WO2016124139A1 - Heterocyclic-substituted n-sulfonylbenzamide derivatives, preparation method for derivatives, and pharmaceutical use of derivatives - Google Patents

Heterocyclic-substituted n-sulfonylbenzamide derivatives, preparation method for derivatives, and pharmaceutical use of derivatives Download PDF

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WO2016124139A1
WO2016124139A1 PCT/CN2016/073385 CN2016073385W WO2016124139A1 WO 2016124139 A1 WO2016124139 A1 WO 2016124139A1 CN 2016073385 W CN2016073385 W CN 2016073385W WO 2016124139 A1 WO2016124139 A1 WO 2016124139A1
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compound
alkyl
group
ring
halogenated
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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 CN201680008177.3A priority Critical patent/CN107406380B/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—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
    • C07D207/10—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 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—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
    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—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
    • C07D295/04—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
    • 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
    • C07D295/155—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 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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.
  • the highly selective inhibitor of Nav1.7 ion channel can be used for a wide range of pain treatments. Therefore, the development of a novel Nav1.7 ion channel highly selective inhibitor is very necessary.
  • 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, -NR a R b ; wherein R a and R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl Or a C 6-20 aryl group;
  • 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;
  • 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 is 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), - N(
  • 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, 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 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, C 3-20 cycloalkoxy.
  • the pyridyl group is 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, C 1-20 alkyl Halogenated C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy.
  • 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 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 I in the examples.
  • the compound of formula I of the present invention is each specific compound noted in the Examples section, especially any of Z-4 to Z-171.
  • 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 change in the number of hind limbs of the rats in the Two ways ANOVA test over time.
  • *, **, and *** indicate that the test compound group was compared with the blank group, P ⁇ 0.05. , 0.01, 0.001.
  • Figure 2 shows the area under the curve of the hind limbs of the corresponding groups in the unpaired t-test.
  • *, **, and *** indicate that the test compound is compared with the blank group, P ⁇ 0.05, 0.01. 0.001.
  • Figure 3 is a graph showing the time course of the hind limbs of the corresponding groups in the Two ways ANOVA test.
  • *, **, and *** indicate that the test compound is compared with the blank group, P ⁇ 0.05, 0.01. 0.001.
  • Figure 4 shows the area under the curve for the time taken by the hind limbs of the corresponding groups in the unpaired t-test; in Figure 4, *, **, and *** indicate that the test compound was compared with the blank group, P ⁇ 0.05, 0.01, 0.001.
  • Figure 5 shows the baseline of rat cold pain test in compound Z-97 in a rat model of spinal nerve ligation.
  • Figure 6 shows that Compound Z-97 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
  • Figure 7 shows the baseline of rat cold pain test in compound Z-40 in a rat model of spinal nerve ligation.
  • Figure 8 shows that Compound Z-40 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
  • Figure 9 shows the baseline of rat cold pain test in compound Z-73, 85 in a rat model of spinal nerve ligation.
  • Figure 10 shows that Compound Z-73, 85 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
  • Figure 11 shows the baseline of rat cold pain test in compound Z-22 in a rat model of spinal nerve ligation.
  • Figure 12 shows that compound Z-22 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
  • the heterocyclic-substituted N-sulfonylbenzamide derivative of the present invention has a high inhibitory activity against Nav1.7, and has an inhibitory activity against Nav1.5. It is weak and has obvious selective inhibitory activity against Nav1.7.
  • 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.
  • 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, cycloheptatriene
  • the alkenyl group, the cyclooctyl 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 ring refers to a saturated or partially unsaturated full carbon having 3 to 7 ring atoms. Single ring. It is preferably 5 to 6 yuan.
  • monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl groups. Ring, cycloheptatrienyl ring, cyclooctyl ring, and 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 compounds of the formula (I) of the present invention can be prepared by referring to the following synthetic route, and the steps in the process can be expanded or combined as needed during the specific operation.
  • 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 have high selective inhibitory activity against Nav1.7 and are useful as drugs for the treatment of a wide range of pains.
  • DMF is dimethylformamide
  • DMSO is dimethyl sulfoxide
  • THF is tetrahydrofuran
  • DIEA is N,N-diisopropylethylamine
  • EA is ethyl acetate
  • PE is petroleum ether
  • BINAP is (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl.
  • room temperature means about 25 °C.
  • Step a Compound 1-a-1 (14.8 g, 0.10 mol) was added to trifluoromethanesulfonic acid (150 ml), the mixture was cooled to 0 ° C, and N-iodosuccinimide (24.75 g) was added portionwise. , 0.110 mol). The mixture was stirred at room temperature for 2 h. The reaction solution was slowly poured into ice water and stirred for about 15 minutes. Extract with petroleum ether (3 x 100 ml). The organic phase was washed with aqueous sodium thiosulfite (100 mL). The filtrate was evaporated to dryness.
  • Step b Compound 1-a-2 (14 g, 0.051 mol) was dissolved in 1,4-dioxane (140 ml) under N 2 and added triethylamine (15.6 g, 0.153 mol). Water (10 ml), 1,1 '-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane complex (2.08 g, 2.55 mmol). The mixture was stirred at 80 ° C for 18 h under a pressure of 10 kg of carbon monoxide. The reaction mixture was slowly warmed to room temperature, then aqueous 1N EtOAc (250 mL). The aqueous phase was adjusted to pH 2 with 1N aqueous HCl.
  • Step c Compound 1-a-3 (7.8 g, 0.041 mol) was dissolved in anhydrous dichloromethane (100 mL) under N 2 and then added 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (11.65 g, 0.061 mol), DMAP (11.07 g, 0.090 mol). The mixture was stirred at room temperature for 10 minutes and methanesulfonamide 2 (4.82 g, 0.061 mol). The mixture was stirred at room temperature for 18 h. 150 ml of water was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 h to separate an aqueous phase.
  • Step a Compound 11-a-1 (5 g, 31.6 mmol) was dissolved in 20 ml of sulfuric acid, cooled to 0 ° C, and added 1,3-dibromo-5,5-dimethylhydan (4.4 g, 15.5 mmol) Stir at 0 ° C for 2 h. After completion of the reaction, the mixture was poured into EtOAc EtOAc (EtOAc m.).
  • Step b To a solution of 11-a-2 (3 g, 12.7 mmol), methylsulfonamide (2.4 g, 25.4 mmol) in 300 ml of dichloromethane, HATU (2-(7-azobenzotriazole) -N,N,N',N'-tetramethyluron hexafluorophosphate) (7.2 g, 19.1 mmol), DIPEA (N,N-diisopropylethylamine) (3.3 g, 25.4 mmol), DMAP (4-Dimethylaminopyridine) (159 mg, 1.3 mmol), stirred at rt overnight.
  • HATU 2-(7-azobenzotriazole) -N,N,N',N'-tetramethyluron hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • DMAP 4-Dimethylaminopyridine
  • Step a Compound 13-a-1 (50 g, 0.40 mol) was added to concentrated hydrochloric acid (400 ml), and the mixture was cooled to 0 ° C, and a solution of sodium nitrite (28.6 g, 0.44 mol) in water (100 ml) was added dropwise. After the mixture was reacted at 0 ° C for 0.5 h, cuprous chloride (91.68 g, 0.48 mol) was added. After the mixture was stirred at room temperature for 0.5 h, it was heated to 100 ° C and stirred for 1 h.
  • Step c Compound 13-a-3 (9.1 g, 48 mmol) was dissolved in anhydrous DCM (150 mL), cooled to 0 <0> Imine hydrochloride (13.76 g, 72 mmol), DMAP (11.8 g, 96 mmol), methanesulfonamide (9.12 g, 96 mmol). After the mixture was stirred at room temperature for 18 h, EtOAc EtOAc m. Dry over anhydrous sodium sulfate and filter.
  • 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 [M-1] -.
  • 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 [M-1] -.
  • 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 a Using the compound 23-a-1 (1 g) as a starting material, the compound of the procedure of the step 2 in Example 29 gave Compound 23-a-2 (683 mg), purity 83.85%, yield 83%, MS m/z (ESI): 168.1 [M+H] + .
  • Step b To a solution of compound 23-a-2 (385 mg, 2.296 mmol) in acetonitrile (5 ml), p. (284 mg, 2.756 mmol), tetrabutylammonium bromide (1479 mg, 4.593 mmol), cuprous bromide (33 mg, 0.23 mmol). After completion of the reaction, the mixture was washed with EtOAc (EtOAc m.
  • the compound 24-a was prepared starting from the compound 4-bromoaniline and referring to the compound 23-a.
  • Compound 32-a was prepared by the method of Compound 15-a except that 15-a-1 in the step was replaced with 5-bromo-3-chloro-2-fluoropyridine, 2-methylpropan-1-ol. Change to propan-2-ol and adjust the reaction conditions to 100 ° C overnight.
  • Compound 33-a was prepared by the method of Compound 15-a except that 15-a-1 in the step was replaced with 4-bromo-2-chlorophenol and 2-methylpropan-1-ol was changed to 2- Iodine propane, the reaction conditions were changed to 80 ° C and stirred for 3 hours.
  • Compound 34-a was prepared by the method of Compound 15-a except that 15-a-1 in the step was replaced with 4-bromo-2-chlorophenol and 2-methylpropan-1-ol was changed to 2- Sodium chloride-2,2-difluoroacetate, and the reaction conditions were changed to 100 ° C for 2 hours.
  • 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
  • BINAP (( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl) (56 mg, 0.089 mmol)
  • potassium tert-butylate (644 mg, 6.7 mmol), 7 ml of 1,4-dioxane, stirred at 90 ° C for 2 h.
  • Step 2 The compound HCl (1.5 ml, 5.53 mmol) was added to a solution of the 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 To a 50 ml single-necked round bottom flask was added compound 5-a (517 mg, 2.98 mmol), hydrochloric acid (4M, 5 ml, 20 mmol) After completion of the reaction, the reaction mixture was concentrated under reduced vacuo. MS m/z (ESI): 74 [M+H] + .
  • Step 2 To a 50 ml sealed tube was added 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (215 mg, 0.781 mmol), compound 4-b (127 mg, 1.159 mmol), Pd 2 (dba) 3 (tris(dibenzylideneacetone)dipalladium) (36 mg, 0.039 mmol), BINAP(( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl) (51 mg) , 0.082 mmol), potassium tert-butoxide (263 mg, 2.344 mmol), 7 ml of 1,4-dioxane, stirred at 90 ° C for 2 h.
  • Step 3 Compound 4-c (135 mg, 0.504 mmol), 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (107 mg, 0.397 mmol), cesium carbonate (260 mg, 0.798 mmol)
  • a mixture of 6 ml of dimethyl sulfoxide was stirred at 220 ° C for 30 minutes under microwave conditions. After completion of the reaction, the mixture was cooled to room temperature, 30 ml of water was added, the pH was adjusted to 6 to 7 and ethyl acetate was extracted. The organic phase was separated and concentrated under reduced pressure to give a crude oil (300 mg). 4 (30 mg), purity 98.77%, yield 69.0%.
  • Step 1 Compound 1-a-3 (1 g, 5.19 mmol h, cooled to room temperature, added N,N-dimethylsulfonamide (1.29 g, 10.39 mmol), DBU (1,8-diazabicycloundec-7-ene) (2.37 g, 15.57 mmol) Stir at 75 ° C for 5 h. At the end of the reaction, the reaction mixture was concentrated under reduced pressure to remove THF. EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. After filtration, the compound 6-b (1.38 g) was obtained as a white solid, which was directly used for the next reaction, purity 91.2%, yield 84.7%. MS m/z (ESI): 299.0 [M+H] + .
  • Step 2 Compound 6-b (306 mg, 1.02 mmol), tert-butyl 3-hydroxyazetidine-l-carboxylic acid tert-butyl ester (215 mg, 1.24 mmol), cesium carbonate (993 mg, 3.05 mmol), 10 ml
  • a mixture of 1,4-dioxane was stirred at 180 ° C for 40 minutes under microwave conditions. After the reaction was completed, it was cooled to room temperature, 30 ml of water was added, the pH was adjusted to 5-6, ethyl acetate was extracted (30 ml x 2), and the organic phase was separated and concentrated under reduced pressure. 6-c (170 mg) was used directly for the next reaction, purity 69.8%, yield 37%.
  • Step 3 To a 50 ml single-necked round bottom flask was added compound 6-c (170 mg, 0.376 mmol), hydrochloric acid (4M, 2 ml, 8 mmol) After completion of the reaction, the reaction mixture was concentrated under reduced pressure toield of Compound 6-d ( 145 mg), which was used for the next reaction, purity 69.9%, yield 99.3%. MS m/z (ESI): 3521. [M+H] + .
  • Step 4 To a 50 ml single-neck round bottom flask was added compound 6-d (145 mg, 0.373 mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (115 mg, 0.397 mmol) Potassium carbonate (150 mg, 1.085 mmol), 5 ml of dimethylacetamide, stirred at room temperature for 4 h. At the end of the reaction, 30 ml of water was added, the pH was adjusted to 5-6, ethyl acetate was extracted (30 ml x 2), and the combined organic phase was separated and concentrated under reduced pressure to give 270 mg of oil. (20.2 mg), purity 97.8%, yield 9.7%.
  • Compound Z-21 was prepared by the method of Example 4 using Compound 4-c as a starting material, except that Compound 1-a in Step 3 was changed to Compound 9-a.
  • Compound Z-165 was prepared in a similar manner to Z-7.
  • Step 1 The compound 7-b (500 mg) was used as a starting material.
  • the compound was obtained by the procedure of Step 2 of Example 4 to give Compound 22-b (220 mg), purity 53%, yield 41%, MS m/z (ESI): 296[M+H] + .
  • Step 2 Compound 22-b (200 mg) was used as a starting material to give the compound Z-22 (60 mg), purity 79%, yield: 16.3%, MS m/z (ESI): 545[M+H] + .
  • Compound Z-23 was prepared by the method of Example 22 using compound 7-a as a starting material, except that 4-bromo-2-chloro-1-(trifluoromethoxy)benzene was replaced in step 1. 4-bromo-1,2-dichlorobenzene.
  • Step 1 To a solution of Compound 8-a (333 mg, 3.294 mmol) in 5 mL THF, 6.6 ml of borane/THF solution (1M) was added dropwise at 0 ° C, and the mixture was stirred and stirred at 60 ° C for 5 h. After completion of the reaction, the mixture was cooled to EtOAc. The next step was carried out without purification.
  • Step 2 Using Compound 24-b (340 mg) as a starting material, the title compound of Step 2 of Example 4 was obtained to afford compound 24-c (130 mg) as a yellow solid.
  • Step 3 Using the compound 24-c (130 mg) as a starting material, the title compound of Step 3 of Example 4 was obtained to give the white solid compound Z-24 (11 mg), purity 100%, yield 7%, MS m/z (ESI) ): 531.0 [M+H] + .
  • Step 1 The compound 4-c (240 mg) was used as a starting material.
  • the compound 1-a was replaced with the compound 11-a by the method of the procedure of the step 3 in Example 4 to obtain a yellow solid compound 26-b (160 mg). Yield 27.8%, MS m/z (ESI): 564 [M+H]+.
  • Step 2 To a solution of compound 26-b (140 mg, 0.25 mmol), cyclopropylboronic acid (43 mg, 0.5 mmol) in 10 ml of dioxane, [1,1'-bis(diphenylphosphino) dioxin Iron] palladium dichloride (22 mg, 0.03 mmol), cesium carbonate (163 mg, 0.5 mmol), argon gas, and stirred at 100 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated, evaporated. MS m/z (ESI): 564 [M+H] + .
  • Step 1 Using the compound 14-a (644 mg) as a starting material.
  • Step 2 Compound 33-b (425 mg) was used as a starting material.
  • the title compound was obtained from the title compound of Example 4 to afford the compound 33-c (520 mg) as a yellow oil, purity 83.4%, yield 80.7%, MS m/z (ESI) ): 282 [M+H] + .
  • Step 3 To a one-neck round bottom flask was added compound 33-c (288 mg, 1.0225 mmol), potassium tert-butoxide (344 mg, 3.065 mmol), THF 10 ml, and stirred for 2 min in ice-bath, and compound 1-a (358 mg, 1.327 mmol) ), stirring for 30 minutes. After completion of the reaction, water (10 ml x 3) and ethyl acetate (10 ml x 3) were added, and the combined organic phase was separated and concentrated under reduced pressure to give a crude compound, which was purified by liquid phase to give solid compound Z-33 (4.6 mg). %, yield 0.7%. MS m/z (ESI): 531 [M+H] + .
  • Step 1 1 -Bromo-4-(trifluoromethoxy)benzene (1 g, 4.15 mmol), compound 7-a (0.63 g, 6.22 mmol), (S)-valine (96 mg, 0.83 mmol), A mixed solution of cuprous iodide (79 mg, 0.415 mmol), potassium carbonate (1.72 g, 12.45 mmol) in dimethyl sulfoxide (10 ml) was stirred at 90 ° C for 4 h under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, poured with water and ethyl acetate. EtOAc was evaporated.
  • Step 2 Compound 50-b (119 mg) was used as a starting material. [MH] - .
  • Compound Z-51 was prepared from compound 7-a using the procedure of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 2,4-Dichlorobenzene, the reaction conditions were changed to 140 ° C and stirred for 30 minutes.
  • Compound Z-52 was prepared starting from compound 7-a by the method of Example 50 except that the 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 4-bromo- 2-Chloro-1-fluorobenzene, the reaction conditions were changed to 90 ° C and stirred overnight.
  • Compound Z-58 was prepared from compound 7-a using the same procedure as in Example 50 except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 2-bromo- 5-chloropyridine, and the reaction conditions were changed to 110 ° C and stirred for 5 hours.
  • Compound Z-67 was prepared by the method of Example 50 using compound 7-a as a starting material, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 4-(Trifluoromethyl)benzene, and the reaction conditions were changed to 100 ° C and stirred for 20 hours.
  • Compound Z-69 was prepared from compound 7-a using the same procedure as in Example 50 except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 4-bromo- 2-fluoro-1-(trifluoromethyl)benzene, and the reaction conditions were changed to 110 ° C and stirred overnight.
  • Compound Z-71 was prepared by the method of Example 50 using compound 7-a as a starting material, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 5-bromo- 2-(Trifluoromethyl)pyridine, the reaction conditions were changed to 100 ° C and stirred overnight, and the reaction conditions of Step 2 were changed to 180 ° C and stirred for 30 minutes.
  • Compound Z-72 was prepared from compound 7-a using the procedure of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 4-(Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C and stirred for 20 hours. In the step 2, the compound 1-a was replaced with the compound 9-a, and the reaction conditions were changed to 200 ° C and stirred for 30 minutes.
  • Compound Z-76 was prepared by the method of Example 50 using compound 7-a as a starting material, except that the 1-bromo-4-(trifluoromethoxy)benzene in the step 1 was replaced with the compound 23-a. .
  • Compound Z-97 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced with compound 30-a, and 1-bromo-4-(trifluoromethoxy)benzene was changed to 4-bromo- 1,2-dichlorobenzene, the reaction conditions in step 2 were changed to 200 ° C and stirred for 60 minutes.
  • Compound Z-104 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced by compound 31-a, and 1-bromo-4-(trifluoromethoxy)benzene was replaced by 1-bromo- 4-(Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C and stirred for 20 h, and the reaction conditions in the step 2 were changed to 200 ° C and stirred for 60 minutes.
  • Compound Z-110 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced by compound 31-a, and 1-bromo-4-(trifluoromethoxy)benzene was changed to 4-bromo- 1,2-dichlorobenzene, the reaction conditions were changed to 100 ° C for 16 h, the compound 1-a in step 2 was changed to the compound 9-a, and the reaction conditions were changed to 200 ° C and stirred for 30 minutes.
  • Compound Z-113 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced by compound 31-a, and 1-bromo-4-(trifluoromethoxy)benzene was replaced by compound 34-a.
  • the reaction conditions were changed to 100 ° C and stirred overnight, and the reaction conditions in the step 2 were changed to 200 ° C and stirred for 60 minutes.
  • Step 1 Compound 22-b (504 mg, 1.704 mmol), p-toluenesulfonyl chloride (415 mg, 2.045 mmol), triethylamine (350 mg, 3.239 mmol), 4-dimethylaminopyridine (25 mg, 0.17 mmol)
  • the mixed solution of methyl chloride was stirred at room temperature for 6 hours. After the reaction was completed, a 1M aqueous solution of hydrochloric acid and sodium hydrogen carbonate solution was added, and the organic phase was separated and evaporated to give crude compound 53-b (754 mg).
  • Step 2 To a solution of compound 53-b (424 mg, 0.942 mmol) in EtOAc (EtOAc) The reaction was completed, cooled to room temperature, extracted with water and ethyl acetate. EtOAc was evaporated. The rate is 49%. MS m/z (ESI): 354.1 [M+H] + .
  • Step 3 Compound 53-c (150 mg) was used as a starting material to give the white solid compound Z-53 (144 mg), purity 96.65%, yield 38%, MS m/z ESI): 561 [M+H] + .
  • Step 1 The compound 22-b (200 mg) was used as a starting material, and the preparation method of the step 3 in Example 4 was used, except that the compound 1-a was replaced with the compound 11-a to give a white solid compound 54-b (110 mg). , purity 72%, yield 18.39%, MS m/z (ESI): 589 [M+H] + .
  • Step 2 Compound 54-b (100 mg, 0.17 mmol), cyclopropylboronic acid (29.13mg, 0.34mmol), potassium carbonate (46.87mg, 0.34mmol), palladium acetate (7.613mg, 0.034mmol), toluene (20ml) To the water (2 ml), tricyclohexylphosphine (47.55 mg, 0.17 mmol) was added, and the mixture was stirred at 100 ° C under nitrogen overnight. After completion of the reaction, the mixture was cooled to room temperature, washed with water and brine, and then evaporated. MS m/z (ESI): 552 [M+H] + .
  • Step 1 Compound 16-a (3 g, 13.7 mmol), methanesulfonamide (1.95 g, 20.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-four
  • HATU methyl urea hexafluorophosphate
  • triethylamine (2.77 mg, 27.4 mmol) in dichloromethane (30 ml) was stirred at room temperature for 16 hours.
  • the reaction was completed, washed with 2N hydrochloric acid solution, washed with water, washed with brine, dried and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated.
  • White solid compound 55-b (1.5 g). MS m/z (ESI): 295.9 [M+H] + .
  • Step 2 Compound 55-b (1 g, 3.38 mmol), zinc cyanide (237 mg, 2.03 mmol), tris(dibenzylideneacetone) dipalladium (31 mg, 0.034 mmol), 1,1'-bis(diphenyl)
  • Step 3 The compound 22-b (100 mg) was used as the starting material, and the preparation method of the step 3 in Example 4 was used, except that the compound 1-a was replaced with the compound 55-c to obtain the yellow solid compound Z-55 (44 mg).
  • Step 1 To a solution of compound 22-b (600 mg, 2.29 mmol) in dichloromethane (20 mL) After completion of the reaction, a sodium hydrogencarbonate solution, a sodium thiosulfate solution, methylene chloride solution, and a sodium hydrogencarbonate solution were evaporated, and the organic phase was separated and concentrated to give a crude yellow oily compound 57-b (575 mg). MS m/z (ESI): 294 [M+H] + .
  • Step 2 Methylmagnesium bromide (1 ml, 2.937 mmol) was added dropwise to a solution of compound 57-b (0.575 g, 1.58 mmol) in THF (5 ml). After the reaction was completed, the ammonium chloride solution was added, and ethyl acetate was evaporated. MS m/z (ESI): 310.1 [M+H] + .
  • Step 3 Add azo to a solution of compound 57-c (339 mg, 1.094 mmol), compound 17-a (224 mg, 1.094 mmol), triphenylphosphine (576 mg, 2.189 mmol) in toluene (5 ml) Diisopropyl diformate (443 mg, 2.189 mmol) was stirred under argon at 60 ° C overnight. After the reaction was completed, it was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with brine, dried and evaporated. Purification by Combi-flash column chromatography gave compound 57-d (276 mg). MS m/z (ESI): 496.1 [M+H] + .
  • Step 1 Using compound 7-a (2.92 g) as a starting material, the preparation was carried out according to the method of Example 50 except that the 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 4 -Bromo-2-chloro-1-(trifluoromethyl)benzene, and the reaction conditions were changed to 100 ° C and stirred for 16 hours.
  • the compound 60-b (2.076 g) was obtained as a yellow oil, which was used directly for the next reaction, purity 91.7%, yield 31%.
  • Step 2 To a solution of the compound 60-b (55 mg, 0.197 mmol) in THF (10 ml), EtOAc (EtOAc, EtOAc. Methyl), naturally warmed to room temperature and stirred for 2 hours. After completion of the reaction, ethyl acetate was extracted, and the aqueous solution was washed to pH 5-6. The organic phase was separated and purified by prep-HPLC to yield white solid compound Z-60 (22 mg). MS m/z (ESI): 511.1 [MH] - .
  • Step 1 Compound 18-a (1 g, 10.407 mmol), 1-bromo-4-chlorobenzene (1.992 g, 10.407 mmol), 4,7-dimethoxy-1,10-phenanthroline (500 mg, 2.081) Methyl), N1, N2-dimethylethane-1,2-diamine (183 mg, 2.081 mmol), cuprous iodide (396 mg, 2.081 mmol), potassium carbonate (4.315 g, 31.221 mmol) A mixed solution of sulfone (20 ml) was stirred at 100 ° C under argon atmosphere overnight.
  • Step 2 To a solution of compound 61-b (257 mg, EtOAc. After completion of the reaction, the ammonium chloride solution was added, and the mixture was extracted with methylene chloride. MS m/z (ESI): 209.1 [M+H] + .
  • Step 3 To a solution of compound 61-c (267 mg, 1.28 mmol) and EtOAc (EtOAc) After completion of the reaction, the mixture was washed with brine and evaporated. MS m/z (ESI): 251.1 [M+H] + .
  • Step 4 Compound 61-d (300 mg) was used as a starting material. MH] - .
  • Step 1 The compound 19-a (1.5 g) was used as a starting material, and the reaction mixture was subjected to the preparative method of the step 1 in Example 61, and the reaction mixture was stirred at 140 ° C for 30 minutes to obtain a compound 62-b (350 mg) as a yellow oil.
  • Step 2 Compound 62-b (130 mg) was obtained from m. + .
  • Step 3 Compound 62-c (264 mg), m. + .
  • Step 4 Compound 62-d (109 mg) was used as a starting material, m.p. H] + .
  • Step 1 Using compound 7-a (728 mg) as a starting material, followed by the procedure of Example 1 Step 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced by 4-bromo- 2-Chloro-l-fluorobenzene, and the reaction mixture was stirred at 90 ° C overnight to afford compound 63-b (120 mg), MS m/z (ESI): 230 [M+H] + .
  • Step 2 The compound 63-b (110 mg) was used as a starting material, and the preparation was carried out in the same manner as in the step 3 of Example 4 except that the compound 1-a was replaced with the compound 11-a, and the reaction conditions were changed to 180 ° C. After stirring for 1 hour, a white solid compound 63-c (120 mg), MS m/z (ESI): 503 [M+H] + .
  • Compound Z-65 was prepared according to the method of Example 63, starting from compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene was replaced with 1-bromo-4- in step 1. chlorobenzene.
  • Compound Z-73 was prepared according to the method of Example 63, starting from compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene was replaced with 1-bromo-4- in step 1. (Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C stirring After 16 hours, the reaction conditions of step 2 were changed to 200 ° C for 30 minutes, and the reaction conditions of step 3 were changed to 80 ° C for 16 hours.
  • Compound Z-115 was prepared by the method of Example 63 except that the compound 7-a in Step 1 was replaced by the compound 31-a, and 4-bromo-2-chloro-1-fluorobenzene was changed to 4-bromo-1. , 2-dichlorobenzene, the reaction conditions were changed to 100 ° C for 16 hours, the reaction conditions of step 2 were changed to 200 ° C for 30 minutes, and the reaction conditions of step 3 were changed to 80 ° C for 16 hours.
  • Step 1 2-Chloro-6-fluoropyridine (2.20 g, 16.72 mmol), compound 7-a (1.27 g, 12.54 mmol), potassium carbonate (2.31 g, 16.72 mmol) in dimethylformamide (22 ml) The solution was stirred at 80 ° C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with water, brine, and evaporated. Purification by Combi-flash column chromatography gave yellow solid compound 64-b (2 g). MS m/z (ESI): 213 [M+H] + .
  • Step 2 Starting from the compound 64-b (500 mg), which was obtained by the procedure of Step 3 of Example 4, except that the reaction conditions were changed to 200 ° C for 1 hour to obtain a white solid compound Z-64 (80 mg). MS m/z (ESI): 462 [M+H] + .
  • Compound Z-70 was prepared according to the method of Example 64 using compound 7-a as a starting material, except that 2-chloro-6-fluoropyridine in step 1 was replaced by 2-bromo-5-(trifluoromethyl). The pyridine was subjected to the reaction conditions in the step 2 and stirred at 180 ° C for 30 minutes.
  • Step 1 To a solution of compound 20-a (1.5 g, 7.128 mmol), EtOAc (EtOAc:EtOAc (EtOAc) A solution of tetrahydrofuran (20 ml) was stirred at room temperature for 1 h. After the reaction was completed, water was added, the organic phase was separated, and the organic phase was separated, and the organic layer was evaporated. One-step reaction, purity 99.01%, yield 89%. MS m/z (ESI): 250 [M+H] + .
  • Step 2 The compound 7-a (407 mg) was used as a starting material, which was prepared by the method of Step 1 of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced in the step.
  • compound 66-b, 95 deg.] C into the reaction conditions stirred overnight to give a white solid compound 66-c (194mg), MS m / z (ESI): 269.1 [m + H] +.
  • Step 3 Starting from the compound 66-c (164 mg), which was obtained by the method of the step 3 of Example 4, except that the reaction conditions in the step were changed to 200 ° C and stirred for 30 minutes to obtain a white solid compound Z-66. (33.06mg), MS m / z (ESI): 518.1 [m + H] +.
  • Step 1 Preparation of Compound 21-a (1 g), m.
  • Step 2 The compound 74-b (100 mg) was used as a starting material, which was obtained by the procedure of Step 3 of Example 61, except that the acetyl chloride in the step was changed to methanesulfonyl chloride to give the compound 74-c as a yellow oil. 146 mg).
  • Step 3 Compound 74-c (124 mg, 0.563 mmol), Compound 22-a (162 mg, 0.563 mmol), EtOAc ( EtOAc, EtOAc After the reaction was completed, it was cooled to room temperature, washed with water, and then dried and evaporated. Purification by Combi-flash column chromatography gave compound 44-d (147 mg). MS m/z (ESI): 412 [M+H] + .
  • Step 4 Compound 74-d (147 mg) H] + .
  • Step 5 Compound 74-e (97 mg) was used as a starting material, m.p. H] + .
  • Step 1 Using the compound (R)-tert-butyl-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.19 g) as a starting material, referring to the preparation method of the step 3 in Example 4, the reaction conditions were carried out. The mixture was stirred for 20 minutes at 180 ° C to give compound 77-b (375 mg), MS m/z (ESI): 351 [M+H-100] + .
  • Step 2 The compound 77-b (375 mg) was used as a starting material, and the reaction was carried out in the same manner as in the step 3 of Example 6, and the reaction was changed to 40 ° C under microwave overnight to obtain Compound 77-c (120 mg), MS m/z ( ESI): 351 [M+H-36] + .
  • Step 3 To a 50 ml single-neck round bottom flask was added 4-chlorobenzoic acid (16 mg, 0.102 mmol), compound 77-c (40 mg, 0.102 mmol), 2-(7-azobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.306 mmol), N,N-diisopropylethylamine (40 mg, 0.306 mmol), m. The reaction was completed, ethyl acetate and water were extracted, and the organic phase was separated, and concentrated under reduced pressure, and purified by preparative liquid phase to give compound Z-77 (5.26 mg), purity 92%, yield 10%.
  • Step 1 Using compound 7-a (6.08 g) as a starting material, followed by the procedure of Step 1 of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced in the step. 1-Bromo-4-(trifluoromethyl)benzene, mp. + .
  • Step 2 The compound 82-b (490 mg) was used as a starting material, and the preparation of the compound in the step of step 57 was carried out, except that the compound 17-a was replaced with the compound 25-a, and the reaction conditions were changed to room temperature stirring. 2 hours to obtain a colorless oil compound 82-c (650mg), MS m / z (ESI): 478.1 [m + H] +.
  • Step 3 The compound 82-c (650 mg) was used as a starting material, and the mixture was subjected to the procedure of Step 4 of Example 57, except that the reaction conditions were changed to 60 ° C and stirred for 2 hours to obtain a white solid compound 82-d (509 mg).
  • Step 4 Compound 82-d (500 mg) was used as a starting material to give a white solid compound 82-e (150 mg), MS m/z (ESI): 539 [M+H ] + .
  • Step 5 Compound 82-e (50 mg, 0.093 mmol), methylboronic acid (7 mg, 0.111 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (7 mg, 0.009) Methyl acetate (30 mg, 0.278 mmol) in dioxane (15 ml) mixture was stirred at 100 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated. MS m/z (ESI): 475.2 [M+H] + .
  • Step 1 To 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (1.63 g, 8.76 mmol), compound 27-a (2 g, 7.3 mmol), cesium carbonate (4.76 g, 14.6 mmol) (Tris(dibenzylideneacetone)dipalladium) (334 mg, 0.37 mmol), ( ⁇ )-2,2'-bis-(diphenylphosphino)-1, was added to a solution of dioxane (25 ml). 1'-binaphthyl (227 mg, 0.37 mmol), argon-protected, stirred at 100 ° C for 5 h.
  • Step 2 Compound 86-b (1.3 g) was used as the starting material.
  • the title compound of Example 4 was obtained by the procedure of Step 1 to give compound 86-c (1 g), MS m/z (ESI): 281 [M+H-36] + .
  • Step 3 Using the compound 86-c (100 mg) as a starting material, refer to the preparation method of the step 3 in Example 4 except that the compound 1-a is replaced with the compound 13-a-5, and the reaction conditions are changed to 70 ° C and stirred for 4 hours.
  • the white solid compound Z-86 (40.41 mg) was obtained, mp.: 99.15%, yield: 22.99%, MS m/z (ESI): 544 [M+H] + .
  • the compound Z-85, Z-88 and Z-145 were prepared starting from the compound 27-a, and the method of Example 86 was carried out, except that the 4-bromo-2-chloro-1-(III) in the step 1 was used. Fluoromethoxy)benzene is replaced by the corresponding substituted bromobenzene.
  • Step 1 Compound 28-a (50 g, 324.7 mmol), MeOH (10.9 g, 194.8 mmol) in dichloromethane (500 ml). Methyl), stirred at room temperature overnight. The reaction was completed, poured into a sodium thiosulfate solution, filtered, and the filtrate was evaporated. MS m / z (ESI): 231 [M-1] -.
  • Step 2 Compound 87-b (17.5 g) was used as the starting material . .
  • Step 3 Compound 87-c (6.109 g, 0.0197 mol), N-bromosuccinimide (5.259 g, 0.0295 mol), azobisisobutyronitrile (1.617 g, 0.0098 mol) in acetonitrile (40 ml) The solution was stirred at 80 ° C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, washed with sodium thiosulfate solution, washed with brine, dried and evaporated. MS m / z (ESI): 467.8 [M-1] -.
  • Step 5 Using the compound 87-e (336 mg) as a starting material, the preparation method of Example 28 was carried out except that the compound 1-c was replaced with the compound 10-a, and the reaction conditions were changed to 80 ° C and stirred for 2 hours to obtain a compound 87- f (335mg), purity 97%, yield 72%, MS m / z ( ESI): 540 [m + H] +.
