WO2016177340A1 - Dérivé de benzènesulfonamide substitué bicyclique, et procédé de préparation et utilisation pharmaceutique de celui-ci - Google Patents

Dérivé de benzènesulfonamide substitué bicyclique, et procédé de préparation et utilisation pharmaceutique de celui-ci Download PDF

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WO2016177340A1
WO2016177340A1 PCT/CN2016/081183 CN2016081183W WO2016177340A1 WO 2016177340 A1 WO2016177340 A1 WO 2016177340A1 CN 2016081183 W CN2016081183 W CN 2016081183W WO 2016177340 A1 WO2016177340 A1 WO 2016177340A1
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compound
alkyl
independently
formula
stereoisomer
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Chinese (zh)
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兰炯
周福生
赵金柱
许峰
施霞
谢婧
徐慧
王莉肖
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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 CN201680003154.3A priority Critical patent/CN106795149B/zh
Publication of WO2016177340A1 publication Critical patent/WO2016177340A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
    • C07D277/52—Nitrogen atoms bound to hetero atoms to sulfur atoms, e.g. sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates in particular to a bicyclic substituted benzenesulfonamide derivative, a process for its preparation and its use as a sodium ion channel (particularly Nav1.7) inhibitor, as well as pharmaceutical compositions and pharmaceutical combinations prepared therefrom Things.
  • 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.
  • 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 a 5- or 6-membered monocyclic heteroaryl group, -CO-(C 1-20 alkyl) or C 3-20 cycloalkyl;
  • L 1 is a bond or -(CH 2 ) r1 -;
  • L 2 is a bond or -(CH 2 ) r2 -;
  • R1, r2 are each independently 1, 2 or 3;
  • R 1 , 2 or 3 -CH 2 - in L 1 or L 2 are optionally and independently of each -C(R y R x )-, -NR y C(O)-, cyclopropylene, C(O)NR y -, -N(R y )SO 2 -, -SO 2 N(R y )-, -S-, -S(O)-, -SO 2 -, -OC(O)- And -C(O)O-, -O-, -N(R y )- or -C(O)-substituted; wherein R y , R x are each independently hydrogen or C 1-20 alkyl;
  • X is a bond, NR z , O or S; R z is hydrogen or C 1-10 alkyl;
  • L 2 is bonded to any ring atom of any one of the double rings
  • Z 3 is not -CH 2 -;
  • the A ring is a structure represented by the formula (A-1), the formula (A-2), the formula (A-3) or the formula (A-4):
  • W 1 , W 2 , W 3 , and W 4 are each independently N or CH; and W 1 , W 2 , W 3 , and W 4 are not N at the same time; U 1 and U 2 are each independently N or CH. ; U 3 is CH 2 , N, O or S; (R a ') m is a hydrogen at any position on the 5- or 6-membered ring substituted by m R a ', m is 0, 1, 2, 3 or 4, each R a 'same or different, each independently hydrogen, halogen, nitro, hydroxy, cyano, C 6-20 aryl, hydrazine, deuterated C 1-20 alkyl, C 1-20 alkane , halo C 1-20 alkyl, C 1-20 alkoxy, halo C 1-20 alkoxy, C 3-20 cycloalkyl, halo C 3-20 cycloalkyl, C 3 20 cycloalkoxy, halo C 3-20 cycloalkoxy,
  • R a and R b are each independently hydrogen, C 1-20 alkyl, C 3-20 cycloalkyl or C 6-20 aryl.
  • the A ring is a structure of the formula (A-1).
  • W 1 , W 2 , W 3 , and W 4 are all CH.
  • W 1 , W 2 , W 3 , W 4 are each independently N or CH; and one of W 1 , W 2 , W 3 , W 4 is N.
  • W 1 , W 3 , and W 4 are both CH; and W 2 is N.
  • W 1 , W 2 , and W 4 are both CH; and W 3 is N.
  • W 1 , W 2 , W 3 , W 4 are each independently N or CH; and two of W 1 , W 2 , W 3 , and W 4 are N.
  • R 2 and R 4 are hydrogen.
  • R 3 is hydrogen, fluorine or chlorine.
  • R 1 is fluorine
  • R 1 is fluorine
  • R 2 and R 4 are hydrogen
  • R 3 is hydrogen or chlorine
  • L 2 is attached to any carbon atom on the A ring.
  • L 2 is bonded to Z 1 , Z 2 , Z 3 or Z 4 .
  • the 5 or 6 membered monocyclic heteroaryl is of the formula a, formula b, formula c or formula d:
  • a 1 is S or O; A 2 , A 3 , and A 4 are each independently N or CR a ”; B 2 is S or O; and B 1 , B 3 , and B 4 are each independently N or CR.
  • b is S or O;
  • C 1 , C 2 , C 4 are each independently N or CR c ”;
  • D 1 , D 2 , D 3 are each independently N or CR d ”; wherein R a ", R b “, R c “, R d " are each independently hydrogen, fluorine, chlorine, C 1-3 alkyl, or C 3-6 cycloalkyl.
  • the 5 or 6 membered monocyclic heteroaryl is selected from the group consisting of:
  • Z 3 is -N(R 31 )- or -CH 2 -; Is a single bond or a double bond;
  • L 2 is attached to Z 1 , Z 2 or Z 3 .
  • L 2 is bonded to any of the carbon atoms of W 1 , W 2 , W 3 , and W 4 .
  • Z 1 is -C(R 11 R 12 )-, -O- or -C(O)-;
  • Z 2 is -C(O)- or -C(R 21 R 22 )-;
  • Z 3 Is -N(R 31 )- or -CH 2 -.
  • Z 3 is -N(R 31 )- or -CH 2 -.
  • the formula (I-a) is a structure represented by the formula (I-a-1) or the formula (I-a-2):
  • Z 12 is -C(R 11 R 12 ) - or -C(O)-;
  • Z 3 is -CH 2 -; Is a single bond or a double bond;
  • R a ', m, R 11 , R 12 , R 13 , R 21 , R 22 , R 24 are as defined above;
  • W 11 , W 21 , W 31 , W 41 , W 12 , W 22 , W 32 , and W 42 are each independently N or CH; and W 11 , W 21 , W 31 , and W 41 are not N at the same time;
  • W 12 , W 22 , W 32 , and W 42 are not N at
  • W 11 , W 21 , W 31 , and W 41 are all CH.
  • one of W 11 , W 21 , W 31 , W 41 is N.
  • W 11 , W 21 , W 41 are all CH; and W 31 is N.
  • two of W 11 , W 21 , W 31 , and W 41 are N.
  • W 12 , W 22 , W 32 , and W 42 are all CH.
  • one of W 12 , W 22 , W 32 , W 42 is N.
  • W 12 , W 32 , W 42 are both CH; and W 22 is N.
  • W 12 , W 22 , and W 42 are both CH; and W 32 is N.
  • two of W 12 , W 22 , W 32 , and W 42 are N.
  • Z 11 is -C(R 11 R 12 )-, -O- or -C(O)-;
  • Z 2 is -C(O)-;
  • R 11 and R 12 are as defined above.
  • R 11 and R 12 are each independently hydrogen or methyl, or R 11 and R 12 together with the carbon atom to be bonded form a cyclopropylene group.
  • Z 12 is -C(R 11 R 12 )- or -C(O)-; and Z 3 is -CH 2 -.
  • L 1 , L 2 are -(CH 2 )-;
  • X is NR z , O or S; and
  • -CH 2 - in L 1 or L 2 is optionally and independently C(R y R x )-, -NR y C(O)-, cyclopropylene, -C(O)NR y -, -N(R y )SO 2 -, -SO 2 N(R y ) -, -S-, -S(O)-, -SO 2 -, -OC(O)-, -C(O)O-, -O-, -N(R y )- or -C(O) a substitution; wherein R z , R y , R x are each independently hydrogen or a C 1-20 alkyl group.
  • L 1 , L 2 are -(CH 2 )-; X is NR z , O or S; and -CH 2 - in L 1 or L 2 is optionally and independently C(R y R x )-, -O- or -C(O)-substituted; wherein R z , R y , R x are each independently hydrogen, methyl, ethyl, propyl or isopropyl.
  • L 1 and L 2 are -(CH 2 )-;
  • X is NR z , O or S; and only -CH 2 - in L 2 is -C(R y R x )-, -NR y C(O)-, cyclopropylene, -C(O)NR y -, -N(R y )SO 2 -, -SO 2 N(R y )-, -S-, -S( O)-, -SO 2 -, -OC(O)-, -C(O)O-, -O-, -N(R y )- or -C(O)-substituted; wherein R z , R y and R x are each independently hydrogen or C 1-20 alkyl.
