得白色固体13-a-3(9.1g，产率:37％). ESI-MS[M-H]-:187。纯度＝80％(UV214)。
步骤c：将化合物13-a-3(9.1g,48mmol)溶解在无水DCM(150mL)中，冷却至0℃，分别加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(13.76g,72mmol)，DMAP(11.8g,96mmol),甲基磺酰胺(9.12g,96mmol)，N,N-二异丙基乙胺(18.57g,114mmol)。混合物在室温搅拌18h后，倒入2N盐酸水溶液(100ml)中，混合物在室温搅拌0.5h后，分出有机相用食盐水(100ml)洗涤。无水硫酸钠干燥，过滤。滤液用旋转蒸发仪旋干得白色固体13-a-4(9.6g，产率:78％).ESI-MS[M+H]+:266.0。纯度＝91％(UV214)。
步骤d：将化合物13-a-4(7.95g,30mmol)溶解在无水DME(100ml)中，加入NBS(12.21g,69mmol)，偶氮二异丁腈(0.59g,3mmol)。混合物在搅拌条件下，回流18h后，用旋转蒸发仪旋干滤液。残留物用HPLC柱制备得白色固体13-a-5(3.1g，产率:30％)。ESI-MS(M+H)+:343.7。纯度＝98.2％(UV214)。1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.12(d,J＝6.8Hz，1H),7.36(d,J＝12.0Hz，1H),4.54(s,2H),3.43(s,3H)。
化合物17-a的制备方法：
Figure PCTCN2017072470-appb-000063
步骤a：向化合物17-a-1(4.5g,28.8mmol)，对甲苯磺酸(499mg,2.9mmol)的二氯甲烷(100ml)溶液中，冷却至零摄氏度缓慢加入N-氯代丁二酰亚胺(4g,30.3mmol)，搅拌2小时，室温搅拌过夜。反应结束，倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩得到白色固体化合物17-a-2(5g)。MS m/z(ESI):189[M-H]-。
步骤b：向化合物17-a-2(5g,26.3mmol)的甲醇(130ml)溶液中逐滴加入浓硫酸(7ml,1mmol)，回流搅拌5小时。反应结束，冷却至室温，倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，加入二氯甲烷室温搅拌20分钟，过滤得到白色固体化合物17-a(4.2g)。MS m/z(ESI):203[M-H]-。
化合物22-a的制备方法：
Figure PCTCN2017072470-appb-000064
步骤a：以化合物17-a(2g)为原料参照实施例57中步骤3的制备方法，不同的是将反应条件换成室温搅拌过夜，得到化合物22-a-2(552mg)，纯度96.57％，产率14％，MS m/z(ESI):322.1[M+H-56]+。
步骤b：以化合物22-a-2(552mg)为原料参照实施例4中步骤1的制备方法，得到化合物22-a(409mg)，纯度100％，产率41％，MS m/z(ESI):288[M+H]+。
化合物25-a的制备方法：
Figure PCTCN2017072470-appb-000065
步骤：向化合物25-a-1(2.03g，11.93mmol)的乙酸(65ml)溶液中加入溴(0.61ml，11.33mmol)，室温搅拌过夜。反应结束，减压浓缩，食盐水洗，乙酸乙酯萃取，干燥分离有机相，减压浓缩得粗品，经Combi-flash柱层析纯化得到化合物25-a(3g)，纯度85％，产率100％。MS m/z(ESI):249[M+H]+。
化合物36-a的制备方法：
Figure PCTCN2017072470-appb-000066
步骤1：向50ml密封管中加入化合物36-a-1(500mg，2.23mmol)，化合物36-a-2(671mg，3.35mmol)，Pd2(dba)3(三(二亚苄基丙酮)二钯)(41mg，0.045mmol)，BI NAP((±)-2,2’-双-(二苯膦基)-1,1’-联萘)(56mg，0.089mmol)，叔丁醇钾(644mg，6.7mmol)，7ml 1,4-二氧六环，90℃搅拌2h。反应结束，冷却至室温，加入30ml水和30ml乙酸乙酯，过滤，乙酸乙酯萃取，分离合并有机相，滤液减压浓缩得到粗品，经Combi-flash柱层析纯化得到黄色油状化合物36-a-3(475mg)，直接用于下一步反应。MS m/z(ESI):289.1[M+H-56]+。
步骤2：将氯化氢甲醇溶液(1.5ml，5.53mmol)加入到化合物36-a-3(475mg)的甲醇溶液中，室温搅拌4小时后浓缩反应液，得化合物化合物36-a的粗品。不经纯化直接使用。
化合物37-a的制备方法：
Figure PCTCN2017072470-appb-000067
在0℃下，用氩气保护，向化合物37-a-1(1.0g,7.09mmol)和碘(9mg,0.035mmol)的二氯甲烷混合溶液中逐滴加入液溴。滴加完毕，将反应液慢慢升至室温。在室温下避光搅拌过夜。反应用亚硫酸氢钠溶液淬灭，二氯甲烷萃取，有机相用饱和食盐水洗涤，干燥浓缩，粗品用乙醇重结晶得白色固体37-a(230mg)，纯度100％，产率14.7％，MS m/z(ESI):N/A。
化合物38-a的制备方法：
Figure PCTCN2017072470-appb-000068
在60℃下，向化合物38-a-1(2.26g,15.59mmol)和铁粉(44mg,0.78mmol)的混合溶 液中逐滴加入液溴(2.49g,15.59mmol),滴加完毕，60℃继续搅拌3h。反应液冷却至室温，用亚硫酸氢钠溶液淬灭反应，用石油醚萃取，有机相用饱和食盐水洗涤，干燥浓缩，粗品经柱层析纯化(100％石油醚)得无色油状化合物38-a(2.82g)，纯度75％，产率81％，MS m/z(ESI):N/A。
化合物39-a的制备方法：
Figure PCTCN2017072470-appb-000069
在室温下，向化合物39-a-1(5g,31.06mmol)，铁粉(87mg,1.55mmol)和碘(39mg,0.15mmol)的四氯化碳混合溶液中逐滴滴加液溴(5.22g,32.61mmol)，滴加完毕后，反应液在室温下搅拌两天。反应液用亚硫酸氢钠溶液淬灭，用二氯甲烷萃取(2*50ml)，有机相用饱和食盐水洗涤(30ml)，干燥浓缩得无色油状化合物39-a(4.77g)，纯度76％，产率64％，MS m/z(ESI):N/A，直接用于下一步反应中。
化合物40-a的制备方法：
Figure PCTCN2017072470-appb-000070
将化合物40-a-1(1g,4.77mmol)的无水四氢呋喃溶液在-50℃下逐滴滴加到LDA(2M,3ml)的四氢呋喃溶液中，滴加完毕，反应液在-50℃下搅拌30分钟。在-50℃下向上述反应液中加入碘甲烷(1037mg,7.30mmol)，反应液自然升至室温。反应液倒入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩，粗品经柱层析纯化(100％石油醚)得无色油状化合物40-a(747mg)，纯度77％，产率70％，MS m/z(ESI):N/A。
化合物41-a的制备方法：
Figure PCTCN2017072470-appb-000071
将化合物41-a-1(500mg,2.5mmol)分散在5ml水中，加入1ml浓盐酸，将溶液降温至0℃。将亚硝酸钠(517mg,7.49mmol)溶解在2ml水中，在0℃下逐滴加入上述溶液中，并保持在0℃搅拌30分钟，加入氯化亚铜(990mg,10.0mmol)，反应液加热至75℃，搅拌1h。反应液冷却至室温后，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩，粗品经柱层析纯化(100％石油醚)得无色油状化合物41-a(218mg)，纯度89％，产率40％，MS m/z(ESI):N/A。
化合物42-a的制备方法：
Figure PCTCN2017072470-appb-000072
步骤1：化合物42-a-1(200mg,0.966mmol)，N-Boc-哌嗪(270mg,1.449mmol)，Pd2(dba)3(44mg，0.097mmol)，Johnphos(30mg，0.193mmol)，叔丁醇钠(280mg，2.898 mmol)的二氧六环混合溶液，在氩气保护下40℃搅拌过夜。反应液冷却至室温，用硅藻土过滤，滤液减压浓缩，粗品经柱层析纯化(PE:EA＝10:1)得黄色油状化合物42-a-2(188mg)，纯度93％，产率50％，MS m/z(ESI):257.2[M+H-56]+。
步骤2：参照中间36-a中步骤2的制备方法得到黄色固体化合物42-a(212mg)。
Figure PCTCN2017072470-appb-000073
中间体化合物如式(I)所示，取代芳环基Ar如下表所示。