  • Step 6 Starting from the compound 87-f (235 mg), refer to the preparation method of the step 5 of Example 82, except that the methylboronic acid was replaced with cyclopropylboronic acid in the step, and the reaction condition was changed to 80 ° C argon gas. protection was stirred overnight, to give the compound Z-87 (23.93mg), purity 98%, yield 8%, MS m / z ( ESI): 500 [m + H] +.
  • Step 1 Using the compound 13-a-3 (11.219 g) as a starting material, refer to the preparation method of the step b in the compound 17-a, except that the reaction conditions were changed to 80 ° C and stirred for 7 hours to obtain a compound 91-b (11.144 g). MS m/z (ESI): 203 [M+H] + .
  • Step 2 Compound 91-b (11.144 g) was used as the starting material . .
  • Step 3 Refer to the preparation method of Example 28 using compound 91-c (4.067 g) as a starting material, except that compound 1-c was changed to compound 10-a, and the reaction conditions were changed to 80 ° C and stirred for 2 hours to obtain compound 91. -d (4.722 g), purity 94.63%, yield 77%, MS m/z (ESI): 433.1 [M+H] + .
  • Step 4 The compound 91-d (4.722 g) was used as a starting material, and the preparation was carried out by the method of the step 4 of Example 57, and the reaction conditions were changed to 60 ° C and stirred for 3 hours. Obtained as a white solid compound 91-e (4.163 g), MS m/z (ESI): 419.1 [M+H] + .
  • Step 5 Using the compound 91-e (100 mg) as a starting material, refer to the preparation method of the step 1 in Example 55, except that the methanesulfonamide was changed to the isopropane-2-sulfonamide to obtain the compound Z-91 (10.36 mg). MS m/z (ESI): 524.1 [M+H] + .
  • Step 1 Compound 3-bromo-5-chloropyridine (500 mg, 2.6 mmol), compound 31-a (394 mg, 3.9 mmol), (tris(dibenzylideneacetone) dipalladium) (59 mg, 0.065 mmol), A solution of 2-biphenyl)di-tert-butylphosphine (39 mg, 0.129 mmol), sodium tert-butoxide (749 mg, 7.79 mmol) in toluene (15 ml) was stirred at 40 ° C overnight. After the reaction was completed, it was cooled to room temperature, poured into water, ethyl acetate was evaporated. Was purified by Combi-flash column to give a yellow oil Compound 99-b (70mg), MS m / z (ESI): 213.1 [M + H] +.
  • Step 2 Compound 99-b (70mg) as a raw material, in step 57 in Preparation Method 3 of Reference Example to give the compound 99-c (120mg), MS m / z (ESI): 399.1 [M + H] +.
  • Step 3 Compound 99-c (120mg) as starting material, prepared in Step 4 of Reference Example Example 57, to give compound 99-d (110mg), MS m / z (ESI): 383.1 [MH] -.
  • Step 4 Compound 99-d (110 mg) was used as a starting material to give a white solid compound Z-99 (12 mg), MS m/z (ESI): 462.0 [M+H] ] + .
  • the compound Z-100 was prepared by the method of Example 99 using the compound 31-a as a starting material, except that the 3-bromo-5-chloropyridine in the step 1 was replaced with the compound 32-a, and the reaction conditions were changed. The mixture was stirred at 46 ° C for 5 hours, and the reaction conditions in step 4 were changed to room temperature and stirred for 3 days.
  • the compound Z-101 was prepared by the method of Example 99 using the compound 31-a as a starting material, except that the 3-bromo-5-chloropyridine in the step 1 was replaced with the compound 33-a, and the reaction conditions were changed. Stir at 40 ° C for 5 hours.
  • Compound Z-103 was prepared according to the method of Example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was replaced by 1-bromo-2,4-di. Chlorobenzene, the reaction conditions of step 3 were changed to 50 ° C and stirred for 3 hours.
  • Compound Z-105 was prepared according to the method of Example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to 4-bromo-2-chloro-1. -(Trifluoromethyl)benzene, and the reaction conditions were changed to 40 ° C and stirred for 5 hours.
  • Compound Z-106 was prepared according to the method of Example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to 4-bromo-2-chloro-1. - Fluorobenzene.
  • the compound Z-114 was prepared by the method of Example 99 using the compound 31-a as a starting material, except that the 3-bromo-5-chloropyridine in the step 1 was replaced with the compound 23-a, and the reaction conditions were changed. Stir at 40 ° C for 4 hours.
  • Example 132 4-((4-(3,4-Dichlorophenyl)piperazin-1-yl)methyl)-2-fluoro-N-(isopropylsulfonyl)benzamide (Z- Preparation of 132)
  • Step 1 To a solution of compound 28-a (500 mg, 3.24 mmol), EtOAc (EtOAc) Diimine (1.24 g, 6.49 mmol), 4-dimethylaminopyridine (396 mg, 3.24 mmol) was stirred at room temperature overnight. At the end of the reaction, add 10ml The organic layer was separated and dried under reduced pressure. Purification by Combi-flash column chromatography gave EtOAc (EtOAc: EtOAc)
  • Step 2 To a solution of compound 132-b (510 mg, 1.97 mmol) in EtOAc (5 mL) EtOAc (EtOAc, EtOAc Argon protection, stirring at 80 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and poured into water, and the mixture was evaporated. 665 mg), MS m/z (ESI): 338 [M+H]+.
  • Step 3 To a solution of compound 10-a (68 mg, 0.30 mmol), Compound 132-c (100 mg, 0.30 mmol) in dimethylformamide (3 ml) hour. After the reaction was completed, it was cooled to room temperature, poured into water, EtOAc EtOAc (EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHMS m/z (ESI): 488.1 [M+H]+.
  • Step 1 4-(Bromomethyl)-1,2-dichlorobenzene (1.0 g, 4.17 mmol), Compound 27-a (0.78 g, 4.17 mmol), potassium carbonate (1.15 g, 8.34 mmol) acetonitrile (10 ml) The mixture was stirred at 80 ° C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. b (1.23 g), purity 100%, yield 85.4%. MS m/z (ESI): 345.2 [M+H] + .
  • Step 3 A mixed solution of the compound 166-c (200 mg, 0.71 mmol), Compound 87-e (276 mg, 0.71 mmol), potassium carbonate (196 mg, 1.42 mmol) acetonitrile (5 ml), and stirred at 80 ° C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj %, the yield was 72.5%. MS m/z (ESI): 554.0 [M+H] + .
  • Step 4 Compound 166-d (283 mg, 0.51 mmol), cyclopropylboronic acid (88 mg, 1.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (37 mg, 0.051 mmol), a mixed solution of cesium carbonate (333 mg, 1.02 mmol) in dioxane (5 ml) was stirred at 80 ° C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The purity was 91.36% and the yield was 30.5%. MS m/z (ESI): 514.2 [M+H]+.
  • Step 1 Compound Z-0-1 (20.0 g, 155 mmol) was dissolved in tert-butanol (150 mL), cooled to 0 ° C, diphenyl azide (47 g, 170 mmol), triethylamine (17.3 g, 170 mmol). The mixture was stirred at reflux for 18 h and then dried with a rotary evaporator. The residue was dissolved in dichloromethane (400 mL) and washed with water (200 ⁇ RTIgt; Dry over anhydrous sodium sulfate and suction filtration.
  • Step 2 Dissolve Z-0-2 (8.0 g, 0.04 mol) in dry THF (80 mL) under N 2 and then cooled to -78 ° C and then add dropwise LiHMDS (1M, 48ml, 0.048 mol) THF solution. After the dropwise addition was completed, the mixture was stirred at -78 ° C for 0.5 h. The reaction solution was slowly warmed to room temperature, stirred for 1 h, then cooled to -78 ° C, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (11.11 g, 0.048 mol) in THF (50 ml) was added dropwise. The reaction solution.
  • Step 3 Compound Z-0-4 (50.8 g, 254 mmol) was dissolved in THF (600 mL). After the mixture was stirred at 0 ° C for 2 h, the reaction was quenched with water and then EtOAc (EtOAc) (EtOAc). The filtrate was triturated with a rotary evaporator to give a white solid, Z-0-5 (32.0 g, yield: 73.5%).
  • Step 4 Compound Z-0-5 (32.0 g, 190 mmol) was dissolved in dichloromethane (400 mL) and then th The mixture was heated to reflux with stirring for 3 h under nitrogen. The mixture was cooled to room temperature and the reaction was quenched with water (200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium The filtrate was dried with a rotary evaporator to give a red solid, Z-0-6 (33.0 g, yield: 92.2%).
  • Step 5 Compound Z-0-6 (32 g, 168 mmol) was dissolved in DMSO (200 mL) and sodium cyanide (29 g, 606 mmol). The mixture was heated to 80 ° C under nitrogen for 3 h. The reaction mixture was cooled to room temperature, added with water and filtered. The filter cake was washed with a small amount of water. It was dried to an orange solid Z-0-7 (31 g, yield: 98.3%).
  • Step 7 Compound Z-0-8 (10.5 g, 50.2 mmol) was dissolved in ethanol (150 mL) and tert-butyl hydrazine (7.5 g, 60.3 mmol) was added. The mixture was heated under reflux with stirring for 3.5 h. The reaction mixture was cooled to room temperature and evaporated to dryness crystals crystals crystals
  • Test Example 1 manual patch clamp experiment of hNav1.7 and hNav1.5 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 Tables 1 and 2, respectively.
  • the representative compounds of the present invention have a high inhibitory activity against Nav1.7, and the inhibitory activity against Nav1.5 is significantly weak, so that there is a significant selective inhibition of Nav1.7. active.
  • the different substitution positions on the pyrrole ring carbon have a significant influence on the selectivity.
  • the selectivity of the 2-substituted compound is significantly improved over the selectivity of the 3-substituted compound.
  • the experimental animals were male Wistar rats weighing 250 ⁇ 30 g.
  • the experimental animals were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd., and then purchased in the barrier facility of Shanghai Ruizhi Chemical Research Co., Ltd. (2-3 pieces/cage, temperature 21.0 ⁇ 2°C, humidity 40-70%, The lighting control starts from 5 am, cycle 12h).
  • the experiment was started after the animals were adapted to the feeding environment for at least 5 days.
  • Negative control compound solvent, 5% DMAC (dimethylacetamide) + 5% Solutol (polyethylene glycol-12-hydroxyl Stearate) +90% saline;
  • Negative control group 10ml/kg, animal gavage (p.o.);
  • Positive control drug 1 Morphine (Mor-5mpk): 2.5 mg/ml, 2 ml/kg, intraperitoneal injection (i.p.);
  • Positive control drug 2 Compound Z-0 (Z-0-10mpk): 1 mg/ml, 10 ml/kg, animal gavage (p.o.);
  • Test group to be tested :
  • the experimental system consisted of an experimental cage and a bottom plate.
  • the experimental cage box with an area of 880 square centimeters and a height of 17.5 cm, consists of a top cover, food and water bottle slots, placed on a height-adjustable frame, 2-3 mm from the bottom plate.
  • the bottom plate is placed on a platform equipped with a vibrating susceptor.
  • the animal's behavior is transmitted to the computer through the vibration sensor, automatically recorded and stored in the computer system, and the computer software generates the final experimental data by identifying and analyzing the raw data of the animal behavior.
  • Formalin acute pain model 5%, 50 ⁇ l of formalin solution was injected into the subcutaneous tissue of the left hind paw of rats, and the Laboras system recorded the pain behavior after 60 minutes (the number of paws and the total length of time) ). Animal pain behavior is divided into two phases:
  • Positive control 1 (Mor) was administered from the test compound Z-4, the positive control 2, and the compound solvent to the 10th minute after administration of the rats;
  • Formalin was administered from the test compound Z-4, the positive control 2, and the compound solvent to the 25th minute after administration to the rats;
  • the first phase (phase I) represents the time from the test compound Z-4, the positive control 2, and the compound solvent to the rats 25 minutes after the administration of the solvent (ie, the time to start formalin injection), to 30 minutes (ie, 5 minutes after injection of formalin), which is 25-30 min in Figures 1 and 3; corresponds to 0-5 minutes after formalin injection.
  • phase II indicates that the compound Z-4, the positive control 2, and the compound solvent are administered to the test substance.
  • the rats began 40 minutes after the start (ie 15 minutes after formalin injection) and 55 minutes (30 minutes after the injection of formalin), ie 40-55 min in Figures 1 and 3; Corresponding to the 15-30 minutes after formalin injection.
  • the animal first adapts to the experimental environment, that is, put it into the experimental cage box, and after 60 minutes, it is taken out and put back into the cage box for continuous adaptation for 3 days;
  • the compound solvent and the compound Z-4 are administered 25 minutes before the subcutaneous injection of formalin, and the morphine is administered 10 minutes earlier;
  • the laboratory animal starts the Laboras system immediately after administration and begins recording;
  • the compound Z-4 can inhibit the pain behavior of the one-phase and the two-phase in the formalin-inflamed model of rats, and has an analgesic effect.
  • 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.
  • HYC00012 also known as compound Z-0
  • Drug to be tested compound Z-22, Z-40, Z-97, Z-85, Z-73;
  • the solvent component of the positive control and the test drug is 5% dimethylacetamide, 5% solutol and 90% physiological salt. water.
  • 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 100 mg/kg, respectively, as shown in Table 4.
  • 100mg/kg positive control Weighed 278.6mg positive control, added 0.68mL dimethylacetamide, added 0.68mL solutol after complete dissolution, shake and mix, add 90% physiological saline to the volume to 13.52mL, completely dissolved Orally administered.
  • 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. 6, Fig. 8, Fig. 10 and Fig. 12.
  • the results show that the exemplary compounds Z-22, Z-40, Z-73, Z-85 and Z-97 of the present invention are in the spinal nerve 2 hours after oral administration.
  • the ligation rat model it has a cold allodynia-induced hypersensitivity effect that induces spinal nerve ligation in rats, and has a statistically significant inhibitory effect in a rat neuralgia model.
  • compound Z-40 inhibits cold-stimulated hyperalgesia in a rat model of spinal nerve ligation, *p ⁇ 0.05, ***p ⁇ 0.001, compared with the solvent group, using a one-way ANOVA with Dunnett multiple comparison test.
  • Oral compound Z-40 and the positive control 100 mg/kg inhibited cold allodynia hypersensitivity induced by spinal nerve ligation in rats two hours later.
  • Test Example 4 In vivo test in rats
  • the drug concentration in plasma at different times after administration of the compound of the example by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compound of the present invention in rats was investigated, and its pharmacokinetic characteristics were evaluated.
  • Test animals healthy adult male SD rats (body weight 200-300 g, 6 rats, fasted), provided by Slark;
  • Blood sample collection First, select the animals that meet the experimental requirements before the administration, and weigh the markers. Before the blood sample is collected, the rats are bound, and each rat is administered at a predetermined blood collection time point (administered by gavage: 0.083, 0.25, 0.5, 1, 2, 4 after administration, respectively, before administration). , 8, 24h blood collection, a total of 9 time points), blood collection through the tail vein, about 150 ⁇ L. The blood was transferred to a 1.5 mL tube pre-added to K 2 EDTA. The collected blood samples were placed on wet ice, centrifuged for 5 min (2000 g, 4 ° C), and the plasma was taken out. The whole process was completed within 15 min after blood collection. All samples need to be stored in a -70 ° C refrigerator until sample analysis.
  • the drug concentration was determined by LC/MS/MS method.
  • the pharmacokinetic properties of the compounds in some embodiments of the present invention in the same mode of administration are shown in Table 10:
  • the exemplified compounds of the present invention have good pharmacological absorption, have significant pharmacological absorption effects, and exhibit good bioavailability.
  • the compounds of the present invention have superior properties and can be administered at lower doses, thus being safer or less toxic.

Abstract

Disclosed are heterocyclic-substituted N-sulfonylbenzamide derivatives, a preparation method for the derivatives, and a pharmaceutical use of the derivatives. Specifically, disclosed are compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs of the compounds, a preparation method therefor, and an application. See the description for the definitions of the various groups in the formula.

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Heterocyclic substituted N-sulfonylbenzamide derivatives, their preparation and medicinal use 技术领域Technical field
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。The invention belongs to the field of medical technology. In particular, 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.
背景技术Background technique
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。Recently, Cox et al. of the United Kingdom first reported on the nature of the unexpected results of the SCN9A gene mutation encoding the voltage-gated Nav1.7 channel leading to painlessness in genetic individuals. The genetically altered individual loses pain, but the other functions of the body are completely normal. In addition, recent studies have shown that the voltage-gated Nav1.7 channel expressed in DRG neurons participates in the generation of pain signals and plays a role in controlling the transmission of pain signals. Features. This study suggests that the Nav1.7 channel may be a drug target for selective treatment of pain without side effects.
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。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.
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。A growing body of evidence suggests that Nav1.7 plays an important role in a variety of pain states, including acute, chronic, inflammatory, and/or neuropathic pain. In humans, Nav1.7 protein accumulates in neuromas, Especially the neuroma that causes pain. Mutations in Nav1.7 function (whether hereditary or sporadic) 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. . Additional evidence for the role of Nav1.7 in pain can be seen in the phenotype of mutations in the loss of function of the SCN9A gene. Subsequent studies have shown many different mutations that result in loss of function of the SCN9A gene and CIP phenotype.
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***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。Since 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.
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。Many patients with acute or chronic pain conditions are less responsive to current pain therapies and generally develop resistance and insensitivity to opiates. Furthermore, the efficacy of currently used sodium channel blockers for the above mentioned conditions is largely limited by many side effects. These side effects include various CNS disorders such as blurred vision, dizziness, nausea and sedation, as well as more potentially life-threatening arrhythmias and heart failure.
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，Nav1.7离子通道高度选择性抑制剂可用于广泛的疼痛治疗，因此开发新型Nav1.7离子通道高度选择性抑制剂十分必要。Therefore, in view of the limited efficacy and unacceptable side effects of currently available agents, there is an urgent need to develop more A fully effective analgesic that gives it a higher efficacy and fewer side effects. The Nav1.7 ion channel is an important target for the development of non-addictive analgesic drugs. The highly selective inhibitor of Nav1.7 ion channel can be used for a wide range of pain treatments. Therefore, the development of a novel Nav1.7 ion channel highly selective inhibitor is very necessary.
发明内容Summary of the invention
本发明的目的是提供一种Nav1.7离子通道高度选择性抑制剂及其在医药上应用。It is an object of the present invention to provide a highly selective inhibitor of Nav1.7 ion channels and their use in medicine.
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：A first aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
Figure PCTCN2016073385-appb-000001
Figure PCTCN2016073385-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)；Wherein 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);
R5为氢、C1-20烷基、C3-20环烷基、卤代C1-20烷基；R 5 is hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl, halogenated C 1-20 alkyl;
R6为C6-20芳基、C1-20烷基、-NRaRb；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；R 6 is C 6-20 aryl, C 1-20 alkyl, -NR a R b ; wherein R a and R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl Or a C 6-20 aryl group;
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；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 Alkynyl or C 6-20 aryl; r 1 , r 3 are each independently 0, 1, 2 or 3; r 2 is 0 or 1;
W1、W2各自独立地为C、N、O或S；W 1 and W 2 are each independently C, N, O or 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；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;
(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；(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；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;
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。Wherein the alkyl group, cycloalkyl group, cycloalkoxy group, alkenyl group, alkynyl group, alkoxy group, aryl group, 3 to 7 membered monocyclic ring, 8 to 10 membered bicyclic ring, 3 to 7 membered monoheterocyclic ring, 8 to 10 membered bicyclic heterocyclic ring, 5 or 6 membered monocyclic heteroaryl ring, 8 to 10 membered bicyclic heteroaryl ring, benzo 3 to 7 membered monocyclic ring, benzo 3 to 7 membered single heterocyclic ring, 5 to a 6-membered monocyclic heteroaryl ring and a 3 to 7 membered monocyclic ring, or a 5 to 6 membered monocyclic heteroaryl ring and a 3 to 7 membered monoheterocyclic ring is substituted or unsubstituted; and the substitution is The 1-5 hydrogens in the group are substituted with a substituent selected from the group consisting of halogen, nitro, hydroxy, cyano, C 6-20 aryl, C 1-20 alkyl, halogenated C 1-20 Alkyl, C 1-20 alkoxy, halo 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, halogen C 1-20 alkylthio, C 1-20 alkylamino, halogenated C 1-20 alkylamino, thiol, 3 to 20 membered heterocycloalkyl, 3 to 20 membered heterocycloalkane alkoxy group, C 3-20 cycloalkylthio, halo-C 3-20 cycloalkylthio group, 3-20 yuan A heterocyclic thio group, oxo group, C 1-20 hydroxyalkyl group, a carboxyl group, -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), -SO 2 N(R a R b ), -C(O)O-(C 1-20 alkyl ), -CHO, -OC(O)-(C 1-20 alkyl), -SO 2 -(C 1-20 alkyl), -SO 2 -(C 6-20 aryl), -CO-( C 6-20 aryl); R a , R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl or C 6-20 aryl.
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。In another preferred embodiment, 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. Preferably, L 2 is linked to W 2 .
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。In another preferred embodiment, L 2 is a bond, and A is bonded to any ring atom other than W 1 on the ring.
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。In another preferred embodiment, L 2 is a bond, W 2 is N, O, S or C, and when W 2 is O or S, A is bonded to any carbon atom other than W 1 and W 2 on the ring. When W 2 is N or C, A is bonded to any ring atom other than W 1 on the ring.
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。In another preferred embodiment, W 1 is N, O, S or C, and when W 1 is O or S, L 1 is bonded to any carbon atom other than W 1 and W 2 on the ring, when 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, and preferably, L 1 is bonded to W 1 .
在另一优选例中，所述化合物为式(II)所示化合物：In another preferred embodiment, the compound is a compound of formula (II):
Figure PCTCN2016073385-appb-000002
Figure PCTCN2016073385-appb-000002
Figure PCTCN2016073385-appb-000003
Figure PCTCN2016073385-appb-000003
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。In the formula, 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.
在另一优选例中，每个R0相同或不同，各自独立地为氢。In another preferred embodiment, each R 0 is the same or different and is each independently hydrogen.
在另一优选例中，A为C6-20芳基或5或6元单环杂芳基环。In another preferred embodiment, A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring.
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。In another preferred embodiment, 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.
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。In another preferred embodiment, 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.
在另一优选例中，所述化合物为式(III)所示化合物：In another preferred embodiment, the compound is a compound of formula (III):
Figure PCTCN2016073385-appb-000004
Figure PCTCN2016073385-appb-000004
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。In the formula, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , R y , r1 , r2 , r3 , A, W 1 , W 2 , n, p, m Defined in claim 1.
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。In another preferred embodiment, in the 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.
在另一优选例中，
Figure PCTCN2016073385-appb-000005
选自：
Figure PCTCN2016073385-appb-000006
Figure PCTCN2016073385-appb-000007
In another preferred example,
Figure PCTCN2016073385-appb-000005
From:
Figure PCTCN2016073385-appb-000006
Figure PCTCN2016073385-appb-000007
在另一优选例中，W2为N。In another preferred embodiment, W 2 is N.
在另一优选例中，W1为N、O、S或C。In another preferred embodiment, W 1 is N, O, S or C.
在另一优选例中，
Figure PCTCN2016073385-appb-000008
选自：
Figure PCTCN2016073385-appb-000009
Figure PCTCN2016073385-appb-000010
In another preferred example,
Figure PCTCN2016073385-appb-000008
From:
Figure PCTCN2016073385-appb-000009
Figure PCTCN2016073385-appb-000010
在另一优选例中，
Figure PCTCN2016073385-appb-000011
选自：
Figure PCTCN2016073385-appb-000012
Figure PCTCN2016073385-appb-000013
Figure PCTCN2016073385-appb-000014
其中，A、L1、R0定义同前。In another preferred example,
Figure PCTCN2016073385-appb-000011
From:
Figure PCTCN2016073385-appb-000012
Figure PCTCN2016073385-appb-000013
Figure PCTCN2016073385-appb-000014
Among them, A, L 1 and R 0 are defined as before.
在另一优选例中，
Figure PCTCN2016073385-appb-000015
选自：
Figure PCTCN2016073385-appb-000016
Figure PCTCN2016073385-appb-000017
其中，A、L1、R0定义同前。In another preferred example,
Figure PCTCN2016073385-appb-000015
From:
Figure PCTCN2016073385-appb-000016
Figure PCTCN2016073385-appb-000017
Among them, A, L 1 and R 0 are defined as before.
在另一优选例中，
Figure PCTCN2016073385-appb-000018
选自：
Figure PCTCN2016073385-appb-000019
其中，A、L1、R0定义同前。In another preferred example,
Figure PCTCN2016073385-appb-000018
From:
Figure PCTCN2016073385-appb-000019
Among them, A, L 1 and R 0 are defined as before.
在另一优选例中，
Figure PCTCN2016073385-appb-000020
选自：
Figure PCTCN2016073385-appb-000021
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。In another preferred example,
Figure PCTCN2016073385-appb-000020
From:
Figure PCTCN2016073385-appb-000021
And 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.
在另一优选例中，A为
Figure PCTCN2016073385-appb-000022
其中R1’、R2’、R3’、R4’、R5’如说明书中所定义。In another preferred embodiment, A is
Figure PCTCN2016073385-appb-000022
Wherein R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' are as defined in the specification.
在另一优选例中，A为
Figure PCTCN2016073385-appb-000023
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。In another preferred embodiment, A is
Figure PCTCN2016073385-appb-000023
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), - N(R a )SO 2 -(C 1-20 alkyl), -SO 2 N(R a R b ), -C(O)O-(C 1-20 alkyl), -CHO, -OC( O)-(C 1-20 alkyl), -SO 2 -(C 1-20 alkyl), -SO 2 -(C 6-20 aryl), -CO-(C 1-20 alkyl), -CO-(C 6-20 aryl); R a , R b are as defined above.
在另一优选例中，
Figure PCTCN2016073385-appb-000024
选自：
Figure PCTCN2016073385-appb-000025
其中，A、L1、R0定义同前。 In another preferred example,
Figure PCTCN2016073385-appb-000024
From:
Figure PCTCN2016073385-appb-000025
Among them, A, L 1 and R 0 are defined as before.
在另一优选例中，
Figure PCTCN2016073385-appb-000026
选自：
Figure PCTCN2016073385-appb-000027
其中，A、L1、R0定义同前。In another preferred example,
Figure PCTCN2016073385-appb-000026
From:
Figure PCTCN2016073385-appb-000027
Among them, A, L 1 and R 0 are defined as before.
在另一优选例中，所述化合物为式(IV)所示化合物：In another preferred embodiment, the compound is a compound of formula (IV):
Figure PCTCN2016073385-appb-000028
Figure PCTCN2016073385-appb-000028
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。Wherein 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.
在另一优选例中，r2为0。In another preferred embodiment, r2 is zero.
在另一优选例中，r1、r3为0；r2为1。In another preferred embodiment, r1 and r3 are 0; r2 is 1.
在另一优选例中，r1为1、2或3；r2为1；r3为0。In another preferred embodiment, r1 is 1, 2 or 3; r2 is 1; r3 is 0.
在另一优选例中，r1为0；r2为1；r3为1、2或3。In another preferred embodiment, r1 is 0; r2 is 1; and r3 is 1, 2 or 3.
在另一优选例中，r1、r2、r3为0。In another preferred embodiment, r1, r2, and r3 are zero.
在另一优选例中，所述化合物为式(V)所示化合物：In another preferred embodiment, the compound is a compound of formula (V):
Figure PCTCN2016073385-appb-000029
Figure PCTCN2016073385-appb-000029
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。Wherein 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 , -N(R a )C(O)-(C 1-20 alkyl), -N(R a )SO 2 -(C 1-20 alkyl), -SO 2 N(R a R b ), -C(O)O-(C 1-20 alkyl), -CHO, -OC(O)-(C 1-20 alkyl), -SO 2 -(C 1-20 alkyl), -SO 2 -(C 6-20 aryl), -CO-(C 1-20 alkyl), -CO-(C 6-20 aryl); R a , R b are as defined above.
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。In another preferred embodiment, 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.
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。In another preferred embodiment, 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 .
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。In another preferred embodiment, in the compound of the formula (V), L 1 is -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -, and r1, r2, and r3 are as defined above.
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。In another preferred embodiment, in the compound of the formula (V), 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. When W 1 is N or C, L 1 is bonded to any ring atom other than W 2 on the ring. Preferably, L 1 is bonded to W 1 .
在另一优选例中，式(V)化合物中，W2为N。In another preferred embodiment, in the compound of formula (V), W 2 is 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；In another preferred embodiment, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl;
R5为氢；R 5 is hydrogen;
R6为C1-20烷基、-NRaRb；R 6 is C 1-20 alkyl, -NR a R b ;
其中，Ra、Rb各自独立地为氢、或C1-20烷基；Wherein R a and R b are each independently hydrogen or a C 1-20 alkyl group;
W1、W2各自独立地为C、O、S或N；W 1 , W 2 are each independently C, O, S or N;
L2为一个键；L 2 is a key;
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；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各自独立地为1或2；n, m are each independently 1 or 2;
(R0)p为环上的任意位置的氢被p个R0取代，p为0；(R 0 ) p is a hydrogen at any position on the ring is replaced by p R 0 , p is 0;
A为苯基；A is a phenyl group;
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；And when W 1 and/or W 2 is O or S, L 1 and A are respectively bonded to any carbon atom other than W 1 and W 2 on the ring;
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；When W 1 and/or W 2 is N or C, A is bonded to any ring atom other than W 1 on the ring, and L 1 is bonded to any ring atom other than W 2 on the ring;
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。Wherein the 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.
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。In another preferred embodiment, 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.
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。In another preferred embodiment, 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.
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；In another preferred embodiment, 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;
R5为氢；R 5 is hydrogen;
R6为C1-20烷基、-NRaRb；其中，Ra、Rb各自独立地为氢、C1-20烷基。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.
在另一优选例中，A为C6-20芳基或5或6元单环杂芳基环。In another preferred embodiment, A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring.
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。In another preferred embodiment, 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.
在另一优选例中，每个R0相同或不同，各自独立地为氢。In another preferred embodiment, each R 0 is the same or different and is each independently hydrogen.
在另一优选例中，
Figure PCTCN2016073385-appb-000030
选自：
Figure PCTCN2016073385-appb-000031
Figure PCTCN2016073385-appb-000032
In another preferred example,
Figure PCTCN2016073385-appb-000030
From:
Figure PCTCN2016073385-appb-000031
Figure PCTCN2016073385-appb-000032
A为C6-20芳基或5或6元单环杂芳基环；A is a C 6-20 aryl group or a 5 or 6 membered monocyclic heteroaryl ring;
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；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;
每个R0相同或不同，各自独立地为氢；Each R 0 is the same or different and is each independently hydrogen;
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。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 halogenated C 1-20 alkylamino group, a thiol, a 3- to 20-membered heterocycloalkyl group, a 3- to 20-membered heterocycloalkyloxy group, a C 3-20 cycloalkylthio group, Halogenated C 3-20 cycloalkylthio, 3 to 20 membered heterocycloalkylthio, oxo, C 1-20 hydroxyalkyl, carboxyl, -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), -SO 2 N(R a R b ), -C(O)O-(C 1-20 alkyl), -CHO, -OC(O)-(C 1-20 alkyl), -SO 2 -(C 1-20 alkyl), -SO 2 -(C 6-20 aryl), -CO-(C 6-20 aryl); R a , R b Each is independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl or C 6-20 aryl.
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。In another preferred embodiment, 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.
在另一优选例中，所述苯基为
Figure PCTCN2016073385-appb-000033
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、C3-20环烷氧基。In another preferred embodiment, the phenyl group is
Figure PCTCN2016073385-appb-000033
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, C 3-20 cycloalkoxy.
在另一优选例中，所述吡啶基为
Figure PCTCN2016073385-appb-000034
其中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。In another preferred embodiment, the pyridyl group is
Figure PCTCN2016073385-appb-000034
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, C 1-20 alkyl Halogenated C 1-20 alkyl, halo C 1-20 alkoxy, C 1-20 alkoxy, C 3-20 cycloalkyl, C 3-20 cycloalkoxy.
在另一优选例中，
Figure PCTCN2016073385-appb-000035
选自：
Figure PCTCN2016073385-appb-000036
In another preferred example,
Figure PCTCN2016073385-appb-000035
From:
Figure PCTCN2016073385-appb-000036
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；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;
每个R0相同或不同，各自独立地为氢。Each R 0 is the same or different and is each independently hydrogen.
在另一优选例中，r1为0；r3为1；r2为0。In another preferred embodiment, r1 is 0; r3 is 1; and r2 is 0.
在另一优选例中，
Figure PCTCN2016073385-appb-000037
选自：
Figure PCTCN2016073385-appb-000038
In another preferred example,
Figure PCTCN2016073385-appb-000037
From:
Figure PCTCN2016073385-appb-000038
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；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;
每个R0相同或不同，各自独立地为氢。Each R 0 is the same or different and is each independently hydrogen.
在另一优选例中，r1、r3为0；r2为1。In another preferred embodiment, r1 and r3 are 0; r2 is 1.
在另一优选例中，
Figure PCTCN2016073385-appb-000039
选自：
Figure PCTCN2016073385-appb-000040
In another preferred example,
Figure PCTCN2016073385-appb-000039
From:
Figure PCTCN2016073385-appb-000040
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； 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;
每个R0相同或不同，各自独立地为氢。Each R 0 is the same or different and is each independently hydrogen.
在另一优选例中，r1为1、2或3；r2为1；r3为0。In another preferred embodiment, r1 is 1, 2 or 3; r2 is 1; r3 is 0.
在另一优选例中，r1为1；r2为1；r3为0。In another preferred embodiment, r1 is 1; r2 is 1; and r3 is 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。In another preferred embodiment, 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.
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。In another preferred embodiment, the C 1-20 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl.
在另一优选例中，C3-20环烷基为环丙基。In another preferred embodiment, the C 3-20 cycloalkyl group is a cyclopropyl group.
在另一优选例中，卤代C1-20烷基为三氟甲基。In another preferred embodiment, the halo C 1-20 alkyl group is a trifluoromethyl group.
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。In another preferred embodiment, the halo C 1-20 alkoxy group is a trifluoromethoxy group, a trifluoroethoxy group, or a difluoromethoxy group.
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。In another preferred embodiment, the C 1-20 alkoxy group is a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, or an isobutoxy group.
在另一优选例中，C3-20环烷氧基为环丙氧基。In another preferred embodiment, the C 3-20 cycloalkoxy group is a cyclopropoxy group.
在另一优选例中，卤素为氟或氯。In another preferred embodiment, the halogen is fluorine or chlorine.
在另一优选例中，所述化合物选自下组：In another preferred embodiment, the compound is selected from the group consisting of:
Figure PCTCN2016073385-appb-000041
Figure PCTCN2016073385-appb-000041
Figure PCTCN2016073385-appb-000042
Figure PCTCN2016073385-appb-000042
在另一优选例中，所述化合物选自下组：In another preferred embodiment, the compound is selected from the group consisting of:
Figure PCTCN2016073385-appb-000043
Figure PCTCN2016073385-appb-000043
在另一优选例中，所述化合物选自下组：In another preferred embodiment, the compound is selected from the group consisting of:
Figure PCTCN2016073385-appb-000044
Figure PCTCN2016073385-appb-000044
Figure PCTCN2016073385-appb-000045
Figure PCTCN2016073385-appb-000045
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I化合物中相应的基团。In another preferred embodiment, 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 I in the examples.