  • L 1 and L 2 are -(CH 2 )-; X is NR z , O or S; and only -CH 2 - in L 2 is -C(R y R x )-, -O- or -C(O)-substitution; wherein R z , R y , R x are each independently hydrogen, methyl, ethyl, propyl or isopropyl.
  • X, L 1 , and L 2 are one bond.
  • L 1 and L 2 are a bond;
  • X is NR z , O or S; wherein R z is hydrogen or C 1-20 alkyl (preferably R z is hydrogen, methyl, B) Base, propyl or isopropyl).
  • L 1 is a bond;
  • L 2 is -(CH 2 )-;
  • -CH 2 - in L 2 is -C(R y R x )-, -NR y C(O )-, cyclopropylene, -C(O)NR y -, -N(R y )SO 2 -, -SO 2 N(R y )-, -S-, -S(O)-, -SO 2- , -OC(O)-, -C(O)O-, -O-, -N(R y )- or -C(O)-substituted; wherein R y and R x are each independently hydrogen Or C 1-20 alkyl.
  • L 1 is a bond
  • L 2 is -(CH 2 )-
  • -CH 2 - in L 2 is -C(R y R x )-, -O- or -C (O)-substitution
  • R y is hydrogen, methyl, ethyl, propyl or isopropyl
  • R x is methyl, ethyl, propyl or isopropyl.
  • X and L 1 are one bond; and L 2 is -(CH 2 )-.
  • L 1 is a bond;
  • X is NR z , O or S;
  • L 2 is -(CH 2 )-;
  • -CH 2 - in L 2 is -C(R y R x )- , -NR y C(O)-, cyclopropylene, -C(O)NR y -, -N(R y )SO 2 -, -SO 2 N(R y )-, -S-, -S (O)-, -SO 2 -, -OC(O)-, -C(O)O-, -O-, -N(R y )- or -C(O)-substituted; wherein R z , R y and R x are each independently hydrogen or C 1-20 alkyl.
  • L 1 is a bond
  • X is NR z , O or S
  • L 2 is -(CH 2 )-
  • -CH 2 - in L 2 is -C(R y R x )- Or -C(O)-substituted
  • R z , R y , R x are each independently hydrogen, methyl, ethyl, propyl or isopropyl.
  • L 1 is a bond
  • X is NR z , O or S
  • L 2 is -(CH 2 )-
  • -CH 2 - in L 2 is -C(R y R x )-
  • R z and R y are each independently hydrogen, methyl, ethyl, propyl or isopropyl
  • R x is methyl, ethyl, propyl or isopropyl.
  • L 1 is a bond
  • X is NR z , O or S
  • L 2 is -(CH 2 )-
  • R z is hydrogen, methyl, ethyl, propyl or isopropyl.
  • Z 1a , Z 1b and Z 1c are each independently -O-, -C(R 11 R 12 )-;
  • Z 2a , Z 2b , Z 3a , Z 3c , Z 4b , Z 4c are each independently -C(R 21 R 22 )-;
  • R a ', m, R 11 , R 12 , R 21 , R 22 are as defined above;
  • W 1a , W 2a , W 3a , W 4a , W 1b , W 2b , W 3b , W 4b , W 1c , W 2c , W 3c , W 4c are each independently N or CH; and
  • W 1a , W 2a , W 3a , W 4a are not N at the same time;
  • W 1b , W 2b , W 3b W 4b is not N at the same time;
  • W 1c , W 2c , W 3c , and W 4c are not N at
  • Z 1a , Z 1b , Z 1c are each independently -O- or -CH 2 -.
  • Z 2a , Z 2b , Z 3a , Z 3c , Z 4b , and Z 4c are each independently -CH 2 -.
  • W 1a , W 2a , W 3a , and W 4a are all CH.
  • one of W 1a , W 2a , W 3a , W 4a is N.
  • two of W 1a , W 2a , W 3a , and W 4a are N.
  • W 1b , W 2b , W 3b , and W 4b are all CH.
  • one of W 1b , W 2b , W 3b , W 4b is N.
  • two of W 1b , W 2b , W 3b , and W 4b are N.
  • W 1c , W 2c , W 3c , and W 4c are all CH.
  • one of W 1c , W 2c , W 3c , W 4c is N.
  • two of W 1c , W 2c , W 3c , and W 4c are N.
  • R a ', m, R 13 , R 21 , R 22 , R 23 , R 24 , R 32 , and R 42 are as defined above;
  • Z 1f , Z 3f , Z 4f , Z 1g , Z 3g , and Z 4g are —CH 2 —.
  • Z 2f and Z 2g are -O- or -N(R 23 )-.
  • Z 1g , Z 3g , Z 4g are -CH 2 -; Z 2g is -N(R 23 )-.
  • W 2d , W 3d , and W 4d are all CH.
  • one of W 2d , W 3d , W 4d is N.
  • W 2d is N
  • W 3d is CH
  • W 4d are CH.
  • two of W 2d , W 3d , and W 4d are N.
  • W 1e , W 3e , and W 4e are all CH.
  • one of W 1e , W 3e , W 4e is N.
  • two of W 1e , W 3e , and W 4e are N.
  • W 1f , W 2f , and W 3f are all CH.
  • one of W 1f , W 2f , W 3f is N.
  • two of W 1f , W 2f , and W 3f are N.
  • W 2g , W 3g , and W 4g are both CH.
  • one of W 2g , W 3g , and W 4g is N.
  • two of W 2g , W 3g , and W 4g are N.
  • the compound of formula (I) is a compound of formula (II-1) to formula (II-9):
  • R a1 , R a2 , R a3 , R a4 are as defined as R a ';
  • Z 2 is -C(O)- or -C(R 21 R 22 )-;
  • Y is -O-, -C (R 21 R 22 )- or -N(R 23 )-;
  • R 1 , R 3 , R 5 , X, L 1 , L 2 , R 11 , R 12 , R 21 , R 22 , R 23 are as defined above Defined.
  • R a1 , R a2 , R a3 , and R a4 have the same meanings as R a '; R 23 , R 13 , R 24 , R 32 , and R 42 are as defined above.
  • R a1 , R a2 , R a3 , R a4 are each independently hydrogen, methyl, fluoro, chloro, methoxy, isopropoxy, trifluoromethoxy, trifluoromethyl , piperidinyl, pyrazolyl, dimethylamino.
  • R 23 is hydrogen, methyl, -C(O)-CH 3 .
  • R 13 , R 24 , R 32 , R 42 are each independently hydrogen, methyl, fluoro, chloro, methoxy, isopropoxy, trifluoromethoxy, trifluoromethyl , piperidinyl, pyrazolyl, dimethylamino.
  • the compound is a compound prepared in the examples of the present application:
  • the compound is selected from the group consisting of:
  • 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.