通用步骤：化合物43-a至60-a，以N-Boc-哌嗪和溴取代的芳环或溴取代的吡啶为原料，参照中间体36-a的类似方法制备。化合物58-a，参照42-a的类似方法制备。
Figure PCTCN2017072470-appb-000074
中间体61-a的制备：
Figure PCTCN2017072470-appb-000075
步骤a：向化合物61-a-1(2.01g,0.01mol)，化合物25-a(2.49g,0.01mol)，三苯基膦(5.24g,0.02mol)的四氢呋喃溶液中慢慢滴加DIAD(4.04g,0.02mol)，反应液室温搅拌1h。反应液用饱和食盐水洗涤，干燥浓缩，粗品经柱层析纯化得61-a-2(2.08g)，纯度100％， 产率59％，MS m/z(ESI):376.1[M+H-56]+。
步骤b：向化合物61-a-2(2.08g,4.81mmol)的甲醇溶液中加入4M盐酸二氧六环溶液(5ml)，反应液室温搅拌5h。反应液减压浓缩得61-a(1.6g)，纯度100％，产率98％，MS m/z(ESI):370[M+H]+。
中间体62-a的制备：
Figure PCTCN2017072470-appb-000076
步骤1：化合物62-a-1(1.0g,5.85mmol)，N-Boc-哌嗪(1.3g,7.02mmol)，HATU(2.22g,5.85mmol)和DIPEA(1.51g,11.7mmol)的二氯甲烷混合溶液室温搅拌16h。反应液用二氯甲烷稀释，用2N盐酸溶液、饱和食盐水洗涤，干燥浓缩，粗品经柱层析纯化(PE:EA＝7:3)得化合物62-a-2(1.51g)，纯度100％，产率76％，MS m/z(ESI):283.0[M+H]+。
步骤2：以化合物62-a-2为原料，参照36-a中步骤2的制备方法，得化合物62-a(1.21g)，纯度96％，产率99％，MS m/z(ESI):239.0[M+H]+。
中间体63-a的制备：
Figure PCTCN2017072470-appb-000077
以4-氯苯甲酸为原料，参照化合物62-a的制备方法，得化合物63-a。
实施例80：(R)-5-氯-N-(环丙基磺酰基)-2-氟-4-((1-(4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-80)的制备
Figure PCTCN2017072470-appb-000078
步骤1：化合物80-a(9.0g,40mmol)、化合物7-a(6.08g,60mmol)，(L)-脯氨酸(920mg,8mmol)，碘化亚铜(764mg,4mmol)、碳酸钾(16.56g,120mmol)的二甲亚砜(50ml)混合溶液，在氩气保护下，100℃搅拌16h。反应液冷却至室温后，将反应液倒入水中，乙酸乙酯(3*60ml)萃取，有机相用水(2*150ml)和饱和食盐水(100ml)洗涤，干燥浓缩，粗品经柱层析纯化(PE/EA＝4:1)得黄色油状化合物80-b(3.98g)，纯度100％，收率41％，MS m/z(ESI):246.1[M+H]+。
步骤2：向化合物80-b(956mg,3.9mmol)、化合物17-a(800mg,3.9mmol)、三苯基膦(2.04g,7.8mmol)的四氢呋喃(10ml)混合溶液中逐滴加入DIAD(1.58g,7.8mmol)，室温搅拌1h。反应液减压浓缩，粗品经柱层析纯化(PE/EA＝10:1)得无色油状化合物80-c(1 g)，纯度80％，产率65％，MS m/z(ESI):432.2[M+H]+。
步骤3：向化合物80-c(1.1g,2.55mmol)的甲醇(20ml)溶液中加入2M氢氧化钠溶液(5ml)，混合溶液60℃搅拌2h。减压除去大部分溶剂，剩余物加入20ml水，用2N盐酸溶液调PH值至3-4，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩得淡黄色固体化合物80-d(0.84g)，纯度96％，产率79％，MS m/z(ESI):418.1[M+H]+。
步骤4:化合物80-d(100mg,0.239mmol)、环丙基磺酰胺(58mg,0.478mmol)、HATU(100mg,0.263mmol)、DIPEA(62mg,0.478mmol)、DMAP(3mg,0.024mmol)的二氯甲烷混合溶液，室温搅拌16h。反应液用20ml二氯甲烷稀释，用2N盐酸溶液和饱和食盐水洗涤，有机相干燥浓缩，粗品经Pre-HPLC纯化得白色固体化合物Z-80(12mg)，纯度99％。产率10％，MS m/z(ESI):521.2[M+H]+。1H NMR(DMSO-d6,400MHz):δ7.73(d,J＝7.6Hz,1H),7.42(d,J＝8.8Hz,2H),7.01(d,J＝12.4Hz,1H),6.78(d,J＝8.8Hz,2H),4.24(br.s.,1H),4.05-4.14(m,2H),3.47(t,J＝8.8Hz,1H),3.14-3.21(m,1H),2.84-2.91(m,1H),2.17–2.29(m,1H),1.99–2.07(m,3H),0.78-0.88ppm(m,4H)。
实施例119：(R)-5-氯-N-(环丙基磺酰基)-2-氟-4-((1-(6-(三氟甲基)吡啶-3-基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-119)的制备
Figure PCTCN2017072470-appb-000079
步骤1：化合物119-a(1.13g,5mmol)，化合物7-a(1.01g,10mmol)，碳酸钾(1.38g,10mmol)的DMF混合溶液100℃搅拌48h。反应液冷却至室温后倒入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩，粗品经柱层析纯化(PE:EA＝1:1)得黄色油状化合物119-b(420mg)，纯度100％，产率34％，MS m/z(ESI):247.1[M+H]+。
步骤2：以化合物119-b为原料，参照实施例80中步骤2制备方法得白色固体化合物119-c(318mg)，纯度74％，产率100％，MS m/z(ESI):433.1[M+H]+。
步骤3：以化合物119-c为原料，参照实施例80中步骤3制备方法得白色固体化合物119-d(409mg)，纯度95％，产率52％，MS m/z(ESI):419.1[M+H]+。
步骤4：以化合物119-d为原料，参照实施例80中步骤4制备方法得白色固体化合物Z-119(42mg)，纯度100％，产率38％，MS m/z(ESI):522.1[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.02(br.s.,1H),8.18(d,J＝2.4Hz,1H),7.72(d,J＝7.6Hz,1H),7.56(d,J＝8.8Hz,1H),7.22-7.15(m,2H),4.38(d,J＝8.0Hz,1H),4.20-4.17(m,2H),3.54(t,J＝8.4Hz,1H),3.26-3.20(m,1H),3.06-2.99(m,1H),2.27-2.19(m,1H),2.06-2.03(m,3H), 1.09-1.05(m,4H).
实施例150：(R)-5-氯-N-(环丙基磺酰基)-2-氟-4-((1-(5-(三氟甲基)吡啶-2-基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-150)的制备
Figure PCTCN2017072470-appb-000080
步骤1：化合物22-a(6.87g,0.02mol)、化合物2-氟-5-(三氟甲基)吡啶(3.5g,0.02mol)、碳酸钾(8.29g,0.06mmol)的乙腈混合溶液80℃搅拌过夜。反应液冷却至室温后，加水，用乙酸乙酯萃取，有机相干燥浓缩，粗品经柱层析纯化(PE/EA＝10:1)得淡黄色固体化合物150-a(6.9g)，纯度93％，产率75％，MS m/z(ESI):433.1[M+H]+。
步骤2：以化合物150-a为原料，参照实施例80中步骤3制备方法得白色固体化合物150-b(6.422)，纯度99％，产率92％，MS m/z(ESI):419.1[M+H]+。
步骤3：以化合物150-b为原料，参照实施例80中步骤4制备方法得白色固体化合物Z-150(4.73g)，纯度100％，产率59％，MS m/z(ESI):522.1[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.01(br.s.,1H),8.38(br.s.,1H),7.77(dd,J＝2.4Hz,8.8Hz,1H),7.73(d,J＝7.6Hz,1H),7.38(d,J＝12.4Hz,1H),6.68(d,J＝9.2Hz,1H),4.54-4.51(m,1H),4.30(dd,J＝3.2Hz,10.0Hz,1H),4.18(dd,J＝6.0Hz,9.6Hz,1H),3.54(t,J＝8.4Hz,1H),3.37-3.30(m,1H),3.08-3.00(m,1H),2.31-2.18(m,1H),2.10-1.99(m,3H),1.12-1.07(m,4H).