在另一优选例中，本发明的式I化合物为实施例部分中所注备的各具体化合物，尤其是Z-4至Z-171中任一化合物。In another preferred embodiment, the compound of formula I of the present invention is each specific compound noted in the Examples section, especially any of Z-4 to Z-171.
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。In another preferred embodiment, the compound is a compound prepared in the examples of the present application.
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。A second aspect of the invention provides 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.
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。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.
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***疾病、精神疾病或其组合。In another preferred embodiment, the disease or condition is selected from the group consisting of pain, depression, cardiovascular disease, respiratory disease, mental illness, or a combination thereof.
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***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。 In another preferred embodiment, 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, fibromyalgia, neuroprotection, tachyarrhythmia, atrial fibrillation, and ventricular fibrillation in an ischemic condition caused by stroke or nerve damage.
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。In another preferred embodiment, 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.
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。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.
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。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
附图说明DRAWINGS
图1显示了Two ways ANOVA测试中各组对应的大鼠舔后肢次数随时间变化图；图1中，*、**、***分别表示待测化合物组与空白组相比，P<0.05、0.01、0.001。Figure 1 shows the change in the number of hind limbs of the rats in the Two ways ANOVA test over time. In Figure 1, *, **, and *** indicate that the test compound group was compared with the blank group, P < 0.05. , 0.01, 0.001.
图2显示了unpaired t-测试中各组对应的大鼠舔后肢次数的曲线下面积；图2中，*、**、***分别表示待测化合物与空白组比较，P<0.05、0.01、0.001。Figure 2 shows the area under the curve of the hind limbs of the corresponding groups in the unpaired t-test. In Figure 2, *, **, and *** indicate that the test compound is compared with the blank group, P < 0.05, 0.01. 0.001.
图3显示了Two ways ANOVA测试中各组对应的大鼠舔后肢所用时间变化图；图3中，*、**、***分别表示待测化合物与空白组相比，P<0.05、0.01、0.001。Figure 3 is a graph showing the time course of the hind limbs of the corresponding groups in the Two ways ANOVA test. In Figure 3, *, **, and *** indicate that the test compound is compared with the blank group, P < 0.05, 0.01. 0.001.
图4显示了unpaired t-测试中各组对应的大鼠舔后肢所用时间的曲线下面积；图4中，*、**、***分别表示待测化合物与空白组比较，P<0.05、0.01、0.001。Figure 4 shows the area under the curve for the time taken by the hind limbs of the corresponding groups in the unpaired t-test; in Figure 4, *, **, and *** indicate that the test compound was compared with the blank group, P < 0.05, 0.01, 0.001.
图5显示了化合物Z-97在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。Figure 5 shows the baseline of rat cold pain test in compound Z-97 in a rat model of spinal nerve ligation.
图6显示了化合物Z-97在脊神经结扎大鼠模型中抑制冷刺激痛觉超敏效果。Figure 6 shows that Compound Z-97 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
图7显示了化合物Z-40在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。Figure 7 shows the baseline of rat cold pain test in compound Z-40 in a rat model of spinal nerve ligation.
图8显示了化合物Z-40在脊神经结扎大鼠模型中抑制冷刺激痛觉超敏效果。Figure 8 shows that Compound Z-40 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
图9显示了化合物Z-73、85在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。Figure 9 shows the baseline of rat cold pain test in compound Z-73, 85 in a rat model of spinal nerve ligation.
图10显示了化合物Z-73、85在脊神经结扎大鼠模型中抑制冷刺激痛觉超敏效果。Figure 10 shows that Compound Z-73, 85 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
图11显示了化合物Z-22在脊神经结扎大鼠模型中大鼠冷痛觉测试基线。Figure 11 shows the baseline of rat cold pain test in compound Z-22 in a rat model of spinal nerve ligation.
图12显示了化合物Z-22在脊神经结扎大鼠模型中化合物抑制冷刺激痛觉超敏效果 Figure 12 shows that compound Z-22 inhibits cold stimulating hyperalgesia in a rat model of spinal nerve ligation.
具体实施方式Detailed ways
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具有较高的抑制活性，同时对Nav1.5的抑制活性明显较弱，对Nav1.7具有明显的选择抑制活性。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。The inventors have extensively and intensively studied and unexpectedly discovered that the heterocyclic-substituted N-sulfonylbenzamide derivative of the present invention has a high inhibitory activity against Nav1.7, and has an inhibitory activity against Nav1.5. It is weak and has obvious selective inhibitory activity against Nav1.7. At the same time, 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. On this basis, the inventors completed the present invention.
术语定义Definition of Terms
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。As used herein, "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-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl , 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethyl , 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-B Hexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various A branched isomer or the like; more preferably a C 1-6 alkyl group, most preferably a C 1-3 alkyl group.
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。As used herein, "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, and "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.
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。As used herein, "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, and "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.
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。As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, and "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, cycloheptatriene The alkenyl group, the cyclooctyl 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.
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。As used herein, "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. a heterocycloalkyl group containing from 3 to 20 ring atoms, and wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (where t is an integer from 0 to 2), but excluding -OO - a ring moiety of -OS- or -SS-, the remaining ring atoms are carbon); more preferably a 3- to 10-membered heterocycloalkyl group, wherein 1 to 3 ring atoms are heteroatoms; more preferably 3 a 6-membered heterocycloalkyl group; more preferably a 5- to 6-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.
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***。As used herein, "partially unsaturated" refers to a pi-electron system that contains one or more unsaturated bonds but does not have a complete conjugation.
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。As used herein, "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.
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。As used herein, "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.
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。As used herein, "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 π-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.
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。As used herein, "a bond" refers to the attachment of two groups attached thereto through a covalent bond.
如本文所用，“卤素”指氟、氯、溴或碘。As used herein, "halogen" refers to fluoro, chloro, bromo or iodo.
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。As used herein, "halo" means that one or more (eg 1, 2, 3, 4 or 5) hydrogens in the group are replaced by a halogen.
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。For example, "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. Examples of 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.
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。As another example, "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.
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。As another example, "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. These include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
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。As used herein, "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.
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。As used herein, "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.
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 PCTCN2016073385-appb-000046
As used herein, "amino" means -NH 2, "cyano" refers to -CN, "Nitro" refers to -NO 2, "benzyl" refers to -CH 2 - phenyl, "oxo" refers to = O, "Carboxy" means -C(O)OH, "thiol" means -SH, and "cyclopropylene" structure is:
Figure PCTCN2016073385-appb-000046
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。As used herein, "carboxylate group" refers to -C(O)O-( C1-20 alkyl) or ( C3-20 cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
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。As used herein, "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.
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。As used herein, "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.
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。As used herein, "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.
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。As used herein, "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.
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。As used herein, "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.
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。As used herein, "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 π electrons; and has a group of 1 to 5 hetero atoms in addition to carbon atoms. "Hetero atom" means nitrogen, oxygen or sulfur.
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。As used herein, "3 to 7 membered monocyclic ring" refers to a saturated or partially unsaturated full carbon having 3 to 7 ring atoms. Single ring. It is preferably 5 to 6 yuan. Examples of monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl groups. Ring, cycloheptatrienyl ring, cyclooctyl ring, and the like.
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。As used herein, "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. Examples of 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.
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 PCTCN2016073385-appb-000047
As used herein, "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:
Figure PCTCN2016073385-appb-000047
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。As used herein, "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. Examples of bicyclic heterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.
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、***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。As used herein, 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.
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。As used herein, "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.
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：As used herein, "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. Preferably, the benzo is a 5- to 6-membered monocyclic or benzo 5- to 6-membered monoheterocyclic ring. Non-limiting examples include:
Figure PCTCN2016073385-appb-000048
Figure PCTCN2016073385-appb-000048
Figure PCTCN2016073385-appb-000049
Figure PCTCN2016073385-appb-000049
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：As used herein, "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:
Figure PCTCN2016073385-appb-000050
Figure PCTCN2016073385-appb-000050
Figure PCTCN2016073385-appb-000051
Figure PCTCN2016073385-appb-000051
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。As used herein, "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.
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。As used herein, 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, and 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, and 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. a group independently selected from C 1-20 alkyl, halo C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 1-20 alkoxy, C 1-20 alkane thio, C 1-20 alkylamino , Halogen, thiol, hydroxyl, nitro, cyano, C 3-20 cycloalkyl, 3-20 yuan heterocyclyl, C 6-20 aryl group, 5- or 6-membered monocyclic heteroaryl or 8 Up to 10 membered bicyclic heteroaryl, C 3-20 cycloalkoxy, 3 to 20 membered heterocycloalkyloxy, C 3-20 cycloalkylthio, 3 to 20 membered heterocycloalkylsulfide a group, an oxo group, an amino group, a C 1-20 hydroxyalkyl group, a carboxyl group or a carboxylate group.
制备方法Preparation
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。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.
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。The compounds of the formula (I) of the present invention can be prepared by referring to the following synthetic route, and the steps in the process can be expanded or combined as needed during the specific operation.
路线1Route 1
Figure PCTCN2016073385-appb-000052
Figure PCTCN2016073385-appb-000052
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。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 The displacement reaction with a sulfonamide group in the compound of formula (Ib) occurs in the presence of a compound of formula (Ic).
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。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). Suitable base systems include potassium t-butoxide present in DMSO, sodium hydride present in DMF, potassium carbonate present in DMF, and the like.
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。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.
路线2 Route 2
Figure PCTCN2016073385-appb-000053
Figure PCTCN2016073385-appb-000053
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。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.
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。The reactions in the above various steps are conventional reactions known to those skilled in the art. Unless otherwise stated, the reagents and starting materials used in the synthetic route are either commercially available or can be prepared by those skilled in the art according to known methods of designing different compound structures.
与现有技术相比，本发明的主要优点在于：The main advantages of the present invention over the prior art are:
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具有高选择抑制活性，可用作广泛疼痛治疗的药物。A series of novel heterocyclic substituted N-sulfonylbenzamide derivatives are provided which have high selective inhibitory activity against Nav1.7 and are useful as drugs for the treatment of a wide range of pains.
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。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Unless otherwise defined, the terms used herein have the same meaning as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the present invention.
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，DIEA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。如本文所用，室温是指约为25℃。As used herein, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, THF is tetrahydrofuran, DIEA is N,N-diisopropylethylamine, EA is ethyl acetate, PE is petroleum ether, and BINAP is (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl. As used herein, room temperature means about 25 °C.
化合物1-a的制备方法：Preparation method of compound 1-a:
Figure PCTCN2016073385-appb-000054
Figure PCTCN2016073385-appb-000054
步骤a：将化合物1-a-1(14.8g，0.10mol)加入到三氟甲磺酸(150ml)中，混合物冷却到0℃，分批加入N-碘代丁二酰亚胺(24.75g，0.110mol)。混合物在室温下，搅 拌2h。将反应液慢慢倒入冰水中，搅拌约15分钟。用石油醚(3 x 100ml)萃取。有机相用硫代亚硫酸钠水溶液(100ml)洗涤，硫酸钠干燥。过滤旋干滤液，粗品用柱层析纯化，石油醚洗脱，得到化合物1-a-2(14.0g，产率：55％)为粉红色液体。1H NMR(400MHz,CDCl3)：δ:7.78(dd,J＝8.0，6.4Hz,1H)，6.94(dd,J＝8.8,7.2Hz,1H)。Step a: Compound 1-a-1 (14.8 g, 0.10 mol) was added to trifluoromethanesulfonic acid (150 ml), the mixture was cooled to 0 ° C, and N-iodosuccinimide (24.75 g) was added portionwise. , 0.110 mol). The mixture was stirred at room temperature for 2 h. The reaction solution was slowly poured into ice water and stirred for about 15 minutes. Extract with petroleum ether (3 x 100 ml). The organic phase was washed with aqueous sodium thiosulfite (100 mL). The filtrate was evaporated to dryness. 1 H NMR (400 MHz, CDCl 3 ): δ: 7.78 (dd, J = 8.0, 6.4 Hz, 1H), 6.94 (dd, J = 8.8, 7.2 Hz, 1H).
步骤b：在N2保护下，将化合物1-a-2(14g，0.051mol)溶解在1,4-二氧六环(140ml)中，分别加入加三乙胺(15.6g，0.153mol)，水(10ml)，1,1’-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(2.08g，2.55mmol)。混合物在10公斤的一氧化碳压力下，80℃搅拌18h。将反应液慢慢升温至室温，加入1N NaOH水溶液(250ml)，搅拌10分钟，用乙酸乙酯(250ml)萃取。水相用1N HCl水溶液调pH至2。用乙酸乙酯(3 x 100ml)萃取,有机相用饱和食盐水(100ml)洗涤，有机相用硫酸钠干燥。过滤旋干滤液，得到化合物1-a-3(7.8g，产率：80％)为白色固体。MS m/z(ESI):193[M+H]+。纯度＝98％(UV214)。Step b: Compound 1-a-2 (14 g, 0.051 mol) was dissolved in 1,4-dioxane (140 ml) under N 2 and added triethylamine (15.6 g, 0.153 mol). Water (10 ml), 1,1 '-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane complex (2.08 g, 2.55 mmol). The mixture was stirred at 80 ° C for 18 h under a pressure of 10 kg of carbon monoxide. The reaction mixture was slowly warmed to room temperature, then aqueous 1N EtOAc (250 mL). The aqueous phase was adjusted to pH 2 with 1N aqueous HCl. It was extracted with ethyl acetate (3×100 mL). The filtrate was dried by filtration to give Compound 1-a-3 (7.8 g, yield: 80%) as white solid. MS m/z (ESI): 193 [M+H] + . Purity = 98% (UV214).
步骤c：在N2保护下，将化合物1-a-3(7.8g，0.041mol)溶解在无水二氯甲烷(100ml)中，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(11.65g，0.061mol)，DMAP(11.07g，0.090mol)。混合物在室温搅拌10分钟，加入甲基磺酰胺2(4.82g，0.061mol)。混合物在室温搅拌18h。向反应液中加150ml水中,混合物在室温搅拌0.5h，分出水相。水相用1N HCl水溶液调pH至3后，用二氯甲烷(3 x 100ml)萃取,有机相用饱和食盐水(200ml)洗，硫酸钠干燥，40℃旋干。粗品过柱(100-200目硅胶),石油醚：乙酸乙酯＝(1:1)洗脱，得到化合物1-a(3.8g，产率：35％)为白色固体。MS m/z(ESI):270[M+H]+。纯度＝100％(UV214)。1H NMR(400MHz,CDCl3)：δ:12.41(s,1H)，8.00(t,J＝7.6Hz,1H)，7.74(t,J＝10.0Hz,1H)，3.37(s,3H)。Step c: Compound 1-a-3 (7.8 g, 0.041 mol) was dissolved in anhydrous dichloromethane (100 mL) under N 2 and then added 1-ethyl-(3-dimethylaminopropyl) Carbodiimide hydrochloride (11.65 g, 0.061 mol), DMAP (11.07 g, 0.090 mol). The mixture was stirred at room temperature for 10 minutes and methanesulfonamide 2 (4.82 g, 0.061 mol). The mixture was stirred at room temperature for 18 h. 150 ml of water was added to the reaction mixture, and the mixture was stirred at room temperature for 0.5 h to separate an aqueous phase. The aqueous phase was adjusted to pH 3 with aq. EtOAc. EtOAc (EtOAc) The crude product was purified by chromatography (EtOAc:EtOAc) MS m/z (ESI): 270 [M+H] + . Purity = 100% (UV214). 1 H NMR (400 MHz, CDCl 3 ): δ: 12.41 (s, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 10.0 Hz, 1H), 3.37 (s, 3H).
化合物6-a的制备方法：Preparation method of compound 6-a:
Figure PCTCN2016073385-appb-000055
Figure PCTCN2016073385-appb-000055
步骤：向化合物6-a-1(1g，10mmol)和三乙胺(1.01g，10mmol)的20ml乙腈溶液中，0℃滴加三氟甲磺酸酐(2.82g，10mmol)，室温搅拌2h，加入4-溴-2-氯苯酚(1.25g，6mmol)，碳酸钾(2.76g，20mmol)，60℃搅拌5h。反应结束，冷却至室温，过滤，乙酸乙酯洗，滤液减压浓缩得粗品，经Combi-flash柱层析纯化得到无色油状化合物 6-a(1.4g)，直接用于下一步反应，产率80.5％。Step: To a solution of the compound 6-a-1 (1 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in 20 ml of acetonitrile, trifluoromethanesulfonic anhydride (2.82 g, 10 mmol) was added dropwise at 0 ° C, and stirred at room temperature for 2 h. 4-Bromo-2-chlorophenol (1.25 g, 6 mmol), potassium carbonate (2.76 g, 20 mmol) was added and stirred at 60 ° C for 5 h. The reaction was completed, cooled to room temperature, filtered, and washed with ethyl acetate. 6-a (1.4 g) was used directly in the next reaction, yield 80.5%.
化合物9-a的制备方法：Preparation method of compound 9-a:
Figure PCTCN2016073385-appb-000056
Figure PCTCN2016073385-appb-000056
步骤：向9-a-1(400mg，2.27mmol)的10ml 1,2-二氯乙烷溶液中加入甲基磺酰胺(268mg，2.73mmol)，HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(1.3g，3.41mmol)，DIPEA(N，N-二异丙基乙胺)(880mg，6.81mmol)，DMAP(4-二甲氨基吡啶)(50mg)，60℃搅拌1h。反应结束，冷却至室温，加入二氯甲烷，3N盐酸洗，饱和碳酸氢钠洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，经Combi-flash柱层析纯化得到红色固体化合物9-a(250mg)，直接用于下一步反应，纯度45％，产率44％。MS m/z(ESI):252.0[M-H]+。Step: To a solution of 9-a-1 (400 mg, 2.27 mmol) in 10 ml of 1,2-dichloroethane, methanesulfonamide (268 mg, 2.73 mmol), HATU (2-(7-azobenzotriene) Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (1.3 g, 3.41 mmol), DIPEA (N,N-diisopropylethylamine) (880 mg, 6.81 mmol) , DMAP (4-dimethylaminopyridine) (50 mg), stirred at 60 ° C for 1 h. After completion of the reaction, the mixture was cooled to room temperature, then dichloromethane was evaporated, evaporated, evaporated, evaporated, evaporated, -a (250 mg), used directly in the next reaction, purity 45%, yield 44%. MS m/z (ESI): 252.0 [MH] + .
化合物11-a的制备方法：Preparation method of compound 11-a:
Figure PCTCN2016073385-appb-000057
Figure PCTCN2016073385-appb-000057
步骤a：化合物11-a-1(5g，31.6mmol)溶解于20ml硫酸中，冷却至0℃，加入1,3-二溴-5,5-二甲基海因(4.4g，15.5mmol)，0℃搅拌2h。反应结束，倒入冰水中，过滤得白色固体化合物11-a-2(6.62g)，纯度94.37％，产率88.62％，MS m/z(ESI):237[M+H]+。Step a: Compound 11-a-1 (5 g, 31.6 mmol) was dissolved in 20 ml of sulfuric acid, cooled to 0 ° C, and added 1,3-dibromo-5,5-dimethylhydan (4.4 g, 15.5 mmol) Stir at 0 ° C for 2 h. After completion of the reaction, the mixture was poured into EtOAc EtOAc (EtOAc m.).
步骤b：向11-a-2(3g，12.7mmol)，甲基磺酰胺(2.4g，25.4mmol)的300ml二氯甲烷溶液中加入HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(7.2g，19.1mmol)，DIPEA(N，N-二异丙基乙胺)(3.3g，25.4mmol)，DMAP(4-二甲氨基吡啶)(159mg,1.3mmol)，室温搅拌过夜。反应结束，加入水洗，分离有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，经Combi-flash柱层析纯化得到红色固体化合物11-a(3.6g)，直接用于下一步反应，纯度88.2％，产率90％，MS m/z(ESI):314[M+H]+。 Step b: To a solution of 11-a-2 (3 g, 12.7 mmol), methylsulfonamide (2.4 g, 25.4 mmol) in 300 ml of dichloromethane, HATU (2-(7-azobenzotriazole) -N,N,N',N'-tetramethyluron hexafluorophosphate) (7.2 g, 19.1 mmol), DIPEA (N,N-diisopropylethylamine) (3.3 g, 25.4 mmol), DMAP (4-Dimethylaminopyridine) (159 mg, 1.3 mmol), stirred at rt overnight. After completion of the reaction, the mixture was washed with water, and the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,, Reaction, purity 88.2%, yield 90%, MS m/z (ESI): 314 [M+H]+.
化合物13-a的制备方法：Preparation method of compound 13-a:
Figure PCTCN2016073385-appb-000058
Figure PCTCN2016073385-appb-000058
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)，得到到无色油状化合物13-a-2(24.1g，产率：41％)。1H NMR(400MHz,DMSO-d6)δ:14.10(brs,1H),12.50(brs,1H),7.87(d,J＝6.0Hz，1H),7.76(d,J＝10.0Hz，1H),3.38(s,3H)。Step a: Compound 13-a-1 (50 g, 0.40 mol) was added to concentrated hydrochloric acid (400 ml), and the mixture was cooled to 0 ° C, and a solution of sodium nitrite (28.6 g, 0.44 mol) in water (100 ml) was added dropwise. After the mixture was reacted at 0 ° C for 0.5 h, cuprous chloride (91.68 g, 0.48 mol) was added. After the mixture was stirred at room temperature for 0.5 h, it was heated to 100 ° C and stirred for 1 h. After cooling, it was filtered, and the filtrate was purified with EtOAc EtOAc (EtOAc) PE: EA = 10:1) gave Compound 13-a-2 (24.1 g, yield: 41%) as colorless oil. 1 H NMR (400MHz, DMSO- d 6) δ: 14.10 (brs, 1H), 12.50 (brs, 1H), 7.87 (d, J = 6.0Hz, 1H), 7.76 (d, J = 10.0Hz, 1H) , 3.38 (s, 3H).
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滤液得白色固体13-a-3(9.1g，产率:37％).ESI-MS(M-H)-:187。纯度＝80％(UV214)。Step b: Compound 13-a-2 (18.72 g, 130 mmol) was dissolved in anhydrous THF (200 ml), cooled to -78 ° C, N-BuLi (62.4 ml, 2.4 M/L, 248mmol). The mixture was stirred at -78 ° C for 1 h and then poured onto dry ice. The mixture was stirred at -78 °C for 1 h and then at room temperature for 1 h. The mixture was poured into aq. EtOAc (EtOAc) The organic phase was separated and washed with brine (200 mL). Dry over anhydrous sodium sulfate and filter. The filtrate was triturated with a rotary evaporator to give a white solid 13-a-3 (9.1 g, yield: 37%). ESI-MS (MH) - 187. Purity = 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)。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滤液得白色固体13-a-4(9.6g，产率:78％).ESI-MS(M+H)+:266.0。纯度＝91％(UV214)。Step c: Compound 13-a-3 (9.1 g, 48 mmol) was dissolved in anhydrous DCM (150 mL), cooled to 0 &lt;0&gt; Imine hydrochloride (13.76 g, 72 mmol), DMAP (11.8 g, 96 mmol), methanesulfonamide (9.12 g, 96 mmol). After the mixture was stirred at room temperature for 18 h, EtOAc EtOAc m. Dry over anhydrous sodium sulfate and filter. The filtrate by rotary evaporation with a rotary evaporator to give a white solid the filtrate was 13-a-4 (9.6g, yield: 78%) ESI-MS ( M + H) +:. 266.0. Purity = 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)，偶氮二异丁氰(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)δ:8.80(s,1H),8.12(d,J＝6.8Hz，1H),7.36(d,J＝12.0Hz，1H),4.54(s,2H),3.43(s,3H)。Step d: Compound 13-a-4 (7.95 g, 30 mmol) was dissolved in anhydrous DME (100 ml), and NBS (12.21 g, 69 mmol), azobisisobutylbutane (0.59 g, 3 mmol). The mixture was refluxed for 18 h with stirring and the filtrate was dried with a rotary evaporator. The residue was purified to give a white solid 13-a-5 (3.1 g, yield: 30%). ESI-MS (M+H) + : 343.7. Purity = 98.2% (UV214). 1 H NMR (400MHz, CDCl 3 ) δ: 8.80 (s, 1H), 8.12 (d, J = 6.8Hz, 1H), 7.36 (d, J = 12.0Hz, 1H), 4.54 (s, 2H), 3.43 (s, 3H).
步骤e：将化合物13-a-5(0.686mg,2mmol)加入到2％稀硫酸(25ml)中，搅拌下，加入高碘酸钠(856mg,4mmol)。混合物在100℃反应18h。用乙酸乙酯(3 x 50ml)萃取，有机相用10％硫代硫酸钠洗涤(50ml)。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(DCM:MeOH＝10:1)，得到白色固体13-a(266mg，产率：41.6％)。ESI-MS(M+H)+:295.8。纯度＝98.5％(UV214)。1H NMR(400MHz,DMSO-d6)δ:14.10(brs,1H),12.50(brs,1H),7.87(d,J＝6.0Hz，1H),7.76(d,J＝10.0Hz，1H),3.38(s,3H)。Step e: Compound 13-a-5 (0.686 mg, 2 mmol) was added to 2% dilute sulfuric acid (25 ml), and sodium iodate (856 mg, 4 mmol) was added with stirring. The mixture was reacted at 100 ° C for 18 h. Extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4). ESI-MS (M+H)+: 295.8. Purity = 98.5% (UV214). 1 H NMR (400MHz, DMSO- d6) δ: 14.10 (brs, 1H), 12.50 (brs, 1H), 7.87 (d, J = 6.0Hz, 1H), 7.76 (d, J = 10.0Hz, 1H), 3.38 (s, 3H).
化合物15-a的制备方法：Preparation method of compound 15-a:
Figure PCTCN2016073385-appb-000059
Figure PCTCN2016073385-appb-000059
步骤：将化合物15-a-1(500mg,2.4mmol)溶解在2-甲基丙-1-醇(2.7g，36mmol)中，加入碳酸铯(1.6g,4.8mmol)。180℃搅拌30分钟。反应结束，冷却至室温，倒入水中，用乙酸乙酯(2 x 50ml)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩得到无色油状化合物15-a(400mg，产率：63.5％)。Procedure: Compound 15-a-1 (500 mg, 2.4 mmol) was dissolved in 2-methylpropan-1-ol (2.7 g, 36 mmol), and cesium carbonate (1.6 g, 4.8 mmol) was added. Stir at 180 ° C for 30 minutes. After the reaction was completed, it was cooled to room temperature, poured into water, ethyl acetate (2×50 ml), EtOAcjjjjjjjjj ).
化合物17-a的制备方法：Preparation method of compound 17-a:
Figure PCTCN2016073385-appb-000060
Figure PCTCN2016073385-appb-000060
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-1]-。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 [M-1] -.
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-1]-。 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 EtOAcjjjjjjjjjjjj ). MS m / z (ESI): 203 [M-1] -.
化合物22-a的制备方法：Preparation method of compound 22-a:
Figure PCTCN2016073385-appb-000061
Figure PCTCN2016073385-appb-000061
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]+。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] + .
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]+。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] + .
化合物23-a的制备方法：Preparation method of compound 23-a:
Figure PCTCN2016073385-appb-000062
Figure PCTCN2016073385-appb-000062
步骤a：以化合物23-a-1(1g)为原料参照实施例29中步骤2的制备方法，得到化合物23-a-2(683mg)，纯度83.85％，产率83％，MS m/z(ESI):168.1[M+H]+。Step a: Using the compound 23-a-1 (1 g) as a starting material, the compound of the procedure of the step 2 in Example 29 gave Compound 23-a-2 (683 mg), purity 83.85%, yield 83%, MS m/z (ESI): 168.1 [M+H] + .
步骤b：向化合物23-a-2(385mg，2.296mmol)的乙腈(5ml)溶液中零摄氏度加入对甲基苯磺酸(474mg，2.756mmol)，4-氯苯胺与叔丁基亚硝酸酯(284mg，2.756mmol)，四丁基溴化铵(1479mg，4.593mmol)，溴化亚铜(33mg，0.23mmol)，室温搅拌1小时。反应结束，食盐水洗，干燥分离有机相，减压浓缩得粗品，经Combi-flash柱层析纯化得到无色油状化合物23-a(394mg)，纯度73.57％，产率75％。Step b: To a solution of compound 23-a-2 (385 mg, 2.296 mmol) in acetonitrile (5 ml), p. (284 mg, 2.756 mmol), tetrabutylammonium bromide (1479 mg, 4.593 mmol), cuprous bromide (33 mg, 0.23 mmol). After completion of the reaction, the mixture was washed with EtOAc (EtOAc m.
化合物24-a的制备方法：Preparation method of compound 24-a:
Figure PCTCN2016073385-appb-000063
Figure PCTCN2016073385-appb-000063
化合物24-a以化合物4-溴苯胺为起始原料，参照化合物23-a的方法进行制备。The compound 24-a was prepared starting from the compound 4-bromoaniline and referring to the compound 23-a.
化合物25-a的制备方法： Preparation method of compound 25-a:
Figure PCTCN2016073385-appb-000064
Figure PCTCN2016073385-appb-000064
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]+。Step: To a solution of compound 25-a-1 (2.03 g, 11.93 mmol The reaction was completed, concentrated under reduced pressure, washed with brine, EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj %. MS m/z (ESI): 495 [M+H] + .
化合物30-a的制备方法：Preparation method of compound 30-a:
Figure PCTCN2016073385-appb-000065
Figure PCTCN2016073385-appb-000065
步骤：以化合物30-a-1(10g)为起始原料，参照实施例4步骤1的方法制备，得到化合物30-a(6.5g)。MS m/z(ESI):102[M+H-36]+。The compound 30-a-1 (10 g) was used as a starting material. MS m/z (ESI): 102 [M + H - 36] + .
化合物32-a，33-a，34-a的制备方法：Preparation method of compound 32-a, 33-a, 34-a:
化合物32-a参照化合物15-a的方法进行制备，不同的是将步骤中的15-a-1换成5-溴-3-氯-2-氟吡啶，2-甲基丙-1-醇换成丙-2-醇，反应条件换成100摄氏度搅拌过夜。Compound 32-a was prepared by the method of Compound 15-a except that 15-a-1 in the step was replaced with 5-bromo-3-chloro-2-fluoropyridine, 2-methylpropan-1-ol. Change to propan-2-ol and adjust the reaction conditions to 100 ° C overnight.
化合物33-a参照化合物15-a的方法进行制备，不同的是将步骤中的15-a-1换成4-溴-2-氯苯酚，2-甲基丙-1-醇换成2-碘丙烷，反应条件换成80摄氏度搅拌3小时。Compound 33-a was prepared by the method of Compound 15-a except that 15-a-1 in the step was replaced with 4-bromo-2-chlorophenol and 2-methylpropan-1-ol was changed to 2- Iodine propane, the reaction conditions were changed to 80 ° C and stirred for 3 hours.
化合物34-a参照化合物15-a的方法进行制备，不同的是将步骤中的15-a-1换成4-溴-2-氯苯酚，2-甲基丙-1-醇换成2-氯-2,2-二氟乙酸钠盐，反应条件换成100摄氏度搅拌2小时。Compound 34-a was prepared by the method of Compound 15-a except that 15-a-1 in the step was replaced with 4-bromo-2-chlorophenol and 2-methylpropan-1-ol was changed to 2- Sodium chloride-2,2-difluoroacetate, and the reaction conditions were changed to 100 ° C for 2 hours.
Figure PCTCN2016073385-appb-000066
Figure PCTCN2016073385-appb-000066
化合物35-a的制备方法： Preparation method of compound 35-a:
Figure PCTCN2016073385-appb-000067
Figure PCTCN2016073385-appb-000067
步骤a：化合物13-a-3(23g,121.7mmol),乙烷磺酰胺(19.9g,182.5mmol),1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(46.7g,243.4mmol)，4-二甲氨基吡啶(14.8g,121.7mmol)，N，N-二异丙基乙胺(47.1g,365.1mmol)的二氯甲烷(250mL)混合溶液，室温搅拌48h，反应结束，减压浓缩，加入300毫升水，加入4N盐酸溶液调PH为3至4，乙酸乙酯萃取，有机相用食盐水洗涤。无水硫酸钠干燥，过滤，滤液减压浓缩，乙醇重结晶得白色固体化合物35-a-2(19.3g，产率:56.8％)，MS m/z(ESI):280.1[M+H]+。纯度＝95.27％。Step a: Compound 13-a-3 (23 g, 121.7 mmol), ethanesulfonamide (19.9 g, 182.5 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.7 g, 243.4 mmol), 4-dimethylaminopyridine (14.8 g, 121.7 mmol), N,N-diisopropylethylamine (47.1 g, 365.1 mmol) in dichloromethane (250 mL) After stirring for 48 h, the reaction was completed, concentrated under reduced pressure, water (300 ml) was added, and then, 4N hydrochloric acid solution was added to adjust the pH to 3 to 4, ethyl acetate was extracted, and the organic phase was washed with brine. Drying over anhydrous sodium sulfate, EtOAc (EtOAc m. + . Purity = 95.27%.
步骤b：化合物35-a-2(19g,67.9mmol)，N-溴代丁二酰亚胺(18.1g,101.8mmol)，偶氮二异丁氰(0.56g,3.4mmol)的乙腈(200ml)混合溶液。80摄氏度搅拌2h，反应结束。冷却至室温，减压浓缩，加入乙酸乙酯，食盐水洗，无水硫酸钠干燥，过滤，加入亚磷酸二乙酯(4.69g,34mmol)，N，N-二异丙基乙胺(8.7g,67.9mmol)，室温搅拌5小时，2N盐酸洗，食盐水洗，无水硫酸钠干燥，减压浓缩干燥得白色固体35-a(18.92g，产率:77.5％)。MS m/z(ESI):359.9[M+H]+。纯度＝98.61％。Step b: Compound 35-a-2 (19 g, 67.9 mmol), N-bromosuccinimide (18.1 g, 101.8 mmol), azobisisobutyronitrile (0.56 g, 3.4 mmol) in acetonitrile (200 ml) )mixture. Stir at 80 ° C for 2 h and the reaction is complete. It was cooled to room temperature, concentrated under reduced pressure. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjj The mixture was stirred at room temperature for 5 hours, washed with EtOAc EtOAc EtOAc EtOAc. MS m/z (ESI): 359.9 [M+H] + . Purity = 98.61%.
化合物36-a的制备方法：Preparation method of compound 36-a:
Figure PCTCN2016073385-appb-000068
Figure PCTCN2016073385-appb-000068
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)，BINAP((±)-2,2’-双-(二苯膦基)-1,1’-联萘)(56mg，0.089mmol)，叔丁基醇钾(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]+。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), BINAP ((±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl) (56 mg, 0.089 mmol), potassium tert-butylate (644 mg, 6.7 mmol), 7 ml of 1,4-dioxane, stirred at 90 ° C for 2 h. After the reaction was completed, it was cooled to room temperature, and then added with 30 ml of water and 30 ml of ethyl acetate, filtered, and ethyl acetate was evaporated. -3 (475 mg) was used directly for the next reaction. MS m/z (ESI): 289.1 [M+H - 56] + .
步骤2：将化合物HCl(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。 Step 2: The compound HCl (1.5 ml, 5.53 mmol) was added to a solution of the compound 36-a-3 (475 mg) in methanol, and the mixture was stirred at room temperature for 4 hr. Used directly without purification.