  • the invention also 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, C 1-20 alkyl, C 3-20 cycloalkyl, C 3-20 naphthenic Oxy, 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, -C(O)O-(C 1-20 alkyl), -OC(O)-(C 1-20 alkyl), -SO 2 -(C 1-20 alkane) Or) -SO 2 -(C 6-20 aryl);
  • R 5 is a 5- or 6-membered monocyclic heteroaryl group, -CO-(C 1-20 alkyl) or C 3-20 cycloalkyl;
  • L 1 is a bond or -(CH 2 ) r1 -;
  • L 2 is a bond or -(CH 2 ) r2 -;
  • R1, r2 are each independently 1, 2 or 3;
  • R 1 , 2 or 3 -CH 2 - in L 1 or L 2 are optionally and independently of each -C(R y R x )-, -NR y C(O)-, cyclopropylene, C(O)NR y -, -N(R y )SO 2 -, -SO 2 N(R y )-, -S-, -S(O)-, -SO 2 -, -OC(O)- And -C(O)O-, -O-, -N(R y )- or -C(O)-substituted; wherein R y , R x are each independently hydrogen or C 1-20 alkyl;
  • X is a bond, NR z , O or S; R z is hydrogen or C 1-10 alkyl;
  • L 2 is bonded to any ring atom of any one of the double rings
  • Z 3 is not -CH 2 -;
  • the A ring is a structure represented by the formula (A-1), the formula (A-2), the formula (A-3) or the formula (A-4):
  • W 1 , W 2 , W 3 , and W 4 are each independently N or CH; and W 1 , W 2 , W 3 , and W 4 are not N at the same time; U 1 and U 2 are each independently N or CH. ; U 3 is CH 2 , N, O or S; (R a ) m is a 5- or 6-membered ring at any position in the hydrogen replaced by m R a , m is 0, 1, 2, 3 or 4, Each R a is the same or different and each independently is hydrogen, halogen, nitro, hydroxy, cyano, C 6-20 aryl, anthracene, deuterated C 1-20 alkyl, 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 naphthenic Oxy, halogenated C 3-20 cycloalkoxy, C
  • Z 3 is -N(R 31 )- or -CH 2 -; Is a single bond or a double bond;
  • the formula (I-a) is a structure represented by the formula (I-a-1) or the formula (I-a-2):
  • Z 12 is -C(R 11 R 12 ) - or -C(O)-;
  • Z 3 is -CH 2 -; Is a single bond or a double bond;
  • R a , m, R 11 , R 12 , R 13 , R 21 , R 22 , R 24 are as defined above;
  • W 11 , W 21 , W 31 , W 41 , W 12 , W 22 , W 32 and W 42 are each independently N or CH; and W 11 , W 21 , W 31 , and W 41 are not N at the same time;
  • W 12 , W 22 , W 32 , and W 42 are not N at the same time
  • Z 1a , Z 1b and Z 1c are each independently -O-, -C(R 11 R 12 )-;
  • Z 2a , Z 2b , Z 3a , Z 3c , Z 4b , Z 4c are each independently -C(R 21 R 22 )-;
  • R a , m, R 11 , R 12 , R 21 , R 22 are as defined above;
  • W 1a , W 2a , W 3a , W 4a , W 1b , W 2b , W 3b , W 4b , W 1c , W 2c , W 3c , W 4c are each independently N or CH; and
  • W 1a , W 2a , W 3a , W 4a are not N at the same time;
  • W 1b , W 2b , W 3b , W 4b is not N at the same time;
  • W 1c , W 2c , W 3c , and W 4c are not N
  • R a , m, R 13 , R 21 , R 22 , R 23 , R 24 , R 32 , R 42 are as defined above;
  • the compound of formula (I) is a compound of formula (II-1) to formula (II-9):
  • R a1 , R a2 , R a3 , R a4 are as defined for R a ;
  • Z 2 is —C(O)— or —C(R 21 R 22 )—;
  • Y is —O—, —C ( R 21 R 22 )- or -N(R 23 )-;
  • R 1 , R 3 , R 5 , X, L 1 , L 2 , R 11 , R 12 , R 21 , R 22 , R 23 are as defined above definition.
  • R a1 , R a2 , R a3 , and R a4 are each defined as R a ; R 23 , R 13 , R 24 , R 32 , and R 42 are as defined above.
  • Figure 1 is a baseline graph of a rat cold pain test comprising Compound Z-47.
  • Figure 2 is a graph of the use of one-way ANOVA with compound Dunnett's multiple comparison test for compound Z-47.
  • Figure 3 is a baseline graph of a rat cold pain test comprising compounds Z-49 and Z-56.
  • Figure 4 shows the addition of Dunnett's multiple comparison test using single factor analysis of variance for compounds Z-49 and Z-56.
  • Figure 5 is a baseline graph of a rat cold pain test comprising Compound Z-54.
  • Figure 6 is a graph of compound Z-54 using one-way ANOVA with additional Dunnett multiple comparison test results.
  • Figure 7 is a baseline graph of a rat cold pain test comprising Compounds Z-99 and Z-100.
  • Figure 8 shows the addition of Dunnett's multiple comparison test using the one-way ANOVA of compounds Z-99 and Z-100.
  • the bicyclic substituted benzenesulfonamide derivative of the present invention has a high inhibitory activity against Nav1.7, and the inhibitory activity against Nav1.5 is significantly weaker, on Nav1. .7 has obvious choice Selective inhibitory activity.
  • 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.
  • 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 ⁇ -electron system that contains one or more unsaturated bonds but does not have a complete conjugation. System.
  • 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.
  • C 3- 10 cycloalkyl group preferably a C 3-8 cycloalkoxy group, more preferably C 3-6 cycloalkoxy.
  • 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 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.
  • a wavy line in a structural formula such as Indicates where the structure is connected.
  • double ring in “L 2 is attached to any ring atom of any one of the double rings” means
  • 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 Substitution reaction with a compound of formula (I-1) by a nucleophilic reaction site or group (such as NH, OH, etc.) possessed in the compound of formula (I-2) in the presence of a base system (e.g., affinity substitution reaction, etc.) to form a compound of formula (I-3).
  • a base system e.g., affinity substitution reaction, etc.
  • Suitable base systems include potassium t-butoxide present in DMSO, sodium hydride present in DMF, potassium carbonate present in DMF, and the like.
  • Lev in -1) is a leaving group including, but not limited to, triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzene a sulfonate, a p-toluenesulfonate or the like; an acyloxy group such as an acetoxy group, a trifluoroacetoxy group or the like.
  • PG in formula (I-1) is an amino protecting group, and amino protecting group includes, but is not limited to, tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl. (Fmoc); benzyl (Bn), 2,4-dimethoxybenzyl (DMB), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl ; Trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).
  • Step 2 The compound of the formula (I-3) is subjected to deprotection reaction to give a compound of the formula (I) under suitable conditions.
  • the deprotection method can be referred to a conventional method in the art.
  • the compound of the formula (I-2) and the formula (I-1) in the route 1 can be commercially available depending on the specific structure, or can be produced by a method known to a person skilled in the art.
  • the compound of formula (I-4) can be substituted with a compound of formula (I-5) to form a compound of formula (I-3), followed by deprotection to give a compound of formula (I), the reaction conditions and group definition being the same as in Scheme 1.
  • a series of novel bicyclic substituted benzenesulfonamide 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.
  • DMB is 2,4-dimethoxybenzyl
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE is petroleum ether
  • Ac 2 O is acetic anhydride
  • NBS is N-bromosuccinimide.
  • DCM is dichloromethane
  • AIBN is azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl Is tert-butyldimethylchlorosilane
  • NCS is N-chlorosuccinimide
  • DHP is dihydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB is p-methoxybenzyl
  • LiHMDS is two (three Methylsilyl) lithium amide
  • Pd 2 (dba) 3 is tris(dibenzylideneacetone)dipalladium
  • RuPhos is 2-dicyclohexylphosphorin-2',6'-diisopropoxy-1,1 '-Biphenyl
  • DMAP is 4-dimethylaminopyridine
  • room temperature means about 20-25 °C.
  • Step 1 Compound ZA-1-a (35 g, 0.2 mol) was dissolved in methanol (500 mL) and concentrated sulfuric acid (5 mL) was slowly added. The reaction was stirred at 70 ° C for 18 h under N 2 . Most of the solvent was spun off, then water (200 mL) was added, and ethyl acetate (3 ⁇ 250 mL) was evaporated.
  • Step 2 Compound ZA-1-b (38 g, 0.2 mol) was dissolved in THF (200 mL) and methanol (50 mL), and sodium borohydride (15.4 g, 0.4 mol) was slowly added at 0 ° C. Stir for 2 h. TLC was used to monitor the disappearance of the reaction mixture. The reaction mixture was cooled to 0 ° C, then 300 mL of water was added, and the mixture was extracted with dichloromethane (3 ⁇ 300 mL). The organic phase was washed with saturated sodium bicarbonate (500 mL). c (32 g, yield 99%).
  • Step 4 In a three-necked flask, compound ZA-1-d (27.5 g, 0.1 mol) was dissolved in anhydrous THF (300 mL), and the reaction solution was cooled to -65 ° C, and slowly added dropwise under N 2 protection. butyl lithium (2.4M, 50mL, 0.12mol), after 1h and then quickly added SO 2 (54g, 0.5mol). The reaction was held at -65 ° C for 1 h and the reaction starting material was monitored to disappear. The solvent was sparged to give a yellow solid (35 g). To this yellow solid was added dichloromethane (400 mL) then NCS (13.6 g, 0.1 mol). The reaction was stirred at room temperature for 2 h.
  • the reaction was stirred at 0 ° C for half an hour, and the reaction material was observed to disappear by LC-MS, and then 10 mL of tetrabutylammonium chloride (4.4 g, 15.8 mmol) in dichloromethane was added.
  • the reaction solution It was then slowly warmed to room temperature and stirred at room temperature for 2 h.
  • Step 1 Under a nitrogen atmosphere, a solution of the compound ZA-2-a (30 g, 180.72 mmol) and the compound ZA-2-b (24 g, 237.62 mmol) in xylene (500 ml) was heated under reflux (140 ° C) and After 6 h, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) ESI-MS: 250 (M+H) + .