实施例125：(R)-5-环丙基-N-(环丙基)-2-氟-4-((1-(4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-125)的制备
Figure PCTCN2017072470-appb-000081
步骤1：4-溴-三氟甲基苯(20g,0.089mol)，化合物7-a(13.486g,0.133mol)，(L)-脯氨酸(2.047g,0.017mol)，碘化亚铜(1.693g,0.009mol)和碳酸钾(30.854g,0.267mol)的二甲亚砜混合溶液在氩气保护下，90℃搅拌过夜，反应液冷却至室温后倒入水中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩，粗品经柱层析纯化(PE:EA＝3:1)得黄色油状化合物125-b(8.872g)，纯度100％，产率41％，MS m/z(ESI):246.1[M+H]+。
步骤2：向化合物125-b(1.48g,6.02mmol)，化合物25-a(1.5g,6.02mmol)，三苯基膦(3.15g,12.04mmol)的四氢呋喃溶液中逐滴加入DIAD(2.43g,12.04mmol)，滴加完毕，反应液在室温下继续搅拌1h。反应液减压浓缩，粗品经柱层析纯化后(PE:EA＝10:1)，用10ml甲醇打浆，过滤，滤饼用甲醇洗涤，干燥得白色固体化合物125-c(1.24g)，纯度98％，产率43％，MS m/z(ESI):478.1[M+H]+。
步骤3：化合物125-c(1.13g,2.6mmol)，环丙基硼酸(0.45g,5.2mmol)，Pd(dppf)Cl2(0.19g,0.26mmol)，碳酸铯(1.7g,5.2mmol)的二氧六环溶液在氩气保护下，90℃搅拌24h。反应液冷却至室温后过滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩，粗品经柱层析纯化(PE:EA＝10:1)得白色固体化合物125-d(1.13g)，纯度100％，产率99％，MS m/z(ESI):438.2[M+H]+。
步骤4：向化合物125-d(1.053g,2.407mmol)的甲醇溶液中加入1M氢氧化钠溶液(10ml)，反应液在60℃下搅拌2h。反应液减压浓缩除去甲醇，加水，用1M盐酸溶液调PH值至2-3，过滤，滤饼用水洗涤，干燥，得白色固体125-e(1.16g)，纯度100％，产率100％，MS m/z(ESI):424.1[M+H]+。
步骤5：化合物125-e(200mg,0.472mmol)，环丙基磺酰胺(290mg,2.362mmol)，EDCI(270mg,1.417mmol),DMAP(170mg,1.417mmol),DIPEA(370mg,2.834mmol)的二氯甲烷混合溶液室温搅拌过夜。反应液用水洗涤，干燥浓缩，粗品经Pre-HPLC纯化得白色固体化合物Z-125(72mg)，纯度100％，产率29％，MS m/z(ESI):527[M+H]+。1H NMR(500MHz,DMSO):δ11.815(s,1H),7.453(d,J＝10.5Hz,2H),7.110(d,J＝10.5Hz,1H),6.956(d,J＝16Hz,1H),6.819(m,J＝11Hz,2H),4.341-4.321(m,1H),4.114-4.087(m,2H),3.514(t,J＝11Hz,1H),3.226-3.208(m,1H),3.069-3.057(m,1H),2.216-1.923(m,5H),1.117-1.079(m,4H),0.882-0.763(m,2H),0.657-0.644(m,2H).
实施例142：(R)-5-环丙基-N-(环丙基磺酰基)-2-氟-4-((1-(5-(三氟甲基)吡啶-2-基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-142)的制备
Figure PCTCN2017072470-appb-000082
步骤1：化合物61-a(1.6g,4.34mmol)，2-氟-5-三氟甲基吡啶(0.72g,4.34mmol)，碳酸钾(1.8g,13.02mmol)的乙腈混合溶液80℃搅拌20h。反应液冷却至室温，用乙酸乙酯稀释，用水、饱和食盐水洗涤，有机相干燥浓缩，粗品用甲醇打浆，过滤，滤饼用甲醇洗涤，干燥得白色固体化合物142-a(1.1g)，纯度100％，产率53％，MS m/z(ESI):479.1[M+H]+。
步骤2：以化合物142-a(1.0g,2.1mmol)为原料，参照实施例125中步骤3制备方法得白色固体化合物142-b(0.9g)，纯度95％，产率98％，MS m/z(ESI):439.2[M+H]+。
步骤3：以化合物142-b(0.9g,2.05mmol)为原料，参照实施例125中步骤4制备方法得白色固体化合物142-c(0.8g)，纯度96％，产率92％，MS m/z(ESI):425.2[M+H]+。
步骤4：以化合物142-c(100mg,0.236mmol)为原料，参照实施例125中步骤5制备方法得白色固体化合物Z-142(26mg)，纯度100％，产率24％，MS m/z(ESI):528.2[M+H]+。1H NMR(DMSO-d6,400MHz):δ11.79(br.s.,1H),8.38(s,1H),7.77(dd,J＝8.8,2.4Hz,1H),7.11(d,J＝8.4Hz,1H),7.04(d,J＝13.2Hz,1H),6.68(d,J＝9.2Hz,1H),4.54(br.s.,1H),4.23(dd,J＝9.6,3.6Hz,1H),4.07(dd,J＝9.8,6.8Hz,1H),3.54(t,J＝9.2Hz,1H),3.32-3.41(m,1H),2.92-3.07(m,1H),2.11-2.27(m,1H),1.88-2.09(m,4H),0.95-1.08(m,4H),0.74-0.91(m,2H),0.61ppm(dd,J＝5.2,1.6Hz,2H).
实施例89：5-氯-N-(环丙基磺酰基)-4-((4-(3,4-二氯苯基)哌嗪-1-基)甲基)-2-氟苯甲酰胺(Z-89)的制备
Figure PCTCN2017072470-appb-000083
步骤1：以化合物13-a-3(300mg)为原料参照实施例125中步骤5的制备方法，得到化合物89-c(456mg)，MS m/z(ESI):290[M-H]-。
步骤2：以化合物89-c(452mg)为原料参照中间体13-a中步骤d的制备方法，得到化合物89-d(419mg)，MS m/z(ESI):372[M+H]+。
步骤3：化合物89-d(109mg)、化合物10-a、碳酸钾的乙腈混合溶液80℃搅拌3h。反应液冷却至室温，加水，乙酸乙酯萃取，有机相干燥浓缩，粗品经Pre-HPLC纯化得到化合物Z-89(23.34mg)，纯度100％，产率15％，MS m/z(ESI):520.1[M+H]+。1H NMR(400MHz,DMSO-d6):δ7.71(d,J＝6.4Hz,1H),7.40(d,J＝11.2Hz,1H),7.36(d,J＝9.2Hz,1H),7.10(d,J＝2.8Hz,1H),6.90(dd,J＝3.2Hz,9.2Hz,1H),3.63(s,2H),3.20-3.18(m,4H),3.12-2.94(m,1H),2.56-2.55(m,4H),1.03-0.96(m,4H).
实施例92、159、164：
化合物Z-92、Z-159、Z-164以89-d为原料与相应的苯基取代的或吡啶基取代的哌嗪参照实施例89中步骤3相似的方法制备。
Figure PCTCN2017072470-appb-000084
实施例117：5-氯-N-(环丙基磺酰基)-4–((1-(3,4-二氯苯基)哌啶-4-基)氧基)-2-氟苯甲酰胺(Z-117)的制备
Figure PCTCN2017072470-appb-000085
步骤1：4-溴-1,2-二氯苯(200g,0.885mol)、化合物117-a(224g,2.218mol)、(L)-脯氨酸(10.2g,0.089mol)，碘化亚铜(34.2g,0.180mol)和碳酸钾(366g,2.652mol)的二甲亚砜(1.0L)混合溶液在氩气保护下，100℃搅拌16h。反应液冷却至室温，加入2.0L乙酸乙酯，过滤除去不溶的物质，滤饼用乙酸乙酯洗涤，滤液用饱和食盐水洗涤，干燥浓缩，得到化合物117-b(175g)的粗品，纯度88％，MS m/z(ESI):247[M+H]+。
步骤2：在0℃下，向化合物117-b(4.7g,16.26mmol)，化合物17-a(3.34g,16.26mmol)，三苯基膦(8.52g,32.52mmol)的四氢呋喃(20ml)溶液中逐滴加入DIAD(6.5g,32.52mmol)，反应液在氮气保护下室温搅拌12h。反应液倒入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩，得化合物117-c(6.7g)的粗品，纯度89％，MS m/z(ESI):432[M+H]+。
步骤3：向化合物117-c(6.7g,15.5mmol)的四氢呋喃溶液中加入4M氢氧化钠溶液(15ml)，反应液室温搅拌过夜。减压浓缩除去四氢呋喃，用1M盐酸溶液将PH值调至 5-6，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩得到化合物117-d(6.4g)的粗品，纯度90％，MS m/z(ESI):419[M+H]+。
步骤4：化合物117-d(100mg,0.239mmol)、环丙基磺酰胺(58mg,0.478mmol)、HATU(100mg,0.263mmol)、三乙胺(48mg,0.478mmol)、DMAP(3mg,0.024mmol)的二氯甲烷溶液室温搅拌12h。反应液加入20ml二氯甲烷稀释，用2N盐酸溶液洗涤，有机相干燥浓缩，粗品经Pre-HPLC纯化得化合物Z-117(15mg)，纯度100％，产率12％，MS m/z(ESI):523.1[M+H]+。1H NMR(DMSO-d6,400MHz):δ11.99(br.s.,1H),7.74(d,J＝7.6Hz,1H),7.29-7.45(m,2H),7.14(d,J＝2.8Hz,1H),6.94(dd,J＝9.2,2.8Hz,1H),4.78-4.93(m,1H),3.39-3.54(m,2H),3.13-3.26(m,2H),2.96-3.10(m,1H),1.90-2.07(m,2H),1.61-1.78(m,2H),0.94-1.22ppm(m,4H).
