WO2016124141A1 - Dérivés de n-sulfonylbenzamide substitués hétérocycliques, procédé de préparation de ces dérivés, et utilisation pharmaceutique de ces dérivés - Google Patents

Dérivés de n-sulfonylbenzamide substitués hétérocycliques, procédé de préparation de ces dérivés, et utilisation pharmaceutique de ces dérivés Download PDF

Info

Publication number
WO2016124141A1
WO2016124141A1 PCT/CN2016/073388 CN2016073388W WO2016124141A1 WO 2016124141 A1 WO2016124141 A1 WO 2016124141A1 CN 2016073388 W CN2016073388 W CN 2016073388W WO 2016124141 A1 WO2016124141 A1 WO 2016124141A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
group
ring
halogenated
Prior art date
Application number
PCT/CN2016/073388
Other languages
English (en)
Chinese (zh)
Inventor
兰炯
周福生
赵金柱
黄栋
谢婧
胡毅
吕强
Original Assignee
上海海雁医药科技有限公司
扬子江药业集团有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海海雁医药科技有限公司, 扬子江药业集团有限公司 filed Critical 上海海雁医药科技有限公司
Priority to CN201680007532.5A priority Critical patent/CN107428683B/zh
Publication of WO2016124141A1 publication Critical patent/WO2016124141A1/fr