  • Step 2 Compound ZA-2-c (40 g, 160.64 mmol) was dissolved in methanol (1 L), and sodium borohydride (12.2 g, 321.29 mmol) was added portionwise to a methanol solution at room temperature and then stirred overnight. The water (100 ml) was added dropwise to the reaction mixture, and the mixture was stirred for about 5 minutes. The methanol in the reaction mixture was evaporated to dryness. Washed, dried over anhydrous sodium sulfate, filtered, EtOAc EtOAc EtOAc. ESI-MS 252 (M+H) + .
  • Step 3 Under N 2 protection at a temperature of -63 deg.] C, the ether solution of the compound ZA-2-d (10g, 32mmol) THF (160ml) was added dropwise LiHMDS (1M, 70ml, 70mmol) was At this temperature, stir for 2 h, allow the reaction solution to slowly warm to room temperature, stir for 1 h, then cool to -63 ° C, add sulfonyl chloride (9.4 g, 38 mmol) to the above reaction solution, maintain the temperature, stir 1 h, warmed to room temperature, and stirred for 2 h. The reaction solution was added to a saturated aqueous solution of ammonium chloride (150 ml), and the mixture was evaporated, evaporated, evaporated.
  • the reaction was stirred at 0 ° C for half an hour, and the reaction material was observed to disappear by LC-MS, and then a solution of 8 mL of tetrabutylammonium chloride (1.1 g, 4 mmol) in dichloromethane was added. The reaction solution was then slowly warmed to room temperature and stirred at room temperature for 2 h.
  • Step 1 15 ml of chlorosulfonic acid was added to a solution of the compound Z-A-5-a (3 g, 20.8 mmol) in dichloromethane, and the reaction mixture was stirred at 90 ° C for 2 h. The reaction solution was poured into ice water and extracted with EA. The organic phase was washed with saturated NaCI The organic layer was dried (MgSO4)ield
  • Step 3 1,4-dioxane solution of the compound ZA-5-c (2.9g, 13mmol) was added Ac 2 O (10ml), the reaction solution was stirred at 120 °C 2h, the reaction mixture was added to the EA , washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. .
  • Step 4 To a solution of the compound ZA-5-d (0.53 g, 2 mmol) in hexanes (10 ml), NBS (0.43 g, 2.4 mmol) and AIBN (110 mg). The reaction mixture was stirred at 90 ° C for 4 h. To the reaction mixture was added DCM, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid (330mg), ESI-MS 344.0 (M + H) +.
  • the preparation method is basically the same as the preparation of the compound ZA-2, except that the 5-chloro-2,4-difluorobenzene-1-sulfonyl chloride in the step 3 is replaced with 2,4,5-trifluorobenzene-1. - Sulfonyl chloride.
  • Step 1 2,4-Dimethoxybenzaldehyde (35.2 g, 0.21 mol) and compound ZA-7-a (20.2 g, 0.20 mol) were added to xylene (350 ml). Heat to 140 ° C under nitrogen for 6 h, the reaction was cooled to room temperature and concentrated to give a yellow solid. The yellow solid was dissolved in 400 ml of methanol. Sodium borohydride (11.4 g, 0.30 mol) was added portionwise to the reaction mixture at room temperature and stirred at room temperature overnight. 500 ml of water was slowly added dropwise to the reaction solution, maintained at room temperature, and stirred for about 15 minutes.
  • Step 2 Under N 2 protection at a temperature of -78 deg.] C, the solution of the ZA-7-b (10g, 0.039mol) in THF (200ml) was added dropwise LiHMDS (1M, 48ml, 0.048mol) in The THF solution was stirred at this temperature for 0.5 h, the reaction solution was allowed to slowly warm to room temperature, stirred for 1 h, then cooled to -78 ° C, and a solution of sulfonyl chloride (11.81 g, 0.048 mol) dissolved in THF was added dropwise. The reaction solution was stirred at this temperature for 1 h, warmed to room temperature, and stirred for 2 h.
  • LiHMDS 1M, 48ml, 0.048mol
  • reaction liquid was added to a saturated aqueous solution of ammonium chloride (300 ml), and extracted with ethyl acetate (400 ml ⁇ 3), and the organic phase was washed with saturated brine (100 ml), dried, and dried.
  • ESI-MS 484.0 (M+Na) + .
  • Step 1 Compound Z-A-8-a (25 g, 0.114 mol) was dissolved in methanol (250 mL) and thionyl chloride (50 mL) was slowly added dropwise. The reaction was stirred at 75 ° C for 6 h. The majority of the solvent was spun off, then 100 mL of water was added, the pH was adjusted to 8 with 2N aqueous sodium hydroxide, then extracted with ethyl acetate (3 ⁇ 220 mL), dried and dried to give white solid ZA-8-b (26.2 g, yield 100%).
  • Step 3 Compound Z-A-8-c (18.3 g, 0.09 mol) was dissolved in DMF (150 mL) and then, then, then, then, then,,,, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,
  • Step 4 In a three-necked flask, compound ZA-8-d (10 g, 0.031 mol) was dissolved in anhydrous THF (100 mL), the reaction solution was cooled to -65 ° C, and n-butyl was slowly added dropwise under N 2 protection. lithium (2.4M, 15.7mL, 0.038mol), was added after 1h and then quickly SO 2 (10g, 0.155mol). The reaction was held at -65 ° C for 1 h and the reaction starting material was monitored to disappear. The solvent was sparged to give a yellow solid (9.7 g). To this yellow solid was added dichloromethane (150 mL) then NCS (4.2 g, 0.031 mol). The reaction was stirred at room temperature overnight.
  • dichloromethane 150 mL
  • NCS 4.2 g, 0.031 mol
  • the preparation method is the same as the preparation of the compound ZA-1 except that the ZA-1-a in the step 1 is replaced with 2,5-difluorobenzoic acid.
  • Step 1 6-Fluoropyridin-2-amine (6 g, 0.0536 mol) was dissolved in 1,2-dichloroethane (100 mL), and ZA-2-a (8.9 g, 0.0536 mol) and cyano boron were added. Sodium hydride (4.4 g, 0.07 mol). The reaction solution was stirred at normal temperature for 16 h. The residue was extracted with EtOAc (EtOAc (EtOAc)EtOAc. .
  • Steps 2 to 4 The compound ZA-10-a (1.4 g, 0.0053 mol) was used as a starting material, and was obtained by the procedure of the step 5 to 7 of the compound ZA-1 to obtain a pale yellow solid ZA-10 (780 mg, yield 79%) ).
  • Step 1 The compound 2-chloro-5-fluoropyrimidine (5.28 g, 0.04 mol) and (2,4-dimethoxyphenyl)ethylamine (8.01 g, 0.048 mol) were added to ethanol (60 ml). Triethylamine (6.36 g, 0.06 mol) was added to the mixture, heated to 60 ° C under nitrogen and stirred for 48 h. The reaction mixture was concentrated with EtOAc (EtOAc m.). %), the product is a white solid.
  • Step 2 Compound Z-A-11-a (2.63 g, 0.010 mol) was dissolved in THF (30 mL), cooled to -40 ° C, then KHMDS (1 M/L, 13 mL) was slowly added. The reaction was stirred at -40 °C for 1 h, warmed to room rt and stirred 1 hr. The mixture was cooled to -40 ° C, and then a solution of compound Z-A-1 (4.84 g, 0.013 mol) in THF (20 mL) was slowly added dropwise, and the mixture was slowly warmed to room temperature and stirred at room temperature for 18 h.
  • Step 4 Compound ZA-11-c (1.7 g, 0.0035 mol) was dissolved in dichloromethane (20 mL), cooled to 0 ° C then slowly added triethylamine (0.54 g, 0.0053 mol) and methanesulfonyl chloride ( 0.48 g, 0.0042 mol). The reaction was stirred at 0 ° C for 1 h, and the reaction material was observed to disappear by LC-MS.
  • Step 5 To a dichloromethane solution of the above compound ZA-11-d, tetrabutylammonium chloride (3.10 g, 0.011 mol) was added. The reaction was stirred at room temperature for 3 h. 30 mL of water was added and extracted with dichloromethane (2 ⁇ 50 mL). The organic phase was washed with saturated brine (50 mL), dried and evaporated. The residue was purified to silicagel elut elut elut elut elut elut elut elut ESI-MS (M+Na) + : 525.7.
  • the preparation method was the same as the compound Z-A-1 to obtain a white solid Z-A-12 (yield: 70%).
  • Step 1 Compound ZA-1-g (1.89 g, 4 mmol) was dissolved in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with methylene chloride (30 mL). After suction filtration, the filtrate was concentrated with EtOAc EtOAcjjjjj ESI-MS: 493.9 (M+H) + .