实施例4：5-氯-4-(1-(3-氯-4-(三氟甲氧基)苯基)氮杂环丁烷-3-基氧基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-4)的制备Example 4: 5-Chloro-4-(1-(3-chloro-4-(trifluoromethoxy)phenyl)azetidin-3-yloxy)-2-fluoro-N-( Preparation of Methylsulfonyl)benzamide (Z-4)
Figure PCTCN2016073385-appb-000069
Figure PCTCN2016073385-appb-000069
步骤1：向50ml单口圆底烧瓶中加入化合物5-a(517mg，2.98mmol)，盐酸(4M，5ml，20mmol)，甲醇5ml，室温搅拌过夜。反应结束，反应液减压浓缩得到固体化合物4-b(325mg)，直接用于下一步反应，产率99.4％。MS m/z(ESI):74[M+H]+。Step 1: To a 50 ml single-necked round bottom flask was added compound 5-a (517 mg, 2.98 mmol), hydrochloric acid (4M, 5 ml, 20 mmol) After completion of the reaction, the reaction mixture was concentrated under reduced vacuo. MS m/z (ESI): 74 [M+H] + .
步骤2：向50ml密封管中加入4-溴-2-氯-1-(三氟甲氧基)苯(215mg，0.781mmol)，化合物4-b(127mg，1.159mmol)，Pd2(dba)3(三(二亚苄基丙酮)二钯)(36mg，0.039mmol)，BINAP((±)-2,2’-双-(二苯膦基)-1,1’-联萘)(51mg，0.082mmol)，叔丁基醇钾(263mg，2.344mmol)，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4-c(215mg)，直接用于下一步反应，纯度73.3％，产率89.6％。MS m/z(ESI):268.0[M+H]+。Step 2: To a 50 ml sealed tube was added 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (215 mg, 0.781 mmol), compound 4-b (127 mg, 1.159 mmol), Pd 2 (dba) 3 (tris(dibenzylideneacetone)dipalladium) (36 mg, 0.039 mmol), BINAP((±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl) (51 mg) , 0.082 mmol), potassium tert-butoxide (263 mg, 2.344 mmol), 7 ml of 1,4-dioxane, stirred at 90 ° C for 2 h. After the reaction was completed, it was cooled to room temperature, and then added with 30 ml of water and 30 ml of ethyl acetate, filtered, and ethyl acetate was evaporated. (215 mg), directly used in the next reaction, purity 73.3%, yield 89.6%. MS m/z (ESI): 268.0 [M+H] + .
步骤3：化合物4-c(135mg，0.504mmol)，5-氯-2,4-二氟-N-(甲基磺酰基)苯甲酰胺(107mg，0.397mmol)，碳酸铯(260mg，0.798mmol)，6ml二甲基亚砜的混合物，在微波条件下，220℃搅拌30分钟。反应结束，冷却至室温，加入30ml水，调pH为6～7，乙酸乙酯萃取，分离有机相，减压浓缩得到深度油状物300mg，经Combi-flash柱层析纯化得到白色固体化合物Z-4(30mg)，纯度98.77％，产率69.0％。MS m/z(ESI):517.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.18(s,1H),7.86(d,J＝7.8Hz,1H),7.37(d,J＝8.8Hz,1H),7.12(d,J＝12Hz,1H),6.73(d,J＝2.8Hz,1H),6.51～6.54(dd,J1＝8.8Hz,J2＝2.8Hz,1H),5.31～5.36(m,1H),4.39～4.44(m,2H),3.90～3.94(m,2H),3.36(s,3H)。Step 3: Compound 4-c (135 mg, 0.504 mmol), 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (107 mg, 0.397 mmol), cesium carbonate (260 mg, 0.798 mmol) A mixture of 6 ml of dimethyl sulfoxide was stirred at 220 ° C for 30 minutes under microwave conditions. After completion of the reaction, the mixture was cooled to room temperature, 30 ml of water was added, the pH was adjusted to 6 to 7 and ethyl acetate was extracted. The organic phase was separated and concentrated under reduced pressure to give a crude oil (300 mg). 4 (30 mg), purity 98.77%, yield 69.0%. MS m/z (ESI): 517.0 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): δ12.18 (s, 1H), 7.86 (d, J = 7.8Hz, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.12 (d, J =12 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 6.51 to 6.54 (dd, J 1 = 8.8 Hz, J 2 = 2.8 Hz, 1H), 5.31 to 5.36 (m, 1H), 4.39 - 4.44 (m, 2H), 3.90 to 3.94 (m, 2H), 3.36 (s, 3H).
实施例5：5-氯-4-(1-(3-氯-4-(三氟甲氧基)苯甲酰基)氮杂环丁烷-3-基氧基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-5)的制备 Example 5: 5-Chloro-4-(1-(3-chloro-4-(trifluoromethoxy)benzoyl)azetidin-3-yloxy)-2-fluoro-N- Preparation of (methylsulfonyl)benzamide (Z-5)
Figure PCTCN2016073385-appb-000070
Figure PCTCN2016073385-appb-000070
步骤：向50ml单口圆底烧瓶中加入3-氯-4-(三氟甲氧基)苯甲酸(31g，0.129mmol)，化合物2-c(65mg，0.181mmol)，HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(99mg，0.260mmol)，DIPEA(N，N-二异丙基乙胺)(56mg，0.433mmol)，二甲基甲酰胺3ml，室温搅拌过夜。反应结束，加入20ml水，调节pH为4～5，乙酸乙酯萃取(20ml x 3)，分离有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到油状物(120mg)，经制备液相分离纯化得白色固体化合物Z-5(10mg)纯度100％，产率14.2％。MS m/z(ESI):545.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ7.96((d,J＝2.0Hz,1H),7.77～7.83(m,2H),7.64～7.67(dd,J1＝8.4Hz,J2＝1.6Hz,1H),6.82(d,J＝12Hz,1H),5.18～5.21(m,1H),4.79～4.83(m,1H),4.59～4.64(m,1H),4.46～4.49(m,1H),4.07(d,J＝9.6Hz,1H),2.91(s,3H)。Procedure: To a 50 ml single-neck round bottom flask was added 3-chloro-4-(trifluoromethoxy)benzoic acid (31 g, 0.129 mmol), compound 2-c (65 mg, 0.181 mmol), HATU (2-(7-) Azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate) (99 mg, 0.260 mmol), DIPEA (N,N-diisopropylethylamine) (56 mg , 0.433 mmol), 3 ml of dimethylformamide, stirred at room temperature overnight. After the reaction was completed, 20 ml of water was added, the pH was adjusted to 4 to 5, ethyl acetate was extracted (20 ml x 3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give an oil (120 mg). The white solid compound Z-5 (10 mg) was purified by phase separation to yield 100%, yield 14.2%. MS m/z (ESI): 545.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.96 ((d,J=2.0 Hz, 1H), 7.77 to 7.83 (m, 2H), 7.64 to 7.67 (dd, J 1 = 8.4 Hz, J 2 =1.6 Hz, 1H), 6.82 (d, J = 12 Hz, 1H), 5.18 to 5.21 (m, 1H), 4.79 to 4.83 (m, 1H), 4.59 to 4.64 (m, 1H), 4.46 to 4.49 (m) , 1H), 4.07 (d, J = 9.6 Hz, 1H), 2.91 (s, 3H).
实施例6：5-氯-4-(1-(3-氯-4-(三氟甲氧基)苄基)氮杂环丁烷-3-基氧基)-N-(N，N-二甲基氨磺酰)-2-氟苯甲酰胺(Z-6)的制备Example 6: 5-Chloro-4-(1-(3-chloro-4-(trifluoromethoxy)benzyl)azetidin-3-yloxy)-N-(N,N- Preparation of dimethylsulfamoyl)-2-fluorobenzamide (Z-6)
Figure PCTCN2016073385-appb-000071
Figure PCTCN2016073385-appb-000071
步骤1：向100ml单口圆底烧瓶中加入化合物1-a-3(1g，5.19mmol)，CDI(N,N’-羰基二咪唑)(1.87g，11.53mmol),20ml THF，75℃搅拌0.5h，冷却至室温，加入N,N-二甲基磺酰胺(1.29g，10.39mmol)，DBU(1,8-二氮杂二环十一碳-7-烯)(2.37g，15.57 mmol),75℃搅拌5h。反应结束，反应液减压浓缩除去THF，加入50ml水和50ml乙酸乙酯，调节pH为5～6，乙酸乙酯萃取，分离有机相，减压浓缩，加入10ml石油醚和10ml乙酸乙酯打浆，过滤，得到灰白色固体化合物6-b(1.38g)，直接用于下一步反应，纯度91.2％，产率84.7％。MS m/z(ESI):299.0[M+H]+。Step 1: Compound 1-a-3 (1 g, 5.19 mmol h, cooled to room temperature, added N,N-dimethylsulfonamide (1.29 g, 10.39 mmol), DBU (1,8-diazabicycloundec-7-ene) (2.37 g, 15.57 mmol) Stir at 75 ° C for 5 h. At the end of the reaction, the reaction mixture was concentrated under reduced pressure to remove THF. EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. After filtration, the compound 6-b (1.38 g) was obtained as a white solid, which was directly used for the next reaction, purity 91.2%, yield 84.7%. MS m/z (ESI): 299.0 [M+H] + .
步骤2：化合物6-b(306mg，1.02mmol)，叔丁基3-羟基氮杂环丁烷-1-羧酸叔丁酯(215mg，1.24mmol)，碳酸铯(993mg，3.05mmol)，10ml 1,4-二氧六环的混合物，在微波条件下，180℃搅拌40分钟。反应结束，冷却至室温，加入30ml水，调节pH为5～6，乙酸乙酯萃取(30ml x 2)，分离合并有机相，减压浓缩得到粗品，经Combi-flash柱层析纯化得到油状化合物6-c(170mg)，直接用于下一步反应，纯度69.8％，产率37％。MS m/z(ESI):474.1[M+Na]+。Step 2: Compound 6-b (306 mg, 1.02 mmol), tert-butyl 3-hydroxyazetidine-l-carboxylic acid tert-butyl ester (215 mg, 1.24 mmol), cesium carbonate (993 mg, 3.05 mmol), 10 ml A mixture of 1,4-dioxane was stirred at 180 ° C for 40 minutes under microwave conditions. After the reaction was completed, it was cooled to room temperature, 30 ml of water was added, the pH was adjusted to 5-6, ethyl acetate was extracted (30 ml x 2), and the organic phase was separated and concentrated under reduced pressure. 6-c (170 mg) was used directly for the next reaction, purity 69.8%, yield 37%. MS m/z (ESI): 474.1 [M+Na] + .
步骤3：向50ml单口圆底烧瓶中加入化合物6-c(170mg，0.376mmol)，盐酸(4M，2ml，8mmol)，3ml甲醇，室温搅拌过夜。反应结束，反应液减压浓缩得到油状化合物6-d(145mg)，直接用于下一步反应，纯度69.9％，产率99.3％。MS m/z(ESI):352.1[M+H]+。Step 3: To a 50 ml single-necked round bottom flask was added compound 6-c (170 mg, 0.376 mmol), hydrochloric acid (4M, 2 ml, 8 mmol) After completion of the reaction, the reaction mixture was concentrated under reduced pressure toield of Compound 6-d ( 145 mg), which was used for the next reaction, purity 69.9%, yield 99.3%. MS m/z (ESI): 3521. [M+H] + .
步骤4：向50ml单口圆底烧瓶中加入化合物6-d(145mg，0.373mmol)，4-(溴甲基)-2-氯-1-(三氟甲氧基)苯(115mg，0.397mmol)，碳酸钾(150mg，1.085mmol)，5ml二甲基乙酰胺，室温搅拌4h。反应结束，加入30ml水，调pH为5～6，乙酸乙酯萃取(30ml x 2)，分离合并有机相，减压浓缩得到油状物270mg，经制备液相分离纯化得白色固体化合物Z-6(20.2mg)，纯度97.8％，产率9.7％。MS m/z(ESI):559.9[M+H]+。1H NMR(400MHz,DMSO-d6):δ7.76(d,J＝7.6Hz,1H),7.74(d,J＝1.6Hz,1H),7.52～7.55(dd,J1＝8.4Hz,J2＝1.2Hz,1H),7.41～7.44(dd,J1＝8.4Hz,J2＝2.0Hz,1H),6.95(d,J＝11.6Hz,1H),5.01(m,1H),3.86(m,2H),3.74(s,2H),3.20(m,2H),2.81(s,6H)。Step 4: To a 50 ml single-neck round bottom flask was added compound 6-d (145 mg, 0.373 mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (115 mg, 0.397 mmol) Potassium carbonate (150 mg, 1.085 mmol), 5 ml of dimethylacetamide, stirred at room temperature for 4 h. At the end of the reaction, 30 ml of water was added, the pH was adjusted to 5-6, ethyl acetate was extracted (30 ml x 2), and the combined organic phase was separated and concentrated under reduced pressure to give 270 mg of oil. (20.2 mg), purity 97.8%, yield 9.7%. MS m/z (ESI): 559.9 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): δ7.76 (d, J = 7.6Hz, 1H), 7.74 (d, J = 1.6Hz, 1H), 7.52 ~ 7.55 (dd, J 1 = 8.4Hz, J 2 = 1.2 Hz, 1H), 7.41 to 7.44 (dd, J 1 = 8.4 Hz, J 2 = 2.0 Hz, 1H), 6.95 (d, J = 11.6 Hz, 1H), 5.01 (m, 1H), 3.86 (m, 2H), 3.74 (s, 2H), 3.20 (m, 2H), 2.81 (s, 6H).
实施例7、9-14、18-21、165Examples 7, 9-14, 18-21, 165
化合物Z-7、Z-9、Z-10、Z-11、Z-12、Z-13、Z-14、Z-18、Z-19、Z-20以化合物4-b为起始原料，参照实施例4的方法进行制备，不同的是将步骤2中4-溴-2-氯-1-(三氟甲氧基)苯分别换成4-溴-1,2-二氯苯、1-溴-3-氯苯、1-溴-3,5-二氯苯、1-溴-4-氯苯、1-溴-4-(三氟甲氧基)苯、1-溴-4-氟苯、化合物6-a、1-溴-2-(三氟甲氧基)苯、4-溴-2-氯-1-(三氟甲基)苯、化合物15-a。Compounds Z-7, Z-9, Z-10, Z-11, Z-12, Z-13, Z-14, Z-18, Z-19, Z-20 start from compound 4-b. The preparation was carried out in accordance with the method of Example 4 except that the 4-bromo-2-chloro-1-(trifluoromethoxy)benzene in the step 2 was replaced with 4-bromo-1,2-dichlorobenzene, respectively. -bromo-3-chlorobenzene, 1-bromo-3,5-dichlorobenzene, 1-bromo-4-chlorobenzene, 1-bromo-4-(trifluoromethoxy)benzene, 1-bromo-4- Fluorobenzene, compound 6-a, 1-bromo-2-(trifluoromethoxy)benzene, 4-bromo-2-chloro-1-(trifluoromethyl)benzene, compound 15-a.
化合物Z-21以化合物4-c为起始原料，参照实施例4的方法进行制备，不同的是将步骤3中化合物1-a换成化合物9-a。 Compound Z-21 was prepared by the method of Example 4 using Compound 4-c as a starting material, except that Compound 1-a in Step 3 was changed to Compound 9-a.
化合物Z-165参照Z-7类似方法制备。Compound Z-165 was prepared in a similar manner to Z-7.
Figure PCTCN2016073385-appb-000072
Figure PCTCN2016073385-appb-000072
Figure PCTCN2016073385-appb-000073
Figure PCTCN2016073385-appb-000073
实施例22：(R)-5-氯-4-((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-22)的制备Example 22: (R)-5-chloro-4-((1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl)methoxy)-2-fluoro Preparation of -N-(methylsulfonyl)benzamide (Z-22)
Figure PCTCN2016073385-appb-000074
Figure PCTCN2016073385-appb-000074
步骤1：以化合物7-a(500mg)为原料参照实施例4中步骤2的制备方法，得到化合物22-b(220mg)，纯度53％，产率41％，MS m/z(ESI):296[M+H]+。Step 1: The compound 7-b (500 mg) was used as a starting material. The compound was obtained by the procedure of Step 2 of Example 4 to give Compound 22-b (220 mg), purity 53%, yield 41%, MS m/z (ESI): 296[M+H] + .
步骤2：以化合物22-b(200mg)为原料参照实施例4中步骤3的制备方法，得到 化合物Z-22(60mg)，纯度79％，产率16.3％，MS m/z(ESI):545[M+H]+。1H NMR(500MHz,DMSO-d6)δ12.14(s,1H),7.78(d,J＝7.5Hz,1H),7.31(d,J＝9.0Hz,1H),7.19(d,J＝12.1Hz,1H),6.91(d,J＝2.5Hz,1H),6.71(dd,J＝9.5,2.9Hz,1H),4.25(s,1H),4.16(m,2H),3.48(t,J＝8.6Hz,1H),3.24(s,3H),3.15(d,J＝6.5Hz,1H),2.23(d,J＝7.5Hz,1H),2.12–1.92(m,3H).Step 2: Compound 22-b (200 mg) was used as a starting material to give the compound Z-22 (60 mg), purity 79%, yield: 16.3%, MS m/z (ESI): 545[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.14 (s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 12.1 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.71 (dd, J = 9.5, 2.9 Hz, 1H), 4.25 (s, 1H), 4.16 (m, 2H), 3.48 (t, J = 8.6 Hz, 1H), 3.24 (s, 3H), 3.15 (d, J = 6.5 Hz, 1H), 2.23 (d, J = 7.5 Hz, 1H), 2.12 - 1.92 (m, 3H).
实施例23：Example 23
化合物Z-23以化合物7-a为起始原料，参照实施例22的方法进行制备，不同的是将步骤1中4-溴-2-氯-1-(三氟甲氧基)苯换成4-溴-1,2-二氯苯。Compound Z-23 was prepared by the method of Example 22 using compound 7-a as a starting material, except that 4-bromo-2-chloro-1-(trifluoromethoxy)benzene was replaced in step 1. 4-bromo-1,2-dichlorobenzene.
Figure PCTCN2016073385-appb-000075
Figure PCTCN2016073385-appb-000075
实施例26：(S)-5-氯-4-((1-(3-氯-4-(三氟甲氧基)苯基)氮杂环丁-2-基)甲氧基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-24)的制备Example 26: (S)-5-Chloro-4-((1-(3-chloro-4-(trifluoromethoxy)phenyl)azetidin-2-yl)methoxy)-2 -Preparation of fluoro-N-(methylsulfonyl)benzamide (Z-24)
Figure PCTCN2016073385-appb-000076
Figure PCTCN2016073385-appb-000076
步骤1：向化合物8-a(333mg，3.294mmol)的5ml THF溶液中，零℃滴加6.6ml硼烷/THF溶液(1M)，滴加完毕，60℃搅拌5h。反应结束，冷却至室温，加入甲醇，减压浓缩，加入乙酸乙酯稀释，过滤，滤液减压浓缩得无色油状化合物24-b(340mg)。不经纯化直接下一步。Step 1: To a solution of Compound 8-a (333 mg, 3.294 mmol) in 5 mL THF, 6.6 ml of borane/THF solution (1M) was added dropwise at 0 ° C, and the mixture was stirred and stirred at 60 ° C for 5 h. After completion of the reaction, the mixture was cooled to EtOAc. The next step was carried out without purification.
步骤2：以化合物24-b(340mg)为原料参照实施例4中步骤2的制备方法，得到黄色固体化合物24-c(130mg)，纯度65％，产率18％。Step 2: Using Compound 24-b (340 mg) as a starting material, the title compound of Step 2 of Example 4 was obtained to afford compound 24-c (130 mg) as a yellow solid.
步骤3：以化合物24-c(130mg)为原料参照实施例4中步骤3的制备方法，得到 白色固体化合物Z-24(11mg)，纯度100％，产率7％，MS m/z(ESI):531.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ7.81(d,J＝6Hz,1H),7.33(d,J＝7.2Hz,1H),7.19(s,1H),7.02(d,J＝2Hz,1H),6.69(dd,J＝7.2,2.4Hz,1H),4.50(d,J＝3.2Hz,1H),4.39-4.34(m,2H),4.03-3.99(m,1H),3.69(d,J＝7.2Hz,1H),3.32(s,3H),3.04-3.02(m,2H)。Step 3: Using the compound 24-c (130 mg) as a starting material, the title compound of Step 3 of Example 4 was obtained to give the white solid compound Z-24 (11 mg), purity 100%, yield 7%, MS m/z (ESI) ): 531.0 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ7.81 (d, J = 6Hz, 1H), 7.33 (d, J = 7.2Hz, 1H), 7.19 (s, 1H), 7.02 (d, J = 2Hz , 1H), 6.69 (dd, J = 7.2, 2.4 Hz, 1H), 4.50 (d, J = 3.2 Hz, 1H), 4.39-4.34 (m, 2H), 4.03 - 3.99 (m, 1H), 3.69 ( d, J = 7.2 Hz, 1H), 3.32 (s, 3H), 3.04 - 3.02 (m, 2H).
实施例28：5-氯-4-(4-(3,4-二氯苯基)哌嗪-1-基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-25)的制备Example 28: 5-Chloro-4-(4-(3,4-dichlorophenyl)piperazin-1-yl)-2-fluoro-N-(methylsulfonyl)benzamide (Z-25 Preparation
Figure PCTCN2016073385-appb-000077
Figure PCTCN2016073385-appb-000077
步骤：向化合物10-a(211.6mg，0.92mmol)的2ml二甲基亚砜溶液中加入化合物1-a(250mg，0.92mmol)，碳酸钾(254mg，1.84mmol)，在微波下，140℃搅拌0.5h。反应结束，冷却至室温，加入乙酸乙酯，饱和碳酸氢钠洗，分离有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。经制备液相分离纯化得白色固体化合物Z-25(21.2mg)，纯度100％，产率4.8％。MS m/z(ESI):480.0[M+H]+。1H NMR(400MHz,DMSO-d6):δ7.45(d,J＝8.8Hz,1H),7.40(d,J＝8.8Hz,1H),7.19(d,J＝3.2Hz,1H),7.00(m,1H),6.90(d,J＝12.4Hz,1H),3.32(m,4H),3.17(m,4H),3.09(s,3H).The compound 1-a (250 mg, 0.92 mmol), potassium carbonate (254 mg, 1.84 mmol) was added to a solution of compound 10-a (211.6 mg, 0.92 mmol) in 2 ml of dimethyl sulfoxide, under microwave, 140 ° C Stir for 0.5 h. After completion of the reaction, the mixture was cooled to room temperature. EtOAc was evaporated. The white solid compound Z-25 (21.2 mg) was obtained by preparative liquid phase separation, purity 100%, yield 4.8%. MS m/z (ESI): 480.0 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): δ7.45 (d, J = 8.8Hz, 1H), 7.40 (d, J = 8.8Hz, 1H), 7.19 (d, J = 3.2Hz, 1H), 7.00 (m, 1H), 6.90 (d, J = 12.4 Hz, 1H), 3.32 (m, 4H), 3.17 (m, 4H), 3.09 (s, 3H).
实施例29：4-(1-(3-氯-4-(三氟甲氧基)苯基)氮杂环丁烷-3-基氧基)-5-环丙基-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-26)的制备Example 29: 4-(1-(3-Chloro-4-(trifluoromethoxy)phenyl)azetidin-3-yloxy)-5-cyclopropyl-2-fluoro-N Preparation of -(methylsulfonyl)benzamide (Z-26)
Figure PCTCN2016073385-appb-000078
Figure PCTCN2016073385-appb-000078
步骤1：以化合物4-c(240mg)为原料参照实施例4中步骤3的制备方法，将化合物1-a换成化合物11-a得到黄色固体化合物26-b(160mg)，纯度26.11％，产率27.8％，MS m/z(ESI):563[M+H]+。Step 1: The compound 4-c (240 mg) was used as a starting material. The compound 1-a was replaced with the compound 11-a by the method of the procedure of the step 3 in Example 4 to obtain a yellow solid compound 26-b (160 mg). Yield 27.8%, MS m/z (ESI): 564 [M+H]+.
步骤2：向化合物26-b(140mg，0.25mmol)，环丙基硼酸(43mg，0.5mmol)的10ml二氧六环溶液中加入[1,1’-双(二苯基膦基)二茂铁]二氯化钯(22mg，0.03mmol)，碳酸铯(163mg，0.5mmol),氩气保护，100℃搅拌过夜。反应结束，冷却至室温，过 滤，倒入水中，乙酸乙酯萃取，无水硫酸钠干燥有机相，减压浓缩得粗品，经制备液相分离纯化得白色固体化合物Z-26(20mg)。MS m/z(ESI):523[M+H]+。1H NMR(500MHz,DMSO-d6):δ12.00(s,1H),7.36(d,J＝8.0Hz,1H),7.21(d,J＝5.5Hz,1H),6.74(d,J＝3.0Hz,1H),6.67(d,J＝12.5,1H),6.53(dd,J＝9.0,2.5Hz,1H),5.29-5.22(m,1H),4.42(t,J＝6.5Hz,2H),3.91(dd,J＝3.5,9.0Hz,2H),3.06(s,3H),2.11-2.07(m,1H),0.93-0.89(m,2H),0.65-0.64(3m,2H)。Step 2: To a solution of compound 26-b (140 mg, 0.25 mmol), cyclopropylboronic acid (43 mg, 0.5 mmol) in 10 ml of dioxane, [1,1'-bis(diphenylphosphino) dioxin Iron] palladium dichloride (22 mg, 0.03 mmol), cesium carbonate (163 mg, 0.5 mmol), argon gas, and stirred at 100 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, evaporated, evaporated, evaporated, evaporated. MS m/z (ESI): 564 [M+H] + . 1 H NMR (500MHz, DMSO- d 6): δ12.00 (s, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.21 (d, J = 5.5Hz, 1H), 6.74 (d, J =3.0 Hz, 1H), 6.67 (d, J = 12.5, 1H), 6.53 (dd, J = 9.0, 2.5 Hz, 1H), 5.29 - 5.22 (m, 1H), 4.42 (t, J = 6.5 Hz, 2H), 3.91 (dd, J=3.5, 9.0 Hz, 2H), 3.06 (s, 3H), 2.11-2.07 (m, 1H), 0.93-0.89 (m, 2H), 0.65-0.64 (3 m, 2H) .
实施例31：5-氯-4-(3-(3-氯-4-(三氟甲氧基)苯基)氮杂环丁烷-1-羰基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-31)的制备Example 31: 5-Chloro-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)azetidin-1-carbonyl)-2-fluoro-N-(methyl Preparation of sulfonyl)benzamide (Z-31)
Figure PCTCN2016073385-appb-000079
Figure PCTCN2016073385-appb-000079
步骤：化合物30-c(30mg，0.104mmol)，化合物13-a(30mg，0.101mmol)，DIPEA(N，N-二异丙基乙胺)(36mg，0.355mmol)，HATU(2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)(67mg，0.176mmol)，6ml二氯甲烷的混合物，室温搅拌1h。反应结束，2N盐酸洗，二氯甲烷萃取，饱和食盐水洗，有机相减压浓缩得粗品，经制备柱层析纯化得到化合物Z-31(24mg)，纯度94％，产率44％。MS m/z(ESI):529[M-H]+。1H NMR(500MHz,DMSO-d6):δ7.758-7.716(m,2H),7.587-7.509(m,2H),7.383(d,J＝9.5Hz,1H),4.459(s,1H),4.278(s,1H),4.01-4.00(m,3H),2.838(s,3H).Step: Compound 30-c (30 mg, 0.104 mmol), Compound 13-a (30 mg, 0.101 mmol), DIPEA (N,N-diisopropylethylamine) (36 mg, 0.355 mmol), HATU (2-(7) A mixture of -azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67 mg, 0.176 mmol), 6 ml of dichloromethane was stirred at room temperature for 1 h. After completion of the reaction, the mixture was washed with EtOAc EtOAc EtOAc EtOAc. MS m/z (ESI): 495 [MH] + . 1 H NMR (500MHz, DMSO- d 6): δ7.758-7.716 (m, 2H), 7.587-7.509 (m, 2H), 7.383 (d, J = 9.5Hz, 1H), 4.459 (s, 1H) , 4.278 (s, 1H), 4.01-4.00 (m, 3H), 2.838 (s, 3H).
实施例32：5-氯-4-((3-(3-氯-4-(三氟甲氧基)苯基)氮杂环丁烷-1-基)甲基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-32)的制备Example 32: 5-Chloro-4-((3-(3-chloro-4-(trifluoromethoxy)phenyl)azetidin-1-yl)methyl)-2-fluoro-N Preparation of -(methylsulfonyl)benzamide (Z-32)
Figure PCTCN2016073385-appb-000080
Figure PCTCN2016073385-appb-000080
步骤：向25ml单口圆底烧瓶中加入化合物30-c(67mg，0.232mmol)，化合物13-a-5(40mg，0.117mmol)，碳酸钾(64mg，0.463mmol)，7ml乙腈，室温搅拌过夜。反应结束，加入水(10ml x 3)和乙酸乙酯萃取(10ml x 3)，分离合并有机相，减压浓缩得到粗品，经液相制备纯化得到固体化合物Z-32(29mg)，纯度100％，产率24％。MS m/z(ESI):515[M+H]+。1H NMR(500MHz,DMSO-d6):δ7.731(d,J＝1Hz,1H),7.684(d,J＝7,1H),7.518-7.555(m,2H),7.199(d,J＝11.5Hz,1H),6.089(s,2H),3.737-3.681(m,5H),2.829(s,3H).The compound 30-c (67 mg, 0.232 mmol), compound 13-a-5 (40 mg, 0.117 mmol), potassium carbonate (64 mg, 0.463 mmol), 7 ml of acetonitrile, and stirred at room temperature overnight. After completion of the reaction, water (10 ml x 3) and ethyl acetate (10 ml x 3) were added, and the combined organic phases were separated and concentrated under reduced pressure to give a crude compound, which was purified by liquid phase to give solid compound Z-32 (29 mg). The yield is 24%. MS m/z (ESI): 515 [M+H] + . 1 H NMR (500MHz, DMSO- d 6): δ7.731 (d, J = 1Hz, 1H), 7.684 (d, J = 7,1H), 7.518-7.555 (m, 2H), 7.199 (d, J =11.5 Hz, 1H), 6.089 (s, 2H), 3.737-3.681 (m, 5H), 2.829 (s, 3H).
实施例33：(R)-5-氯-4-(1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-3-基氧基)-2-氟-N-(甲基磺酰基)苯甲酰胺(Z-33)的制备Example 33: (R)-5-chloro-4-(1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-3-yloxy)-2-fluoro-N- Preparation of (methylsulfonyl)benzamide (Z-33)
Figure PCTCN2016073385-appb-000081
Figure PCTCN2016073385-appb-000081
步骤1：以化合物14-a(644mg)为原料参照实施例4步骤1的制备方法，得黄色固体化合物33-b(425mg)，产率100％。Step 1: Using the compound 14-a (644 mg) as a starting material.
步骤2：以化合物33-b(425mg)为原料参照实施例4中步骤2的制备方法，得到黄色油状化合物33-c(520mg)，纯度83.4％，产率80.7％，MS m/z(ESI):282[M+H]+。Step 2: Compound 33-b (425 mg) was used as a starting material. The title compound was obtained from the title compound of Example 4 to afford the compound 33-c (520 mg) as a yellow oil, purity 83.4%, yield 80.7%, MS m/z (ESI) ): 282 [M+H] + .
步骤3：向单口圆底烧瓶中加入化合物33-c(288mg，1.0225mmol)，叔丁醇钾(344mg，3.065mmol)，THF10ml，冰浴搅拌2分钟，加入化合物1-a(358mg，1.327mmol)，搅拌30分钟。反应结束，加入水(10ml x 3)和乙酸乙酯萃取(10ml x 3)，分离合并有机相，减压浓缩得到粗品，经液相制备纯化得到固体化合物Z-33(4.6mg)，纯度100％，产率0.7％。MS m/z(ESI):531[M+H]+。1H NMR(500MHz,DMSO-d6)δ7.765(d,J＝8Hz,1H),7.315(d,J＝8Hz,1H),7.110(d,J＝12Hz,1H),6.765(d,J＝3Hz,1H),6.583-6.607(m,1H),5.312(s,1H),3.701(dd,J＝11.5,4.5Hz,1H),3.446-3.410(m,3H),3.328(s,2H),2.818(s,3H). Step 3: To a one-neck round bottom flask was added compound 33-c (288 mg, 1.0225 mmol), potassium tert-butoxide (344 mg, 3.065 mmol), THF 10 ml, and stirred for 2 min in ice-bath, and compound 1-a (358 mg, 1.327 mmol) ), stirring for 30 minutes. After completion of the reaction, water (10 ml x 3) and ethyl acetate (10 ml x 3) were added, and the combined organic phase was separated and concentrated under reduced pressure to give a crude compound, which was purified by liquid phase to give solid compound Z-33 (4.6 mg). %, yield 0.7%. MS m/z (ESI): 531 [M+H] + . 1 H NMR (500MHz, DMSO- d 6) δ7.765 (d, J = 8Hz, 1H), 7.315 (d, J = 8Hz, 1H), 7.110 (d, J = 12Hz, 1H), 6.765 (d, J=3 Hz, 1H), 6.583-6.607 (m, 1H), 5.312 (s, 1H), 3.701 (dd, J=11.5, 4.5 Hz, 1H), 3.446-3.410 (m, 3H), 3.328 (s, 2H), 2.818 (s, 3H).
实施例40-41、43-47、49：Examples 40-41, 43-47, 49:
化合物Z-40至41，Z-43至47、Z-49可参照本发明实施例1-33的类似方法制备。Compounds Z-40 to 41, Z-43 to 47, and Z-49 can be produced by a similar method to Examples 1-33 of the present invention.
Figure PCTCN2016073385-appb-000082
Figure PCTCN2016073385-appb-000082
实施例50：(R)-5-氯-2-氟-N-(甲基磺酰基)-4-((1-(4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-50)的制备Example 50: (R)-5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((1-(4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl Preparation of methoxy)benzamide (Z-50)
Figure PCTCN2016073385-appb-000083
Figure PCTCN2016073385-appb-000083
步骤1：1-溴-4-(三氟甲氧基)苯(1g，4.15mmol)，化合物7-a(0.63g，6.22mmol),(S)-脯氨酸(96mg，0.83mmol)，碘化亚铜(79mg，0.415mmol)，碳酸钾(1.72g，12.45mmol)的二甲基亚砜(10ml)混合溶液，氮气保护90℃搅拌4h。反应结束，冷却至室温，倒入水和乙酸乙酯萃取，食盐水洗，干燥分离有机相，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50-b(186mg)，直接用于下一步反应，纯度82％，产率17％。MS m/z(ESI):262.1[M+H]+。 Step 1: 1 -Bromo-4-(trifluoromethoxy)benzene (1 g, 4.15 mmol), compound 7-a (0.63 g, 6.22 mmol), (S)-valine (96 mg, 0.83 mmol), A mixed solution of cuprous iodide (79 mg, 0.415 mmol), potassium carbonate (1.72 g, 12.45 mmol) in dimethyl sulfoxide (10 ml) was stirred at 90 ° C for 4 h under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, poured with water and ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Directly used in the next reaction, purity 82%, yield 17%. MS m/z (ESI): 2621. [M+H] + .