实施例172：(R)-5-氯-N-(环丙基磺酰基)-4-((4-(3,4-二氯苯基)-2-甲基哌嗪-1-基)甲基)-2-氟苯甲酰胺(Z-172)的制备
Figure PCTCN2017072470-appb-000086
化合物36-a(100mg,0.408mmol)，化合物89-d(151mg,0.408mmol)和碳酸钾的DMF混合溶液，80℃搅拌3h。反应液冷却至室温，将反应液倒入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥浓缩，粗品经Pre-HPLC纯化得白色固体化合物Z-172(70mg)，纯度100％，产率32％，MS m/z(ESI):533.8[M+H]+。1H NMR(dmso,400MHz):δ12.18(brs.,1H),7.71(d,J＝6.0Hz,1H),7.49(d,J＝11.2Hz,1H),7.35(d,J＝9.2Hz,1H),7.11(d,J＝2.8Hz,1H),6.91(dd,J＝8.8,2.8Hz,1H),3.97(d,J＝14.8Hz,1H),3.54(d,J＝8.4Hz,1H),3.35-3.50(m,2H),2.96-3.09(m,1H),2.86(t,J＝10.4Hz,1H),2.57-2.77(m,3H),2.36(br.s.,1H),0.97-1.17ppm(m,7H)
实施例173-188：
化合物Z-173至Z-188以化合物89-d为起始原料，参照实施例172的方法进行制备，不同的是将36-a换成相应的取代的溴苯。
Figure PCTCN2017072470-appb-000087
Figure PCTCN2017072470-appb-000088
Figure PCTCN2017072470-appb-000089
实施例189：N-(环丙基磺酰基)-5-乙基-2-氟-4-((4-(4-(三氟甲氧基)苯基)哌嗪-1-基)甲基)苯甲酰胺(Z-189)的制备
Figure PCTCN2017072470-appb-000090
步骤1：以化合物87-b为原料，参照实施例89中步骤1制备方法，得到化合物189-a。
步骤2：以化合物189-a为原料，参照实施例89中步骤2制备方法，得到化合物189-b。
步骤3：以化合物189-b为原料，参照实施例89中步骤3制备方法，得到化合物189-c。
步骤4：化合物189-c、乙烯基三氟硼酸钾、Pd(dppf)Cl2，三乙胺的乙醇混合溶液在氩气保护下，90℃搅拌6h。反应液冷却至室温，用硅藻土过滤，滤液浓缩，得到189-d粗品，直接用于下一步反应。
步骤5：向化合物189-d的甲醇溶液中，加入钯/炭，反应液在氢气氛围下室温搅拌过夜。反应液用硅藻土过滤，滤液减压浓缩，经Pre-HPLC纯化得白色固体化合物Z-189(39.12mg)，纯度100％，产率10％，MS m/z(ESI):529.9[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.01(br.s.,1H),7.48(d,J＝7.2Hz,1H),7.28(d,J＝11.6Hz,1H),7.19(d,J＝8.8Hz,2H),7.00(d,J＝9.2Hz,2H),3.59(s,2H),3.20-3.16(m,4H),3.11-3.05(m,1H),2.70(q,J＝7.6Hz,2H),2.60-2.56(m,4H),1.18(t,J＝7.6Hz,3H),1.13-1.08(m,4H).
实施例190-193：
化合物Z-190至Z-193以化合物189-b为原料，参照实施例189中步骤3-5制备方法，不同的是Z-191至Z-193的制备中，将步骤5中的钯炭换成二氧化铂。
Figure PCTCN2017072470-appb-000091
Figure PCTCN2017072470-appb-000092
实施例194：N-(环丙基磺酰基)-5-乙基-2-氟-4-((4-(5-(三氟甲氧基)吡啶-2-基)哌嗪-1-基)甲基)苯甲酰胺(Z-194)的制备
Figure PCTCN2017072470-appb-000093
步骤1：以化合物57-a为原料，参照实施例189中步骤3制备方法，得化合物194-a。
步骤2：以化合物194-a为原料，参照实施例189中步骤4制备方法，得化合物194-b。
步骤3：以化合物194-b为原料，参照实施例189中步骤5制备方法，得化合物Z-194
513.2[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),8.15(d,J＝2.4Hz,1H),7.60(dd,J1＝9.2Hz,J2＝2.0Hz,1H),7.48(d,J＝7.2Hz,1H),7.29(d,J＝11.6Hz,1H),6.91(d,J＝9.2Hz,1H),3.58(s,2H),3.53(m,4H),3.04-3.11(m,1H),2.67-2.73(q,J＝7.2Hz,2H),2.49-2.50(m,4H),1.18(t,J＝7.6Hz,3H),1.09-1.12(m,4H).
实施例195：(R)-N-(环丙基)-2-氟-5-甲基-4-((1-(5-(三氟甲基)吡啶-2-基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-195)的制备
Figure PCTCN2017072470-appb-000094
步骤1：以化合物142-a(520mg,1.09mmol)为原料，参照实施例125中步骤3制备方法，不同的是将环丙基硼酸换成甲基硼酸，得白色固体化合物195-b(440mg)，纯度100％，产率98％，MS m/z(ESI):413.2[M+H]+。
步骤2：以化合物195-b(440mg,1.07mmol)为原料，参照实施例125中步骤4制备方法得白色固体化合物195-c(420mg)，纯度92％，产率98％，MS m/z(ESI):399.2[M+H]+。
步骤3：以化合物195-c(100mg,0.25mmol)为原料，参照实施例125中步骤5制备方法得白色固体化合物Z-195(25.75mg)，纯度100％，产率21％，MS m/z(ESI):N/A。1H NMR(DMSO-d6,400MHz):δ11.78(br.s.,1H),8.38(s,1H),7.77(dd,J＝9.2,2.4Hz,1H), 7.46(d,J＝8.4Hz,1H),7.07(d,J＝12.8Hz,1H),6.68(d,J＝9.2Hz,1H),4.51(br.s.,1H),4.14-4.28(m,1H),4.01-4.06(m,1H),3.48-3.61(m,1H),3.30-3.39(m,1H),2.96-3.06(m,1H),1.91-2.21(m,7H),0.94-1.15ppm(m,4H)。
实施例196：(环丙基磺酰基)-4-((4-(3,4-二氯苯基)哌嗪-1-基)甲基)-2-氟苯甲酰胺(Z-196)的制备
Figure PCTCN2017072470-appb-000095
步骤1：以化合物189-b为原料，参照实施例89中步骤3制备方法，得化合物196-a。
步骤2：以化合物196-a为原料，参照实施例125中步骤3制备方法，得化合物Z-196。
MS m/z(ESI):NA。1H NMR(400MHz,DMSO-d6):δ11.96(br.s.,1H),7.36(d,J＝8.8Hz,1H),7.27(d,J＝11.6Hz,1H),7.20(d,J＝6.8Hz,1H),7.10(d,J＝2.8Hz,1H),6.90(dd,J＝2.8,8.8Hz,1H),3.73(s,2H),3.22-3.18(m,4H),3.07-3.02(m,1H),2.58-2.54(m,4H),2.10-2.02(m,1H),1.10-1.06(m,4H),0.94-0.88(m,2H),0.68-0.63(m,2H).
实施例197：(环丙基磺酰基)-4-((4-(3,5-二氯苯基)哌嗪-1-基)甲基)-2-氟苯甲酰胺(Z-197)的制备
Figure PCTCN2017072470-appb-000096
步骤1：以化合物189-b为原料，参照实施例89中步骤3制备方法，不同的是将化合物10-a换成化合物59-a，得化合物197-a。
步骤2：以化合物197-a为原料，参照实施例125中步骤3制备方法，得化合物Z-197
MS m/z(ESI):NA。1H NMR(400MHz,DMSO-d6):δ12.03(br.s.,1H),7.26-7.22(m,2H),6.94(d,J＝1.6Hz,2H),6.86(t,J＝1.6Hz,1H),3.71(s,2H),3.27-3.24(m,4H),3.05-3.00(m,1H),2.57-2.53(m,4H),2.10-2.05(m,1H),1.05-0.97(m,4H),0.96-0.91(m,2H),0.67-0.63(m,2H).