  • Step 2 Compound ZA-13-a (1.40 g, 3 mmol) was dissolved in acetone (20 mL). A solution of potassium permanganate (2.37 g, 15 mmol) in water (15 ml) was added. After the mixture was stirred at room temperature for 2 h, aqueous sodium sulfide solution was added until the purple color was removed. After filtration, the filtrate was swirled off to remove the organic solvent. Extracted with ethyl acetate (3x 50 mL). After suction filtration, the filtrate was concentrated with EtOAc EtOAcjjjjj ESI-MS: 486 (MH) - .
  • Step 1 Compound ZA-14-a (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 mL? Dry over anhydrous sodium sulfate and suction filtration.
  • Step 2 Compound ZA-14-b (8.0 g, 0.04 mol) was dissolved in anhydrous THF (80 mL) under N 2 EtOAc. The mixture was cooled to -78 ° C, and LiHMDS (1M, 48ml, 0.048) was added dropwise. Mol) solution of THF. After the dropwise addition was completed, the mixture was stirred at -78 ° C for 0.5 h. The reaction solution was gradually warmed to room temperature, stirred for 1 h, then cooled to -78 ° C, and a solution of sulfonyl chloride (11.1 g, 0.048 mol) in THF (50 ml) was added dropwise to the reaction mixture.
  • ZA-11-a (2.46 g, 0.01 mol) was dissolved in anhydrous THF (25 ml) under N 2 and the mixture was cooled to -40 ° C, and THF (1M, 15 ml, 0.015 mol) of THF was added dropwise. Solution. After the dropwise addition was completed, the mixture was stirred at -40 ° C for 0.5 h. The reaction solution was slowly warmed to room temperature, stirred for 1 h, then cooled to -40 ° C, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (3.95 g, 0.015 mol) in THF (15 ml) was added dropwise. The reaction solution.
  • the preparation method was the same as the compound Z-A-1 to obtain the compound Z-A-17 in a yield of 75.3%.
  • the compounds ZA-18, ZA-20, ZA-21, and ZA-22 are prepared from ZA-1-e by the method of the compound ZA-17, except that the 5-chlorothiazol-2-amine in the step 1 is respectively Switch to 3-methyl-1,2,4-thiadiazol-5-amine, isoxazol-3-amine, pyrimidin-2-amine, 5-fluoropyridin-2-amine.
  • Compound ZA-19 was prepared from ZA-1-e by the method of Compound ZA-1 except that ZA-2-d was replaced with N-(2,4-dimethoxybenzyl) in Step 5. Thiazol-2-amine.
  • Step 1 To a solution of the compound ZB-1-a (0.94 g, 3.06 mmol) and the compound ZB-1-b (0.5 g, 2.7 mmol) in 1,4-dioxane was added Pd(dppf)Cl 2 ( 0.186 g, 0.3 mmol), cesium carbonate (1 g, 5.4 mmol).
  • reaction mixture was stirred at 95 °C 5h, the reaction solution was cooled to room temperature and poured into 50ml of water and extracted with DCM (50mlx3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and Combi- flash column chromatography to give 400mg white solid ZB-1-c, ESI- MS: 301 (M + H) +.
  • Step 2 To a solution of the compound ZB-1-c (0.38 g, 1.27 mmol) in 20 ml of MeOH, EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. The reaction solution was filtered, and concentrated to give 300 mg of Compound ZB-1.
  • Step 1 In a three-necked flask, the compound ZB-3-a (10 g, 41.67 mmol) was dissolved in anhydrous THF (200 mL), and the reaction mixture was cooled to -78 ° C, and LDA was slowly added dropwise under N 2 (2.5 M, 18 mL, 45.84 mmol). After 1 h, 1,1,2-trichloro-1,2,2-trifluoroethane (8.5 g, 45.84 mmol) was slowly added dropwise. The reaction was held at -78 ° C for five h and the reaction starting material was monitored to disappear. The reaction was quenched with 50 mL EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • Step 3 Dissolve ammonium chloride (2.65 g, 50 mmol) in water (80 mL), add iron powder (4.2 g, 75 mmol), heat the system for 30 minutes, then slowly add the compound ZB-3-c (8 g, 25mmol). The reaction was stirred at reflux for 16 h. The system was filtered, and the filtrate was evaporated to ethyl acetate (3 ⁇
  • Step 4 The compound Z-B-3-d (4 g, 12.5 mmol) was dissolved in methanol (60 mL), and Pd/C (200 mg) was added and hydrogen was passed. The reaction was stirred at room temperature for 16 h, and the reaction mixture was evaporated, and filtered, and then filtered and evaporated to dryness to give a white solid, Z-B-3-e (1.9 g, yield 73%).
  • Step 5 Compound Z-B-3-e (1.9 g, 9 mmol) was dissolved in concentrated hydrochloric acid (1OmL), cooled to 0 <0>C, and then an aqueous solution of sodium nitrite (0.76 g, 11 mmol) was slowly added. The reaction was stirred at 0 ° C for 1 h, then 3 mL of a solution of sodium chloride (3.4 g, 18 mmol) in hydrochloric acid was slowly added dropwise, and the mixture was stirred at 0 ° C for 1 h. The reaction mixture was filtered, and the solid was evaporated.
  • Step 1 20 ml of an aqueous solution of sodium nitrite (1.12 g, 16.27 mmol) was added to a solution of compound Z-B-5-a (2.0 g, 15.49 mmol) in HCl (6M, 50 ml). After the reaction mixture was stirred at 0 ° C for 30 minutes, a solution of tin chloride (6.43 g, 30.98 mmol) in HCl (6M, 75 ml) was added dropwise at 0 °C. After completion of the dropwise addition, the reaction mixture was stirred at 0 ° C for 1 hr, and the obtained solid was washed with EA and evaporated in vacuo.
  • Step 2 To a solution of the compound ZB-5-b (2.2 g, 11.17 mmol) and isobutyraldehyde (886 mg, 12.28 mmol) in chloroform (100 ml) was added TFA (6.37 g, 55.83 mmol). The mixture was reacted overnight at 55 °C. The reaction was cooled to 0 ° C, sodium borohydride (633 mg, 16.75 mmol) was added, and the mixture was reacted at 0 ° C for 2 h. The pH of the reaction mixture was adjusted to 8 with aqueous ammonia, extracted with DCM, washed with brine, dried and concentrated. The crude product was purified by Combi-flash column chromatography to yieldd of the oil, ZB-5 (180 mg). ESI-MS: 200 (M+H) + .
  • the preparation method is the same as the preparation of the compound ZB-5 except that the ZB-5-a in the step 1 is replaced with 3,4-difluorobenzylamine.
  • Step 1 To a solution of the compound ZB-7-a (0.5 g, 2.16 mmol) in THF (10 ml) The mixture was quenched with EtOAc (EtOAc) (EtOAc) The organic phase was washed with EtOAc (20 mL). (M+H) + .
  • Step 2 To a solution of the compound ZB-7-b (220 mg, 1.09 mmol) in EtOAc (5 mL) EtOAc. The potassium oxide solution was adjusted to a pH of 7-8, extracted with EA (3 ⁇ 20 ml), and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by Combi-flash column chromatography. oil ZB-7 (yield 68.6%), ESI-MS: 204.1 (M + H) +.
  • Step 1 To a solution of compound ZB-8-a (0.2 g, 1.24 mmol) in water (7 ml), hydrochloric acid (37%, 0.5 ml), 2,2,2-trichloroethane-1,1-diol (0.22 g, 1.34 mmol), hydroxylamine hydrochloride (0.26 g, 3.72 mmol) and sodium sulfate (1.4 g). The reaction mixture was stirred at 110 <0>C for 1 h, cooled, filtered and filtered and washed with water. ESI-MS: 233 (M+H) + .
  • Step 2 1 ml of concentrated sulfuric acid was added to the compound ZB-8-b (50 mg, 0.22 mmol), and the mixture was stirred at 60 ° C for 15 minutes and then at 80 ° C for 15 minutes. The reaction mixture was poured into ice water and extracted with EtOAc. EtOAc (EtOAc m. , ESI-MS: 215.0 (M+H) + .
  • Steps 3 to 4 The compound ZB-8-c was used as a starting material, and the compound ZB-7 was obtained by the method of the compound ZB-7 to give a blue solid ZB-8, ESI-MS: 188.1 (M+H) + .