步骤2：以化合物50-b(119mg)为原料，参照实施例4中步骤3的制备方法，得到白色固体化合物Z-50(52.17mg)，纯度100％，MS m/z(ESI):509[M-H]-。1H NMR(500MHz,DMSO-d6):δ12.11(s,1H),7.78(d,J＝7.5Hz,1H),7.16(m,3H),6.74(d,9.0Hz,2H)，4.18(d,J＝7.0Hz,2H),4.13-4.08(m,1H),3.46(t,J＝6.8Hz,1H),3.20(s,3H),3.17-3.11(m,1H),2.27-2.21(m,1H),2.10-2.04(m,2H),2.05-2.00(m,1H).Step 2: Compound 50-b (119 mg) was used as a starting material. [MH] - . 1 H NMR (500MHz, DMSO- d 6): δ12.11 (s, 1H), 7.78 (d, J = 7.5Hz, 1H), 7.16 (m, 3H), 6.74 (d, 9.0Hz, 2H), 4.18 (d, J = 7.0 Hz, 2H), 4.13-4.08 (m, 1H), 3.46 (t, J = 6.8 Hz, 1H), 3.20 (s, 3H), 3.17 - 3.11 (m, 1H), 2.27 -2.21 (m, 1H), 2.10-2.04 (m, 2H), 2.05-2.00 (m, 1H).
实施例51-52、58、67、69、71-72、76、97、104、110、113Examples 51-52, 58, 67, 69, 71-72, 76, 97, 104, 110, 113
化合物Z-51以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成1-溴-2,4-二氯苯，反应条件换成140℃搅拌30分钟。Compound Z-51 was prepared from compound 7-a using the procedure of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 2,4-Dichlorobenzene, the reaction conditions were changed to 140 ° C and stirred for 30 minutes.
化合物Z-52以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-2-氯-1-氟苯，反应条件换成90℃搅拌过夜。Compound Z-52 was prepared starting from compound 7-a by the method of Example 50 except that the 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 4-bromo- 2-Chloro-1-fluorobenzene, the reaction conditions were changed to 90 ° C and stirred overnight.
化合物Z-58以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成2-溴-5-氯吡啶，反应条件换成110℃搅拌5小时。化合物Z-67以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌20小时。Compound Z-58 was prepared from compound 7-a using the same procedure as in Example 50 except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 2-bromo- 5-chloropyridine, and the reaction conditions were changed to 110 ° C and stirred for 5 hours. Compound Z-67 was prepared by the method of Example 50 using compound 7-a as a starting material, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 4-(Trifluoromethyl)benzene, and the reaction conditions were changed to 100 ° C and stirred for 20 hours.
化合物Z-69以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-2-氟-1-(三氟甲基)苯，反应条件换成110℃搅拌过夜。Compound Z-69 was prepared from compound 7-a using the same procedure as in Example 50 except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 4-bromo- 2-fluoro-1-(trifluoromethyl)benzene, and the reaction conditions were changed to 110 ° C and stirred overnight.
化合物Z-71以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成5-溴-2-(三氟甲基)吡啶，反应条件换成100℃搅拌过夜，步骤2反应条件换成180℃搅拌30分钟。Compound Z-71 was prepared by the method of Example 50 using compound 7-a as a starting material, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 5-bromo- 2-(Trifluoromethyl)pyridine, the reaction conditions were changed to 100 ° C and stirred overnight, and the reaction conditions of Step 2 were changed to 180 ° C and stirred for 30 minutes.
化合物Z-72以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌20小时，步骤2中化合物1-a换成化合物9-a，反应条件换成200℃搅拌30分钟。Compound Z-72 was prepared from compound 7-a using the procedure of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene in step 1 was replaced with 1-bromo- 4-(Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C and stirred for 20 hours. In the step 2, the compound 1-a was replaced with the compound 9-a, and the reaction conditions were changed to 200 ° C and stirred for 30 minutes.
化合物Z-76以化合物7-a为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成化合物23-a。Compound Z-76 was prepared by the method of Example 50 using compound 7-a as a starting material, except that the 1-bromo-4-(trifluoromethoxy)benzene in the step 1 was replaced with the compound 23-a. .
化合物Z-97参照实施例50的方法进行制备，不同的将步骤1的化合物7-a换成化合物30-a，1-溴-4-(三氟甲氧基)苯换成4-溴-1,2-二氯苯，步骤2中反应条件换成200℃搅拌60分钟。 Compound Z-97 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced with compound 30-a, and 1-bromo-4-(trifluoromethoxy)benzene was changed to 4-bromo- 1,2-dichlorobenzene, the reaction conditions in step 2 were changed to 200 ° C and stirred for 60 minutes.
化合物Z-104参照实施例50的方法进行制备，不同的将步骤1的化合物7-a换成化合物31-a，1-溴-4-(三氟甲氧基)苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌20h，步骤2中反应条件换成200℃搅拌60分钟。Compound Z-104 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced by compound 31-a, and 1-bromo-4-(trifluoromethoxy)benzene was replaced by 1-bromo- 4-(Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C and stirred for 20 h, and the reaction conditions in the step 2 were changed to 200 ° C and stirred for 60 minutes.
化合物Z-110参照实施例50的方法进行制备，不同的将步骤1的化合物7-a换成化合物31-a，1-溴-4-(三氟甲氧基)苯换成4-溴-1,2-二氯苯，反应条件换成100℃搅拌16h，步骤2中化合物1-a换成化合物9-a，反应条件换成200℃搅拌30分钟。Compound Z-110 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced by compound 31-a, and 1-bromo-4-(trifluoromethoxy)benzene was changed to 4-bromo- 1,2-dichlorobenzene, the reaction conditions were changed to 100 ° C for 16 h, the compound 1-a in step 2 was changed to the compound 9-a, and the reaction conditions were changed to 200 ° C and stirred for 30 minutes.
化合物Z-113参照实施例50的方法进行制备，不同的将步骤1的化合物7-a换成化合物31-a，1-溴-4-(三氟甲氧基)苯换成化合物34-a，反应条件换成100℃搅拌过夜，步骤2中反应条件换成200℃搅拌60分钟。Compound Z-113 was prepared by the method of Example 50, except that compound 7-a of Step 1 was replaced by compound 31-a, and 1-bromo-4-(trifluoromethoxy)benzene was replaced by compound 34-a. The reaction conditions were changed to 100 ° C and stirred overnight, and the reaction conditions in the step 2 were changed to 200 ° C and stirred for 60 minutes.
Figure PCTCN2016073385-appb-000084
Figure PCTCN2016073385-appb-000084
Figure PCTCN2016073385-appb-000085
Figure PCTCN2016073385-appb-000085
Figure PCTCN2016073385-appb-000086
Figure PCTCN2016073385-appb-000086
实施例53：(R)-5-氯-4-(((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲基)硫基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-53)的制备Example 53: (R)-5-Chloro-4-(((1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl)methyl)thio))- Preparation of 2-fluoro-N-(methylsulfonyl)benzamide (Z-53)
Figure PCTCN2016073385-appb-000087
Figure PCTCN2016073385-appb-000087
步骤1：化合物22-b(504mg，1.704mmol)，对甲苯磺酰氯(415mg，2.045mmol)，三乙胺(350mg，3.239mmol)，4-二甲氨基吡啶(25mg，0.17mmol)的10ml二氯甲烷混合溶液，室温搅拌6小时。反应结束，加入1M盐酸溶液和碳酸氢钠溶液洗，干燥分离有机相，减压浓缩得粗品化合物53-b(754mg)。MS m/z(ESI):450.1[M+H]+。Step 1: Compound 22-b (504 mg, 1.704 mmol), p-toluenesulfonyl chloride (415 mg, 2.045 mmol), triethylamine (350 mg, 3.239 mmol), 4-dimethylaminopyridine (25 mg, 0.17 mmol) The mixed solution of methyl chloride was stirred at room temperature for 6 hours. After the reaction was completed, a 1M aqueous solution of hydrochloric acid and sodium hydrogen carbonate solution was added, and the organic phase was separated and evaporated to give crude compound 53-b (754 mg). MS m/z (ESI): 450.1 [M+H] + .
步骤2：化合物53-b(424mg，0.942mmol)的二甲基甲酰胺(5ml)溶液中加入硫代乙酰钾(548mg，4.807mmol)，140℃搅拌1小时。反应结束，冷却至室温，加入水和乙酸乙酯萃取，干燥分离有机相，减压浓缩得粗品，经Combi-flash柱层析纯化得到黄色油状化合物53-c(156mg)，纯度100％，产率49％。MS m/z(ESI):354.1[M+H]+。Step 2: To a solution of compound 53-b (424 mg, 0.942 mmol) in EtOAc (EtOAc) The reaction was completed, cooled to room temperature, extracted with water and ethyl acetate. EtOAc was evaporated. The rate is 49%. MS m/z (ESI): 354.1 [M+H] + .
步骤3：以化合物53-c(150mg)为原料，参照实施例4中步骤3的制备方法，得到白色固体化合物Z-53(144mg)，纯度96.65％，产率38％，MS m/z(ESI):561[M+H]+。1H NMR(DMSO-d6,400MHz):＝7.74(d,J＝7.2Hz,1H),7.25-7.35(m,2H),6.69(d, J＝2.8Hz,1H),6.57(dd,J＝9.2,2.8Hz,1H),4.04(br.s.,1H),3.39-3.49(m,1H),3.08-3.28(m,3H),2.96(s,3H),2.10-2.22(m,1H),1.90-2.10ppm(m,3H)。Step 3: Compound 53-c (150 mg) was used as a starting material to give the white solid compound Z-53 (144 mg), purity 96.65%, yield 38%, MS m/z ESI): 561 [M+H] + . 1 H NMR (DMSO-d 6 , 400 MHz): = 7.74 (d, J = 7.2 Hz, 1H), 7.25-7.35 (m, 2H), 6.69 (d, J = 2.8 Hz, 1H), 6.57 (dd, J=9.2, 2.8 Hz, 1H), 4.04 (br.s., 1H), 3.39-3.49 (m, 1H), 3.08-3.28 (m, 3H), 2.96 (s, 3H), 2.10-2.22 (m) , 1H), 1.90-2.10 ppm (m, 3H).
实施例54:(R)-4-((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)-5-环丙基-2-氟-N-(甲磺酰基)苯甲酰胺(Z-54)的制备Example 54: (R)-4-((1-(3-Chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl)methoxy)-5-cyclopropyl-2 -Preparation of fluoro-N-(methylsulfonyl)benzamide (Z-54)
Figure PCTCN2016073385-appb-000088
Figure PCTCN2016073385-appb-000088
步骤1：以化合物22-b(200mg)为原料，参照实施例4中步骤3的制备方法，不同的是将化合物1-a换成化合物11-a，得到白色固体化合物54-b(110mg)，纯度72％，产率18.39％，MS m/z(ESI):589[M+H]+。Step 1: The compound 22-b (200 mg) was used as a starting material, and the preparation method of the step 3 in Example 4 was used, except that the compound 1-a was replaced with the compound 11-a to give a white solid compound 54-b (110 mg). , purity 72%, yield 18.39%, MS m/z (ESI): 589 [M+H] + .
步骤2：化合物54-b(100mg，0.17mmol)，环丙基硼酸(29.13mg，0.34mmol),碳酸钾(46.87mg，0.34mmol)，醋酸钯(7.613mg，0.034mmol)加入甲苯(20ml)和水(2ml)中，加入三环己基膦(47.55mg，0.17mmol)，氮气保护100℃搅拌过夜。反应结束，冷却至室温，水洗，食盐水洗，分离有机相，减压浓缩得到粗品，经Combi-flash柱层析纯化得到化合物Z-54(32mg)。MS m/z(ESI):551[M+H]+。1H NMR(DMSO-d6,500MHz):＝11.92(br.s.,1H),7.30(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),6.84-6.95(m,2H),6.72(dd,J＝9.5,3.0Hz,1H),4.30(d,J＝5.5Hz,1H),4.07(d,J＝5.5Hz,2H),3.50(t,J＝8.0Hz,1H),3.10-3.25(m,4H),2.12-2.25(m,1H),1.90-2.11(m,4H),0.83-0.94(m,1H),0.54-0.76ppm(m,3H)Step 2: Compound 54-b (100 mg, 0.17 mmol), cyclopropylboronic acid (29.13mg, 0.34mmol), potassium carbonate (46.87mg, 0.34mmol), palladium acetate (7.613mg, 0.034mmol), toluene (20ml) To the water (2 ml), tricyclohexylphosphine (47.55 mg, 0.17 mmol) was added, and the mixture was stirred at 100 ° C under nitrogen overnight. After completion of the reaction, the mixture was cooled to room temperature, washed with water and brine, and then evaporated. MS m/z (ESI): 552 [M+H] + . 1 H NMR (DMSO-d 6 , 500 MHz): = 11.92 (br.s., 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.84-6.95 (m, 2H), 6.72 (dd, J = 9.5, 3.0 Hz, 1H), 4.30 (d, J = 5.5 Hz, 1H), 4.07 (d, J = 5.5 Hz, 2H), 3.50 (t, J = 8.0 Hz, 1H), 3.10-3.25 (m, 4H), 2.12-2.25 (m, 1H), 1.90-2.11 (m, 4H), 0.83-0.94 (m, 1H), 0.54-0.76 ppm (m, 3H) )
实施例55：(R)-4-((1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)甲氧基)-3-氰基-N-(甲磺酰基)苯甲酰胺(Z-55)的制备Example 55: (R)-4-((1-(3-Chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl)methoxy)-3-cyano-N- Preparation of (methanesulfonyl)benzamide (Z-55)
Figure PCTCN2016073385-appb-000089
Figure PCTCN2016073385-appb-000089
步骤1：化合物16-a(3g，13.7mmol)，甲磺酰胺(1.95g，20.5mmol),2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)(5.73g，15.07mmol)，三乙胺(2.77mg，27.4mmol)的二氯甲烷(30ml)混合溶液，室温搅拌16小时。反应结束，2N 盐酸溶液洗，水洗，食盐水洗，干燥分离有机相，减压浓缩得到粗品，经Combi-flash柱层析纯化得到化合物，加入乙酸乙酯和石油醚，过滤，石油醚洗，得白色固体化合物55-b(1.5g)。MS m/z(ESI):295.9[M+H]+。Step 1: Compound 16-a (3 g, 13.7 mmol), methanesulfonamide (1.95 g, 20.5 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-four A mixed solution of methyl urea hexafluorophosphate (HATU) (5.73 g, 15.07 mmol), triethylamine (2.77 mg, 27.4 mmol) in dichloromethane (30 ml) was stirred at room temperature for 16 hours. The reaction was completed, washed with 2N hydrochloric acid solution, washed with water, washed with brine, dried and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. White solid compound 55-b (1.5 g). MS m/z (ESI): 295.9 [M+H] + .
步骤2：化合物55-b(1g，3.38mmol)，氰化锌(237mg，2.03mmol),三(二亚苄基丙酮)二钯(31mg，0.034mmol)，1,1’-双(二苯基膦)二茂铁(38mg，0.068mmol)，锌(9mg，0.135mmol)，醋酸锌(25mg，0.135mmol)的二氧六环(15ml)混合溶液，110℃搅拌5小时。反应结束，冷却至室温，过滤，乙酸乙酯洗，减压浓缩，加入乙酸乙酯和石油醚，过滤，石油醚洗，干燥，经Combi-flash柱层析纯化得到化合物得黄色固体化合物55-c(238mg)。MS m/z(ESI):241[M-H]-。Step 2: Compound 55-b (1 g, 3.38 mmol), zinc cyanide (237 mg, 2.03 mmol), tris(dibenzylideneacetone) dipalladium (31 mg, 0.034 mmol), 1,1'-bis(diphenyl) A mixture of ferrocene (38 mg, 0.068 mmol), zinc (9 mg, 0.135 mmol), zinc acetate (25 mg, 0.135 mmol) in dioxane (15 ml) was stirred at 110 ° C for 5 hours. After the reaction was completed, it was cooled to room temperature, filtered, ethyl acetate washed, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. c (238 mg). MS m/z (ESI): 241 [MH] - .
步骤3：以化合物22-b(100mg)为原料，参照实施例4中步骤3的制备方法，不同的是将化合物1-a换成化合物55-c，得到黄色固体化合物Z-55(44mg)，MS m/z(ESI):518[M+H]+。Step 3: The compound 22-b (100 mg) was used as the starting material, and the preparation method of the step 3 in Example 4 was used, except that the compound 1-a was replaced with the compound 55-c to obtain the yellow solid compound Z-55 (44 mg). MS m/z (ESI): 518 [M+H] + .
1H NMR(DMSO-d6,500MHz):＝8.21(d,J＝2.5Hz,1H),8.16(dd,J＝9.0,2.0Hz,1H),7.29(dd,J＝9.0,2.0Hz,2H),6.83(d,J＝3.0Hz,1H),6.75(dd,J＝9.5,2.5Hz,1H),4.25(d,J＝7.0Hz,2H),4.11-4.23(m,1H),3.49(t,J＝8.5Hz,1H),3.12-3.21(m,1H),3.08(s,3H),2.22-2.35(m,1H),2.05-2.15(m,2H),2.01ppm(br.s.,1H) 1 H NMR (DMSO-d 6 , 500 MHz): = 8.21 (d, J = 2.5 Hz, 1H), 8.16 (dd, J = 9.0, 2.0 Hz, 1H), 7.29 (dd, J = 9.0, 2.0 Hz, 2H), 6.83 (d, J = 3.0 Hz, 1H), 6.75 (dd, J = 9.5, 2.5 Hz, 1H), 4.25 (d, J = 7.0 Hz, 2H), 4.11-4.23 (m, 1H), 3.49 (t, J = 8.5 Hz, 1H), 3.12-3.21 (m, 1H), 3.08 (s, 3H), 2.22 - 2.35 (m, 1H), 2.05 - 2.15 (m, 2H), 2.01 ppm (br) .s.,1H)
实施例57：(R)-5-氯-4-(1-(1-(3-氯-4-(三氟甲氧基)苯基)吡咯烷-2-基)乙氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-57)的制备Example 57: (R)-5-Chloro-4-(1-(1-(3-chloro-4-(trifluoromethoxy)phenyl)pyrrolidin-2-yl)ethoxy)-2 -Preparation of fluoro-N-(methylsulfonyl)benzamide (Z-57)
Figure PCTCN2016073385-appb-000090
Figure PCTCN2016073385-appb-000090
步骤1：向化合物22-b(600mg，2.029mmol)的二氯甲烷(20ml)溶液中0℃加入戴斯-马丁氧化剂(1.033g，2.435mmol)，0℃搅拌30分钟。反应结束，加入碳酸氢钠溶液，硫代硫酸钠溶液，二氯甲烷萃取，碳酸氢钠溶液洗，干燥分离有机相，减压浓缩得到粗品黄色油状化合物57-b(575mg)。MS m/z(ESI):294[M+H]+。 Step 1: To a solution of compound 22-b (600 mg, 2.29 mmol) in dichloromethane (20 mL) After completion of the reaction, a sodium hydrogencarbonate solution, a sodium thiosulfate solution, methylene chloride solution, and a sodium hydrogencarbonate solution were evaporated, and the organic phase was separated and concentrated to give a crude yellow oily compound 57-b (575 mg). MS m/z (ESI): 294 [M+H] + .
步骤2：向化合物57-b(0.575g，1.958mmol)的四氢呋喃(5ml)溶液中0℃逐滴加入甲基溴化镁(1ml，2.937mmol)，自然升至室温搅拌1小时。反应结束，加入氯化铵溶液，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩得到粗品黄色油状化合物57-c(339mg)。MS m/z(ESI):310.1[M+H]+。Step 2: Methylmagnesium bromide (1 ml, 2.937 mmol) was added dropwise to a solution of compound 57-b (0.575 g, 1.58 mmol) in THF (5 ml). After the reaction was completed, the ammonium chloride solution was added, and ethyl acetate was evaporated. MS m/z (ESI): 310.1 [M+H] + .
步骤3：向化合物57-c(339mg，1.094mmol)，化合物17-a(224mg，1.094mmol)，三苯基膦(576mg，2.189mmol)的甲苯(5ml)溶液中氩气保护下加入偶氮二甲酸二异丙酯(443mg，2.189mmol)，氩气保护60℃搅拌过夜。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到黄色油状化合物57-d(276mg)。MS m/z(ESI):496.1[M+H]+。Step 3: Add azo to a solution of compound 57-c (339 mg, 1.094 mmol), compound 17-a (224 mg, 1.094 mmol), triphenylphosphine (576 mg, 2.189 mmol) in toluene (5 ml) Diisopropyl diformate (443 mg, 2.189 mmol) was stirred under argon at 60 ° C overnight. After the reaction was completed, it was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with brine, dried and evaporated. Purification by Combi-flash column chromatography gave compound 57-d (276 mg). MS m/z (ESI): 496.1 [M+H] + .
步骤4：向化合物57-d(276mg，0.556mmol)的甲醇(10ml)溶液中加入氢氧化钠(89mg，2.224mmol)的水(1ml)溶液，室温搅拌过夜。反应结束，减压浓缩，加入水，1N盐酸调节PH为1，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩得到化合物得黄色油状化合物57-e(266mg)。MS m/z(ESI):482[M+H]+。A solution of sodium hydroxide (89 mg, 2.224 mmol) in water (1 mL). The reaction was completed, and the mixture was evaporated to dryness. MS m/z (ESI): 482 [M+H] + .
步骤5：以化合物57-e(266mg)和甲磺酰胺为起始原料，参照实施例5的方法合成，得到化合物得黄色油状化合物Z-57(57mg)。MS m/z(ESI):559[M+H]+。1H NMR(500MHz,DMSO-d6):δ12.06-12.02(br.s.,1H),7.75(d,J＝7.5Hz,1H),7.30(d,J＝9.0Hz,1H),7.07(d,J＝7.0Hz,1H),6.78(d,J＝2.5Hz,1H),6.64(dd,J＝2.5Hz,9.0Hz,1H),4.99-4.95(m,1H),4.01(d,J＝8.5Hz,1H),3.37-3.34(m,1H),3.16(s,3H),3.14-3.09(m,1H),2.37-2.31(m,1H),2.28-2.23(m,1H),2.06-1.99(m,1H),1.98-1.92(m,1H),1.32(d,J＝6.0Hz,3H).Step 5: Compound 57-e (266 mg) m. MS m/z (ESI): 559 [M+H] + . 1 H NMR (500MHz, DMSO- d 6): δ12.06-12.02 (br.s., 1H), 7.75 (d, J = 7.5Hz, 1H), 7.30 (d, J = 9.0Hz, 1H), 7.07 (d, J = 7.0 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.64 (dd, J = 2.5 Hz, 9.0 Hz, 1H), 4.99 - 4.95 (m, 1H), 4.01 ( d, J = 8.5 Hz, 1H), 3.37-3.34 (m, 1H), 3.16 (s, 3H), 3.14 - 3.09 (m, 1H), 2.37 - 2.31 (m, 1H), 2.28-2.23 (m, 1H), 2.06-1.99 (m, 1H), 1.98-1.92 (m, 1H), 1.32 (d, J = 6.0 Hz, 3H).
实施例60：(R)-4-((1-(3-氯-4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)-2,5-二氟-N-(甲磺酰基)苯甲酰胺(Z-60)的制备Example 60: (R)-4-((1-(3-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methoxy)-2,5-difluoro-N -(Methanesulfonyl)benzamide (Z-60) Preparation
Figure PCTCN2016073385-appb-000091
Figure PCTCN2016073385-appb-000091
步骤1：以化合物7-a(2.92g)为起始原料，参照实施例50的方法进行制备，不同的是将步骤1中1-溴-4-(三氟甲氧基)苯换成4-溴-2-氯-1-(三氟甲基)苯，反应条件换成100℃搅拌16小时。得到黄色油状化合物60-b(2.076g)，直接用于下一步反应，纯度91.7％，产率31％。MS m/z(ESI):280.1[M+H]+。Step 1: Using compound 7-a (2.92 g) as a starting material, the preparation was carried out according to the method of Example 50 except that the 1-bromo-4-(trifluoromethoxy)benzene in step 1 was changed to 4 -Bromo-2-chloro-1-(trifluoromethyl)benzene, and the reaction conditions were changed to 100 ° C and stirred for 16 hours. The compound 60-b (2.076 g) was obtained as a yellow oil, which was used directly for the next reaction, purity 91.7%, yield 31%. MS m/z (ESI): 280.1 [M+H] + .
步骤2：向化合物60-b(55mg，0.197mmol)的四氢呋喃(10ml)溶液中0℃加入叔丁 醇钾(66mg，0.592mmol)，0℃搅拌10分钟，加入化合物9-a(50mg，0.197mmol)，自然升至室温搅拌2小时。反应结束，乙酸乙酯萃取，盐酸溶液洗至PH为5-6，干燥分离有机相，经prep-HPLC纯化得到白色固体化合物Z-60(22mg)。MS m/z(ESI):511.1[M-H]-。1H NMR(500MHz,DMSO-6):δ12.08(s,1H),7.60-7.57(m,1H),7.53(d,J＝9.0Hz,1H),7.28-7.25(m,1H),6.92(d,J＝2.0Hz,1H),6.73(dd,J＝9.0Hz,4.0Hz,1H),4.34-4.33(m,1H),4.20-4.13(m,2H),3.52-3.49(m,1H),3.35(s,3H),3.24-3.21(m,1H),2.18-2.15(m,1H),2.11-2.05(m,3H).Step 2: To a solution of the compound 60-b (55 mg, 0.197 mmol) in THF (10 ml), EtOAc (EtOAc, EtOAc. Methyl), naturally warmed to room temperature and stirred for 2 hours. After completion of the reaction, ethyl acetate was extracted, and the aqueous solution was washed to pH 5-6. The organic phase was separated and purified by prep-HPLC to yield white solid compound Z-60 (22 mg). MS m/z (ESI): 511.1 [MH] - . 1 H NMR (500MHz, DMSO- 6): δ12.08 (s, 1H), 7.60-7.57 (m, 1H), 7.53 (d, J = 9.0Hz, 1H), 7.28-7.25 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 9.0 Hz, 4.0 Hz, 1H), 4.34 - 4.33 (m, 1H), 4.20 - 4.13 (m, 2H), 3.52-3.49 (m , 1H), 3.35 (s, 3H), 3.24 - 3.21 (m, 1H), 2.18-2.15 (m, 1H), 2.11-2.05 (m, 3H).
实施例61：5-氯-4-((1-(4-氯苯基)-1H-咪唑-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-61)的制备Example 61: 5-Chloro-4-((1-(4-chlorophenyl)-1H-imidazol-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzamide ( Preparation of Z-61)
Figure PCTCN2016073385-appb-000092
Figure PCTCN2016073385-appb-000092
步骤1：化合物18-a(1g，10.407mmol)，1-溴-4-氯苯(1.992g，10.407mmol)，4,7-二甲氧基-1,10-菲咯啉(500mg，2.081mmol)，N1，N2-二甲基乙烷-1,2-二胺(183mg，2.081mmol)，碘化亚铜(396mg，2.081mmol)，碳酸钾(4.315g，31.221mmol)的氯化亚砜(20ml)混合溶液，氩气保护100℃搅拌过夜。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，食盐水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到黄色固体化合物61-b(257mg)。MS m/z(ESI):207.1[M+H]+。Step 1: Compound 18-a (1 g, 10.407 mmol), 1-bromo-4-chlorobenzene (1.992 g, 10.407 mmol), 4,7-dimethoxy-1,10-phenanthroline (500 mg, 2.081) Methyl), N1, N2-dimethylethane-1,2-diamine (183 mg, 2.081 mmol), cuprous iodide (396 mg, 2.081 mmol), potassium carbonate (4.315 g, 31.221 mmol) A mixed solution of sulfone (20 ml) was stirred at 100 ° C under argon atmosphere overnight. After the reaction was completed, it was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with brine, dried and evaporated. Purification by Combi-flash column chromatography gave yellow solid compound 61-b (257 mg). MS m/z (ESI): 207.1 [M+H] + .
步骤2：向化合物61-b(257mg，1.244mmol)的甲醇(10ml)溶液中加入硼氢化钠(25mg，0.622mmol)，室温搅拌2小时。反应结束，加入氯化铵溶液，二氯甲烷萃取，干燥分离有机相，减压浓缩得到黄色油状化合物61-c(267mg)。MS m/z(ESI):209.1[M+H]+。Step 2: To a solution of compound 61-b (257 mg, EtOAc. After completion of the reaction, the ammonium chloride solution was added, and the mixture was extracted with methylene chloride. MS m/z (ESI): 209.1 [M+H] + .
步骤3：向化合物61-c(267mg，1.28mmol)和三乙胺(259mg，2.559mmol)的甲醇(10ml)溶液中0℃加入乙酰氯(151mg，1.919mmol)，室温搅拌3小时。反应结束，食盐水洗，二氯甲烷萃取，干燥分离有机相，减压浓缩得到绿色固体化合物61-d(300mg)。MS m/z(ESI):251.1[M+H]+。Step 3: To a solution of compound 61-c (267 mg, 1.28 mmol) and EtOAc (EtOAc) After completion of the reaction, the mixture was washed with brine and evaporated. MS m/z (ESI): 251.1 [M+H] + .
步骤4：以化合物61-d(300mg)为原料，参照实施例4中步骤3的制备方法，得到黄色固体化合物Z-61(10mg)，纯度99％，MS m/z(ESI):456[M-H]-。1H NMR(500 MHz,DMSO-d6):δ7.79(d,J＝8.0Hz,1H),7.73(s,1H),7.63(m,5H),7.39(s,1H),5.35(s,2H),3.32(s,3H).Step 4: Compound 61-d (300 mg) was used as a starting material. MH] - . 1 H NMR (500 MHz, DMSO-d 6 ): δ 7.79 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.63 (m, 5H), 7.39 (s, 1H), 5.35 ( s, 2H), 3.32 (s, 3H).
实施例62：(R)-5-氯-4-((1-(4-氯苯基)-5-氧代吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-62)的制备Example 62: (R)-5-Chloro-4-((1-(4-chlorophenyl)-5-oxopyrrolidin-2-yl)methoxy)-2-fluoro-N-(A) Preparation of sulfonyl)benzamide (Z-62)
Figure PCTCN2016073385-appb-000093
Figure PCTCN2016073385-appb-000093
步骤1：以化合物19-a(1.5g)为原料，参照实施例61中步骤1的制备方法，将反应条件换成140℃微波搅拌30分钟，得到黄色油状化合物62-b(350mg)。Step 1: The compound 19-a (1.5 g) was used as a starting material, and the reaction mixture was subjected to the preparative method of the step 1 in Example 61, and the reaction mixture was stirred at 140 ° C for 30 minutes to obtain a compound 62-b (350 mg) as a yellow oil.
步骤2：以化合物62-b(130mg)为原料，参照实施例57中步骤3的制备方法，得到黄色油状化合物62-c(364mg)，MS m/z(ESI):412.1[M+H]+。Step 2: Compound 62-b (130 mg) was obtained from m. + .
步骤3：以化合物62-c(264mg)为原料，参照实施例57中步骤4的制备方法，得到黄色油状化合物62-d(109mg)，MS m/z(ESI):398.1[M+H]+。Step 3: Compound 62-c (264 mg), m. + .
步骤4：以化合物62-d(109mg)为原料，参照化合物11-a中步骤b的制备方法，得到白色固体化合物Z-62(32.01mg)，MS m/z(ESI):474.8[M+H]+。1H NMR(500MHz,DMSO-d6):δ12.09(br.s.,1H),7.76(d,J＝7.0Hz,1H),7.53(d,J＝9.0Hz,2H),7.43(d,J＝9.0Hz,2H),7.16(d,J＝12.0Hz,1H),4.83-4.80(m,1H),4.23(dd,J＝3.0Hz,10.5Hz,1H),4.16(dd,J＝3.0Hz,10.0Hz,1H),3.35(s,3H),2.84-2.78(m,1H),2.49-2.37(m,2H),2.12-2.06(m,1H).Step 4: Compound 62-d (109 mg) was used as a starting material, m.p. H] + . 1 H NMR (500 MHz, DMSO-d 6 ): δ 12.09 (br.s., 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.43 ( d, J = 9.0 Hz, 2H), 7.16 (d, J = 12.0 Hz, 1H), 4.83-4.80 (m, 1H), 4.23 (dd, J = 3.0 Hz, 10.5 Hz, 1H), 4.16 (dd, J=3.0 Hz, 10.0 Hz, 1H), 3.35 (s, 3H), 2.84-2.78 (m, 1H), 2.49-2.37 (m, 2H), 2.12-2.06 (m, 1H).
实施例81、122、137、152、153Examples 81, 122, 137, 152, 153
化合物Z-81、Z-122、Z-137、Z-152、Z-153均以化合物7-a为起始原料，参照化合物62的方法进行制备。不同的是根据各自结构，将步骤1中1-溴-4-氯苯换成分别换成1-溴-4-(三氟甲基)苯、2-溴-5-(三氟甲基)吡啶，将步骤4中的甲基磺酰胺或分别换成乙烷磺酰胺、异丙烷磺酰胺。Compounds Z-81, Z-122, Z-137, Z-152 and Z-153 were all prepared starting from compound 7-a and referring to compound 62. The difference is that the 1-bromo-4-chlorobenzene in step 1 is replaced by 1-bromo-4-(trifluoromethyl)benzene and 2-bromo-5-(trifluoromethyl) according to the respective structures. Pyridine, the methylsulfonamide in step 4 is replaced by ethanesulfonamide or isopropanesulfonamide, respectively.
Figure PCTCN2016073385-appb-000094
Figure PCTCN2016073385-appb-000094
Figure PCTCN2016073385-appb-000095
Figure PCTCN2016073385-appb-000095
Figure PCTCN2016073385-appb-000096
Figure PCTCN2016073385-appb-000096
实施例63：(R)-4-((1-(3-氯-4-氟苯基)吡咯烷-2-基)甲氧基)-5-环丙基-2-氟-N-(甲磺酰基)苯甲酰胺(Z-63)的制备Example 63: (R)-4-((1-(3-Chloro-4-fluorophenyl)pyrrolidin-2-yl)methoxy)-5-cyclopropyl-2-fluoro-N-( Preparation of methanesulfonyl)benzamide (Z-63)
Figure PCTCN2016073385-appb-000097
Figure PCTCN2016073385-appb-000097
步骤1：以化合物7-a(728mg)为起始原料，参照实施例50步骤1的方法制备，不同的是将1-溴-4-(三氟甲氧基)苯换成4-溴-2-氯-1-氟苯，反应条件换成90℃搅拌过夜，得到白色固体化合物63-b(120mg)，MS m/z(ESI):230[M+H]+。Step 1: Using compound 7-a (728 mg) as a starting material, followed by the procedure of Example 1 Step 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced by 4-bromo- 2-Chloro-l-fluorobenzene, and the reaction mixture was stirred at 90 ° C overnight to afford compound 63-b (120 mg), MS m/z (ESI): 230 [M+H] + .
步骤2：以化合物63-b(110mg)为起始原料，参照实施例4步骤3的方法进行制备，不同的是将步骤中化合物1-a换成化合物11-a，反应条件换成180℃搅拌1小时，得到白色固体化合物63-c(120mg)，MS m/z(ESI):523[M+H]+。Step 2: The compound 63-b (110 mg) was used as a starting material, and the preparation was carried out in the same manner as in the step 3 of Example 4 except that the compound 1-a was replaced with the compound 11-a, and the reaction conditions were changed to 180 ° C. After stirring for 1 hour, a white solid compound 63-c (120 mg), MS m/z (ESI): 503 [M+H] + .