对比例1：5-(环丙基磺酰基)-4–((4-(3,5-二氯苄基)哌嗪-1-基)甲基)-2-氟苯甲酰胺(C1)的制备
Figure PCTCN2017072470-appb-000097
步骤1：化合物1-1(1.96g,10.0mmol),N-Boc-哌嗪(1.95g,10.5mmol),碳酸钾(2.76g,20.0mmol)的乙腈(20ml)混合溶液，80℃搅拌16h。反应液冷却至室温，减压除去溶剂后，加水，用乙酸乙酯(2*50ml)萃取，有机相用饱和食盐水(30ml)洗涤，干燥分离有机相，滤液减压浓缩得到黄色油状化合物1-2(3.5g),纯度90.26％，产率100％。MS m/z(ESI):345.0[M+H]+。
步骤2：化合物1-2的甲醇(50ml)溶液中加入盐酸二氧六环溶液(10ml,40.58mmol)，混合物室温搅拌16h，减压浓缩得到黄色固体化合物1-3(2.9g)，纯度91.49％，产率100％。MS m/z(ESI):245.0[M+H]+。
步骤3：化合物1-3(2.9g,10.28mmol)，化合物1-4(3.35g,10.28mmol)，碳酸钾(2.84g,20.56mmol)的乙腈(50ml)混合溶液，80℃搅拌16h。反应液冷却至室温，减压除去溶剂后，加水，用乙酸乙酯(2*50ml)萃取，有机相用饱和食盐水(30ml)洗涤，干燥分离有机相，滤液减压浓缩得到粗品，经柱层析纯化得到黄色油状化合物1-5(2.6g)，纯度100％，产率51.7％，MS m/z(ESI):491.0[M+H]+。
步骤4：化合物1-5(1.0g,2.04mmol)，环丙基硼酸(0.35g,4.08mmol)，Pd(dppf)Cl2(149mg,0.204mmol)，碳酸铯(1.33g,4.08mmol)的二氧六环(10ml)溶液，在氩气保护下，80℃搅拌16h。反应液冷却至室温，过滤除去固体，滤饼用乙酸乙酯洗涤，滤液减压浓缩，经柱层析纯化得到无色油状化合物1-6(130mg)，纯度97.42％。产率14.1％，MS m/z(ESI):451.0[M+H]+。
步骤5：向化合物1-6(130mg,0.265mmol)的甲醇(10ml)溶液中加入氢氧化钠溶液(5M,2ml)，混合物在60℃搅拌2h。减压除去大部分溶剂，剩余物加水溶解，用1N盐酸溶液调PH值至7左右，用乙酸乙酯萃取(2*10ml)，有机相用饱和食盐水洗涤(10ml)，有机相干燥浓缩得到无色油状化合物1-7(110mg)，纯度97.7％，产率94.8％，MS m/z(ESI):437.0[M+H]+。
步骤6：化合物1-7(110mg,0.252mmol)，环丙基磺酰胺(46mg,0.378mmol)，EDCI(97mg,0.504mmol)，DMAP(31mg,0.252mmol)，DIPEA(98mg,0.756mmol)的二氯甲烷(5ml)混合溶液室温搅拌20h。反应液用二氯甲烷稀释，用水、饱和食盐水洗涤，有机相干燥浓缩后经pre-HPLC纯化后得到白色固体化合物C1(35mg)，纯度100％，产率25.7％，MS m/z(ESI):540.1[M+H]+。1H NMR(dmso,400MHz):δ12.10(br.s.,1H),7.66 (br.s.,1H),7.52(br.s.,2H),7.34(d,J＝10.8Hz,1H),7.21(d,J＝7.2Hz,1H),4.13(br.s.,4H),2.84-3.32(m,9H),2.01-2.12(m,1H),1.04-1.15(m,4H),0.87-0.97(m,2H),0.65-0.72ppm(m,2H)
对比例2、11
化合物C2以3,4-二氯苄溴为原料，参照对比例1的制备方法进行制备，不同的是将步骤6中的环丙基磺酰胺换成甲基磺酰胺。
化合物C11参照对比例1的制备方法进行制备，不同的是将步骤6中环丙基磺酰胺换成甲基磺酰胺。
Figure PCTCN2017072470-appb-000098
对比例4：5-氯-4-((4-(4-氯-3-甲基苄基)哌嗪-1-基)甲基)-N-(环丙基磺酰基)-2-氟苯甲酰胺(C4)的制备
Figure PCTCN2017072470-appb-000099
步骤1：向化合物3-1(1g,5.85mmol)的四氢呋喃溶液中逐滴加入硼烷四氢呋喃溶液(1M,5.9ml)，反应液室温搅拌16h。向反应液中逐滴加入甲醇淬灭反应，减压浓缩，粗品经柱层析纯化(PE:EA＝7:3)得淡黄色固体化合物4-1(910mg)，纯度100％，产率99％，MS m/z(ESI):N/A。
步骤2：向化合物4-1(650mg,4.14mmol)和DIPEA(1.07g,8.28mmol)的二氯甲烷混合溶液中逐滴加入甲基磺酰氯(524mg,4.55mmol)的二氯甲烷溶液，反应液室温搅拌16h。反应液用2N盐酸溶液和饱和食盐水洗涤，干燥浓缩得棕色油状化合物4-2(780mg)，纯度97％，产率80％，MS m/z(ESI):N/A。
步骤3：以化合物4-2为原料，参照对比例1中步骤1制备方法得黄色油状化合物4-3(950mg)，纯度100％，产率88％，MS m/z(ESI):325.0[M+H]+。
步骤4：以化合物4-3为原料，参照对比例1中步骤2制备方法得白色固体化合物4-4(750mg)，纯度100％，产率95％，MS m/z(ESI):225.0[M+H]+。
步骤5：以化合物4-4为原料，参照对比例1中步骤3制备方法得白色固体化合物C4(140mg)，纯度100％，产率70％，MS m/z(ESI):513.8[M+H]+。1H NMR(dmso,400MHz):δ12.32(br.s.,1H),9.79(br.s.,1H),7.74(d,J＝6.4Hz,1H),7.40-7.55(m,3H),7.32(d,J＝8.0Hz,1H),4.26(br.s.,2H),3.94(br.s.,4H),3.69(br.s.,2H),3.26(br.s.,2H),2.97-3.18(m,1H),2.92(br.s.,2H),2.33(s,3H),1.03-1.18ppm(m,4H).
对比例3、5、6、12、13
化合物C3、C5分别以62-a和63-a为原料，参照对比4中步骤5制备方法进行制备。
化合物C6以4-氯苯甲酸为原料，参照对比4的制备方法进行制备。
化合物C12、C13以相应的苯基取代的哌嗪为原料，参照对比例4中步骤5的制备方法，不同的是将化合物89-d换成13-a。
Figure PCTCN2017072470-appb-000100
Figure PCTCN2017072470-appb-000101
对比例7：(R)-5-氯-4-((1-(4-氯苄基)吡咯烷-2-基)甲氧基)-N-(环丙基磺酰基)(C7)的制备
Figure PCTCN2017072470-appb-000102
步骤1:化合物22-a(75mg,0.463mmol)，化合物7-1(150mg,0.463mmol)，碳酸钾(192mg,1.388mmol)的乙腈混合溶液，80℃搅拌3h。反应液冷却至室温后，反应液倒入水中，用乙酸乙酯萃取，有机相干燥浓缩得黄色油状化合物7-2(165mg)，纯度84.4％，产率87％，MS m/z(ESI):412.2[M+H]+。
步骤2：向化合物7-2的甲醇溶液中加入氢氧化钠溶液(2M,0.8ml)，混合物室温搅拌3h。反应液减压浓缩，剩余物用水溶解后用1M盐酸溶液调节PH至1-2，过滤，滤饼用水洗涤，干燥得白色固体化合物7-3(121mg)，纯度95.33％，产率76％，MS m/z(ESI):398.1[M+H]+。
步骤3：以化合物7-3为原料，参照对比例2中步骤6的制备方法得白色固体化合物C7(19mg)，MS m/z(ESI):500.9[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.06(br.s.,1H),7.81(d,J＝7.2Hz,1H),7.57-7.51(m,4H),7.29(d,J＝12.0Hz,1H),4.72-4.68(m,1H),4.49-4.45(m,1H),4.40-4.35(m,2H),4.08(br.s.,1H),3.26-3.23(m,2H),3.08-3.03(m,1H),2.31-2.26(m,1H),2.04(br.s.,1H),1.94-1.79(m,2H),1.13-1.08(m,4H).
对比例8：(R)-5-氯-N-(环丙基磺酰基)-2-氟-4-((1-(4-(三氟甲基)苄基)吡咯烷-2-基)甲氧基)(C8)的制备
Figure PCTCN2017072470-appb-000103
以化合物8-1为原料，参照对比例7制备方法得白色固体化合物C8(48mg)，MS m/z(ESI):534.9[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.09(br.s.,1H),7.84-7.74(m,5H),7.30(d,J＝12.0Hz,1H),4.80-4.77(m,1H),4.50-4.38(m,3H),4.10-4.08(m,1H),3.26-3.24(m,2H),3.09-3.02(m,1H),2.32-2.29(m,1H),2.05-2.03(m,1H),1.92-1.80(m, 2H),1.13-1.08(m,4H).
对比例9：(R)-5-氯-4-((1-(4-氯苯甲酰基)吡咯烷-2-基)甲氧基)-N-(环丙基磺酰基)(C9)的制备
Figure PCTCN2017072470-appb-000104
步骤1：化合物9-1(100mg,0.639mmol)的二氯亚砜(2ml)溶液，80℃搅拌3h。反应液冷却至室温，减压浓缩除去溶剂。剩余物用二氯甲烷(10ml)溶解，加入化合物22-a(207mg,0.639mmol)，三乙胺(291mg,1.916mmol)，反应液室温搅拌4h。反应液用1M的盐酸和饱和食盐水洗涤，有机相干燥浓缩得黄色油状化合物9-2(228mg)，纯度92.16％，产率84％，MS m/z(ESI):426.1[M+H]+。
步骤2：以化合物9-2(228mg,0.535mmol)为原料，参照对比例7中步骤2制备方法得白色固体化合物9-3(178mg)，MS m/z(ESI):412.0[M+H]+。
步骤3：以化合物9-3(100mg,0.242mmol)为原料，参照对比例2中步骤6制备方法得到白色固体化合物C9(23mg),MS m/z(ESI):515.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.05(br.s.,1H),7.78(d,J＝7.2Hz,1H),7.52-7.46(m,4H),7.37(d,J＝12.4Hz,1H),4.48-4.46(m,1H),4.38-4.37(m,2H),3.42-3.35(m,2H),3.09-3.04(m,1H),2.17-2.09(m,1H),2.03-1.95(m,2H),1.80-1.74(m,1H),1.14-1.10(m,4H).
对比例10：(R)-5-氯-N-(环丙基磺酰基)-2-氟-4-((1-(4-(三氟甲基)苯甲酰基)吡咯烷-2-基)甲氧基)(C10)的制备
Figure PCTCN2017072470-appb-000105
以化合物10-1(110mg,0.247mmol)为原料，参照对比例9制备方法得白色固体化合物C10(13mg)，MS m/z(ESI):549.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.04(br.s.,1H),7.81-7.75(m,3H),7.65-7.62(m,2H),7.36(d,J＝12.8Hz,1H),4.48-4.46(m,1H),4.39-4.37(m,2H),3.48-3.44(m,2H),3.06-3.03(m,1H),2.14-2.11(m,1H),2.01-1.96(m,2H),1.80-1.75(m,1H),1.12-1.08(m,4H).