  • Step 1 A solution of compound ZB-9-a (1 g, 7.52 mmol), 2-bromopropane (2.77 g, 22.56 mmol) and potassium carbonate (3.11 g, 22.56 mmol) in DMF (10 ml) After adding 20 ml of water, EtOAc (2 ⁇ 20 mL) ZB-9-b, yield 43%, ESI-MS: 176.1 (M + H) +.
  • Step 2 The compound ZB-9-b was used as the starting material, and the compound ZB-2 was obtained by the method of the compound ZB-2 to give the compound ZB-9 as a yellow oil, ESI-MS: 178.1 (M+H) + .
  • the preparation method is the same as the preparation of the compound ZA-4 except that the ZB-4-a in the step 1 is replaced with 1-(3,4-dichlorophenyl)phosphonium hydrochloride.
  • ESI-MS 216.1 (M+H) + .
  • Step 1 A mixture of phosphorus oxychloride (1.55 g, 10.11 mmol) and 3 ml of DMF was cooled under ice-cooling, and a solution of compound ZB-7-b (1.01 g, 5.02 mmol) in 10 ml of DMF. The reaction mixture was poured into ice water, and the mixture was adjusted to pH 10 with a potassium hydroxide solution, filtered, washed with water and dried to give 810 mg of white solid ZB-11-a.
  • ESI-MS 230.1 (M+H) + .
  • Step 2 A mixture of the compound ZB-11-a (770 mg, 3.36 mmol) and 20 ml of DMF was cooled under ice-cooling, and LiAlH 4 (300 mg, 7.91 mmol) was added portionwise, added to 70 ° C, stirred for 2 h, and cooled to room temperature. Add 0.5 ml of water, 0.5 ml of 15% sodium hydroxide solution, and filter, the filtrate is washed with water, EA (2x20 ml), the organic phase is dried over anhydrous sodium sulfate 60.9%.
  • Step 1 To a solution of the compound ZB-8-c (500 mg, 2.33 mmol) in DMF (10 mL) 1-(Bromomethyl)-4-methoxybenzene (558 mg, 2.79 mmol) was added. The reaction mixture was stirred at 0<0>C for 2 h, poured over EtOAc EtOAc EtOAc (EtOAcjjjjjj , ESI-MS: 336 (M+H) + .
  • Step 2 To a solution of compound ZB-13-a (530 mg, 1.58 mmol) in hexanes (25 ml) was added potassium hydroxide (531 mg, 9.49 mmol), hydrazine hydrate (13.3 g, 265.8 mmol). The mixture was stirred at 70 ° C for 1 h, poured into water, extracted with EtOAc (2 ⁇ 50 ml), dried over anhydrous sodium sulfate, and evaporated to give a yellow solid solid, ZB-13-b, yield 98.4%, ESI-MS: 322 (M+H) + .
  • Step 3 To a solution of the compound ZB-13-b (200 mg, 0.62 mmol) in DMF (10 ml), sodium hydride (100 mg, 2.49 mmol), and the mixture was stirred at 0 ° C for 30 minutes, and potassium iodide was added dropwise. 264 mg, 1.86 mmol), stirred at 0<0>C for 4 h, poured into ice water, EtOAc (EtOAc (EtOAc) Yield 55.3%, ESI-MS: 350 (M+H) + .
  • Step 4 The compound ZB-13-c (100 mg, 0.29 mmol) in trifluoroacetic acid (2.5 ml) was subjected to microwave reaction at 150 ° C for 30 minutes, concentrated under reduced pressure, and saturated sodium hydrogen carbonate solution and EA (2 x 50 ml) Drying over anhydrous sodium sulfate and concentrating to give 60 mg of compound ZB-13, without further purification, ESI-MS: 228 (MH) - .
  • Step 1 An aqueous solution (1.3 ml) of sodium nitrite (0.56 g, 8.13 mmol) was added to a solution of compound Z-B-14-a (1 g, 8.06 mmol) in acetic acid (8 ml). The reaction mixture was stirred at 0 ° C for 1 h then ni. The reaction mixture was stirred at room temperature for 16 h, then EtOAc EtOAc m m m m m m -b, ESI-MS: 221.9 (MH)-.
  • Step 2 To Compound ZB-14-b (900mg, 4mmol) in methanol (10ml) was added Pd / C (100mg), under H 2 atmosphere at room temperature was stirred for 4h, the reaction mixture was filtered, the filtrate was concentrated to give 600mg as a yellow solid ZB-14-c, ESI-MS: 192.0 (MH)-.
  • Step 3 To a solution of compound ZB-14-c (230 mg, 1.19 mmol) in DMF (2 ml) washed with sodium solution, dried over anhydrous sodium sulfate, concentrated and purified by Combi-flash column chromatography to give 20mg brown solid ZB-14, ESI-MS: 218.0 (MH) -.
  • Step 1 A mixture of the compound ZB-8-c (1.568 g, 7.258 mmol), potassium hydroxide (2.439 g, 43.551 mmol), hydrazine hydrate (5 ml) and 15 ml of ethylene glycol was stirred at 70 ° C for 2 h and cooled. Add water, adjust the pH to 7 with 10% hydrochloric acid solution, extract with EA, wash the organic phase with brine, dry over anhydrous sodium sulfate, and concentrate, and then purified by Combi-flash column chromatography to obtain 700 mg of yellow solid ZB-15- a, yield 53%, ESI-MS: 200.0 (MH)-.
  • Step 2 Under N 2 atmosphere, Compound ZB-15-a (467mg, 2.3mmol), di-tert-butyl ester (1.28g, 5.865mmol), sodium bicarbonate (780mg, 9.285mmol) and THF (20ml ) was stirred at room temperature for 2 days, concentrated and purified by Combi-flash column chromatography to give 420mg pink solid ZB-15-b, a yield of 56.1%, ESI-MS: 202.1 (M-100) +.
  • Step 3 A mixture of the compound ZB-15-b (290 mg, 0.96 mmol), 15 ml of DMF and sodium hydride (73 mg, 60%, 1.825 mmol) was stirred at room temperature for 1 h and dibromoethane (240 mg, 1.278 mmol) of DMF was added. The solution (5 ml) was stirred at room temperature for 1 h, then sodium hydride (73 mg, 60%, 1. After cooling to 0 ° C, it was quenched with EtOAc EtOAc (EtOAc) (EtOAc) -c, yield 20.6%, ESI-MS: 228 (M-100) +.
  • EtOAc EtOAc EtOAc
  • Step 4 A mixture of the compound ZB-15-c (65 mg, 0.198 mmol), 4 ml of methanol and hydrochloric acid (1 ml, 4N, 4 mmol) was stirred at room temperature overnight and concentrated to give 43 mg of white solid ZB-15, yield 95.2%.
  • Steps 1 to 2 The compound ZB-16-a was used as a starting material, and the compound ZB-16-c, ESI-MS: 232.0 (M+H) + was obtained .
  • Step 3 A mixture of the compound ZB-16-c (2 g, 8.658 mmol) and hydrazine hydrate (20 ml) was stirred at 135 ° C for 3 h, cooled in an ice bath, poured into ice water, and adjusted to pH with a 6 mol/L hydrochloric acid solution. The resulting solid was filtered, washed with water and dried in vacuo to give compound ZB-16-d.
  • Step 4 After adding TBEDA (427 mg, 3.68 mmol) to a solution of the compound ZB-16-d (200 mg, 0.92 mmol) in THF, stirring, and then adding n-BuLi (236 mg, 3.68 mmol), the reaction mixture The mixture was stirred at -78 °C for 1 h, EtOAc (EtOAc (EtOAc) (EtOAc) Purification by flash column chromatography gave 100 mg of compound ZB-16 (yield: 44.24%). ESI-MS: 244 (MH) - .
  • Step 1 Potassium tert-butoxide (6.96 g) was added to a mixture of compound ZB-17-a (6 g, 31.089 mmol), methyl chloroacetate (4.7 g, 49.743 mmol) and THF (40 ml). , 62.2 mmol) THF (40 ml), EtOAc EtOAc (EtOAc) MS: 265 (M+H) + .
  • Step 2 To a solution of the compound ZB-17-b (3.21 g, 12.1 mmol) in 20 ml of EtOAc, EtOAc (4 g, 72.7 mmol). The organic phase was dried over anhydrous sodium sulfate, and concentrated to give 400mg compound ZB-17-c, yield 16%, ESI-MS: 203 (M + H) +.
  • Steps 3 to 5 The compound ZB-17-c is used as a raw material, and is prepared by the method of the steps 2 to 4 in the compound ZB-15 except that the dibromoethane in the step 3 is replaced with methyl iodide to obtain a white solid ZB. -17, ESI-MS: 229 (MH) - .