Links

Images

Classifications

    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—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 (II), 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 is attached at any different position on the ring and is 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 and R x are each independently 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-
  • 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;
  • A, L 1 and R 0 are as defined above.
  • 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 .
  • 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.
  • 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; and / or
  • Each R 0 is the same or different and is each independently hydrogen.
  • 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 or a C 1-20 alkyl group.
  • the compound is a compound of formula (III):
  • 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 are as defined above Defined.
  • 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 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(
  • 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.
  • L 1 is -(CR y R x ) r1 (O) r2 (CR y R x ) r3 -, r1 and r3 are 0; and r2 is 1.
  • 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 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.
  • 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, C 1-20 alkyl;
  • 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
  • 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.
  • r1 and r3 are 0; r2 is 1.
  • 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 N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , L 1 , R y , R x , W 1 , W 2 , n And m, R 0 , A and the like are each independently the corresponding group of each of the compounds of the specific formula II in the examples.
  • the compound of formula II of the present invention is each specific compound prepared in the Examples section, especially any of Z-4 to Z-165.
  • 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, osteoarthritis, atherosclerosis, sudden dystonia, myasthenia gravis, myotonia, malignant hyperthermia, cystic fibrosis, false Hyperaldosteronism, 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, fibromy
  • 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-4 in a rat model of spinal nerve ligation.
  • Figure 8 shows that Compound Z-4 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, cycloheptene
  • 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 refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing from 3 to 7 ring atoms. It is preferably 5 to 6 yuan.
  • monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, 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 can determine (by experiment or theory) that it may or may not be possible without much effort. Replacement. 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 (II), which compounds can be readily prepared by a variety of synthetic procedures which are well known to those skilled in the art. Exemplary methods of preparation of these compounds can include, but are not limited to, the procedures described below.
  • the compound of the formula (II) of the present invention can be produced by referring to the following synthetic route, and the steps in the method 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 (II), 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 (II), 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 ⁇ ). MS m / z (ESI): 203 [M-1] -.
  • 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.
  • 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 Change to 4-bromo-2-chlorophenol, 2-methylpropan-1-ol to sodium 2-chloro-2,2-difluoroacetate, and the reaction conditions were changed to 100 ° C for 2 hours.
  • 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 6-7, ethyl acetate was extracted, and the organic phase was separated and concentrated under reduced pressure to give a deep oil (300 mg). 4 (30 mg), purity 98.77%, yield 69.0%.
  • 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 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] + .
  • Compound Z-27 was prepared by the method of Example 26 except that the compound 8-a in Step 1 was replaced by (R)-azetidine-2-carboxylic acid, and 4-(bromo) in Step 2 Methyl)-2-chloro-1-(trifluoromethoxy)benzene was replaced by 4-bromo-1,2-dichlorobenzene.
  • 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 Zinc powder (1.769 g, 27.215 mmol) was added to 50 ml of dimethylformamide solution, and 1,2-dibromoethane (511 mg, 2.720 mmol), trimethylchlorosilane (295 mg, 2.715 mmol), The mixture was stirred under nitrogen for 15 minutes at room temperature. A solution of 12-a (5.653 g, 0.0199 mol) in 5 ml of dimethylformamide was added and stirred at room temperature for 1 h, then 4-bromo-2-chloro-1-(trifluoromethoxy) was added.
  • Step 2 The compound 30-b (7.244 g) was used as a starting material.
  • Step 3 Using the compound 30-c (40 mg) as a starting material, m.p. ): 501.0 [M+H]+.
  • Compound Z-95 was prepared by the procedure of Example 4, except that compound 4-b of Step 2 was replaced by compound 30-a, and compound 1-a of Step 3 was replaced by compound 9-a.
  • Compound Z-97 was prepared by the method of Example 4, and the compound 4-b of Step 2 was replaced by the compound 30-a, 4-bromo-2-chloro-1-(trifluoromethyl)benzene was changed to 4 -Bromo-1,2-dichlorobenzene.