测试例1：钠离子(hNav1.7、hNav1.5和hNaV1.8)和钙离子(hCav3.2)通道的手动膜片钳实验
hNav1.7、hNav1.5手动膜片钳实验：
膜片电压钳电生理学可以直接测量并定量电压门控钠通道(各种Nav)的电流阻断并可以测定阻断的时间和电压依赖，其已被解释为对钠通道的静息、开放和失活状态的结合差异来反映化合物的抑制或激活效应(Hille,B.,Journal of General Physiology(1977),69:497-515)。
本发明代表性的化合物采用手动膜片钳实验进行，本研究的目的是应用手动膜片钳的方法在转染特定离子通道的稳定细胞株上测试化合物对该离子通道电流的作用。其使用的稳定细胞株CHO-hNav1.7和HEK-hNav1.5分别来自Genionics公司和WuXi Apptec(上海)公司。
手动膜片钳实验方案如下：
(一)溶液及化合物的配制：采用全细胞膜片钳技术记录hNav1.7和hNav1.5电流。实验中，细胞外液的组成成分(mM)：HEPES：5,NaCl：40,KCl：3,CaCl2：1,MgCl2：1,CdCl2：0.1,TEA-Cl：20。用NaOH调节pH值至7.3，同时用蔗糖调节渗透压至310-320mOsm，过滤后4℃保存。细胞内液的组成成分(mM)：HEPES：10,NaCl：10,CsOH：5,CsF：140,EGTA：1。用CsOH调节pH值至7.3，同时用蔗糖调节渗透压至280-290mOsm，过滤后-20℃保存。
阳性对照药和待测化合物先溶于100％DMSO(Sigma-Aldrich,D2650，配置成一定浓度(100nM，1000nM)的储备溶液。实验前用DMSO将上述储备溶液进行系列稀释，然后再用细胞外液进一步稀释得到所需浓度的测试溶液。细胞外液中DMSO最终浓度不超过0.30％。
(二)手动膜片钳实验：取细胞悬液加于35mm的培养皿中，置于倒置显微镜载物台上。待细胞贴壁后，用细胞外液灌流，流速为1–2mL/min。玻璃微电极由微电极拉制仪两步拉制，其入水电阻值为2-5MΩ。通过Digidata 1440(Molecular Devices)和pCLAMP软件(10.2版，Molecular Devices)A/D–D/A数模转换，进行刺激发放及信号采集；膜片钳放大器(Multiclamp 700B，Molecular Devices)放大信号，滤波为4KHz。
在hNav1.7和hNav1.5手动膜片钳实验中运用两种不同的电压刺激程序。
一种是失活刺激程序，钳制电位设置在相对应通道的V1/2，即大约50％的通道处于失活状态。接着给予电压至-120mV，持续50ms。然后去极化至-10mV，持续20ms引出钠电流，最后回到钳制电位。这种刺激程序也可以称之为通道状态依赖的电压刺激程序。
另一种是非失活刺激程序，保持钳制电位在-120mV,给予电压刺激至-10mV，持续20ms引出钠电流，最后回到钳制电位。也就是说在该种刺激程序条件下，所有的通道都没有经历过失活状态，而是直接从静息状态进行激活。
上述两种电压刺激程序的时间间隔均为10s。化合物的抑制效应通过加药前后的电流变化来进行计算，而IC50数值由Hill方程进行拟合所得。如果化合物在上述两种不同的电压刺激下显示出对通道效应有一定倍数的差异，那么该化合物对该通道是具有状态 依赖性的。结果见表1。
hNav1.8手动膜片钳实验
重组HEK293细胞系稳定表达人电压门控钠通道亚型1.8(hNaV1.8).cDNA严格遵循GenBank序列号:NM_014191.2。稳定表达钠通道的HEK293或CHO细胞系在含有10％胎牛血清及0.8mg/mL G418的F12/DMEM培养基中培养，培养温度为37℃，二氧化碳浓度为5％。细胞外液:140mM NaCl,4mM KCl,1mM MgCl2,2mM CaCl2,5mM D-Glucose monohydrate,10mM HEPES,pH＝7.4 with NaOH。电极内液:145CsCl,0.1CaCl2,2MgCl2,10NaCl,0.5Na2-GTP(鸟苷三磷酸二钠盐),2Mg-ATP(腺嘌呤核甘三磷酸镁盐),1.1EGTA(乙二醇双(2-氨基乙基醚)四乙酸),10HEPES(4-羟乙基哌嗪乙磺酸),pH7.2with CsOH。
用微电极拉制仪(P97，Sutter Instruments)将毛细玻璃管(BF150-86-10，Sutter Instruments)拉制成记录电极。在倒置显微镜(IX71，Olympus)下操纵微电极操纵仪(MP285，Sutter Instruments)将记录电极接触到细胞上，给予负压抽吸，形成GΩ封接。形成GΩ封接后进行快速电容补偿，然后继续给予负压，吸破细胞膜，形成全细胞记录模式。然后进行慢速电容的补偿并记录膜电容及串联电阻。不给予漏电补偿。记录钠电流，数据由EPC-10放大器(HEKA)进行采集并储存于PatchMaster(HEKA)软件中。
当全细胞记录的钠电流稳定后开始顺序给药，每个药物测试5-6个浓度，每个药物浓度作用至5分钟或达到稳态后检测下一个浓度，每个细胞以其自身为对照。每个浓度至少独立重复检测3个细胞。所有电生理实验均在室温下进行。
钠电流电压刺激方案如下：当形成全细胞封接后细胞膜电压钳制于-90mV，去极化电压阶跃从-90mV除极至-10mV维持40ms，每隔10秒重复采集数据，观察药物对钠电流的作用。
首先将每一个浓度作用下的电流与给药前电流进行标准化并计算每一个药物浓度对应的抑制率(1-(待测化合物电流峰值)/(对照组电流峰值))。对每一个浓度计算平均数和标准误，并用以下的方程计算每种化合物的半抑制浓度。抑制率＝1/(1+(IC50/C)h)
用以上方程对剂量依赖效应进行非线性拟合，其中C代表药物浓度，IC50为的半抑制浓度，h代表希尔系数。
hCav3.2通道的手动膜片钳实验：
用于手动膜片钳实验的稳定细胞株HEK-hCav3.2来自于WuXi Apptec(上海)公司。
溶液及化合物的配制：采用全细胞膜片钳技术记录hCav3.2电流。实验中细胞外液的组成成分(毫摩尔)：HEPES 10,CsCl 6,CaCl2 2,TEA-Cl 140。用CsOH调节pH值至7.4，同时用蔗糖调节渗透压至310-320mOsm，过滤后4℃保存。细胞内液的的组成成分(毫摩尔)：HEPES 10,CsCl 55,CsSO4 75,MgCl2 10,EGTA 0.1。用CsOH调节pH值至7.2，同时用蔗糖调节渗透压至280-290mOsm，过滤后-20℃保存。阳性对照药和待检测的化 合物先溶于100％DMSO(Sigma-Aldrich,D2650，配置成一定浓度的储备溶液。实验前用DMSO将上述储备溶液进行系列稀释，然后再用细胞外液进一步稀释得到所需浓度的测试溶液。细胞外液中DMSO最终浓度不超过0.30％。
手动膜片钳实验：取细胞悬液加于35mm的培养皿中，置于倒置显微镜载物台上。待细胞贴壁后，用细胞外液灌流，流速为1-2mL/min。玻璃微电极由微电极拉制仪两步拉制，其入水电阻值为2-5MΩ。通过Digidata 1440(Molecular Devices)和pCLAMP软件(10.2版，Molecular Devices)A/D–D/A数模转换，进行刺激发放及信号采集；膜片钳放大器(Multiclamp 700B，Molecular Devices)放大信号，滤波为4KHz。下面的电压刺激程序运用到hCav 3.2手动膜片钳实验中，即钳制电位设置在-110mV,给予-85mV脉冲电压持续500ms，然后再去极化至-40mV持续50ms引出hCav3.2钙通道电流，最后回到钳制电位。该刺激程序每15s重复一次，持续记录。化合物的抑制效应通过加药前后的电流变化来进行计算，而IC50数值由Hill方程进行拟合所得。
表1：本发明代表性化合物在两种浓度下对Nav1.7的抑制率
化合物 100nM(％) 1000nM(％)
Z-80 90.47 96.83
Z-89 94.85 99.69
Z-92 94.54 97.28
Z-117 89.31 96.13
Z-142 92.17 97.75
Z-150 93.33 96.70
Z-159 90.58 97.32
Z-164 89.66 101.53
Z-172 89.11 97.24
Z-173 93.85 100.05
Z-174 78.01 95.12
Z-177 89.18 98.05
Z-178 89.08 98.70
Z-180 70.42 97.77
Z-182 77.25 97.62
Z-183 90.80 99.47
Z-184 70.30 98.48
Z-185 85.31 94.93
Z-186 83.26 100.00
Z-187 89.70 100.26
Z-188 81.83 98.10
Z-189 83.85 99.16
Z-191 73.26 94.95
Z-192 77.66 98.36
Z-193 72.58 95.66
Z-195 76.72 92.69
Z-196 85.03 93.02
Z-197 83.63 100.39
C1 52.03 64.05
C2 49.22 64.84
C3 17.56 52.26
C4 18.58 58.91
C5 17.19 36.76
C6 11.15 57.25
C7 31.14 67.54
C8 46.99 66.80
C9 5.49 29.06
C10 7.83 24.67
C11 23.06 51.85
表2化合物Z-164对其他离子通道的选择性
化合物 Z-164 化合物 Z-164
Nav1.7(IC50/nM) 24.57 Nav1.8(IC50/nM) 18900
Nav1.5(IC50/nM) 6160 Cav3.2(IC50/nM) >30000
从表1可以看出，本发明代表性化合物对Nav1.7具有较高的抑制活性。此外研究发现，相较于对比化合物(如C1-C11)，五元(吡咯环)和六元(哌嗪环)含氮杂环上氮原子和苯环或吡啶环上碳原子直接相连时，对Nav1.7的抑制活性有明显的影响，研究表明当氮原子不与苯环或吡啶环直接相连时，即苯环或吡啶环通过亚甲基或羰基等基团与氮原子相连时，对Nav1.7的抑制活性有明显的降低(如C1与Z-197，C4与Z-164)。