  • Steps 1 to 2 The compound ZB-18-a was used as a starting material, and was obtained by the procedure of Steps 1 to 2 of the compound ZB-8 to give a red solid ZB-18-c, ESI-MS: 164 (MH) - .
  • Step 3-6 The compound ZB-18-c as a raw material, preparation of a compound ZB-15 in steps 1 to 4 with reference to give a yellow oil ZB-18, ESI-MS: 176 (MH) -.
  • the compound 3-chloro-4-fluoroaniline is used as a raw material, and is prepared by referring to the step of the compound ZB-18, except that the reaction condition of the step 4 is changed to 60 ° C and stirred overnight, and the step 5 is replaced with methyl iodide, and the reaction conditions are changed. Stir at room temperature overnight.
  • Step 1 A mixture of the compound ZB-19-a (800 mg, 3.6 mol), Pd/C (800 mg, 10% wt) and ethanol (10 ml) was stirred at room temperature for 16 h, filtered and concentrated to give 650 mg of compound. ZB-19-b, yield 94%.
  • Step 2 Compound ZB-19-b (0.1 g, 0.52 mmol) and 2-(ethoxymethylene)malononitrile (1.04 mol, 0.12 g) in isopropanol (2 ml) at 80 ° C was stirred for 16 h, the reaction solution was concentrated, the residue was purified to give compound ZB-19, ESI-MS: 203 (M + H) +.
  • Step 1 A mixture of the compound ZB-20-a (1 g, 5.88 mmol) and chlorosulfoxide (5 ml) was reacted at 80 ° C for 3 h, cooled to room temperature and concentrated to give a residue. It was treated with aqueous ammonia at 0 ° C, stirred at room temperature overnight, and concentrated. The residue was suspended in water, filtered, the filter cake was washed with water and dried to yield 0.72g white solid ZB-20-b, it was used directly in the next step, ESI-MS: 170 (M + H) +.
  • Step 2 A mixture of the compound ZB-20-b (3 g, 17.8 mmol) and chlorosulfoxide (10 ml) was reacted at 70 ° C for 6 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The organic layer was washed with EtOAc (EtOAc m.
  • Step 3 The compound ZB-20-c (2.64 g, 17.51 mmol) and hydrazine hydrate (3 g, 60 mmol) in n-butanol (15 ml) was refluxed for 4h, cooled to room temperature and concentrated under reduced pressure. ZB-20-d, used directly in the next step, ESI-MS: 164 (M+H) + .
  • Step 4 A mixture of the compound ZB-20-d (3.15 g, 19.32 mmol) and isobenzofuran-1,3-dione (5.99 g, 40.51 mmol) was reacted at 170 ° C for 30 minutes to cool the reaction mixture. EA was added prior to rt and the resulting solid was filtered to give 4.8g yellow solid ZB-20-e, ESI- MS: 294.1 (M + H) +.
  • Step 5 The compound ZB-20-e (1 g, 3.4 mmol), iodomethane (0.49 g, 3.44 mmol), potassium carbonate (0.95 g, 6.88 mmol) in DMF was reacted at 60 ° C for 8 h, cooled and poured into water. The resulting solid was filtered to give 0.6g yellow solid ZB-20-f, yield 57%, ESI-MS: 308.1 (M + H) +.
  • Step 6 Add boron tribromide (9 ml, 1 M, 8.78 mmol) dropwise to a solution of compound ZB-20-f (0.54 g, 1.76 mmol) in DCM. water, DCM, the organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to give 2.5g yellow solid ZB-20, ESI-MS: 294.1 (M + H) +.
  • Step 2 Compound ZB-21-b (100 mg, 0.32 mmol), dimethylamine (0.32 ml, 0.64 mmol), LiHMDS (0.5 ml, 0.5 mmol), Pd 2 (dba) 3 (15 mg, 0.016 mmol) , a mixture of RuPhos (30 mg, 0.064 mmol) and THF (5 ml) was reacted in an argon atmosphere at 65 ° C for 18 h, 20 ml of water was added, EA was extracted (2 ⁇ 20 ml), and the combined organic phases were dried over anhydrous sodium sulfate. column chromatography to give 50mg yellow oil ZB-21-c, a yield of 56.8%, ESI-MS: 277.2 (M + H) +.
  • Step 3 To a solution of compound ZB-21-c (1.95 g, 7.06 mmol) in EtOAc (EtOAc) The filtrate was concentrated to give a white solid 1.43g ZB-21, a yield of 95.3%, ESI-MS: 177 (M + H) +.
  • Step 1 A solution of borane in THF (42.46 ml) was slowly added to a solution of compound Z-B-22-a (5 g, 21.23 mmol) in THF (40 ml). The reaction mixture was stirred at room temperature overnight, and the mixture was evaporated. mjjjjjjjjjj
  • Step 2 To a solution of the compound ZB-22-b (1 g, 4.5 mmol) and triethylamine (2.28 g, 22.6 mmol) in DCM (20 ml), methanesulfonyl chloride (1.55 g, 13.5 mmol) The reaction mixture was stirred at room temperature for 2 h, EtOAc EtOAc EtOAcjjjjjjjjjjj . The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc.
  • Step 3 To a solution of the compound ZB-22-c (760 mg, 2.46 mmol) in 20 mL of DCM, EtOAc (EtOAc, EtOAc, EtOAc. The reaction mixture was stirred at room temperature overnight, poured into ice water, extracted with EtOAc, EtOAc EtOAc.
  • Step 4 To a solution of aluminum trichloride (1.15 g) in 20 mL of EtOAc (EtOAc m. The combined organic phases were purified by Combi-flash column chromatography eluting elut
  • Step 5 To a solution of the compound ZB-22-e (20 mg, 0.083 mmol) in acetic acid (2 ml) was added sodium borohydride (6 mg, 0.166 mmol), and the mixture was stirred at room temperature for 30 minutes, poured into water, and adjusted to pH with aqueous ammonia to 8, EA and extracted, concentrated to give 40mg oil ZB-22-f, yield 56%, ESI-MS: 246 (M + H) +.
  • Step 6 Compound ZB-22-f (180 mg, 0.73 mmol), ZB-22-g (304 mg, 1.1 mmol), Pd(dppf)Cl 2 (16 mg, 0.022 mmol) and sodium carbonate (155 mg) , 1.46 mmol) of dioxane (5 ml) and water (1 ml) were reacted at 80 ° C for 6 h, the reaction mixture was poured into water, extracted with DCM, concentrated, and the crude product was purified by Combi-flash column chromatography was ZB-22, a yield of 64.64%, ESI-MS: 318.1 (M + H) +.
  • Step 1 To a solution of the compound ZB-23-a (2 g, 0.0169 mol) in DMF was added iodine (8.57 g, 0.0338 mmol), potassium hydroxide (3.69 g, 0.0659 mmol). The reaction mixture was reacted at room temperature for 3 h, then quenched with EtOAc EtOAc EtOAc (EtOAc) H) + .
  • Step 2 Compound ZB-23-b (100 mg, 0.41 mmol), compound ZB-22-g (114 mg, 0.41 mmol), tetratriphenylphosphine palladium (47 mg, 0.041 mmol) and sodium carbonate (43 mg, 0.41 mmol)
  • the mixture was reacted in a microwave at 120 ° C for 30 minutes, extracted with EtOAc, washed with EtOAc EtOAc EtOAc EtOAc
  • Step 1 At -78 ° C, n-BuLi (4 ml, 10 mmol) was added dropwise to a solution of compound ZB-24-a (1.04 g, 5 mmol) in THF. The reaction mixture was stirred at -78 ° C for 0.5 h, then DMF was added. (1.46 g, 20 mmol), EtOAc (EtOAc) m. The combined organic phases were washed with brine, dried over anhydrous sodium sulfatesssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss
  • Step 2 To a solution of the compound ZB-24-b (335 mg, 2.13 mmol) in MeOH (10 mL) , extracted with EA (3 x 20 mL), a colorless over sodium sulfate, concentrated and purified by Combi-flash column chromatography to give 210mg yellow oil ZB-24, a yield of 62.1%, ESI-MS: 160 (M + H) +.
  • Step 1 To a solution of the compound ZB-25-a (11 g, 54.7 mmol) and Compound ZB-25-b (10.23 g, 821. The mixture was washed with aq. EtOAc (EtOAc m.
  • Step 2 To a solution of the compound ZB-25-c (2.89 g, 10 mmol) in EtOAc (50 mL), EtOAc (EtOAc) The solution was quenched and concentrated. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m
  • Steps 3 to 4 The compound ZB-25-d was used as a starting material, and was obtained by the procedure of Steps 1 to 2 in the compound ZB-24 to give white solid ZB-25, ESI-MS: 165 (M+H) + .