  • Compound Z-98 was prepared by the method of Example 4, and the compound 4-b of Step 2 was replaced by the compound 30-a, 4-bromo-2-chloro-1-(trifluoromethyl)benzene was changed to 1 -Bromo-4-chlorobenzene.
  • Compound Z-104 was prepared by the method of Example 4, and the compound 4-b of Step 2 was replaced by the compound 30-a, and 4-bromo-2-chloro-1-(trifluoromethyl)benzene was changed to 1. -Bromo-4-(trifluoromethyl)benzene.
  • Compound Z-110 was prepared by the method of Example 4, and the compound 4-b of Step 2 was replaced by the compound 30-a, 4-bromo-2-chloro-1-(trifluoromethyl)benzene was changed to 4 -Bromo-1,2-dichlorobenzene, replacing compound 1-a of step 3 with compound 9-a.
  • Compound Z-113 was prepared by the method of Example 4, and the compound 4-b of Step 2 was replaced by the compound 30-a, 4-bromo-2-chloro-1-(trifluoromethyl)benzene was replaced by a compound. 34-a.
  • Step 1-2 Using compound 31-a as a starting material, which was obtained by the procedure of Step 2-3 of Example 4 to give Compound 115-c. The difference is that the 4-bromo-2-chloro-1-(trifluoromethoxy)benzene in step 2 is replaced by 4-bromo-1,2-dichlorobenzene, and the compound 1-a in step 3 is replaced by a compound. 11-a.
  • Step 3 Starting from the compound 115-c, the title compound was obtained by the procedure of Step 2 of Example 29 to give Compound Z-115. MS m/z (ESI): 495 [M+H] + .
  • Step 1 To a solution of compound 29-a (25.7 g, 0.106 mol) in EtOAc/EtOAc (EtOAc) Heat to 70 ° C and stir for 1.5 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered, and evaporated, evaporated, evaporated, evaporated, evaporated. MS m / z (ESI): 210 [M-1] -.
  • Step 2 Compound 94-b (18.472 g, 0.087 mol) was added to a solution of 98% sulfuric acid (15 ml), water (45 ml), and an aqueous solution of sodium nitrite (6.631 g, 0.096 mol) was added dropwise in an ice bath (18 ml).
  • Step 3 Using compound 94-c (500 mg) as a starting material, refer to the preparation method of Step 2 in Example 4, except that the compound 4-b is replaced with piperidin-4-ol (R) hydrochloride. The mixture was stirred with argon gas for 120 minutes to give compound 94-d (70 mg), MS m/z (ESI): 269.1 [M+H] + .
  • Step 4 Add azo to a solution of compound 94-d (70 mg, 0.236 mmol), compound 17-a (48 mg, 0.236 mmol), triphenylphosphine (124 mg, 0.472 mmol) in toluene (5 ml) Diisopropyl diformate (95.5 mg, 0.472 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. Was purified by Combi-flash column to give a yellow oily compound 94-e, MS m / z (ESI): 482.1 [M + H] +.
  • Step 6 Compound 94-f (50 mg, 0.11 mmol), methanesulfonamide (15 mg, 0.16 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-four
  • HATU urea hexafluorophosphate
  • dichloromethane 5 ml
  • 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. Purified by Combi-flash chromatography column to give a yellow oil Compound 99-b (70mg), MSm / z (ESI) by: 213.1 [M + H] + .
  • Step 2 Compound 99-b (70mg) as a raw material, referring to the step of the method in Example 944 embodiment, to give compound 99-c (120mg), MS m / z (ESI): 399.1 [M + H] +.
  • Step 3 Compound 99-c (120mg) as a raw material, referring to the preparation of Example 945 Step embodiment, 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] ] + .
  • Compound Z-96 was prepared starting from compound 31-a using the procedure of Example 99, except that 3-bromo-5-chloropyridine in Step 1 was changed to 1-bromo-4-fluorobenzene.
  • 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-102 was prepared according to the method of Example 99 using Compound 31-a as a starting material, except that 3-bromo-5-chloropyridine in Step 1 was changed to 1-bromo-3-chlorobenzene. The reaction conditions were changed to 40 ° C and stirred for 6 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.
  • Compound Z-107 was prepared starting from compound 31-a using the procedure of Example 99, except that 3-bromo-5-chloropyridine in Step 1 was replaced by 1-bromo-4-(trifluoro). Methoxy)benzene, the reaction conditions were changed to 40 ° C for 6 hours, the reaction conditions of step 3 were changed to room temperature and stirred for 2 hours, and the reaction conditions of step 4 were changed to room temperature and stirred for 2 hours.
  • Compound Z-109 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-1-chloro-2. -Fluorobenzene, the reaction conditions were changed to 95 ° C and stirred overnight, and the reaction conditions of Step 2 were changed to room temperature and stirred for 1 hour.
  • Compound Z-111 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 5-bromo-2,3-di. Chloropyridine, the reaction conditions of step 4 were changed to room temperature and stirred for 30 minutes.
  • 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.
  • Compound Z-116 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 4-bromo-1,2-di. Chlorobenzene, the reaction conditions are changed to 100 ° C After stirring for 16 hours, the reaction conditions of the step 2 were changed to room temperature and stirred overnight, and the methylsulfonamide in the step 4 was changed to ethanesulfonamide, and the reaction conditions were changed to room temperature and stirred for 16 hours.
  • Step 1 a mixed solution of 5-chloro-2-fluoropyridine (996 mg, 7.6 mmol), compound 31-a (576 mg, 5.7 mmol), potassium carbonate (1.05 g, 7.6 mmol) in dimethylformamide (10 ml). Stir 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. Was purified by Combi-flash column to give a yellow solid compound 108-b (700mg), MSm / z (ESI): 213.1 [M + H] +.