此外，若将苯环或吡啶环通过亚甲基或羰基等基团与氮原子相连，并且R6为甲基时，对Nav1.7的抑制活性有明显的降低(如C2与Z-196，C11与Z-197)。
从表2可以看出，化合物Z-164还显示了对其他离子通道，特别是Nav1.5、Nav1.8钠离子通道和钙离子通道的选择抑制活性。
测试例2：对hERG钾离子通道的作用
2.1细胞培养
2.1.1本试验所用的细胞为转染有hERG cDNA与稳定表达hERG通道的CHO细胞系(由丹麦Sophion Bioscience公司提供)，细胞代数为P15。细胞培养在含有下列成分的培养基中(皆来源于Invitrogen)：Ham’s F12培养基，10％(v/v)灭活的胎牛血清，100μl/ml潮霉素B，100μl/ml Geneticin。
2.1.2 CHO hERG细胞生长于含上述培养液的培养皿中，并在37℃、含5％CO2的培养箱中进行培养。电生理实验之前24到48小时，CHO hERG细胞被转移放置于培养皿中的圆形玻璃片上，并在以上相同的培养液及培养条件下生长。每个圆形玻璃片上CHO hERG细胞的密度需要达到绝大多数细胞是独立、单个的要求。
2.2实验溶液
如表3所示，下列溶液(由Sophion提供)用于电生理记录。本试验所用试剂由Sigma提供。
表3细胞内液与外液的组成成分
试剂 外液(mM) 內液(mM)
CaCl2 2 5.37
MgCl2 1 1.75
KCl 4 120
NaCl 145 -
Glucose 10 -
HEPES 10 10
EGTA - 5
Na-ATP - 4
PH 7.4(用NaOH调节) 7.25(用KOH调节)
渗透压 渗透压～305mOsm 渗透压～295mOsm
2.3电生理记录系统
本实验采用手动膜片钳系统(HEKA EPC-10信号放大及数字转换系统，购自德国HEKA Electronic)作全细胞电流的记录。表面生长有CHO hERG细胞的圆形玻璃片被放置于倒置显微镜下的电生理记录槽中。记录槽内以细胞外液作持续灌流(大约每分钟1毫升)。实验过程采用常规全细胞膜片钳电流记录技术。如无特殊说明，实验都是在常规室温下进行(～25℃)。细胞钳制在-80mV的电压下。细胞钳制电压去极化到+20mV以激活hERG钾通道，5秒后再钳制到-50mV以消除失活并产生尾电流。尾电流峰值用作hERG电流大小的数值。上述步骤记录的hERG钾电流在记录槽内持续的细胞外液灌流下达到稳定后则可以叠加灌流待测试药物，直到药物对hERG电流抑制作用达到稳定状态。一般以最近的连续3个电流记录线重合作为判断是否稳定状态的标准。达到稳定态势以后以细胞外液灌流冲洗直到hERG电流回复到加药物之前的大小。一个细胞上可以测试一个或多个药物，或者同一种药物的多个浓度，但是在不同药物之间需要以细胞外液冲洗。Cisapride(西沙比利，购自Sigma)被用于实验中作为阳性对照以保证所使用的细胞质量正常。
2.4化合物处理和稀释
化合物先用DMSO溶解成10mM的浓度，然后再直接用细胞外液将化合物1000倍稀释成最终的10μM测试浓度。化合物测试液中DMSO的最终浓度为等于0.1％。阳性对照Cisapride(西沙比利)的测试浓度为0.1μM。所有贮备液和测试溶液都经过常规的5-10分钟的超声和振荡以保证化合物完全溶解。
2.5数据分析
试验数据由HEKA Patchmaster(V2x73.2)，Microsoft Excel以及Graphpad Prism 5.0提供的数据分析软件进行分析。实验结果如表4所示。
表4本发明代表性化合物对hERG钾离子通道的抑制
化合物 hERG抑制浓度IC50(μM)
Z-164 >10μM
Z-172 >10μM
Z-173 >10μM
Z-177 >10μM
Z-178 >10μM
Z-183 >10μM
Z-186 >10μM
Z-187 >10μM
Z-189 >10μM
从表4可以看出，本发明代表性化合物对hERG钾离子通道的抑制活性很小，因此对钾离子通道具有选择性抑制。
测试例3：冷刺激痛觉超敏法SNL
实验动物为雄性Sprague-Dawley大鼠，实验开始时体重140-150g。实验用动物均采购于斯莱克公司，购买后采用自由采食的方式进行食物和水供应，分笼饲养，4只/笼，采用动物尾部标记法进行动物标记。
检测化合物及分组：
溶剂组(Vehicle)：5％二甲基乙酰胺(国药科技)，5％solutol(Sigma)和90％生理盐水
阳性对照物：普瑞巴林；
待测药物：化合物Z-164；
阳性对照物和待测药物的溶剂成分为5％二甲基乙酰胺,5％solutol和90％生理盐水。
阳性对照物和测试物分别以剂量30mg/kg口服2小时后抑制大鼠脊神经结扎造成的冷痛觉超敏，如表5所示
表5化合物在脊神经结扎大鼠中药效测试分组
Figure PCTCN2017072470-appb-000106
30mg/kg化合物Z-164：称取148.11mg Z-164，加入1.23mL二甲基乙酰胺，待完全溶解后加入1.23mL solutol，震荡混匀后加入90％生理盐水定容至21.44mL，充分混匀后口服给药。
30mg/kg普瑞巴林：称取129.48mg普瑞巴林，加入1.08mL二甲基乙酰胺，待完全溶解后加入1.08mL solutol，震荡混匀后加入90％生理盐水定容至21.58mL，充分混匀后口服给药
实验方法：
1.1.脊神经结扎模型
·手术过程执行无菌操作。
·手术器械(剪刀，镊子，手术刀，手术棉，缝合线，撑开器)在手术前已消毒。
·使用戊巴比妥那(50mg/kg，腹腔注射)麻醉动物。挤压动物脚趾以确认动物手术前已经完全麻醉。在动物眼部涂抹眼用软膏以防止动物角膜干燥。
·剃去动物下半身手术区域毛发，使用碘伏和70％乙醇对手术区域皮肤消毒三遍。待皮肤干燥后开始手术。
·使用手术刀在动物腰部荐骨后部开一纵向切口，暴露左侧椎旁肌，使用撑开器分离肌肉组织以暴露脊椎骨。
·分离左侧脊神经L5和L6，使用6-0丝线结扎。
·缝合伤口。
·清洁手术器械，使用热珠灭菌器灭菌。
·手术后将动物放置在电热毯上，皮下注射5mL生理盐水以防止脱水。等动物完全苏醒后(可自由活动)将动物放回笼中。
1.2.冷痛觉超敏基线测试和分组
给药前两天，对大鼠进行冷痛觉超敏基线测试，使用移液器将100μl丙酮涂在动物术侧后足部皮肤。记录动物在一分钟内拍打，缩脚，抬脚，舔舐术侧足部的时间。丙酮测试共进行两次，两次间隔10分钟。两次时间之和记录为大鼠冷痛觉超敏反应时间。根据给药前一天的冷痛觉超敏反应测试结果将动物随机分组。
1.3.冷痛觉超敏测试
给药两小时后，使用移液器将100μl丙酮涂在动物术侧后脚趾部皮肤。记录动物在一分钟内拍打，缩脚，抬脚，舔舐受影响的脚部的时间。丙酮测试共进行两次，两次间隔10分钟。两次时间之和记录为大鼠冷痛觉超敏反应时间。
1.4.给药
冷刺激痛觉测试2小时前口服给药。
1.5.数据收集和分析
使用Excel软件收集数据。使用Prism软件分析数据。
结论：
表6大鼠冷痛觉超敏测试结果(化合物Z-164)
Figure PCTCN2017072470-appb-000107
实验结果如图1和图2所示，结果表明，口服2小时后，本发明化合物Z-164在脊神经结扎大鼠模型中具有抑制大鼠脊神经结扎诱导的冷痛觉超敏效果，在大鼠体内神经痛模型中是有统计学意义的抑制效果。
图2中，化合物Z-164在脊神经结扎大鼠中的药效，**p<0.01，***p<0.001与溶剂组比较，使用单因素方差分析附加Dunnett多重比较检验。口服化合物Z-164和阳性对照物30mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。
测试例4：代谢稳定性测试
1.缓冲液的配制
缓冲液A：配制1L含有1mM EDTA(Sigma，V900157-100G)，100mM的磷酸二氢钾溶液。
缓冲液B：配制1L含有1mM EDTA，100mM的磷酸氢二钾溶液。
缓冲液C：取700mL缓冲液B，用缓冲液A滴定，调至PH为7.4即可。
2.待测化合物和阳性对照药(酮色林(Sigma S006-10MG))的配制
2.1取10mM待测化合物和10mM酮色林各10uL，再各加190uL的纯乙腈，分别配成500uM待测化合物和酮色林溶液。
2.2取20uL(20mg/mL)人肝微粒体(Corning Lot.NO.4133007)储存液加入到513.4uL的缓冲液C，在湿冰上操作。配制得到0.75mg/mL肝微粒体溶液。
2.3各取1.5uL上述待测化合物和酮色林溶液，分别加入到498.5uL(0.75mg/mL)的肝微粒体溶液中，在湿冰上操作。配制得到1.5uM待测化合物混合液和酮色林混合液。
2.4按照时间点0、5、15、30、45、60min，每孔30uL，分别将待测化合物混合液和酮色林混合液分装到反应板上，在湿冰上操作。
2.5称取5mg还原型辅酶Ⅱ(Roche，10621706001)，溶于1mL缓冲液C中。配制成6mM还原型辅酶Ⅱ溶液。将还原型辅酶Ⅱ溶液分装到反应板中。
2.6将丙米嗪溶成10mM的溶液，取100mL空白乙腈，加入10uL丙米嗪溶液。配成内标。
2.7在0min，每孔加入135uL含有内标的冰乙腈(Merck(Lot.1778229518))，再加入15uL缓冲液C。
2.8将反应板放入37度水浴恒温箱内预热5min。在反应板中，每孔加15uL还原型辅酶Ⅱ溶液开始反应并计时。在5、15、30、45、60min时间点，每孔加入135uL含有内标的冰乙腈终止反应。
2.9将反应板用铝膜封好，放在震荡混合器上，500rpm，5min。再将反应板放在离心机中离心，15min，3750rpm。
2.10取样品和纯水按照1:1比例稀释，LC/MS检测。将得到的数值按照以下公式计算得到如表7所示的半衰期和清除率。
半衰期：0.693/K(孵化时间与浓度对数值作图出来的斜率)
清除率：(0.693/半衰期)*(1/蛋白质浓度(0.5mg\mL))*(比例因子)
其中K值和比例因子为本领域技术人员根据现有方法以及肝微粒体产品说明书记载的方法计算得到的。