步骤3以化合物63-c(110mg)为起始原料，参照实施例29步骤2的方法进行制备，得到白色固体化合物Z-63(10mg)，MS m/z(ESI):485[M+H]+。1H NMR(500MHz,DMSO-d6):δ11.907(s,1H),7.218-7.192(m,2H),6.836-6.818(m,1H),6.759(d,J＝12.5Hz,1H),6.673-6.648(m,1H),4.187(s,1H),4.020-3.989(m,2H),3.466(t,J＝8.0Hz,1H),3.127-3.077(m,1H),2.902(s,3H),2.169-2.054(m,1H),2.036-1.956(m,4H),0.910-0.862(m,1H),0.795-0.770(m,1H),0.555-0.545(m,2H),Step 3 Preparation of Compound 63-c (110 mg), m. m. ] + . 1 H NMR (500MHz, DMSO- d 6): δ11.907 (s, 1H), 7.218-7.192 (m, 2H), 6.836-6.818 (m, 1H), 6.759 (d, J = 12.5Hz, 1H) , 6.673-6.648 (m, 1H), 4.187 (s, 1H), 4.020-3.989 (m, 2H), 3.466 (t, J = 8.0 Hz, 1H), 3.127-3.077 (m, 1H), 2.902 (s , 3H), 2.169-2.054 (m, 1H), 2.036-1.956 (m, 4H), 0.910-0.862 (m, 1H), 0.795-0.770 (m, 1H), 0.555-0.545 (m, 2H),
实施例65、73、115Examples 65, 73, 115
化合物Z-65以化合物7-a为起始原料，参照实施例63的方法进行制备，不同的是将步骤1中4-溴-2-氯-1-氟苯换成1-溴-4-氯苯。Compound Z-65 was prepared according to the method of Example 63, starting from compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene was replaced with 1-bromo-4- in step 1. chlorobenzene.
化合物Z-73以化合物7-a为起始原料，参照实施例63的方法进行制备，不同的是将步骤1中4-溴-2-氯-1-氟苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌 16小时，步骤2反应条件换成200℃搅拌30分钟，步骤3反应条件换成80℃搅拌16小时。Compound Z-73 was prepared according to the method of Example 63, starting from compound 7-a, except that 4-bromo-2-chloro-1-fluorobenzene was replaced with 1-bromo-4- in step 1. (Trifluoromethyl)benzene, the reaction conditions were changed to 100 ° C stirring After 16 hours, the reaction conditions of step 2 were changed to 200 ° C for 30 minutes, and the reaction conditions of step 3 were changed to 80 ° C for 16 hours.
化合物Z-115参照实施例63的方法进行制备，不同的是将步骤1中化合物7-a换成化合物31-a，4-溴-2-氯-1-氟苯换成4-溴-1,2-二氯苯，反应条件换成100℃搅拌16小时，步骤2反应条件换成200℃搅拌30分钟，步骤3反应条件换成80℃搅拌16小时。Compound Z-115 was prepared by the method of Example 63 except that the compound 7-a in Step 1 was replaced by the compound 31-a, and 4-bromo-2-chloro-1-fluorobenzene was changed to 4-bromo-1. , 2-dichlorobenzene, the reaction conditions were changed to 100 ° C for 16 hours, the reaction conditions of step 2 were changed to 200 ° C for 30 minutes, and the reaction conditions of step 3 were changed to 80 ° C for 16 hours.
Figure PCTCN2016073385-appb-000098
Figure PCTCN2016073385-appb-000098
实施例64：(R)-5-氯-4-((1-(6-氯吡啶-2-基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-64)的制备Example 64: (R)-5-Chloro-4-((1-(6-chloropyridin-2-yl)pyrrolidin-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl) Preparation of benzamide (Z-64)
Figure PCTCN2016073385-appb-000099
Figure PCTCN2016073385-appb-000099
步骤1：2-氯-6-氟吡啶(2.20g，16.72mmol)，化合物7-a(1.27g，12.54mmol)，碳 酸钾(2.31g，16.72mmol)的二甲基甲酰胺(22ml)混合溶液，80℃搅拌5小时。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，水洗，食盐水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到黄色固体化合物64-b(2g)。MS m/z(ESI):213[M+H]+。Step 1: 2-Chloro-6-fluoropyridine (2.20 g, 16.72 mmol), compound 7-a (1.27 g, 12.54 mmol), potassium carbonate (2.31 g, 16.72 mmol) in dimethylformamide (22 ml) The solution was stirred at 80 ° C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with water, brine, and evaporated. Purification by Combi-flash column chromatography gave yellow solid compound 64-b (2 g). MS m/z (ESI): 213 [M+H] + .
步骤2：以化合物64-b(500mg)为起始原料，参照实施例4步骤3的方法进行制备，不同的是反应条件换成200℃搅拌1小时，得到白色固体化合物Z-64(80mg)，MS m/z(ESI):462[M+H]+。1H NMR(DMSO-d6,400MHz):δ7.78(d,J＝7.6Hz,1H),7.53(d,J＝7.5Hz,1H),7.18(d,J＝12.4Hz,1H),6.64(d,J＝7.2Hz,1H),6.54(d,J＝8.4Hz,1H),4.37-4.26(m,2H),4.06-4.10(m,1H),3.42-3.52(m,2H),2.81(s,3H),2.09-2.05(m,4H).Step 2: Starting from the compound 64-b (500 mg), which was obtained by the procedure of Step 3 of Example 4, except that the reaction conditions were changed to 200 ° C for 1 hour to obtain a white solid compound Z-64 (80 mg). MS m/z (ESI): 462 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ7.78 (d, J = 7.6Hz, 1H), 7.53 (d, J = 7.5Hz, 1H), 7.18 (d, J = 12.4Hz, 1H), 6.64 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.37-4.26 (m, 2H), 4.06-4.10 (m, 1H), 3.42-3.52 (m, 2H) , 2.81 (s, 3H), 2.09-2.05 (m, 4H).
实施例70Example 70
化合物Z-70以化合物7-a为起始原料，参照实施例64的方法进行制备，不同的是将步骤1中2-氯-6-氟吡啶换成2-溴-5-(三氟甲基)吡啶，步骤2中的反应条件换成180℃搅拌30分钟。Compound Z-70 was prepared according to the method of Example 64 using compound 7-a as a starting material, except that 2-chloro-6-fluoropyridine in step 1 was replaced by 2-bromo-5-(trifluoromethyl). The pyridine was subjected to the reaction conditions in the step 2 and stirred at 180 ° C for 30 minutes.
Figure PCTCN2016073385-appb-000100
Figure PCTCN2016073385-appb-000100
实施例66：(R)-5-氯-4-((1-(5-氯-6-环丙氧基吡啶-3-基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-66)的制备Example 66: (R)-5-Chloro-4-((1-(5-chloro-6-cyclopropoxypyridin-3-yl)pyrrolidin-2-yl)methoxy)-2-fluoro Preparation of -N-(methylsulfonyl)benzamide (Z-66)
Figure PCTCN2016073385-appb-000101
Figure PCTCN2016073385-appb-000101
步骤1：向化合物20-a(1.5g，7.128mmol)，环丙醇(0.621g，10.692mmol)的N-甲基吡咯烷酮(20ml)的溶液中加入叔丁醇钾(1.2g，10.692mmol)的四氢呋喃(20ml)溶液,室温搅拌1h。反应结束，加入水，分离有机相，食盐水洗，干燥分离有机相，滤液减压浓缩得到粗品，经Combi-flash柱层析纯化得到无色油状化合物66-b(1.58g)，直接用于下一步反应，纯度99.01％，产率89％。MS m/z(ESI):250[M+H]+。Step 1: To a solution of compound 20-a (1.5 g, 7.128 mmol), EtOAc (EtOAc:EtOAc (EtOAc) A solution of tetrahydrofuran (20 ml) was stirred at room temperature for 1 h. After the reaction was completed, water was added, the organic phase was separated, and the organic phase was separated, and the organic layer was evaporated. One-step reaction, purity 99.01%, yield 89%. MS m/z (ESI): 250 [M+H] + .
步骤2：以化合物7-a(407mg)为起始原料，参照实施例50步骤1的方法进行制 备，不同的是将步骤中将1-溴-4-(三氟甲氧基)苯换成化合物66-b，反应条件换成95℃搅拌过夜，得到白色固体化合物66-c(194mg)，MS m/z(ESI):269.1[M+H]+。Step 2: The compound 7-a (407 mg) was used as a starting material, which was prepared by the method of Step 1 of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced in the step. compound 66-b, 95 deg.] C into the reaction conditions stirred overnight to give a white solid compound 66-c (194mg), MS m / z (ESI): 269.1 [m + H] +.
步骤3：以化合物66-c(164mg)为起始原料，参照实施例4步骤3的方法进行制备，不同的是将步骤中反应条件换成200℃搅拌30分钟，得到白色固体化合物Z-66(33.06mg)，MS m/z(ESI):518.1[M+H]+。1H NMR(500MHz,DMSO-d6):δ12.12(br.s.,1H),7.77(d,J＝7.5Hz,1H),7.62(d,J＝2.5Hz,1H),7.40(d,J＝2.5Hz,1H),7.25(d,J＝12.0Hz,1H),4.20-4.17(m,4H),3.49(t,J＝7.5Hz,1H),3.36(s,3H),3.10(q,J＝8.5Hz,1H),2.20(q,J＝10.0Hz,1H),2.10-1.97(m,3H),0.75-0.71(m,2H),0.65-0.62(m,2H).Step 3: Starting from the compound 66-c (164 mg), which was obtained by the method of the step 3 of Example 4, except that the reaction conditions in the step were changed to 200 ° C and stirred for 30 minutes to obtain a white solid compound Z-66. (33.06mg), MS m / z (ESI): 518.1 [m + H] +. 1 H NMR (500MHz, DMSO- d 6): δ12.12 (br.s., 1H), 7.77 (d, J = 7.5Hz, 1H), 7.62 (d, J = 2.5Hz, 1H), 7.40 ( d, J = 2.5 Hz, 1H), 7.25 (d, J = 12.0 Hz, 1H), 4.20 - 4.17 (m, 4H), 3.49 (t, J = 7.5 Hz, 1H), 3.36 (s, 3H), 3.10 (q, J = 8.5 Hz, 1H), 2.20 (q, J = 10.0 Hz, 1H), 2.10 - 1.97 (m, 3H), 0.75 - 0.71 (m, 2H), 0.65 - 0.62 (m, 2H) .
实施例74：(R)-5-氯-4-((1-(4-氯苄基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-74)的制备Example 74: (R)-5-Chloro-4-((1-(4-chlorobenzyl)pyrrolidin-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzene Preparation of amide (Z-74)
Figure PCTCN2016073385-appb-000102
Figure PCTCN2016073385-appb-000102
步骤1：以化合物21-a(1g)为起始原料，参照实施例61步骤2的方法进行制备，得到白色固体化合物74-b(984mg)。Step 1: Preparation of Compound 21-a (1 g), m.
步骤2：以化合物74-b(100mg)为起始原料，参照实施例61步骤3的方法进行制备，不同的是将步骤中的乙酰氯换成甲烷磺酰氯，得到黄色油状化合物74-c(146mg)。Step 2: The compound 74-b (100 mg) was used as a starting material, which was obtained by the procedure of Step 3 of Example 61, except that the acetyl chloride in the step was changed to methanesulfonyl chloride to give the compound 74-c as a yellow oil. 146 mg).
步骤3：化合物74-c(124mg，0.563mmol)，化合物22-a(162mg，0.563mmol)，碳酸钾(156mg，1.127mmol)的乙腈(10ml)混合溶液，60℃搅拌2小时。反应结束，冷却至室温，水洗，干燥分离有机相，减压浓缩。经Combi-flash柱层析纯化得到无色油状化合物74-d(147mg)。MS m/z(ESI):412[M+H]+。Step 3: Compound 74-c (124 mg, 0.563 mmol), Compound 22-a (162 mg, 0.563 mmol), EtOAc ( EtOAc, EtOAc After the reaction was completed, it was cooled to room temperature, washed with water, and then dried and evaporated. Purification by Combi-flash column chromatography gave compound 44-d (147 mg). MS m/z (ESI): 412 [M+H] + .
步骤4：以化合物74-d(147mg)为起始原料，参照实施例57中步骤4的制备方法，得到白色固体化合物74-e(136mg)，MS m/z(ESI):398.1[M+H]+。Step 4: Compound 74-d (147 mg) H] + .
步骤5：以化合物74-e(97mg)为原料，参照化合物11-a中步骤b的制备方法，得到白色固体化合物Z-74(21.04mg)，MS m/z(ESI):475.1[M+H]+。1H NMR(500MHz,DMSO-d6):δ7.80(d,J＝7.5Hz,1H),7.43(br.s.,4H),7.15(d,J＝12.0Hz,1H),4.47-4.36 (m,1H),4.21(s,2H),3.89-3.61(m,1H),3.34(m,2H),3.10(s,3H),2.99-2.93(m,1H),2.14-2.07(m,1H),1.84-1.72(m,3H)Step 5: Compound 74-e (97 mg) was used as a starting material, m.p. H] + . 1 H NMR (500MHz, DMSO- d 6): δ7.80 (d, J = 7.5Hz, 1H), 7.43 (br.s., 4H), 7.15 (d, J = 12.0Hz, 1H), 4.47- 4.36 (m,1H), 4.21 (s, 2H), 3.89-3.61 (m, 1H), 3.34 (m, 2H), 3.10 (s, 3H), 2.99-2.93 (m, 1H), 2.14-2.07 ( m, 1H), 1.84-1.72 (m, 3H)
实施例77：(R)-5-氯-4-((1-(4-氯苯甲酰基)吡咯烷-2-基)甲氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-77)的制备Example 77: (R)-5-Chloro-4-((1-(4-chlorobenzoyl)pyrrolidin-2-yl)methoxy)-2-fluoro-N-(methylsulfonyl)benzene Preparation of formamide (Z-77)
Figure PCTCN2016073385-appb-000103
Figure PCTCN2016073385-appb-000103
步骤1：以化合物(R)-叔丁基-2-(羟甲基)吡咯烷-1-甲酸叔丁酯(1.19g)为原料，参照实施例4中步骤3的制备方法，将反应条件换成180℃微波搅拌20分钟，得到化合物77-b(375mg)，MS m/z(ESI):351[M+H-100]+。Step 1: Using the compound (R)-tert-butyl-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.19 g) as a starting material, referring to the preparation method of the step 3 in Example 4, the reaction conditions were carried out. The mixture was stirred for 20 minutes at 180 ° C to give compound 77-b (375 mg), MS m/z (ESI): 351 [M+H-100] + .
步骤2：以化合物77-b(375mg)为原料，参照实施例6中步骤3的制备方法，将反应条件换成40℃微波搅拌过夜，得到化合物77-c(120mg)，MS m/z(ESI):351[M+H-36]+。Step 2: The compound 77-b (375 mg) was used as a starting material, and the reaction was carried out in the same manner as in the step 3 of Example 6, and the reaction was changed to 40 ° C under microwave overnight to obtain Compound 77-c (120 mg), MS m/z ( ESI): 351 [M+H-36] + .
步骤3：向50ml单口圆底烧瓶中加入4-氯苯甲酸(16mg，0.102mmol)，化合物77-c(40mg，0.102mmol)，2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(118mg，0.306mmol)，N，N-二异丙基乙胺(40mg，0.306mmol)，二氯甲烷10ml，室温搅拌1.5h。反应结束，乙酸乙酯和水萃取，分离有机相，减压浓缩，经制备液相分离纯化得化合物Z-77(5.26mg)，纯度92％，产率10％。MS m/z(ESI):489[M+H]+。1H NMR(500MHz,DMSO):δ7.799(d,J＝6Hz,1H),7.509-7.502m,4H),7.135(d,J＝11.5Hz,1H),4.487-4.453(m,1H),4.318-4.299(m,2H),3.513-3.497(m,1H),2.906(s,3H),2.125-2.022(m,3H),1.796-1.784(m,1H),1.252-1.250(m,1H).Step 3: To a 50 ml single-neck round bottom flask was added 4-chlorobenzoic acid (16 mg, 0.102 mmol), compound 77-c (40 mg, 0.102 mmol), 2-(7-azobenzotriazole)-N, N,N',N'-tetramethyluronium hexafluorophosphate (118 mg, 0.306 mmol), N,N-diisopropylethylamine (40 mg, 0.306 mmol), m. The reaction was completed, ethyl acetate and water were extracted, and the organic phase was separated, and concentrated under reduced pressure, and purified by preparative liquid phase to give compound Z-77 (5.26 mg), purity 92%, yield 10%. MS m/z (ESI): 495 [M+H] + . 1 H NMR (500 MHz, DMSO): δ 7.799 (d, J = 6 Hz, 1H), 7.59-7. 502 m, 4H), 7.135 (d, J = 11.5 Hz, 1H), 4.487 - 4.453 (m, 1H) , 4.318-4.299 (m, 2H), 3.513-3.497 (m, 1H), 2.906 (s, 3H), 2.125-2.022 (m, 3H), 1.796-1.784 (m, 1H), 1.252-1.250 (m, 1H).
实施例82：(R)-2-氟-5-甲基-N-(甲磺酰基)-4-((1-(4-(三氟甲基)苯基)吡咯烷-2-基)甲氧基)苯甲酰胺(Z-82)的制备 Example 82: (R)-2-Fluoro-5-methyl-N-(methylsulfonyl)-4-((1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-yl) Preparation of methoxy)benzamide (Z-82)
Figure PCTCN2016073385-appb-000104
Figure PCTCN2016073385-appb-000104
步骤1：以化合物7-a(6.08g)为起始原料，参照实施例50步骤1的方法进行制备，不同的是将步骤中1-溴-4-(三氟甲氧基)苯换成1-溴-4-(三氟甲基)苯，反应条件换成100℃搅拌16小时，得到黄色油状化合物82-b(3.98g)，MS m/z(ESI):246.1[M+H]+。Step 1: Using compound 7-a (6.08 g) as a starting material, followed by the procedure of Step 1 of Example 50, except that 1-bromo-4-(trifluoromethoxy)benzene was replaced in the step. 1-Bromo-4-(trifluoromethyl)benzene, mp. + .
步骤2：以化合物82-b(490mg)为起始原料，参照实施例57步骤3的方法进行制备，不同的是将步骤中化合物17-a换成化合物25-a，反应条件换成室温搅拌2小时，得到无色油状化合物82-c(650mg)，MS m/z(ESI):478.1[M+H]+。Step 2: The compound 82-b (490 mg) was used as a starting material, and the preparation of the compound in the step of step 57 was carried out, except that the compound 17-a was replaced with the compound 25-a, and the reaction conditions were changed to room temperature stirring. 2 hours to obtain a colorless oil compound 82-c (650mg), MS m / z (ESI): 478.1 [m + H] +.
步骤3：以化合物82-c(650mg)为起始原料，参照实施例57步骤4的方法进行制备，不同的是将反应条件换成60℃搅拌2小时，得到白色固体化合物82-d(509mg)，MS m/z(ESI):462.1[M+H]+。Step 3: The compound 82-c (650 mg) was used as a starting material, and the mixture was subjected to the procedure of Step 4 of Example 57, except that the reaction conditions were changed to 60 ° C and stirred for 2 hours to obtain a white solid compound 82-d (509 mg). MS m/z (ESI): 462.1 [M+H] + .
步骤4：以化合物82-d(500mg)为原料，参照化合物11-a中步骤b的制备方法，得到白色固体化合物82-e(150mg)，MS m/z(ESI):539[M+H]+。Step 4: Compound 82-d (500 mg) was used as a starting material to give a white solid compound 82-e (150 mg), MS m/z (ESI): 539 [M+H ] + .
步骤5：化合物82-e(50mg，0.093mmol)，甲基硼酸(7mg，0.111mmol)，1,1’-双(二苯膦基)二茂铁二氯化钯(II)(7mg，0.009mmol)，碳酸钠(30mg，0.278mmol)的二氧六环(15ml)混合溶液，100℃搅拌过夜。反应结束，冷却至室温，过滤，滤液减压浓缩，经液相制备纯化得到棕色固体化合物Z-82(7.39mg)。MS m/z(ESI):475.2[M+H]+。1H NMR(500MHz,DMSO-d6):δ7.51(d,J＝8.5Hz,1H),7.46(d,J＝9.0Hz,2H),6.85(d,J＝13.0Hz,1H),6.81(d,J＝8.5Hz,2H),4.33-4.24(br.s.,1H),4.09-4.01(m,2H),3.51(m,1H),3.24-3.20(m,1H),3.13(s,3H),2.22-2.16(m,1H),2.10-1.94(m,6H)Step 5: Compound 82-e (50 mg, 0.093 mmol), methylboronic acid (7 mg, 0.111 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (7 mg, 0.009) Methyl acetate (30 mg, 0.278 mmol) in dioxane (15 ml) mixture was stirred at 100 ° C overnight. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated. MS m/z (ESI): 475.2 [M+H] + . 1 H NMR (500MHz, DMSO- d 6): δ7.51 (d, J = 8.5Hz, 1H), 7.46 (d, J = 9.0Hz, 2H), 6.85 (d, J = 13.0Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 4.33-4.24 (br.s., 1H), 4.09-4.01 (m, 2H), 3.51 (m, 1H), 3.24-3.20 (m, 1H), 3.13 (s, 3H), 2.22-2.16 (m, 1H), 2.10- 1.94 (m, 6H)
实施例120、143-144、154-155、167-168Examples 120, 143-144, 154-155, 167-168
化合物Z-120、Z-143至Z-144、Z-154、Z-155、Z-167、Z-168以化合物7-a为起始原料，参照实施例82的方法进行制备，不同的是根据各自结构，将步骤1中1-溴-4-(三氟甲基)苯或换成2-溴-5-(三氟甲基)吡啶，将步骤4中甲基磺酰胺或分别换成乙 烷磺酰胺、环丙烷磺酰胺、异丙烷磺酰胺，将步骤5中甲基硼酸或换成乙基硼酸、异丙基硼酸、环丙基硼酸。Compounds Z-120, Z-143 to Z-144, Z-154, Z-155, Z-167, and Z-168 were prepared starting from compound 7-a by the method of Example 82, except that According to the respective structures, the 1-bromo-4-(trifluoromethyl)benzene in step 1 or the 2-bromo-5-(trifluoromethyl)pyridine is replaced by the methylsulfonamide in step 4 or separately. B Alkane sulfonamide, cyclopropane sulfonamide, isopropane sulfonamide, or methyl bromide in step 5 or ethyl bromide, isopropyl boronic acid, cyclopropyl boric acid.
Figure PCTCN2016073385-appb-000105
Figure PCTCN2016073385-appb-000105
Figure PCTCN2016073385-appb-000106
Figure PCTCN2016073385-appb-000106
实施例86：5-氯-4-((4-(3-氯-4-(三氟甲氧基)苯基)哌嗪-1-基)甲基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-86)的制备Example 86: 5-Chloro-4-((4-(3-chloro-4-(trifluoromethoxy)phenyl)piperazin-1-yl)methyl)-2-fluoro-N-(A Preparation of sulfonyl)benzamide (Z-86)
Figure PCTCN2016073385-appb-000107
Figure PCTCN2016073385-appb-000107
步骤1：向4-溴-2-氯-1-(三氟甲氧基)苯(1.63g，8.76mmol)，化合物27-a(2g，7.3mmol)，碳酸铯(4.76g，14.6mmol)的二氧六环(25ml)溶液中加入(三(二亚苄基丙酮)二钯)(334mg，0.37mmol)，(±)-2,2’-双-(二苯膦基)-1,1’-联萘(227mg，0.37mmol),氩气保护，100℃搅拌5h。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，干燥分离 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固体化合物86-b(1.3g)，纯度97.21％，产率46.93％。MS m/z(ESI):325[M+H-56]+。Step 1: To 4-bromo-2-chloro-1-(trifluoromethoxy)benzene (1.63 g, 8.76 mmol), compound 27-a (2 g, 7.3 mmol), cesium carbonate (4.76 g, 14.6 mmol) (Tris(dibenzylideneacetone)dipalladium) (334 mg, 0.37 mmol), (±)-2,2'-bis-(diphenylphosphino)-1, was added to a solution of dioxane (25 ml). 1'-binaphthyl (227 mg, 0.37 mmol), argon-protected, stirred at 100 ° C for 5 h. After completion of the reaction, the mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. EtOAc was evaporated. %, the yield was 46.93%. MS m/z (ESI): 325 [M + H - 56] + .
步骤2：以化合物86-b(1.3g)为原料参照实施例4中步骤1的制备方法，得到化合物86-c(1g)，MS m/z(ESI):281[M+H-36]+。Step 2: Compound 86-b (1.3 g) was used as the starting material. The title compound of Example 4 was obtained by the procedure of Step 1 to give compound 86-c (1 g), MS m/z (ESI): 281 [M+H-36] + .
步骤3：以化合物86-c(100mg)为原料参照实施例4中步骤3的制备方法，不同的是将化合物1-a换成化合物13-a-5，反应条件换成70℃搅拌4小时，得到白色固体化合物Z-86(40.41mg)，纯度99.15％，产率22.99％，MS m/z(ESI):544[M+H]+。1H NMR(500MHz,DMSO-d6):δ12.149(s,1H),7.689(d,J＝6.5Hz,1H),7.351(d,J＝10.5Hz,1H),7.286(d,J＝9.0Hz,1H),7.080(d,＝3.0Hz,1H),6.919(dd,J＝2.9Hz,J＝9.0Hz,1H),3.605(s,2H),3.187(s,4H),3.078(s,3H),2.542(s,4H).Step 3: Using the compound 86-c (100 mg) as a starting material, refer to the preparation method of the step 3 in Example 4 except that the compound 1-a is replaced with the compound 13-a-5, and the reaction conditions are changed to 70 ° C and stirred for 4 hours. The white solid compound Z-86 (40.41 mg) was obtained, mp.: 99.15%, yield: 22.99%, MS m/z (ESI): 544 [M+H] + . 1 H NMR (500MHz, DMSO- d 6): δ12.149 (s, 1H), 7.689 (d, J = 6.5Hz, 1H), 7.351 (d, J = 10.5Hz, 1H), 7.286 (d, J = 9.0 Hz, 1H), 7.080 (d, = 3.0 Hz, 1H), 6.919 (dd, J = 2.9 Hz, J = 9.0 Hz, 1H), 3.605 (s, 2H), 3.187 (s, 4H), 3.078 (s, 3H), 2.542 (s, 4H).
实施例85、88、145Examples 85, 88, 145
化合物Z-85、Z-88、Z-145以化合物27-a为起始原料，参照实施例86的方法进行制备，不同的是将步骤1中4-溴-2-氯-1-(三氟甲氧基)苯换成相应的取代的溴苯。The compound Z-85, Z-88 and Z-145 were prepared starting from the compound 27-a, and the method of Example 86 was carried out, except that the 4-bromo-2-chloro-1-(III) in the step 1 was used. Fluoromethoxy)benzene is replaced by the corresponding substituted bromobenzene.
Figure PCTCN2016073385-appb-000108
Figure PCTCN2016073385-appb-000108
Figure PCTCN2016073385-appb-000109
Figure PCTCN2016073385-appb-000109
实施例162：(R)-5-氯-4-((4-(3,4-二氯苯基)-2-甲基哌嗪-1-基)甲基)-N-(乙基磺酰基)-2-氟苯(Z-162)的制备Example 162: (R)-5-Chloro-4-((4-(3,4-dichlorophenyl)-2-methylpiperazin-1-yl)methyl)-N-(ethyl sulfonate Preparation of acyl)-2-fluorobenzene (Z-162)
Figure PCTCN2016073385-appb-000110
Figure PCTCN2016073385-appb-000110
以化合物36-a和化合物35-a为原料，参照实施例86的步骤3制备，得化合物Z-162。MS m/z(ESI):522[M+H]+。Starting from the compound 36-a and the compound 35-a, the compound of the compound Z-162 was obtained. MS m/z (ESI): 522 [M+H] + .
实施例87：5-环丙基-4-((4-(3,4-二氯苯基)哌嗪-1-基)甲基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-87)的制备Example 87: 5-Cyclopropyl-4-((4-(3,4-dichlorophenyl)piperazin-1-yl)methyl)-2-fluoro-N-(methylsulfonyl)benzene Preparation of amide (Z-87)
Figure PCTCN2016073385-appb-000111
Figure PCTCN2016073385-appb-000111
步骤1：化合物28-a(50g,324.7mmol)，铁(10.9g,194.8mmol)的二氯甲烷(500ml)溶液室温搅拌一会，加热至40℃搅拌，逐滴加入溴(153.9g,974.1mmol)，室温搅拌过 夜。反应结束，倒入硫代硫酸钠溶液中，过滤，滤液减压浓缩得到黄色固体化合物87-b(70g)。MS m/z(ESI):231[M-1]-。Step 1: Compound 28-a (50 g, 324.7 mmol), MeOH (10.9 g, 194.8 mmol) in dichloromethane (500 ml). Methyl), stirred at room temperature overnight. The reaction was completed, poured into a sodium thiosulfate solution, filtered, and the filtrate was evaporated. MS m / z (ESI): 231 [M-1] -.
步骤2：以化合物87-b(17.5g)为原料参照实施例55中步骤1的制备方法，得到化合物87-c(15.3g)，MS m/z(ESI):309.9[M+H]+。Step 2: Compound 87-b (17.5 g) was used as the starting material . .
步骤3：化合物87-c(6.109g,0.0197mol)，N-溴代丁二酰亚胺(5.259g,0.0295mol)，偶氮二异丁腈(1.617g,0.0098mol)的乙腈(40ml)溶液，80℃搅拌4小时。反应结束，冷却至室温，硫代硫酸钠溶液洗，食盐水洗，干燥分离有机相，滤液减压浓缩得到化合物87-d(12.4g)。MS m/z(ESI):467.8[M-1]-。Step 3: Compound 87-c (6.109 g, 0.0197 mol), N-bromosuccinimide (5.259 g, 0.0295 mol), azobisisobutyronitrile (1.617 g, 0.0098 mol) in acetonitrile (40 ml) The solution was stirred at 80 ° C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, washed with sodium thiosulfate solution, washed with brine, dried and evaporated. MS m / z (ESI): 467.8 [M-1] -.
步骤4：向化合物87-d(12.4g,0.0229mol)的乙酸乙酯(50ml)溶液中加入N，N-二异丙基乙胺(4.871g,0.0382mol)，亚磷酸二乙酯(1.39g,0.01mol)，氩气保护，室温搅拌4小时。反应结束，盐酸洗，干燥分离有机相，滤液减压浓缩得到粗品，经Combi-flash柱层析纯化得到黄色固体化合物87-e(6.613g)，纯度94.5％，产率74％。MS m/z(ESI):387.9[M-1]-。Step 4: To a solution of compound 87-d (12.4 g, 0.0229 mol) in ethyl acetate (50 ml), N,N-diisopropylethylamine (4.871 g, 0.0382 mol), diethyl phosphite (1.39) g, 0.01 mol), protected with argon and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was washed with EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH MS m / z (ESI): 387.9 [M-1] -.
步骤5：以化合物87-e(336mg)为原料参照实施例28的制备方法，不同的是将化合物1-c换成化合物10-a，反应条件换成80℃搅拌2小时，得到化合物87-f(335mg)，纯度97％，产率72％，MS m/z(ESI):540[M+H]+。Step 5: Using the compound 87-e (336 mg) as a starting material, the preparation method of Example 28 was carried out except that the compound 1-c was replaced with the compound 10-a, and the reaction conditions were changed to 80 ° C and stirred for 2 hours to obtain a compound 87- f (335mg), purity 97%, yield 72%, MS m / z ( ESI): 540 [m + H] +.
步骤6：以化合物87-f(235mg)为起始原料，参照实施例82步骤5的制备方法，不同的是将步骤中甲基硼酸换成环丙基硼酸，反应条件换成80℃氩气保护搅拌过夜，得到化合物Z-87(23.93mg)，纯度98％，产率8％，MS m/z(ESI):500[M+H]+。1H NMR(500MHz,DMSO):δ7.320(d,J＝9Hz,1H),7.187(d,J＝7Hz,1H),7.151(d,J＝11.5Hz,1H),7.060(d,J＝2.5Hz,1H),6.865(dd,J＝2.5,9Hz,1H),3.652(s,2H),3.147(t,J＝4Hz,4H),3.110(s,3H),2.508(m,4H),2.036-1.982(m,1H),0.883-0.846(m,2H),0.583-0.573(m,2H).Step 6: Starting from the compound 87-f (235 mg), refer to the preparation method of the step 5 of Example 82, except that the methylboronic acid was replaced with cyclopropylboronic acid in the step, and the reaction condition was changed to 80 ° C argon gas. protection was stirred overnight, to give the compound Z-87 (23.93mg), purity 98%, yield 8%, MS m / z ( ESI): 500 [m + H] +. 1 H NMR (500MHz, DMSO) : δ7.320 (d, J = 9Hz, 1H), 7.187 (d, J = 7Hz, 1H), 7.151 (d, J = 11.5Hz, 1H), 7.060 (d, J =2.5 Hz, 1H), 6.865 (dd, J = 2.5, 9 Hz, 1H), 3.652 (s, 2H), 3.147 (t, J = 4 Hz, 4H), 3.110 (s, 3H), 2.508 (m, 4H) ), 2.036-1.982 (m, 1H), 0.883-0.846 (m, 2H), 0.583-0.573 (m, 2H).
实施例146-148、157-158、160-161、170、171Examples 146-148, 157-158, 160-161, 170, 171
化合物Z-146至Z-148、Z-157、Z-158、Z-160、Z-161、Z-170、Z-171以化合物7-a为起始原料，参照实施例87的方法进行制备，不同的是根据各自结构，将步骤2中甲基磺酰胺或分别换成乙烷磺酰胺，将步骤5中化合物10-a或换成相应的苯基取代的哌嗪，将步骤6中环丙基硼酸换成甲基硼酸、乙基硼酸。Compounds Z-146 to Z-148, Z-157, Z-158, Z-160, Z-161, Z-170, and Z-171 were prepared by the method of Example 87 using the compound 7-a as a starting material. The difference is that according to the respective structures, the methylsulfonamide in step 2 is replaced by ethanesulfonamide, and the compound 10-a in step 5 is replaced by the corresponding phenyl-substituted piperazine. The boronic acid is replaced by methyl boric acid and ethyl boric acid.
Figure PCTCN2016073385-appb-000112
Figure PCTCN2016073385-appb-000112
Figure PCTCN2016073385-appb-000113
Figure PCTCN2016073385-appb-000113
Figure PCTCN2016073385-appb-000114
Figure PCTCN2016073385-appb-000114
实施例91：5-氯-4-((4-(3,4-二氯苯基)哌嗪-1-基)甲基)-2-氟-N-(异丙基磺酰基)苯甲酰胺(Z-91)的制备 Example 91: 5-Chloro-4-((4-(3,4-dichlorophenyl)piperazin-1-yl)methyl)-2-fluoro-N-(isopropylsulfonyl)benzene Preparation of amide (Z-91)
Figure PCTCN2016073385-appb-000115
Figure PCTCN2016073385-appb-000115
步骤1：以化合物13-a-3(11.219g)为原料参照化合物17-a中步骤b的制备方法，不同的是将反应条件换成80℃搅拌7小时，得到化合物91-b(11.144g)，MS m/z(ESI):203[M+H]+。Step 1: Using the compound 13-a-3 (11.219 g) as a starting material, refer to the preparation method of the step b in the compound 17-a, except that the reaction conditions were changed to 80 ° C and stirred for 7 hours to obtain a compound 91-b (11.144 g). MS m/z (ESI): 203 [M+H] + .
步骤2：以化合物91-b(11.144g)为原料参照实施例87中步骤3的制备方法，得到化合物91-c(12.907g)，MS m/z(ESI):281[M+H]+。Step 2: Compound 91-b (11.144 g) was used as the starting material . .