  • Step 2 Compound 108-b (200mg) as starting material, reference to step Preparation Example 94 4 embodiment, to give compound 108-c (300mg), MS m / z (ESI): 399.1 [M + H] +.
  • Step 3 Compound 108-c (300 mg) was used to give compound 108-d (280 mg), MS m/z (ESI): 383.1 [MH] - .
  • Step 4 compound 108-d (180mg) as starting material, prepared 11-a in step b of reference compound, to give a yellow solid compound Z-108 (36mg), MS m / z (ESI): 460.1 [MH] - .
  • Step 1 Compound 1-a (304 mg, 1.13 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (610 mg, 3.52 mmol), cesium carbonate (1130 mg, 3.47 mmol), 13 ml
  • a mixture of 1,4-dioxane was stirred at 180 ° C for 20 minutes under microwave conditions. After completion of the reaction, the mixture was cooled to room temperature, and then added with 20 ml of water, and the mixture was adjusted to pH 2 to 3, ethyl acetate (20 ml x 2), and the organic phase was dried over anhydrous sodium sulfate. Purification by flash column chromatography gave the compound 2-b (390 mg), which was used for the next reaction, purity 52%, yield 81.8%. MS m/z (ESI): 445.0 [M+Na] + .
  • Step 2 To a 25 ml single-necked round bottom flask was added compound 2-b (390 mg, 0.92 mmol), 4 ml hydrochloric acid / dioxane solution (4M), and stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was evaporated to dryness crystals crystals crystals MS m/z (ESI): 323 [M+H] + .
  • Step 3 To a 25 ml single-neck round bottom flask was added compound 2-c (130 mg, 0.362 mmol), 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene (105 mg, 0.363 mmol). Potassium carbonate (151 mg, 1.093 mmol), 7 ml of dimethylformamide, stirred at room temperature for 3 h.
  • Compound C2 was prepared starting from compound 2-c by the method of Comparative Example 1, except that 4-(bromomethyl)-2-chloro-1-(trifluoromethoxy)benzene was added in Step 3. Change to 4-(bromomethyl)-1,2-dichlorobenzene.
  • Step 1 Compound 1-a-3 (1 g, 5.19 mmol h, cooled to room temperature, and 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 organic phase was separated and concentrated under reduced pressure to give 270 mg of oil. Mg), purity 97.8%, yield 9.7%.
  • Compounds C5-C7 can be prepared by the methods of the above examples, and the methods used are well known to those skilled in the art.
  • 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.sub.2, then the mixture was cooled to -78[deg.] C. 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), and the mixture was cooled to 0 ° C in an ice bath, and lithium aluminum hydride (8.4 g, 220 mmol) was added portionwise. 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 then quenched with water (20 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 are carried out using manual patch clamp experiments, the purpose of which is to apply manual
  • the patch clamp method tests the effect of a compound on the ion channel current on a stable cell line transfected with a particular ion channel.
  • 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 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-hydroxystearate) + 90% physiological 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 40 minutes after administration of the test compound Z-4, the positive control 2, and the compound solvent to the rats (i.e., 15 minutes after the formalin injection), to 55 minutes ( That is, 30 minutes after the injection of formalin), which is 40-55 min in Figures 1 and 3; the corresponding 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
  • the solvent components of the positive control and the test drug were 5% dimethylacetamide, 5% solutol and 90% physiological saline.
  • the positive control and the test substance inhibited the cold pain hypersensitivity caused by spinal nerve ligation in rats after oral administration for 2 hours at a dose of 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 and Fig. 8.
  • the results show that after 2 hours of oral administration, the exemplary compounds Z-97 and Z-4 of the present invention have a cold allodynia-induced hypersensitivity effect induced by spinal nerve ligation in a rat model of spinal nerve ligation. It has a statistically significant inhibitory effect on the neuralgia model in rats.
  • 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 8:
  • the exemplified compounds of the present invention have good pharmacological absorption, have a remarkable pharmacological absorption effect, and exhibit excellent bioavailability.
  • the compound of the present invention represented by Z-97 has more excellent properties and can be administered at a lower dose, so that it is safer or has less toxic side effects.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des dérivés de N-sulfonylbenzamide substitués hétérocycliques, un procédé de préparation de ces dérivés, et l'utilisation pharmaceutique de ces dérivés. L'invention concerne en particulier des composés de formule (II) ou des sels, stéréoisomères, solvates ou promédicaments pharmaceutiquement acceptables de ceux-ci, un procédé de préparation de ceux-ci et une application correspondante. Les définitions de chaque groupe de ladite formule se trouvent dans la description.
PCT/CN2016/073388 2015-02-04 2016-02-03 Dérivés de n-sulfonylbenzamide substitués hétérocycliques, procédé de préparation de ces dérivés, et utilisation pharmaceutique de ces dérivés WO2016124141A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680007532.5A CN107428683B (zh) 2015-02-04 2016-02-03 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