表7人肝微粒体代谢稳定性实验结果
Figure PCTCN2017072470-appb-000108
Figure PCTCN2017072470-appb-000109
从表7可以看出，本发明化合物具有很好的代谢稳定性，研究发现取代基R6的变化对代谢稳定性有明显的影响，尤其地，当由环丙基变为甲基时，代谢稳定性明显降低(如C12与Z-173，C13与Z-164)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (19)

  1. 一种式(II)所示的化合物，或其药学上可接受的盐、溶剂化物、立体异构体或前药：
    Figure PCTCN2017072470-appb-100001
    式中，
    R1、R2、R3、R4各自独立地为氢、羟基、CN、NO2、卤素、-NRaRb、C1-20烷基、C3-20环烷基、C3-20环烷氧基、C2-20烯基、C2-20炔基、C1-20烷氧基、-CHO、-CO-(C1-20烷基)、-CO-(C6-20芳基)、C6-20芳基、-CONRaRb、-C(O)O-(C1-20烷基)、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)或-SO2-(C6-20芳基)；
    R5为氢、C1-20烷基、C3-20环烷基、卤代C1-20烷基；
    R6为C3-10环烷基或C3-8杂环基，所述C3-8杂环基含1-3个选自N、O、S的杂原子；
    Figure PCTCN2017072470-appb-100002
    选自：
    Figure PCTCN2017072470-appb-100003
    L1连接在环上的任意不同的位置，为一个键、或-C(O)N(Ry)-、-N(Ry)C(O)-、-N(Ry)SO2-、-SO2N(Ry)-、-OC(O)-、-C(O)O-、-(CRyRx)r1(O)r2(CRyRx)r3-、-S(O)-、-SO2-、-N(Ry)-、-O-、-S-、-C(O)-或亚环丙基；其中，Ry、Rx各自独立地为氢、卤素、羟基、CN、NO2、C1-20烷基、卤代C1-20烷基、C3-20环烷基、C2-20烯基、C2-20炔基或C6-20芳基；r1、r3各自独立地为0、1、2或3；r2为0或1；
    每个R0相同或不同，各自独立地为氢、氘、C1-20烷基、氘代C1-20烷基或卤代C1-20烷基；或任意两个R0通过单键或-(CH2)p1-连接，p1为1、2或3；
    A为C6-20芳基、3至7元单环、8至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、5至6元单环杂芳基环并3至7元单杂环；
    其中，所述烷基、环烷基、环烷氧基、烯基、炔基、烷氧基、芳基、3至7元单环、8至10元双环、3至7元单杂环、8至10元双杂环、5或6元单环杂芳基环、8至10元双环杂芳基环、苯并3至7元单环、苯并3至7元单杂环、5至6元单环杂芳基环并3至7元单环、或5至6元单环杂芳基环并3至7元单杂环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20 环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、C1-20烷硫基、卤代C1-20烷硫基、C1-20烷基氨基、卤代C1-20烷基氨基、硫醇、3元至20元的杂环烷基、3元至20元的杂环烷基氧基、C3-20环烷硫基、卤代C3-20环烷硫基、3元至20元的杂环烷基硫基、氧代基、C1-20羟烷基、羧基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C6-20芳基)；Ra、Rb各自独立地为氢、C1-20烷基、C3-20环烷基或C6-20芳基。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，所述R6为环丙基、环丁基、环戊基、环己基。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基、C3-20环烷氧基或C1-20烷氧基。
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R2和R4为氢，且R1、R3各自独立地为氢、卤素、C3-20环烷基、C1-20烷基、C3-20环烷氧基或C1-20烷氧基。
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R5为氢。
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，A为C6-20芳基或5或6元单环杂芳基环；所述的芳基或5或6元单环杂芳基环为取代的或未取代的；且所述的取代是指基团中的1-5个氢被选自下组的取代基所取代：卤素、C1-20烷基、卤代C1-20烷基、C1-20烷氧基、卤代C1-20烷氧基、C3-20环烷基、和C3-20环烷氧基。
  7. 如权利要求6所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，所述A中，所述C6-20芳基为苯基；所述5或6元单环杂芳基环为吡啶基。
  8. 如权利要求7所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，所述苯基为
    Figure PCTCN2017072470-appb-100004
    其中R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；和/或
    所述吡啶基为
    Figure PCTCN2017072470-appb-100005
    其中R21、R31、R41、R51、R12、R32、R42、R52、R13、R23、R43、R53各自独立地为氢、卤素、硝基、羟基、氰基、C6-20芳基、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、卤代C3-20环烷基、C3-20环烷氧基、卤代C3-20环烷氧基、C2-20烯基、卤代C2-20烯基、C2-20炔基、卤代C2-20炔基、-NRaRb、-C(O)NRaRb、-N(Ra)C(O)-(C1-20烷基)、-N(Ra)SO2-(C1-20烷基)、-SO2N(RaRb)、-C(O)O-(C1-20烷基)、-CHO、-OC(O)-(C1-20烷基)、-SO2-(C1-20烷基)、-SO2-(C6-20芳基)、-CO-(C1-20烷基)、-CO-(C6-20芳基)；Ra、Rb如上所定义。
  9. 如权利要求8所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R1’、R2’、R3’、R4’、R5’各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
  10. 如权利要求8所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，R21、R31、R41、R51、R12、R32、R42、R52、R13、R23、R43、R53各自独立地为氢、卤素、C1-20烷基、卤代C1-20烷基、卤代C1-20烷氧基、C1-20烷氧基、C3-20环烷基、C3-20环烷氧基。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1、r3各自独立地为0、1、2或3；r2为0或1。
  12. 如权利要求11所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，r2为0。
  13. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，每个R0各自独立地为氢。
  14. 如权利要求1所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，其特征在于，
    Figure PCTCN2017072470-appb-100006
    选自：
    Figure PCTCN2017072470-appb-100007
    L1为一个键、或-(CRyRx)r1(O)r2(CRyRx)r3-；其中，Ry、Rx各自独立地为氢；r1为0；r3为1；r2为0；每个R0相同或不同，各自独立地为氢。
  15. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2017072470-appb-100008
    Figure PCTCN2017072470-appb-100009
  16. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药，其特征在于，所述化合物选自下组：
    Figure PCTCN2017072470-appb-100010
  17. 一种药物组合物，所述组合物包括权利要求1至16中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体。
  18. 如权利要求1至16中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或如权利要求17所述药物组合物在制备治疗疾病或病症的药物中的应用，所述疾病或病症选自疼痛、抑郁症、心血管疾病、呼吸系统疾病、精神疾病或其组合。
  19. 一种治疗哺乳动物疾病或病症的方法，所述方法包括给需要的对象施用治疗有效量的权利要求1至16中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或如权利要求17所述药物组合物。
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