步骤3：以化合物91-c(4.067g)为原料参照实施例28的制备方法，不同的是将化合物1-c换成化合物10-a，反应条件换成80℃搅拌2小时，得到化合物91-d(4.722g)，纯度94.63％，产率77％，MS m/z(ESI):433.1[M+H]+。Step 3: Refer to the preparation method of Example 28 using compound 91-c (4.067 g) as a starting material, except that compound 1-c was changed to compound 10-a, and the reaction conditions were changed to 80 ° C and stirred for 2 hours to obtain compound 91. -d (4.722 g), purity 94.63%, yield 77%, MS m/z (ESI): 433.1 [M+H] + .
步骤4：以化合物91-d(4.722g)为起始原料，参照实施例57步骤4的方法进行制备，将反应条件换成60℃搅拌3小时。得到白色固体化合物91-e(4.163g)，MS m/z(ESI):419.1[M+H]+。Step 4: The compound 91-d (4.722 g) was used as a starting material, and the preparation was carried out by the method of the step 4 of Example 57, and the reaction conditions were changed to 60 ° C and stirred for 3 hours. Obtained as a white solid compound 91-e (4.163 g), MS m/z (ESI): 419.1 [M+H] + .
步骤5：以化合物91-e(100mg)为原料参照实施例55中步骤1的制备方法，不同的是将甲磺酰胺换成异丙烷-2-磺酰胺，得到化合物Z-91(10.36mg)，MS m/z(ESI):524.1[M+H]+。1H NMR(400MHz,DMSO-d6):δ12.52(br.s.,1H),7.65(d,J＝6.8Hz,1H),7.35(d,J＝9.2Hz,1H),7.31(d,J＝11.2Hz,1H),7.09(d,J＝2.8Hz,1H),6.91(dd,J＝2.8Hz,9.2Hz,1H),3.60(s,2H),3.57-3.53(m,1H),3.20-3.17(m,4H),2.56-2.53(m,4H),1.18(d,J＝6.8Hz,6H).Step 5: Using the compound 91-e (100 mg) as a starting material, refer to the preparation method of the step 1 in Example 55, except that the methanesulfonamide was changed to the isopropane-2-sulfonamide to obtain the compound Z-91 (10.36 mg). MS m/z (ESI): 524.1 [M+H] + . 1 H NMR (400MHz, DMSO- d 6): δ12.52 (br.s., 1H), 7.65 (d, J = 6.8Hz, 1H), 7.35 (d, J = 9.2Hz, 1H), 7.31 ( d, J = 11.2 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.91 (dd, J = 2.8 Hz, 9.2 Hz, 1H), 3.60 (s, 2H), 3.57-3.53 (m, 1H), 3.20-3.17 (m, 4H), 2.56-2.53 (m, 4H), 1.18 (d, J = 6.8 Hz, 6H).
实施例90、93、129-131、133、136、138、139、140、149、151、156、163、169Examples 90, 93, 129-131, 133, 136, 138, 139, 140, 149, 151, 156, 163, 169
化合物Z-90、Z-93、Z-129至Z-131、Z-133、Z-136、Z-138、Z-139、Z-140、Z-149、Z-151、Z-156、Z-163和Z-169参照实施例91的方法进行制备，不同的是根据自身结构将步骤3中的化合物10-a换成各类苯基或吡啶基取代的哌嗪，将步骤5中的异丙烷-2-磺酰胺或换成乙烷磺酰胺。Compounds Z-90, Z-93, Z-129 to Z-131, Z-133, Z-136, Z-138, Z-139, Z-140, Z-149, Z-151, Z-156, Z -163 and Z-169 were prepared according to the method of Example 91 except that the compound 10-a in the step 3 was replaced with a variety of phenyl or pyridyl-substituted piperazines according to the structure, and the difference in the step 5 was Propane-2-sulfonamide or ethanesulfonamide.
Figure PCTCN2016073385-appb-000116
Figure PCTCN2016073385-appb-000116
Figure PCTCN2016073385-appb-000117
Figure PCTCN2016073385-appb-000117
Figure PCTCN2016073385-appb-000118
Figure PCTCN2016073385-appb-000118
Figure PCTCN2016073385-appb-000119
Figure PCTCN2016073385-appb-000119
Figure PCTCN2016073385-appb-000120
Figure PCTCN2016073385-appb-000120
实施例99：5-氯-4-((1-(5-氯吡啶-3-基)哌啶-4-基)氧基)-2-氟-N-(甲磺酰基)苯甲酰胺(Z-99)的制备 Example 99: 5-Chloro-4-((1-(5-chloropyridin-3-yl)piperidin-4-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide ( Preparation of Z-99)
Figure PCTCN2016073385-appb-000121
Figure PCTCN2016073385-appb-000121
步骤1：化合物3-溴-5-氯吡啶(500mg，2.6mmol)，化合物31-a(394mg，3.9mmol)，(三(二亚苄基丙酮)二钯)(59mg，0.065mmol)，(2-联苯基)二叔丁基膦(39mg，0.129mmol)，叔丁醇钠(749mg，7.79mmol)的甲苯(15ml)溶液，40℃搅拌过夜。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，分离有机相，减压浓缩。经Combi-flash柱层析纯化得到黄色油状化合物99-b(70mg)，MS m/z(ESI):213.1[M+H]+。Step 1: Compound 3-bromo-5-chloropyridine (500 mg, 2.6 mmol), compound 31-a (394 mg, 3.9 mmol), (tris(dibenzylideneacetone) dipalladium) (59 mg, 0.065 mmol), A solution of 2-biphenyl)di-tert-butylphosphine (39 mg, 0.129 mmol), sodium tert-butoxide (749 mg, 7.79 mmol) in toluene (15 ml) was stirred at 40 ° C overnight. After the reaction was completed, it was cooled to room temperature, poured into water, ethyl acetate was evaporated. Was purified by Combi-flash column to give a yellow oil Compound 99-b (70mg), MS m / z (ESI): 213.1 [M + H] +.
步骤2：以化合物99-b(70mg)为原料，参照实施例57中步骤3的制备方法，得到化合物99-c(120mg)，MS m/z(ESI):399.1[M+H]+。Step 2: Compound 99-b (70mg) as a raw material, in step 57 in Preparation Method 3 of Reference Example to give the compound 99-c (120mg), MS m / z (ESI): 399.1 [M + H] +.
步骤3：以化合物99-c(120mg)为原料，参照实施例57中步骤4的制备方法，得到化合物99-d(110mg)，MS m/z(ESI):383.1[M-H]-。Step 3: Compound 99-c (120mg) as starting material, prepared in Step 4 of Reference Example Example 57, to give compound 99-d (110mg), MS m / z (ESI): 383.1 [MH] -.
步骤4：以化合物99-d(110mg)为原料，参照化合物11-a中步骤b的制备方法，得到白色固体化合物Z-99(12mg)，MS m/z(ESI):462.0[M+H]+。1H NMR(500MHz,DMSO-6):12.10(s,1H),8.32(d,J＝2.5Hz,1H),7.97(d,J＝2.0Hz,1H),7.80(d,J＝7.5Hz,1H),7.50-7.49(m,1H),7.45(d,J＝12.5Hz,1H),4.92-4.91(m,1H),3.60-3.58(m,2H),3.36(s,3H),3.34-3.31(m,2H),2.06-2.04(m,2H),1.77-1.75(m,2H).Step 4: Compound 99-d (110 mg) was used as a starting material to give a white solid compound Z-99 (12 mg), MS m/z (ESI): 462.0 [M+H] ] + . 1 H NMR (500MHz, DMSO- 6): 12.10 (s, 1H), 8.32 (d, J = 2.5Hz, 1H), 7.97 (d, J = 2.0Hz, 1H), 7.80 (d, J = 7.5Hz , 1H), 7.50-7.49 (m, 1H), 7.45 (d, J = 12.5 Hz, 1H), 4.92-4.91 (m, 1H), 3.60-3.58 (m, 2H), 3.36 (s, 3H), 3.34-3.31 (m, 2H), 2.06-2.04 (m, 2H), 1.77-1.75 (m, 2H).
实施例100-101、103、105-106、114Examples 100-101, 103, 105-106, 114
化合物Z-100以化合物31-a为起始原料，参照实施例99的方法进行制备，不同的是将步骤1中的3-溴-5-氯吡啶换成化合物32-a，反应条件换成46℃搅拌5小时，步骤4反应条件换成室温搅拌3天。The compound Z-100 was prepared by the method of Example 99 using the compound 31-a as a starting material, except that the 3-bromo-5-chloropyridine in the step 1 was replaced with the compound 32-a, and the reaction conditions were changed. The mixture was stirred at 46 ° C for 5 hours, and the reaction conditions in step 4 were changed to room temperature and stirred for 3 days.
化合物Z-101以化合物31-a为起始原料，参照实施例99的方法进行制备，不同的是将步骤1中的3-溴-5-氯吡啶换成化合物33-a，反应条件换成40℃搅拌5小时。The compound Z-101 was prepared by the method of Example 99 using the compound 31-a as a starting material, except that the 3-bromo-5-chloropyridine in the step 1 was replaced with the compound 33-a, and the reaction conditions were changed. Stir at 40 ° C for 5 hours.
化合物Z-103以化合物31-a为起始原料，参照实施例99的方法进行制备，不同的是将步骤1中的3-溴-5-氯吡啶换成1-溴-2,4-二氯苯，步骤3反应条件换成50℃搅拌3小时。 Compound Z-103 was prepared according to the method of Example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was replaced by 1-bromo-2,4-di. Chlorobenzene, the reaction conditions of step 3 were changed to 50 ° C and stirred for 3 hours.
化合物Z-105以化合物31-a为起始原料，参照实施例99的方法进行制备，不同的是将步骤1中的3-溴-5-氯吡啶换成4-溴-2-氯-1-(三氟甲基)苯，反应条件换成40℃搅拌5小时。Compound Z-105 was prepared according to the method of Example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to 4-bromo-2-chloro-1. -(Trifluoromethyl)benzene, and the reaction conditions were changed to 40 ° C and stirred for 5 hours.
化合物Z-106以化合物31-a为起始原料，参照实施例99的方法进行制备，不同的是将步骤1中的3-溴-5-氯吡啶换成4-溴-2-氯-1-氟苯。Compound Z-106 was prepared according to the method of Example 99, starting from compound 31-a, except that 3-bromo-5-chloropyridine in step 1 was changed to 4-bromo-2-chloro-1. - Fluorobenzene.
化合物Z-114以化合物31-a为起始原料，参照实施例99的方法进行制备，不同的是将步骤1中的3-溴-5-氯吡啶换成化合物23-a，反应条件换成40℃搅拌4小时。The compound Z-114 was prepared by the method of Example 99 using the compound 31-a as a starting material, except that the 3-bromo-5-chloropyridine in the step 1 was replaced with the compound 23-a, and the reaction conditions were changed. Stir at 40 ° C for 4 hours.
Figure PCTCN2016073385-appb-000122
Figure PCTCN2016073385-appb-000122
Figure PCTCN2016073385-appb-000123
Figure PCTCN2016073385-appb-000123
实施例132：4-((4-(3,4-二氯苯基)哌嗪-1-基)甲基)-2-氟-N-(异丙基磺酰基)苯甲酰胺(Z-132)的制备Example 132: 4-((4-(3,4-Dichlorophenyl)piperazin-1-yl)methyl)-2-fluoro-N-(isopropylsulfonyl)benzamide (Z- Preparation of 132)
Figure PCTCN2016073385-appb-000124
Figure PCTCN2016073385-appb-000124
步骤1：向化合物28-a(500mg，3.24mmol)，丙烷-2-磺酰胺(799mg，6.49mmol)的二氯甲烷(5ml)溶液中逐滴加入三乙胺(985mg，9.73mmol)，碳化二亚胺(1.24g，6.49mmol)，4-二甲氨基吡啶(396mg，3.24mmol)，室温搅拌过夜。反应结束，加入10ml 水，饱和食盐水洗，无水硫酸钠干燥，分离有机相，减压浓缩。经Combi-flash柱层析纯化得到白色固体化合物132-b(560mg)，MS m/z(ESI):260[M+H]+。Step 1: To a solution of compound 28-a (500 mg, 3.24 mmol), EtOAc (EtOAc) Diimine (1.24 g, 6.49 mmol), 4-dimethylaminopyridine (396 mg, 3.24 mmol) was stirred at room temperature overnight. At the end of the reaction, add 10ml The organic layer was separated and dried under reduced pressure. Purification by Combi-flash column chromatography gave EtOAc (EtOAc: EtOAc)
步骤2：向化合物132-b(510mg，1.97mmol)的乙腈(5ml)溶液中加入N-溴代丁二酰亚胺(455mg，2.56mmol)，偶氮二异丁腈(32mg，0.20mmol)，氩气保护，80摄氏度搅拌3小时。反应结束，冷却至室温，倒入水中，盐酸(4N)调PH为3，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，分离有机相，减压浓缩得到黄色油状化合物132-c(665mg)，MS m/z(ESI):338[M+H]+。Step 2: To a solution of compound 132-b (510 mg, 1.97 mmol) in EtOAc (5 mL) EtOAc (EtOAc, EtOAc Argon protection, stirring at 80 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and poured into water, and the mixture was evaporated. 665 mg), MS m/z (ESI): 338 [M+H]+.
步骤3：向化合物10-a(68mg，0.30mmol)，化合物132-c(100mg，0.30mmol)的二甲基甲酰胺(3ml)溶液中加入碳酸钾(102mg，0.75mmol)，85摄氏度搅拌2小时。反应结束，冷却至室温，倒入水中，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，分离有机相，减压浓缩，经Pre-HPLC纯化得到白色固体化合物Z-132(33.66mg)，MS m/z(ESI):488.1[M+H]+。1H NMR(400MHz,DMSO-d6):δ7.59(t,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,2H),7.09(d,J＝4.0Hz,1H),6.89-6.92(m,1H),3.64-3.71(m,1H),3.58(s,2H),3.17-3.19(m,4H),2.47-2.51(m,4H),1.26(s,3H),1.25(s,3H).Step 3: To a solution of compound 10-a (68 mg, 0.30 mmol), Compound 132-c (100 mg, 0.30 mmol) in dimethylformamide (3 ml) hour. After the reaction was completed, it was cooled to room temperature, poured into water, EtOAc EtOAc (EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH MS m/z (ESI): 488.1 [M+H]+. 1 H NMR (400MHz, DMSO- d 6): δ7.59 (t, J = 8.0Hz, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.21 (d, J = 8.0Hz, 2H), 7.09 (d, J=4.0 Hz, 1H), 6.89-6.92 (m, 1H), 3.64-3.71 (m, 1H), 3.58 (s, 2H), 3.17-3.19 (m, 4H), 2.47-2.51 ( m, 4H), 1.26 (s, 3H), 1.25 (s, 3H).
对比例1：5-环丙基-4-((4-(3,4-二氯苄基)哌嗪-1-基)甲基)-2-氟-N-(甲磺酰基)苯甲酰胺(C1)的制备Comparative Example 1: 5-Cyclopropyl-4-((4-(3,4-dichlorobenzyl)piperazin-1-yl)methyl)-2-fluoro-N-(methylsulfonyl)benzene Preparation of amide (C1)
Figure PCTCN2016073385-appb-000125
Figure PCTCN2016073385-appb-000125
步骤1：4-(溴甲基)-1,2-二氯苯(1.0g，4.17mmol)，化合物27-a(0.78g，4.17mmol)，碳酸钾(1.15g，8.34mmol)乙腈(10ml)的混合溶液中，80℃搅拌5h。反应结束，冷却至室温，减压浓缩，加水，乙酸乙酯萃取，食盐水洗有机相，干燥分离有机相，滤液减压浓缩得到粗品，经Combi-flash柱层析纯化得到无色油状化合物166-b(1.23g)，纯度100％，产率85.4％。MS m/z(ESI):345.2[M+H]+。Step 1: 4-(Bromomethyl)-1,2-dichlorobenzene (1.0 g, 4.17 mmol), Compound 27-a (0.78 g, 4.17 mmol), potassium carbonate (1.15 g, 8.34 mmol) acetonitrile (10 ml) The mixture was stirred at 80 ° C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. b (1.23 g), purity 100%, yield 85.4%. MS m/z (ESI): 345.2 [M+H] + .
步骤2：向化合物166-b(1.23g，3.57mmol)的甲醇(10ml)溶液中加入盐酸/二氧六环(4M，4ml，14.28mmol)，室温搅拌2小时。反应结束，反应液减压浓缩得到白色 固体化合物166-c(1.1g)，直接用于下一步反应，纯度96.91％，产率100％。MS m/z(ESI):245.1[M+H]+。Step 2: To a solution of compound 166-b (1. <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt; After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals MS m/z (ESI):245.1 [M+H] + .
步骤3：化合物166-c(200mg，0.71mmol)，化合物87-e(276mg，0.71mmol)，碳酸钾(196mg，1.42mmol)乙腈(5ml)的混合溶液，80℃搅拌2小时。反应结束，冷却至室温，减压浓缩，加水，调PH为7，乙酸乙酯萃取，食盐水洗有机相，干燥分离有机相，滤液减压浓缩得到黄色固体化合物166-d(285mg)，纯度89.3％，产率72.5％。MS m/z(ESI):554.0[M+H]+。Step 3: A mixed solution of the compound 166-c (200 mg, 0.71 mmol), Compound 87-e (276 mg, 0.71 mmol), potassium carbonate (196 mg, 1.42 mmol) acetonitrile (5 ml), and stirred at 80 ° C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjj %, the yield was 72.5%. MS m/z (ESI): 554.0 [M+H] + .
步骤4：化合物166-d(283mg，0.51mmol)，环丙基硼酸(88mg，1.02mmol)，1,1’-双(二苯膦基)二茂铁二氯化钯(II)(37mg，0.051mmol)，碳酸铯(333mg，1.02mmol)的二氧六环(5ml)混合溶液，80℃搅拌24小时。反应结束，冷却至室温，过滤，滤液减压浓缩，经Combi-flash柱层析收集所需产物，浓缩，加入甲醇超声2分钟2次，得到淡黄色固体化合物C1(80mg)。纯度91.36％，产率30.5％。MS m/z(ESI):514.2[M+H]+。1H NMR(DMSO-d6,400MHz):＝11.29(br.s.,1H),7.49-7.64(m,2H),7.30(d,J＝8.0Hz,1H),7.05-7.25(m,2H),3.72(s,2H),3.62(s,2H),3.16(s,3H),2.55(br.s.,8H),1.92-2.09(m,1H),0.85-0.93(m,2H),0.57-0.65ppm(m,2H)。Step 4: Compound 166-d (283 mg, 0.51 mmol), cyclopropylboronic acid (88 mg, 1.02 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride (37 mg, 0.051 mmol), a mixed solution of cesium carbonate (333 mg, 1.02 mmol) in dioxane (5 ml) was stirred at 80 ° C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. The purity was 91.36% and the yield was 30.5%. MS m/z (ESI): 514.2 [M+H]+. 1H NMR (DMSO-d6, 400MHz): = 11.29 (br.s., 1H), 7.49-7.64 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.05-7.25 (m, 2H) , 3.72 (s, 2H), 3.62 (s, 2H), 3.16 (s, 3H), 2.55 (br.s., 8H), 1.92-2.09 (m, 1H), 0.85-0.93 (m, 2H), 0.57-0.65 ppm (m, 2H).
阳性对照药物2(Z-0)的制备Preparation of positive control drug 2 (Z-0)
Figure PCTCN2016073385-appb-000126
Figure PCTCN2016073385-appb-000126
步骤1：将化合物Z-0-1(20.0g,155mmol)溶解在叔丁醇(150mL)中，冷却到0℃，氮气保护下加入叠氮磷酸二苯酯(47g,170mmol),三乙胺(17.3g,170mmol)。混合物回流搅拌18h后，用旋转蒸发仪旋干。残留物溶解在二氯甲烷(400mL)中，用水(200mL x 2)，食盐水(200mL)洗。无水硫酸钠干燥，抽滤。滤液用旋转蒸发仪旋干，残留物用柱层析(PE:EA＝3:1)纯化后得浅黄色固体Z-0-2(15.2g,收率:49％).ESI-MS(M-55)+:145,纯度＝97％(UV214)。1H NMR(400MHz,CDCl3)δ：8.85(brs,1H),8.61(d,1H),7.32(s,1H),1.55(s,9H)。Step 1: Compound Z-0-1 (20.0 g, 155 mmol) was dissolved in tert-butanol (150 mL), cooled to 0 ° C, diphenyl azide (47 g, 170 mmol), triethylamine (17.3 g, 170 mmol). The mixture was stirred at reflux for 18 h and then dried with a rotary evaporator. The residue was dissolved in dichloromethane (400 mL) and washed with water (200 <RTIgt; Dry over anhydrous sodium sulfate and suction filtration. The filtrate was triturated with a rotary evaporator, and the residue was purified by column chromatography (PE: EA=3:1) to yield pale yellow solid Z-0-2 (15.2 g, yield: 49%). ESI-MS (M -55) +: 145, purity = 97% (UV214). 1 H NMR (400 MHz, CDCl 3 ) δ: 8.85 (brs, 1H), 8.61 (d, 1H), 7.32 (s, 1H), 1.55 (s, 9H).
步骤2：在N2保护下，将Z-0-2(8.0g，0.04mol)溶解在无水THF(80ml)中，混合物冷却到-78℃，滴加LiHMDS(1M，48ml，0.048mol)的THF溶液。滴加完成后，混合物在-78℃，搅拌0.5h。将反应液慢慢升温至室温，搅拌1h，然后降温至-78℃，将5-氯-2,4-二氟苯磺酰氯(11.11g，0.048mol)的THF(50ml)溶液滴加到上述反应液。混合物在-78℃，搅拌1h后升至室温，并在室温搅拌16h。向反应液中加入饱和氯化铵水溶液(250ml)中,用乙酸乙酯(3 x 100ml)萃取,合并有机相，用饱和食盐水(200ml)洗，干燥，40℃旋干。粗品过柱(100-200目硅胶),淋洗液为石油醚：乙酸乙酯＝(4:1)，得到Z-0-3(5.11g,产率：31.8％)为白色固体。ESI-MS(M+Na)+:434.0，纯度:95.9％(UV214)。Step 2: Dissolve Z-0-2 (8.0 g, 0.04 mol) in dry THF (80 mL) under N 2 and then cooled to -78 ° C and then add dropwise LiHMDS (1M, 48ml, 0.048 mol) THF solution. After the dropwise addition was completed, the mixture was stirred at -78 ° C for 0.5 h. The reaction solution was slowly warmed to room temperature, stirred for 1 h, then cooled to -78 ° C, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (11.11 g, 0.048 mol) in THF (50 ml) was added dropwise. The reaction solution. The mixture was stirred at -78 ° C for 1 h then warmed to room rt and stirred at room temperature for 16 h. A saturated aqueous solution of ammonium chloride (250 ml) was added, and the mixture was evaporated. The crude product was passed through a column (100-200 mesh silica gel), and the eluent was petroleum ether: ethyl acetate = (4:1) to give Z-0-3 (5.11 g, yield: 31.8%) as a white solid. ESI-MS (M+Na)+: 434.0, purity: 95.9% (UV 214).
步骤3：将化合物Z-0-4(50.8g,254mmol)溶解在THF(600mL)中，在冰浴中冷却至0℃搅拌，分批加入氢化锂铝(8.4g,220mmol)。混合物在0℃搅拌2h后，加水淬灭反应，加盐酸(6N)调节PH＝3,分离水相，有机相无水硫酸钠干燥，抽滤。滤液用旋转蒸发仪旋干，得白色固体Z-0-5(32.0g,收率:73.5％).1H NMR(400MHz,CDCl3)δ7.22–7.16(m,1H),6.77(d,J＝8.7Hz,1H),4.61(d,J＝3.7Hz,2H),3.82(s,3H),2.63(s,1H).Step 3: Compound Z-0-4 (50.8 g, 254 mmol) was dissolved in THF (600 mL). After the mixture was stirred at 0 ° C for 2 h, the reaction was quenched with water and then EtOAc (EtOAc) (EtOAc). The filtrate was triturated with a rotary evaporator to give a white solid, Z-0-5 (32.0 g, yield: 73.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 - 7.16 (m, 1H), 6.77 (d) , J = 8.7 Hz, 1H), 4.61 (d, J = 3.7 Hz, 2H), 3.82 (s, 3H), 2.63 (s, 1H).
步骤4：将化合物Z-0-5(32.0g,190mmol)溶解在二氯甲烷(400mL)中，然后加入氯化亚砜(50mL)。混合物在氮气保护下，加热至回流搅拌3h。混合物降至室温，加水(200mL)淬灭反应，分离有机相，水相用二氯甲烷萃取(200 x 2mL)。合并有机相用食盐水洗涤，无水硫酸钠干燥，抽滤。滤液用旋转蒸发仪旋干，得红色固体Z-0-6(33.0g,收率:92.2％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝2.6Hz,1H),7.25(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.8Hz,1H),4.59(s,2H),3.86(s,3H).Step 4: Compound Z-0-5 (32.0 g, 190 mmol) was dissolved in dichloromethane (400 mL) and then th The mixture was heated to reflux with stirring for 3 h under nitrogen. The mixture was cooled to room temperature and the reaction was quenched with water (200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium The filtrate was dried with a rotary evaporator to give a red solid, Z-0-6 (33.0 g, yield: 92.2%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 2.6 Hz, 1H), 7.25 (dd, J = 8.7, 2.7 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.59 (s, 2H), 3.86 (s, 3H).
步骤5：将化合物Z-0-6(32g,168mmol)溶解在DMSO(200mL)中，加入***(29g,606mmol)。混合物在氮气保护下，加热至80℃搅拌3h。反应混合物冷却至室温，加水分散，抽滤。滤饼用少量水洗涤。风干得桔红色固体Z-0-7(31g,收率:98.3％)。1H NMR(400MHz,CDCl3)δ7.35(d,J＝2.5Hz,1H),7.28(dd,J＝8.5,2.3Hz, 1H),6.82(d,J＝8.7Hz,1H),3.86(s,3H),3.66(s,2H).Step 5: Compound Z-0-6 (32 g, 168 mmol) was dissolved in DMSO (200 mL) and sodium cyanide (29 g, 606 mmol). The mixture was heated to 80 ° C under nitrogen for 3 h. The reaction mixture was cooled to room temperature, added with water and filtered. The filter cake was washed with a small amount of water. It was dried to an orange solid Z-0-7 (31 g, yield: 98.3%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 8.5, 2.3 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.66 (s, 2H).
步骤6：将化合物Z-0-7(32g,177mmol)溶解在甲酸甲酯(400mL)中，加入钠(8.14g,354mmol)。混合物在氮气保护下，加热回流搅拌24h。反应混合物冷却至室温，加水淬灭反应，乙酸乙酯提取(400 x 2mL)，合并有机相水洗(200 x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得黄色固体Z-0-8(10.5g,收率:28.4％)。1H NMR(400MHz,DMSO)δ11.91(s,1H),7.71(d,J＝93.3Hz,1H),7.40–7.32(m,1H),7.29(dd,J＝12.2,2.6Hz,1H),7.08(dd,J＝8.7,3.1Hz,1H),3.82(s,3H)。Step 6: Compound Z-0-7 (32 g, 177 mmol) was dissolved in EtOAc (400 mL). The mixture was heated under reflux with nitrogen for 24 h. The reaction mixture was cooled to room temperature. EtOAc EtOAc m. The oil was evaporated to dryness to give a yellow solid (yield: EtOAc) 1 H NMR (400MHz, DMSO) δ11.91 (s, 1H), 7.71 (d, J = 93.3Hz, 1H), 7.40-7.32 (m, 1H), 7.29 (dd, J = 12.2,2.6Hz, 1H ), 7.08 (dd, J = 8.7, 3.1 Hz, 1H), 3.82 (s, 3H).
步骤7：将化合物Z-0-8(10.5g,50.2mmol)溶解在乙醇(150mL)中，加入叔丁基肼(7.5g,60.3mmol)。混合物在氮气保护下，加热回流搅拌3.5h。反应混合物冷却至室温，减压蒸干得黄色固体(15g)，快速柱层析得黄色固体Z-0-9(14.0g,收率:99.9％)。Step 7: Compound Z-0-8 (10.5 g, 50.2 mmol) was dissolved in ethanol (150 mL) and tert-butyl hydrazine (7.5 g, 60.3 mmol) was added. The mixture was heated under reflux with stirring for 3.5 h. The reaction mixture was cooled to room temperature and evaporated to dryness crystals crystals crystals
步骤8：将化合物Z-0-9(13.5g,48.4mmol)溶解在二氯甲烷(300mL)中，在冰浴中冷却至0℃，加入三氟乙酸酐(30.5g,145.2mmol)，三乙胺(14.7g,145.2mmol)。混合物在氮气保护下，升至室温搅拌4h。反应混合物加入碳酸钠淬灭反应至中性，分离水相，有机相用饱和食盐水洗涤(100 x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得棕色固体Z-0-10(12.0g,收率:66.1％)。ESI-MS(M-H):376,纯度＝89.23％(UV254).Step 8: Compound Z-0-9 (13.5 g, 48.4 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI> </RTI> <RTIgt; Ethylamine (14.7 g, 145.2 mmol). The mixture was stirred under nitrogen for 4 h. The reaction mixture was quenched by the addition of sodium carbonate, and the mixture was evaporated to dryness. The organic phase was washed with saturated brine (100×2 mL) It was evaporated to dryness to give a brown solid (yield: EtOAc) (yield: 66.1%). ESI-MS (M-H): 376, purity = 89.23% (UV254).
步骤9：将化合物Z-0-10(11.0g,29.3mmol)溶解在二氯甲烷(200mL)中，在冰浴中冷却至0℃，加入三溴化硼(36.7g,146.6mmol)。混合物在氮气保护下，升至室温搅拌4h。反应混合物慢慢加入冰水(100mL)，分离水相，有机相用饱和食盐水洗涤(100 x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得棕色固体Z-0-11(6.3g,收率:68.9％)。ESI-MS(M-H):362,纯度＝80.83％(UV254).Step 9: Compound Z-0-10 (11.0 g, 29.3 mmol) was dissolved in dichloromethane (200 mL). The mixture was stirred under nitrogen for 4 h. The reaction mixture was slowly added with ice water (100 mL), EtOAc (EtOAc) The organic solid Z-0-11 (6.3 g, yield: 68.9%) was evaporated to dryness. ESI-MS (M-H): 362, purity = 80.83% (UV254).
步骤10：将化合物Z-0-11(25.0g,69mmol)溶解在甲醇(100mL)中，盐酸二氧六环溶液(4M/L,100mL)。混合物在70℃搅拌18h。冷却至室温后，旋干。将氨的甲醇(50mL)溶液慢慢加入到残留物(100mL)，40℃旋干。粗品过柱(100-200目硅胶),淋洗液为二氯甲烷：甲醇(10:1)，得到灰色固体Z-0-12(8.0g,收率:38％)。ESI-MS(M-H):210.1,纯度＝90％(UV214)。Step 10: Compound Z-0-11 (25.0 g, 69 mmol) was dissolved in methanol (100 mL). The mixture was stirred at 70 ° C for 18 h. After cooling to room temperature, spin dry. A solution of ammonia in methanol (50 mL) was slowly added to the residue (100 mL) and dried at 40 °C. The crude product was passed through a column (100-200 mesh silica gel), and the eluent was methylene chloride:methanol (10:1) to give a white solid, Z-0-12 (8.0 g, yield: 38%). ESI-MS (M-H): 210.1, purity = 90% (UV 214).
步骤11：将化合物Z-0-12(4.18g,20mmol)，Z-0-3(8.20g,20mmol)，碳酸钾(8.28g,60mmol)溶解在DMF(100mL)中，混合物在氮气保护下，加热至40℃搅拌18h。反应混合物加入水(500mL)，二氯甲烷萃取(200mL x 3)，合并有机相用水洗(100mL x 2)，饱和食盐水洗涤(100 x 2mL)，无水硫酸钠干燥，抽滤。减压蒸干得红色固体Z-0-13(15.1g,收率:>100％)。ESI-MS(M+H)+:600.1,纯度＝28％(UV254). Step 11: Compound Z-0-12 (4.18 g, 20 mmol), Z-0-3 (8.20 g, 20 mmol), potassium carbonate (8.28 g, 60 mmol) dissolved in DMF (100 mL) Heat to 40 ° C and stir for 18 h. The reaction mixture was poured into water (500 mL), EtOAc (EtOAc)EtOAc. It was evaporated to dryness under reduced pressure to give a red solid (yield: EtOAc). ESI-MS (M+H)+: 600.1, purity = 28% (UV254).
步骤12：将化合物Z-0-13(12.0g,20mmol)溶解在二氯甲烷(40mL)中，加入三氟乙酸(20mL)。混合物在氮气保护下，室温下搅拌24h。减压蒸干得粗产物为黄色固体，经HPLC制备得类白色固体粉末Z-0(3.04mg,收率:31％)。ESI-MS(M+H)+:499.8,纯度＝100％(UV254)。1H NMR(400MHz,DMSO)δ11.56(s,2H),8.91(d,J＝2.4Hz,1H),7.90(d,J＝6.8Hz,1H),7.69(s,1H),7.43(s,1H),7.32(dd,J＝8.8,2.4Hz,1H),7.22(dd,J＝8.4Hz,1H),7.07(d,J＝2.0Hz,1H),6.73(d,J＝10.8Hz,1H),4.92(s,2H)。Step 12: Compound Z-0-13 (12.0 g, 20 mmol) was dissolved in dichloromethane (40 mL). The mixture was stirred under nitrogen for 24 h at room temperature. The crude product was obtained as a yellow solid (yield: EtOAc (EtOAc: EtOAc) ESI-MS (M+H)+: 499.8, purity = 100% (UV254). 1 H NMR (400MHz, DMSO) δ11.56 (s, 2H), 8.91 (d, J = 2.4Hz, 1H), 7.90 (d, J = 6.8Hz, 1H), 7.69 (s, 1H), 7.43 ( s, 1H), 7.32 (dd, J = 8.8, 2.4 Hz, 1H), 7.22 (dd, J = 8.4 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 10.8) Hz, 1H), 4.92 (s, 2H).
电生理学测定Electrophysiological assay
测试例1hNav1.7和hNav1.5通道的手动膜片钳实验Test Example 1 manual patch clamp experiment of hNav1.7 and hNav1.5 channels
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)。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).
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。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.
手动膜片钳实验方案如下：The manual patch clamp experimental protocol is as follows:
(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。(A) Preparation of solutions and compounds: hNav1.7 and hNav1.5 currents were recorded using whole-cell patch clamp technique. In the experiment, the composition of the extracellular fluid (mM): HEPES: 5, NaCl: 40, KCl: 3, CaCl 2 : 1, MgCl 2 : 1, CdCl 2 : 0.1, TEA-Cl: 20. The pH was adjusted to 7.3 with NaOH while the osmotic pressure was adjusted to 310-320 mOsm with sucrose and stored at 4 ° C after filtration. The composition of the intracellular fluid (mM): HEPES: 10, NaCl: 10, CsOH: 5, CsF: 140, EGTA: 1. The pH was adjusted to 7.3 with CsOH while the osmotic pressure was adjusted to 280-290 mOsm with sucrose and stored at -20 ° C after filtration.
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％。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. 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%.
(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。(B) manual patch clamp experiment: Take the cell suspension and add it to a 35mm petri dish and place it on the inverted microscope stage. After the cells were attached, the cells were perfused with extracellular fluid at a flow rate of 1–2 mL/min. The glass microelectrode is drawn in two steps by a microelectrode drawing device, and its water inlet resistance is 2-5 MΩ. Stimulation and signaling through A/D–D/A digital-to-analog conversion with Digidata 1440 (Molecular Devices) and pCLAMP software (version 10.2, Molecular Devices) Acquisition; patch clamp amplifier (Multiclamp 700B, Molecular Devices) amplifies the signal and filters it to 4 kHz.