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510059270 2015-02-04
CN201510059270.4 2015-02-04

Publications (1)

Publication Number Publication Date
WO2016124141A1 true WO2016124141A1 (fr) 2016-08-11

Family

ID=56563471

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/CN2016/073385 WO2016124139A1 (fr) 2015-02-04 2016-02-03 Dérivés de n-sulfonyl-benzamide à substitution hétérocyclique, procédé de préparation de ces dérivés et utilisation pharmaceutique de dérivés
PCT/CN2016/073388 WO2016124141A1 (fr) 2015-02-04 2016-02-03 Dérivés de n-sulfonylbenzamide substitués hétérocycliques, procédé de préparation de ces dérivés, et utilisation pharmaceutique de ces dérivés
PCT/CN2016/073387 WO2016124140A1 (fr) 2015-02-04 2016-02-03 Dérivés de n-sulfonylbenzamide substitués hétérocycliques, procédé de préparation de ces dérivés, et utilisation pharmaceutique de ces dérivés

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/073385 WO2016124139A1 (fr) 2015-02-04 2016-02-03 Dérivés de n-sulfonyl-benzamide à substitution hétérocyclique, procédé de préparation de ces dérivés et utilisation pharmaceutique de dérivés

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/073387 WO2016124140A1 (fr) 2015-02-04 2016-02-03 Dérivés de n-sulfonylbenzamide substitués hétérocycliques, procédé de préparation de ces dérivés, et utilisation pharmaceutique de ces dérivés

Country Status (2)

Country Link
CN (3) CN107428683B (fr)
WO (3) WO2016124139A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106905184A (zh) * 2017-03-05 2017-06-30 北京化工大学 含有苯甲酰胺基团的氮芥类化合物及其制备方法和用途
CN108430969A (zh) * 2016-02-03 2018-08-21 上海海雁医药科技有限公司 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
WO2019062848A1 (fr) * 2017-09-29 2019-04-04 浙江海正药业股份有限公司 Dérivé de n-(sulfonyle substitué)benzamide, procédé de préparation et utilisation pharmaceutique associés
WO2020192553A1 (fr) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 Dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019019851A1 (fr) * 2017-07-24 2019-01-31 上海海雁医药科技有限公司 Inhibiteur de canal ionique sodique, sel pharmaceutiquement acceptable, polymorphe de celui-ci, et utilisation associée
CN113233957B (zh) * 2021-06-03 2023-05-02 成都工业学院 一种2-溴-5-碘-苄醇的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007861A1 (fr) * 2010-07-12 2012-01-19 Pfizer Limited Dérivés de n-sulfonylbenzamide utiles comme inhibiteurs du canal sodique voltage-dépendant
WO2013118805A1 (fr) * 2012-02-08 2013-08-15 大日本住友製薬株式会社 Dérivé de la proline 3-substitué
WO2013177224A1 (fr) * 2012-05-22 2013-11-28 Genentech, Inc. Benzamides n-substitués et leur utilisation dans le traitement de la douleur
WO2014014050A1 (fr) * 2012-07-19 2014-01-23 大日本住友製薬株式会社 Dérivé de 1-(cycloalkyl-carbonyl)proline
WO2015078374A1 (fr) * 2013-11-27 2015-06-04 Genentech, Inc. Benzamides substitués et leurs méthodes d'utilisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008266230A (ja) * 2007-04-23 2008-11-06 Bayer Cropscience Ag 殺虫性アリールピロリジン類
WO2014008458A2 (fr) * 2012-07-06 2014-01-09 Genentech, Inc. Benzamides n-substitués et leurs procédés d'utilisation
US10815197B2 (en) * 2016-02-03 2020-10-27 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. N-sulfonyl benzamides as voltage-gated sodium channel inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007861A1 (fr) * 2010-07-12 2012-01-19 Pfizer Limited Dérivés de n-sulfonylbenzamide utiles comme inhibiteurs du canal sodique voltage-dépendant
WO2013118805A1 (fr) * 2012-02-08 2013-08-15 大日本住友製薬株式会社 Dérivé de la proline 3-substitué
WO2013177224A1 (fr) * 2012-05-22 2013-11-28 Genentech, Inc. Benzamides n-substitués et leur utilisation dans le traitement de la douleur
WO2014014050A1 (fr) * 2012-07-19 2014-01-23 大日本住友製薬株式会社 Dérivé de 1-(cycloalkyl-carbonyl)proline
WO2015078374A1 (fr) * 2013-11-27 2015-06-04 Genentech, Inc. Benzamides substitués et leurs méthodes d'utilisation

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108430969A (zh) * 2016-02-03 2018-08-21 上海海雁医药科技有限公司 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
CN108430969B (zh) * 2016-02-03 2020-06-02 上海海雁医药科技有限公司 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
CN106905184A (zh) * 2017-03-05 2017-06-30 北京化工大学 含有苯甲酰胺基团的氮芥类化合物及其制备方法和用途
WO2019062848A1 (fr) * 2017-09-29 2019-04-04 浙江海正药业股份有限公司 Dérivé de n-(sulfonyle substitué)benzamide, procédé de préparation et utilisation pharmaceutique associés
CN111212830A (zh) * 2017-09-29 2020-05-29 浙江海正药业股份有限公司 N-(取代磺酰基)苯甲酰胺类衍生物及其制备方法和医药用途
CN111212830B (zh) * 2017-09-29 2023-07-04 浙江海正药业股份有限公司 N-(取代磺酰基)苯甲酰胺类衍生物及其制备方法和医药用途
WO2020192553A1 (fr) * 2019-03-22 2020-10-01 上海海雁医药科技有限公司 Dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale