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。Two different voltage stimulation procedures were used in the hNav1.7 and hNav1.5 manual patch clamp experiments.
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。One is the inactivation stimulation procedure, where the clamping potential is set at V 1/2 of the corresponding channel, ie approximately 50% of the channels are inactive. The voltage is then applied to -120 mV for 50 ms. It is then depolarized to -10 mV for 20 ms to draw the sodium current and finally return to the clamping potential. This stimulation procedure can also be referred to as a channel state dependent voltage stimulation procedure.
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。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.
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。结果分别见表1和表2。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 Tables 1 and 2, respectively.
表1 本发明代表性化合物在两种浓度下对Nav1.7的抑制率Table 1 Inhibition rate of representative compounds of the invention against Nav1.7 at two concentrations
Figure PCTCN2016073385-appb-000127
Figure PCTCN2016073385-appb-000127
Figure PCTCN2016073385-appb-000128
Figure PCTCN2016073385-appb-000128
Figure PCTCN2016073385-appb-000129
Figure PCTCN2016073385-appb-000129
表2 本发明代表性化合物在对Nav1.7和Nav1.5的抑制率Table 2 Inhibition rates of representative compounds of the invention on Nav1.7 and Nav1.5
Figure PCTCN2016073385-appb-000130
Figure PCTCN2016073385-appb-000130
表3 本发明代表性化合物对Nav1.7和Nav1.5的IC50值Table 3 Representative compounds of the invention, 50 values of Nav1.7 and Nav1.5 IC
化合物Compound Nav1.7(IC50/nM)Nav1.7 (IC 50 /nM) Nav1.5(IC50/nM)Nav1.5 (IC 50 /nM) Nav1.5/Nav 1.7Nav1.5/Nav 1.7
Z-4Z-4 30.6230.62 53405340 174174
Z-22Z-22 5.175.17 600600 116116
Z-23Z-23 24.624.6 23802380 9797
Z-41Z-41 6.666.66 42904290 644644
Z-45Z-45 10.5510.55 15301530 145145
Z-47Z-47 8.238.23 15001500 182182
Z-67Z-67 5.955.95 1038010380 17451745
Z-73Z-73 5.615.61 780780 139139
Z-85Z-85 29.9829.98 2912029120 971971
Z-86Z-86 13.7613.76 83608360 608608
Z-97Z-97 14.3514.35 33303330 232232
从表1、表2和表3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，对Nav1.5的抑制活性明显较弱，因此对Nav1.7具有明显的选择抑制活性。As can be seen from Table 1, Table 2 and Table 3, the representative compounds of the present invention have a high inhibitory activity against Nav1.7, and the inhibitory activity against Nav1.5 is significantly weak, so that there is a significant selective inhibition of Nav1.7. active.
从上表可以看出，吡咯环碳上的取代位置不同对选择性具有明显的影响。2-位取代的化合物的选择性比3-位取代的化合物的选择性明显提高很多。As can be seen from the above table, the different substitution positions on the pyrrole ring carbon have a significant influence on the selectivity. The selectivity of the 2-substituted compound is significantly improved over the selectivity of the 3-substituted compound.
四元、五元(吡咯环)和六元(哌啶环，哌嗪环)含氮杂环上氮和碳原子上的取代基以及取代位置的不同，对Nav1.7的抑制活性有明显的影响，研究表明当氮原子不与A环(如苯环或吡啶环)直接相连时，即A环(如苯环或吡啶环)通过亚甲基或羰基等基团与氮原子相连时，抑制活性有明显的降低；并且研究发现，四元或六元氮杂环上碳原子上的取代基的位置(如2-位，3-位取代)和取代基(如-O-，-CH2-O-)的不同，对抑制活性也有较明显的影响。The four-membered, five-membered (pyrrole ring) and six-membered (piperidinyl ring, piperazine ring) nitrogen-containing heterocyclic ring on the nitrogen and carbon atom substituents and the position of substitution, the inhibition activity of Nav1.7 is obvious Influence, studies have shown that when the nitrogen atom is not directly connected to the A ring (such as a benzene ring or a pyridine ring), that is, the A ring (such as a benzene ring or a pyridine ring) is bonded to the nitrogen atom through a group such as a methylene group or a carbonyl group, There is a significant decrease in activity; and studies have found that the positions of the substituents on the carbon atom of the four- or six-membered nitrogen heterocycle (such as 2-position, 3-position substitution) and substituents (such as -O-, -CH 2 The difference between -O-) also has a significant effect on the inhibitory activity.
测试例2疼痛模型(***)测试Test Example 2 Pain Model (Formalin) Test
实验动物为雄性Wistar大鼠，体重250±30g。实验用动物均采购于北京维通利华实验动物有限公司，购买后于上海睿智化学研究有限公司屏障设施内饲养(2-3只/笼，温度21.0±2℃，湿度为40-70％，灯光控制从凌晨5点开始开启，周期12h)。动物适应饲养环境至少5天后开始实验。The experimental animals were male Wistar rats weighing 250 ± 30 g. The experimental animals were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd., and then purchased in the barrier facility of Shanghai Ruizhi Chemical Research Co., Ltd. (2-3 pieces/cage, temperature 21.0±2°C, humidity 40-70%, The lighting control starts from 5 am, cycle 12h). The experiment was started after the animals were adapted to the feeding environment for at least 5 days.
检测化合物：Test compound:
阴性对照：化合物溶剂，5％DMAC(二甲基乙酰胺)+5％Solutol(聚乙二醇-12-羟 基硬脂酸酯)+90％生理盐水；Negative control: compound solvent, 5% DMAC (dimethylacetamide) + 5% Solutol (polyethylene glycol-12-hydroxyl Stearate) +90% saline;
阳性对照药物1：***(Mor)，5mg/kg组：，2ml/kg，I.P.,n＝7；Positive control drug 1: morphine (Mor), 5 mg/kg group: 2 ml/kg, I.P., n=7;
阳性对照药物2：HYC00012(也称为化合物Z-0)，10mg/kg组：10ml/kg，P.O.,n＝10；Positive control drug 2: HYC00012 (also known as compound Z-0), 10 mg/kg group: 10 ml/kg, P.O., n=10;
待测药物：化合物Z-4。Drug to be tested: Compound Z-4.
分组：Grouping:
阴性对照组(Veh)：10ml/kg，动物灌胃(p.o.)；Negative control group (Veh): 10ml/kg, animal gavage (p.o.);
阳性对照药物1:***(Mor-5mpk)：2.5mg/ml，2ml/kg，腹腔注射(i.p.)；Positive control drug 1: Morphine (Mor-5mpk): 2.5 mg/ml, 2 ml/kg, intraperitoneal injection (i.p.);
阳性对照药物2：化合物Z-0(Z-0-10mpk)：1mg/ml，10ml/kg，动物灌胃(p.o.)；Positive control drug 2: Compound Z-0 (Z-0-10mpk): 1 mg/ml, 10 ml/kg, animal gavage (p.o.);
待测药物组：Test group to be tested:
10mg/kg组(Z-4-10mpk)：1mg/ml，10ml/kg，动物灌胃(p.o.)；10mg/kg group (Z-4-10mpk): 1mg/ml, 10ml/kg, animal gavage (p.o.);
30mg/kg组(Z-4-30mpk)：3mg/ml，10ml/kg，动物灌胃(p.o.)；30mg/kg group (Z-4-30mpk): 3mg/ml, 10ml/kg, animal gavage (p.o.);
150mg/kg组(Z-4-150mpk)：15mg/ml，10ml/kg，动物灌胃(p.o.)；150mg/kg group (Z-4-150mpk): 15mg/ml, 10ml/kg, animal gavage (p.o.);
所有药物溶液在实验当天现配。All drug solutions were dispensed on the day of the experiment.
实验方法：experimental method:
1.Laboras***介绍：LABORASTM***，购买于荷兰METRIS公司。实验***包括实验笼盒和底部平板。实验笼盒，面积为880平方厘米，高度为17.5厘米，由顶盖，食物和水瓶槽组成，放置于一个可以调节高度的框架上，距离底部平板2-3毫米。底部平板置于装有振动感受器的平台之上。动物的行为通过振动感受器传输到电脑，自动记录并储存在电脑***，电脑软件通过识别及分析动物行为原始数据产生最终实验数据。1.Laboras system introduction: LABORASTM system, purchased from METRIS in the Netherlands. The experimental system consisted of an experimental cage and a bottom plate. The experimental cage box, with an area of 880 square centimeters and a height of 17.5 cm, consists of a top cover, food and water bottle slots, placed on a height-adjustable frame, 2-3 mm from the bottom plate. The bottom plate is placed on a platform equipped with a vibrating susceptor. The animal's behavior is transmitted to the computer through the vibration sensor, automatically recorded and stored in the computer system, and the computer software generates the final experimental data by identifying and analyzing the raw data of the animal behavior.
2.***急性疼痛模型：5％，50微升***溶液注射到大鼠左侧后爪皮下组织，Laboras***记录动物60分钟后的疼痛行为(舔爪次数和时间总长度)。动物疼痛行为分为两个时相：2. Formalin acute pain model: 5%, 50 μl of formalin solution was injected into the subcutaneous tissue of the left hind paw of rats, and the Laboras system recorded the pain behavior after 60 minutes (the number of paws and the total length of time) ). Animal pain behavior is divided into two phases:
阳性对照物1(Mor)是从待测化合物Z-4、阳性对照物2、以及化合物溶剂给药大鼠后第10分钟给药；Positive control 1 (Mor) was administered from the test compound Z-4, the positive control 2, and the compound solvent to the 10th minute after administration of the rats;
***是从待测化合物Z-4、阳性对照物2、以及化合物溶剂给药大鼠后第25分钟给药；Formalin was administered from the test compound Z-4, the positive control 2, and the compound solvent to the 25th minute after administration to the rats;
第一时相(phase I)表示从待测化合物Z-4、阳性对照物2以及化合物溶剂给药于大鼠后25分钟开始(即开始注射***的时间)，到30分钟(即注射***后的5分钟)这段时间，即图1和图3中的25-30min；对应为***注射后第0-5分钟。The first phase (phase I) represents the time from the test compound Z-4, the positive control 2, and the compound solvent to the rats 25 minutes after the administration of the solvent (ie, the time to start formalin injection), to 30 minutes (ie, 5 minutes after injection of formalin), which is 25-30 min in Figures 1 and 3; corresponds to 0-5 minutes after formalin injection.
第二时相(phase II)表示从待测化合物Z-4、阳性对照物2以及化合物溶剂给药于 大鼠后40分钟开始(即***注射后的15分钟)，到55分钟(即注射***后的30分钟)这段时间，即图1和图3中的40-55min；对应为***注射后第15-30分钟。The second phase (phase II) indicates that the compound Z-4, the positive control 2, and the compound solvent are administered to the test substance. The rats began 40 minutes after the start (ie 15 minutes after formalin injection) and 55 minutes (30 minutes after the injection of formalin), ie 40-55 min in Figures 1 and 3; Corresponding to the 15-30 minutes after formalin injection.
3.动物首先适应实验环境，即放入实验笼盒，60分钟后取出放回饲养笼盒，连续适应3天；3. The animal first adapts to the experimental environment, that is, put it into the experimental cage box, and after 60 minutes, it is taken out and put back into the cage box for continuous adaptation for 3 days;
4.化合物溶剂及化合物Z-4在***皮下注射前25分钟给药，***则是提前10分钟给药；4. The compound solvent and the compound Z-4 are administered 25 minutes before the subcutaneous injection of formalin, and the morphine is administered 10 minutes earlier;
5.实验动物给药后马上启动Laboras***，开始记录；5. The laboratory animal starts the Laboras system immediately after administration and begins recording;
6.***溶液注射入左侧后爪皮下后迅速将动物放回Laboras实验笼盒，Laboras记录动物疼痛行为(舔爪次数和总共时间)60分钟；6. After the formalin solution was injected subcutaneously into the left hind paw, the animals were quickly returned to the Laboras experimental cage box, and Laboras recorded the pain behavior of the animals (the number of paws and the total time) for 60 minutes;
7.统计分析：数据以平均数±标准误形式表达，使用Graph pad Prism 5.0版本统计分析软件包提供的Two ways ANOVA test及unpaired t-test与阴性溶剂组数据对比，P值小于0.05为有统计学显著性差异。7. Statistical analysis: The data were expressed as mean ± standard error. The data of Two ways ANOVA test and unpaired t-test provided by Graph pad Prism version 5.0 statistical analysis software package were compared with the negative solvent group. P value was less than 0.05 for statistical analysis. Learn significant differences.
各剂量下Two ways ANOVA test中待测化合物所对应的大鼠舔后肢次数随时间变化图以及unpaired t-test中待测化合物所对应的大鼠舔后肢次数的曲线下面积分别如图1和图2所示。The change in the number of hind limbs of the rats corresponding to the test compound in the two ways ANOVA test at each dose and the area under the curve of the hind limbs of the rat in the unpaired t-test are shown in Fig. 1 and Fig. 1 respectively. 2 is shown.
各剂量下Two ways ANOVA test中待测化合物所对应的大鼠舔后肢所用时间变化图以及unpaired t-test中待测化合物所对应的大鼠舔后肢所用时间的曲线下面积分别如图3和图4所示。The time-lapse plots of the hind limbs of the rats tested in the two ways ANOVA test at each dose and the area under the curve of the hind limbs of the rats corresponding to the test compound in the unpaired t-test are shown in Figure 3 and Figure 3, respectively. 4 is shown.
从图1-图4可以看出，化合物Z-4能抑制大鼠在***炎症模型中一相和二相的疼痛行为，具有镇痛效果。As can be seen from Fig. 1 to Fig. 4, the compound Z-4 can inhibit the pain behavior of the one-phase and the two-phase in the formalin-inflamed model of rats, and has an analgesic effect.
测试例3冷刺激痛觉超敏法SNLTest Example 3 Cold Stimulation Pain Hypersensitivity Method 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。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.
检测化合物及分组：Test compounds and groupings:
溶剂组(Vehicle)：5％二甲基乙酰胺(国药科技)，5％solutol(Sigma)和90％生理盐水Vehicle group: 5% dimethylacetamide (National Medicine), 5% solutol (Sigma) and 90% saline
阳性对照物：HYC00012(也称为化合物Z-0)；Positive control: HYC00012 (also known as compound Z-0);
待测药物：化合物Z-22，Z-40，Z-97，Z-85，Z-73；Drug to be tested: compound Z-22, Z-40, Z-97, Z-85, Z-73;
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。The solvent component of the positive control and the test drug is 5% dimethylacetamide, 5% solutol and 90% physiological salt. water.
阳性对照物和测试物分别以剂量100mg/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4所示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 100 mg/kg, respectively, as shown in Table 4.
表4 化合物在脊神经结扎大鼠中药效测试分组Table 4 Grouping of compounds in the rat spinal nerve ligation test
Figure PCTCN2016073385-appb-000131
Figure PCTCN2016073385-appb-000131
100mg/kg化合物Z-85：称取295.4mg Z-85，加入0.73mL二甲基乙酰胺，待完全溶解后加入0.73mL solutol，震荡混匀后加入90％生理盐水定容至14.54mL，充分混匀后口服给药。100mg/kg compound Z-85: Weigh 295.4mg Z-85, add 0.73mL dimethylacetamide, add 0.73mL solutol after complete dissolution, shake and mix, add 90% physiological saline to 14.54mL, fully After mixing, it is administered orally.
100mg/kg化合物Z-73：称取289.9mg Z-73，加入0.71mL二甲基乙酰胺，待完全溶解后加入0.71mL solutol，震荡混匀后加入90％生理盐水定容至14.24mL，充分混匀后口服给药。100mg/kg compound Z-73: Weigh 289.9mg Z-73, add 0.71mL dimethylacetamide, add 0.71mL solutol after completely dissolved, shake and mix, add 90% physiological saline to 14.24mL, fully After mixing, it is administered orally.
100mg/kg阳性对照物：称取278.6mg阳性对照物，加入0.68mL二甲基乙酰胺，待完全溶解后加入0.68mL solutol，震荡混匀后加入90％生理盐水定容至13.52mL，完全溶解后口服给药。100mg/kg positive control: Weighed 278.6mg positive control, added 0.68mL dimethylacetamide, added 0.68mL solutol after complete dissolution, shake and mix, add 90% physiological saline to the volume to 13.52mL, completely dissolved Orally administered.
实验方法：experimental method:
1.1.脊神经结扎模型1.1. Spinal nerve ligation model
·手术过程执行无菌操作。• Perform a sterile procedure during the surgical procedure.
·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。• Surgical instruments (scissors, forceps, scalpels, surgical cotton, sutures, spreaders) have been sterilized prior to surgery.
·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。• Animals were anesthetized with pentobarbital (50 mg/kg, ip). The animal's toes were squeezed to confirm that the animals had been fully anesthetized prior to surgery. Apply an ophthalmic ointment to the animal's eye to prevent the animal's cornea from drying out.
·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。 • Shave the hair of the lower limbs of the animal and disinfect the skin of the surgical area three times with iodophor and 70% ethanol. Start surgery after the skin is dry.
·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。• Use a scalpel to open a longitudinal incision in the posterior sac of the animal's waist, expose the left paraspinal muscle, and use a distractor to separate the muscle tissue to expose the vertebrae.
·分离左侧脊神经L5和L6，使用6-0丝线结扎。• The left spinal nerves L5 and L6 were separated and ligated using a 6-0 silk thread.
·缝合伤口。• Suture the wound.
·清洁手术器械，使用热珠灭菌器灭菌。• Clean surgical instruments and sterilize them using a hot bead sterilizer.
·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。• After the operation, the animals were placed on an electric blanket and subcutaneously injected with 5 mL of physiological saline to prevent dehydration. After the animal is completely awakened (freely active), the animal is returned to the cage.
1.2.冷痛觉超敏基线测试和分组1.2. Cold pain hypersensitivity baseline test and grouping
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。Two days before the administration, the rats were subjected to a cold hyperalgesia hypersensitivity baseline test, and 100 μl 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.
1.3.冷痛觉超敏测试1.3. Cold pain hypersensitivity test
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。Two hours after the administration, 100 μl of 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.
1.4.给药1.4. Administration
冷刺激痛觉测试2小时前口服给药。The cold stimulating pain test was orally administered 2 hours before.
1.5.数据收集和分析1.5. Data collection and analysis
使用Excel软件收集数据。使用Prism软件分析数据。Collect data using Excel software. Data was analyzed using Prism software.
结论：in conclusion:
表5 大鼠冷痛觉超敏测试结果(Z-22)Table 5 Test results of cold pain hypersensitivity in rats (Z-22)
Figure PCTCN2016073385-appb-000132
Figure PCTCN2016073385-appb-000132
表6 大鼠冷痛觉超敏测试结果(Z-73、Z-85)Table 6 Test results of cold pain hypersensitivity in rats (Z-73, Z-85)
Figure PCTCN2016073385-appb-000133
Figure PCTCN2016073385-appb-000133
表7 大鼠冷痛觉超敏测试结果(Z-97)Table 7 Test results of cold pain hypersensitivity in rats (Z-97)
Figure PCTCN2016073385-appb-000134
Figure PCTCN2016073385-appb-000134
表8大鼠冷痛觉超敏测试结果(Z-40)Table 8 Rat cold pain hypersensitivity test results (Z-40)
Figure PCTCN2016073385-appb-000135
Figure PCTCN2016073385-appb-000135
实验结果如图6、图8、图10和图12所示，结果表明，口服2小时后，本发明示例化合物Z-22、Z-40、Z-73、Z-85和Z-97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。The results of the experiment are shown in Fig. 6, Fig. 8, Fig. 10 and Fig. 12. The results show that the exemplary compounds Z-22, Z-40, Z-73, Z-85 and Z-97 of the present invention are in the spinal nerve 2 hours after oral administration. In the ligation rat model, it has a cold allodynia-induced hypersensitivity effect that induces spinal nerve ligation in rats, and has a statistically significant inhibitory effect in a rat neuralgia model.
图6中，化合物Z-97在脊神经结扎大鼠中的药效，***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-97和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。In Figure 6, the efficacy of Compound Z-97 in spinal nerve ligation rats, ***p < 0.001 compared with the solvent group, was analyzed by one-way ANOVA with the Dunnett multiple comparison test. Oral compound Z-97 and the positive control 100 mg/kg inhibited cold allodynia hypersensitivity induced by spinal nerve ligation, respectively, two hours later.
图8中，化合物Z-40在脊神经结扎大鼠模型中化合物抑制冷刺激痛觉超敏效果,*p<0.05，***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-40和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。In Figure 8, compound Z-40 inhibits cold-stimulated hyperalgesia in a rat model of spinal nerve ligation, *p<0.05, ***p<0.001, compared with the solvent group, using a one-way ANOVA with Dunnett multiple comparison test. Oral compound Z-40 and the positive control 100 mg/kg inhibited cold allodynia hypersensitivity induced by spinal nerve ligation in rats two hours later.
图10中，化合物Z-73、85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-73、85和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。In Figure 10, the efficacy of compounds Z-73, 85 in spinal nerve ligation rats, **p < 0.01, *** p < 0.001 compared with the solvent group, using the one-way ANOVA plus Dunnett multiple comparison test. Oral compounds Z-73, 85 and the positive control 100 mg/kg inhibited cold allodynia induced by spinal nerve ligation, respectively, two hours later.
图12中**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-22和阳性对照物100mg/kg两小时后分别抑制大鼠脊神经结扎诱导的冷痛觉超敏。**p<0.01, ***p<0.001 in Figure 12 was compared to the solvent group using a one-way ANOVA with additional Dunnett multiple comparison test. Oral compound Z-22 and the positive control 100 mg/kg inhibited cold allodynia hypersensitivity induced by spinal nerve ligation in rats two hours later.
测试例4：大鼠体内试验Test Example 4: In vivo test in rats
应用LC/MS/MS法测定了大鼠灌胃给予实施例化合物后不同时刻血浆中的药物浓度，研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。The drug concentration in plasma at different times after administration of the compound of the example by intragastric administration was determined by LC/MS/MS method. The pharmacokinetic behavior of the compound of the present invention in rats was investigated, and its pharmacokinetic characteristics were evaluated.
实验方案：Experimental program:
试验动物：健康成年雄性SD大鼠(体重200-300g，6只，禁食)，由斯莱克公司提供；Test animals: healthy adult male SD rats (body weight 200-300 g, 6 rats, fasted), provided by Slark;
给药方式与剂量：给予SD大鼠灌胃给药，给药剂量和口服溶液浓度和配方如下：Mode of administration and dosage: Administration of SD rats by intragastric administration, dosage and oral solution concentration and formulation are as follows:
表9Table 9
Figure PCTCN2016073385-appb-000136
Figure PCTCN2016073385-appb-000136
Figure PCTCN2016073385-appb-000137
Figure PCTCN2016073385-appb-000137
血样采集：首先对给药前挑选符合实验要求的动物，称重标记。采集血样前，绑定大鼠，每一只给药的大鼠在预定的采血时间点(灌胃给药：分别于给药前，给药后的0.083,0.25,0.5,1,2,4,8,24h采血,共9个时间点)，通过尾静脉采血，约150μL。血液转移至预先加入K2EDTA的1.5mL试管中。采完的血样放在湿冰上，离心5min(2000g,4℃)，取出血浆，整个过程在采血后15min内完成。所有的样品都需要存放于-70℃冰箱直到样品分析。Blood sample collection: First, select the animals that meet the experimental requirements before the administration, and weigh the markers. Before the blood sample is collected, the rats are bound, and each rat is administered at a predetermined blood collection time point (administered by gavage: 0.083, 0.25, 0.5, 1, 2, 4 after administration, respectively, before administration). , 8, 24h blood collection, a total of 9 time points), blood collection through the tail vein, about 150μL. The blood was transferred to a 1.5 mL tube pre-added to K 2 EDTA. The collected blood samples were placed on wet ice, centrifuged for 5 min (2000 g, 4 ° C), and the plasma was taken out. The whole process was completed within 15 min after blood collection. All samples need to be stored in a -70 ° C refrigerator until sample analysis.
应用LC/MS/MS法测定药物浓度，本发明部分实施例化合物在相同给药方式下，大鼠体内的药代动力学性质参数如表10所示：The drug concentration was determined by LC/MS/MS method. The pharmacokinetic properties of the compounds in some embodiments of the present invention in the same mode of administration are shown in Table 10:
表10 化合物在大鼠体内药代动力学参数Table 10 Pharmacokinetic parameters of compounds in rats
  Z-73Z-73 Z-85Z-85 Z-4Z-4 Z-97Z-97
Tmax(hr)Tmax(hr) 2.02.0 1.01.0 0.50.5 0.830.83
半衰期T1/2(hr)Half-life T1/2 (hr) 9.739.73 2.522.52 1.891.89 1.371.37
口服相对生物利用度FOral relative bioavailability F 90.3％90.3% 83.4％83.4% 66.1％66.1% 87.5％87.5%
最高血药浓度Cmax(ng/mL)Maximum blood concentration Cmax (ng/mL) 56955695 23772377 861861 949949
曲线下面积AUC(hr*ng/mL)Area under the curve AUC (hr*ng/mL) 6735767357 1087810878 19631963 31903190
从表10可以看出，本发明示例化合物的药代吸收好，具有明显的药代吸收效果，同时表现出良好的生物利用度。本发明化合物具有更优异的性能，能够以更低地剂量给药，因此安全性更好或毒副作用更低。As can be seen from Table 10, the exemplified compounds of the present invention have good pharmacological absorption, have significant pharmacological absorption effects, and exhibit good bioavailability. The compounds of the present invention have superior properties and can be administered at lower doses, thus being safer or less toxic.
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。 All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (22)

  1. 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：a compound of formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof:
    Figure PCTCN2016073385-appb-100001
    Figure PCTCN2016073385-appb-100001
    式中，In the formula,
    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)；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);
    R5为氢、C1-20烷基、C3-20环烷基、卤代C1-20烷基；R 5 is hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl, halogenated C 1-20 alkyl;
    R6为C6-20芳基、C1-20烷基、-NRaRb；R 6 is C 6-20 aryl, C 1-20 alkyl, -NR a R b ;
    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；Wherein R a and R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl or C 6-20 aryl;
    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；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 Alkynyl or C 6-20 aryl; r 1 , r 3 are each independently 0, 1, 2 or 3; r 2 is 0 or 1;
    W1、W2各自独立地为C、N、O或S；W 1 and W 2 are each independently C, N, O or 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；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;
    (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；(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；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;
    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。Wherein the alkyl group, cycloalkyl group, cycloalkoxy group, alkenyl group, alkynyl group, alkoxy group, aryl group, 3 to 7 membered monocyclic ring, 8 to 10 membered bicyclic ring, 3 to 7 membered monoheterocyclic ring, 8 to 10 membered bicyclic heterocyclic ring, 5 or 6 membered monocyclic heteroaryl ring, 8 to 10 membered bicyclic heteroaryl ring, benzo 3 to 7 membered monocyclic ring, benzo 3 to 7 membered single heterocyclic ring, 5 to a 6-membered monocyclic heteroaryl ring and a 3 to 7 membered monocyclic ring, or a 5 to 6 membered monocyclic heteroaryl ring and a 3 to 7 membered monoheterocyclic ring is substituted or unsubstituted; and the substitution is The 1-5 hydrogens in the group are substituted with a substituent selected from the group consisting of halogen, nitro, hydroxy, cyano, C 6-20 aryl, C 1-20 alkyl, halogenated C 1-20 Alkyl, C 1-20 alkoxy, halo 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, halogen C 1-20 alkylthio, C 1-20 alkylamino, halogenated C 1-20 alkylamino, thiol, 3 to 20 membered heterocycloalkyl, 3 to 20 membered heterocycloalkane Alkoxy group, C 3-20 cycloalkylthio group, halogenated C 3-20 cycloalkylthio group, 3 to 20 yuan Heterocycloalkylthio, oxo, C 1-20 hydroxyalkyl, carboxy, -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), -SO 2 N(R a R b ), -C(O)O-(C 1-20 alkane Base), -CHO, -OC(O)-(C 1-20 alkyl), -SO 2 -(C 1-20 alkyl), -SO 2 -(C 6-20 aryl), -CO- (C 6-20 aryl); R a , R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl or C 6-20 aryl.
  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，所述化合物为式(II)所示化合物：The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein the compound is a compound of formula (II):
    Figure PCTCN2016073385-appb-100002
    Figure PCTCN2016073385-appb-100002
    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。In the formula, 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.
  3. 如权利要求2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 PCTCN2016073385-appb-100003
    选自：
    Figure PCTCN2016073385-appb-100004
    Figure PCTCN2016073385-appb-100005
    Figure PCTCN2016073385-appb-100006
    The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
    Figure PCTCN2016073385-appb-100003
    From:
    Figure PCTCN2016073385-appb-100004
    Figure PCTCN2016073385-appb-100005
    Figure PCTCN2016073385-appb-100006
    其中，A、L1、R0如权利要求1所定义。Wherein A, L 1 and R 0 are as defined in claim 1.
  4. 如权利要求2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 PCTCN2016073385-appb-100007
    选自：
    Figure PCTCN2016073385-appb-100008
    Figure PCTCN2016073385-appb-100009
    其中，A、L1、R0如权利要求1所定义。    The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
    Figure PCTCN2016073385-appb-100007
    From:
    Figure PCTCN2016073385-appb-100008
    Figure PCTCN2016073385-appb-100009
    Wherein A, L 1 and R 0 are as defined in claim 1.
  5. 如权利要求2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 PCTCN2016073385-appb-100010
    选自：
    Figure PCTCN2016073385-appb-100011
    其中，A、L1、R0如权利要求1所定义。。    The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
    Figure PCTCN2016073385-appb-100010
    From:
    Figure PCTCN2016073385-appb-100011
    Wherein A, L 1 and R 0 are as defined in claim 1. .
  6. 如权利要求2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 PCTCN2016073385-appb-100012
    选自：
    Figure PCTCN2016073385-appb-100013
    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。    The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
    Figure PCTCN2016073385-appb-100012
    From:
    Figure PCTCN2016073385-appb-100013
    And 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.
  7. 如权利要求2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 PCTCN2016073385-appb-100014
    选自：
    Figure PCTCN2016073385-appb-100015
    其中，A、L1、R0如权利要求1所定义。     The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
    Figure PCTCN2016073385-appb-100014
    From:
    Figure PCTCN2016073385-appb-100015
    Wherein A, L 1 and R 0 are as defined in claim 1.
  8. 如权利要求2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 PCTCN2016073385-appb-100016
    选自：
    Figure PCTCN2016073385-appb-100017
    其中，A、L1、R0如权利要求1所定义。    The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
    Figure PCTCN2016073385-appb-100016
    From:
    Figure PCTCN2016073385-appb-100017
    Wherein A, L 1 and R 0 are as defined in claim 1.
  9. 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，所述化合物为式(III)所示化合物：The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein the compound is a compound of formula (III):
    Figure PCTCN2016073385-appb-100018
    Figure PCTCN2016073385-appb-100018
    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。In the formula, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , R y , r1 , r2 , r3 , A, W 1 , W 2 , n, p, m Defined in claim 1.
  10. 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，所述化合物为式(IV)所示化合物：The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein the compound is a compound of formula (IV):
    Figure PCTCN2016073385-appb-100019
    Figure PCTCN2016073385-appb-100019
    式中，R0、R1、R2、R3、R4、R5、R6、Rx、Ry、r1、r2、r3、A、W2、n、p、m如权利要求1定义；W1为N或C。Wherein 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 claimed in claim 1 Definition; W 1 is N or C.
  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，所述化合物为式(V)所示化合物：The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein the compound is a compound of formula (V):
    Figure PCTCN2016073385-appb-100020
    Figure PCTCN2016073385-appb-100020
    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如权利要求1所定义。Wherein 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 , -N(R a )C(O)-(C 1-20 alkyl), -N(R a )SO 2 -(C 1-20 alkyl), -SO 2 N(R a R b ), -C(O)O-(C 1-20 alkyl), -CHO, -OC(O)-(C 1-20 alkyl), -SO 2 -(C 1-20 alkyl), -SO 2 -(C 6-20 aryl), -CO-(C 1-20 alkyl), -CO-(C 6-20 aryl); R a , R b are as defined in claim 1.
  12. 如权利要求1-11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，其特征在于，A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein
    R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl;
    R5为氢；R 5 is hydrogen;
    R6为C1-20烷基、-NRaRb；其中，Ra、Rb各自独立地为氢、或C1-20烷基。R 6 is C 1-20 alkyl, -NR a R b ; wherein R a and R b are each independently hydrogen or a C 1-20 alkyl group.
  13. 如权利要求1-11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，其特征在于，A为C6-20芳基或5或6元单环杂芳基环。The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein A is C 6-20 aryl or 5 or 6 A monomonocyclic heteroaryl ring.
  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，L2为一个键。The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein L 2 is a bond.
  15. 如权利要求1、2、3、4或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，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。The compound according to claim 1, 2, 3, 4 or 8 or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein 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.
  16. 如权利要求1-11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，其特征在于，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。The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein A is a phenyl or pyridyl group; Or a pyridyl group is substituted or unsubstituted; and said 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.
  17. 如权利要求1-11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，其特征在于，所述苯基为
    Figure PCTCN2016073385-appb-100021
    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、C3-20环烷氧基。    The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein the phenyl group is
    Figure PCTCN2016073385-appb-100021
    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, C 3-20 cycloalkoxy.
  18. 如权利要求1-11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，其特征在于，每个R0相同或不同，各自独立地为氢。A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, wherein each R 0 is the same or different and each independently hydrogen.
  19. 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，The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, wherein
    R1、R2、R3、R4各自独立地为氢、卤素、C1-20烷基、C3-20环烷基；R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-20 alkyl, C 3-20 cycloalkyl;
    R5为氢；R 5 is hydrogen;
    R6为C1-20烷基、-NRaRb；R 6 is C 1-20 alkyl, -NR a R b ;
    其中，Ra、Rb各自独立地为氢、或C1-20烷基；Wherein R a and R b are each independently hydrogen or a C 1-20 alkyl group;
    W1、W2各自独立地为C、O、S或N；W 1 , W 2 are each independently C, O, S or N;
    L2为一个键；L 2 is a key;
    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；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;
    A为苯基；A is a phenyl group;
    n、m各自独立地为1或2；n, m are each independently 1 or 2;
    (R0)p为环上的任意位置的氢被p个R0取代，p为0；(R 0 ) p is a hydrogen at any position on the ring is replaced by p R 0 , p is 0;
    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；And when W 1 and/or W 2 is O or S, L 1 and A are respectively bonded to any carbon atom other than W 1 and W 2 on the ring;
    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；When W 1 and/or W 2 is N or C, A is bonded to any ring atom other than W 1 on the ring, and L 1 is bonded to any ring atom other than W 2 on the ring;
    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。Wherein the 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.
  20. 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：The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2016073385-appb-100022
    Figure PCTCN2016073385-appb-100022
    Figure PCTCN2016073385-appb-100023
    Figure PCTCN2016073385-appb-100023
  21. 一种药物组合物，所述组合物包括权利要求1至20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。A pharmaceutical composition, comprising the compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof; and pharmaceutically acceptable Carrier.
  22. 如权利要求1至20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21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***疾病、精神疾病或其组合。 The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition according to claim 21, in the preparation of a disease or Use in a medicament for a condition selected from the group consisting of pain, depression, cardiovascular disease, respiratory disease, mental illness, or a combination thereof.
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