Also Published As

Publication number Publication date
CN107406380B (zh) 2020-04-28
CN107406380A (zh) 2017-11-28
WO2016124139A1 (fr) 2016-08-11
CN107207430B (zh) 2020-04-28
CN107428683A (zh) 2017-12-01
CN107207430A (zh) 2017-09-26
CN107428683B (zh) 2020-06-02
WO2016124140A1 (fr) 2016-08-11

Similar Documents

Publication Publication Date Title
WO2016124141A1 (fr) Dérivés de n-sulfonylbenzamide substitués hétérocycliques, procédé de préparation de ces dérivés, et utilisation pharmaceutique de ces dérivés
WO2016177340A1 (fr) Dérivé de benzènesulfonamide substitué bicyclique, et procédé de préparation et utilisation pharmaceutique de celui-ci
TWI263497B (en) Pyridinoylpiperidines as 5-HT1F agonists
DK172076B1 (da) Derivater af 4-benzyl-1-(2H)-phthalazinon, fremgangsmåde til fremstilling heraf, forbindelserne til terapeutisk anvendelse, anvendelse af forbindelserne til fremstilling af lægemidler, lægemidler indeholdende forbindelserne samt fremgangsmåde til fremstilling af sådanne lægemidler
CN103804358B (zh) 一类二芳基乙内酰脲衍生物、其制备方法、药物组合物和应用
TWI333950B (en) New benzimidazole derivatives
WO2017133591A1 (fr) Dérivé n-sulfonyle benzamide à substituant hétérocyclique, son procédé de préparation et son application pharmaceutique
TW200526631A (en) Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
BR112019022002A2 (pt) Novo composto sólido cristalino de cloridrato de 3-fenil-4-propil-1-(piridin-2-il)-1-h-pirazol-5-ol
CN108290835A (zh) Alk和srpk的抑制剂和使用方法
WO2012001120A1 (fr) Sel de rupatadine utilisé en tant qu'agent antihistaminique
RU2314305C2 (ru) Производные 4-(тио- или селеноксантен-9-илиден)-пиперидина или акридина, фармацевтическая композиция на их основе и применение
WO2020228789A1 (fr) Composé propylamine hétéroaryle 3-aryloxyl-3 à cinq chaînons, forme cristalline et utilisation associée
CA2841897A1 (fr) Nouveau compose ayant une activite d'inhibition de parp
DE102009003975A1 (de) Benzothiazolonderivate
AU2002350603A1 (en) Derivatives of 4-(thio- or selenoxanthene-9-ylidene)-piperidine or acridine and its use as a selective 5-ht?2b? receptor antagonist
WO2011038662A1 (fr) Composés utilisés en tant qu'inhibiteurs de trpv1, compositions pharmaceutiques en contenant et leurs utilisations médicales
WO2022063197A1 (fr) Composé pyrimidine carboxamide et son application
TWI280242B (en) Pharmaceutical compounds
JP7194828B2 (ja) コリダルミンの結晶性塩
WO2020199683A1 (fr) Dérivé de sulfonylbenzamide substitué par un hétérocycle azoté, son procédé de préparation et son utilisation en médecine
WO2023078392A1 (fr) 2-(aryl-2-yl)morpholine et dérivé deutéré de celle-ci, son procédé de préparation et son application
KR100504647B1 (ko) 오피에이트 수용체 리간드로서의 3-아자비시클로[3.1.0.]헥산 유도체
WO2020192553A1 (fr) Dérivé de formamide benzohétérocyclique substitué par sulfonyle, son procédé de préparation et son utilisation médicale
WO2020119590A1 (fr) Composé de 3-cyanopyridine, composition pharmaceutique le contenant, son procédé de préparation et ses applications

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16746136

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16746136

Country of ref document: EP

Kind code of ref document: A1