  • Step 1 To a solution of compound ZB-14-c (500 mg, 2.59 mmol), TEBAC (590 mg, 2.59 mmol) and sodium bicarbonate (870 mg, 10.36 mmol) in DCM (30 mL) (351mg, 3.11mmol), the reaction mixture was stirred at 0 ° C for 2 h, then EtOAc (2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Combi-flash column chromatography purified 400 mg of brown solid ZB-26-b, yield 66%, ESI-MS: 232 (MH)-.
  • Step 2 To a solution of compound Z-B-26-b (250 mg, 1.07 mmol) in THF (5 ml) The reaction mixture was stirred with EtOAc EtOAc EtOAc m.
  • the preparation method of the compound ZB-27 to ZB-29 is the same as the preparation of the compound ZB-2, except that the ZB-2-a in the step is replaced with 5,6-dichloro-1H-indole, 6-chloro- 1H-indole and 5-(trifluoromethyl)-1H-indole.
  • Step 1 ZB-38-a (4.6 g, 0.022 mol) was dissolved in dichloromethane (500 mL) and triethylamine (5.7mL) and Boc anhydride (5.7 g, 0.026 mol). The reaction was stirred at room temperature for 2 h. Add 50 mL of water, extract with methylene chloride (3 ⁇ 50 mL), dry with EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , yield 92%). LC-MS: 256.0 (M- 55) +, 96.5% purity.
  • Step 2 The compound (5g, 16mmol) ZB-38 -b was dissolved in methanol (50mL), was added Pd (dppf) 2 Cl 2 ( 0.6g, 0.8mmol), triethylamine (4.1mL, 32mmol), 0.6 Stir at 100 ° C for 18 h under MPa carbon monoxide pressure. The mixture was dried with EtOAc (EtOAc:EtOAc:EtOAc) LC-MS: 236.1 (M-55) + , 100% purity.
  • Step 1 Compound ZB-38-a (8.1 g, 26 mmol) was dissolved in acetonitrile (100 mL). EtOAc (13.0 g, 130 mmol), triethylamine (8.0 g, 78 mmol), triphenyl Phosphorus (0.69 g, 2.6 mmol). After the reaction system was replaced with nitrogen three times, palladium acetate (0.66 g, 2.6 mmol) was obtained. The mixture was heated to 95 ° C under nitrogen and stirred for 18 h. After cooling, it was suction filtered, and the filtrate was evaporated to dryness eluted with EtOAc (EtOAc) ESI-MS: 332.1 (M+H) + .
  • Step 3 The crude ZB-39-b (5.80g) was dissolved in DCM (50mL) was added (BOC) 2 O (5.5g, 0.025mol), triethylamine (4.3g, 0.042mol). The mixture was stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 1 To a solution of methanol (6.3 mg, 0.5 mmol) in THF (7 mL), EtOAc (EtOAc,EtOAc. A solution of 6 (150 mg, 0.33 mmol) in THF (1 mL) End of the reaction, warm to ambient temperature, the reaction mixture was poured into water and extracted with ethyl acetate, dried organic phase was separated, and concentrated under reduced pressure and purification of the compound Z-90-a (80mg) , ESI-MS: 457 (M + H) +.
  • Step 2 Compound ZB-43, ESI-MS: 308 (M+H) + was obtained from compound Z-90-a.
  • the compounds Z-2 to Z-4 were prepared in the same manner as in Example 1, except that the compound Z-1-a was replaced with 5-chloroporphyrin, 5-methoxyporphyrin and 5-methyloxime, respectively. Porphyrin.
  • the compound Z-5 was prepared in the same manner as in Example 1, except that the compound Z-1-a and the compound Z-A-1 were replaced with 5-chloroporphyrin and the compound Z-A-12, respectively.
  • Step 1 Preparation Example 1 of the reference embodiment, a yellow oil Z-6-a, yield 42.3%, ESI-MS: 608 (M + H) +.
  • Step 2 To a solution of the compound Z-6-a (120 mg, 0.2 mmol) in EtOAc (EtOAc) Z-6, yield 4.6%, ESI-MS: 508 (M+H) + .
  • Step 1 Compound ZB-2 (83 mg, 0.44 mmol), compound ZA-1 (219 mg, 0.44 mmol), potassium carbonate (122 mg, 0.68 mmol), sodium iodide (7 mg, 0.044 mmol) and acetonitrile (3 ml) The mixture was subjected to a microwave reaction at 120 ° C for 15 minutes, filtered, washed with DCM, and the filtrate was concentrated and purified by Combi-flash column chromatography to yield 60 mg of compound Z-7-a.
  • Step 2 A mixture of the compound Z-7-a (60 mg, 0.093 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 2 h, diluted with 20 ml of toluene and concentrated and purified by HPLC to yield 12.5 mg of a yellow solid.
  • the compound Z-100 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-15, and the compound Z-A-1 was replaced with the compound Z-A-10, and the reaction conditions were changed to 80 ° C and stirred for 1 hour.
  • the compound Z-106 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-17, and the compound Z-A-1 was replaced with the compound Z-A-11, and the reaction conditions were changed to 80 ° C and stirred for 1 h.
  • the compound Z-107 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-17, and the compound Z-A-1 was replaced with the compound Z-A-10, and the reaction conditions were changed to 80 ° C and stirred for 1 hour.
  • the compound Z-108 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-13, and the compound Z-A-1 was replaced with the compound Z-A-19, and the reaction conditions were changed to 90 ° C and stirred for 3 hours.
  • the compound Z-112 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-17, and the compound Z-A-1 was replaced with the compound Z-A-19, and the reaction conditions were changed to 90 ° C and stirred for 3 hours.
  • the compound Z-115 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-13, and the compound Z-A-1 was replaced with the compound Z-A-10, and the reaction conditions were changed to 80 ° C and stirred for 3 hours.
  • the compound Z-118 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-15, and the compound Z-A-1 was replaced with the compound Z-A-19, and the reaction was changed to 90 ° C for 1 h.
  • the compound Z-124 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-16, and the compound Z-A-1 was replaced with the compound Z-A-10, and the reaction conditions were changed to 80 ° C and stirred for 3 hours.
  • the compound Z-125 was prepared in the same manner as in Example 7, except that the compound Z-B-2 in the step 1 was replaced with the compound Z-B-36, and the compound Z-A-1 was replaced with the compound Z-A-10, and the reaction conditions were changed to 80 ° C and stirred for 3 hours.
  • Compounds Z-12 to Z-17 can be prepared by the method of Example 11, except that:
  • Step 1 Mix a mixture of 5-chloroisoindoline hydrochloride (66 mg, 0.347 mmol), compound ZA-4 (150 mg, 0.279 mmol), potassium carbonate (120 mg, 0.868 mmol) and 8 ml of acetonitrile at room temperature for 5 h , filtered, the filter cake was washed with EA, and the filtrate was concentrated and the crude product was purified by Combi-flash column chromatography to give 113mg white solid Z-18-a, ESI- MS: 609.1 (M + H) +.
  • Step 2 The compound Z-18-a was used as a starting material, which was obtained by the procedure of Step 2 of Example 7 to give white solid, Z-18, ESI-MS: 459 (M+H) + .
  • the compound Z-B-2 in the step 1 of Example 7 was replaced with the compound Z-B-30, and the compound Z-A-1 was replaced with the compound Z-A-12.
  • the compound Z-B-2 in the step 1 of Example 7 was replaced with the compound Z-B-10, and the compound Z-A-1 was replaced with the compound Z-A-11.
  • Step 1 A mixture of compound ZA-1 (878 mg, 1.71 mmol), EtOAc (EtOAc m. ESI-MS: 340 (MH)-.
  • Step 1 Preparation of 5-Chloro-1H-indole as reference material
  • Compound ZB-2 gave Compound Z-42-a, ESI-MS: 154 (M+H) + .
  • Step 2 To a solution of the compound ZA-5 (134 mg, 0.87 mmol) in acetonitrile was added Z-42-a (300 mg, 0.87 mmol) and potassium carbonate (240 mg, 1.74 mmol), and the reaction mixture was reacted at 100 ° C for 1 h, filtered and concentrated. The filtrate was prepared by Prep-HPLC to give 3.5mg as a yellow solid Z-42, ESI-MS: 417 (M + H) +.
  • Step 1 The compound ZB-12 and ZA-1 were used as a starting material, which was obtained by the method of Example 1 to give Compound Z-43-a, yield 43.4%, ESI-MS: 575 (M+H) + .
  • Step 2 To a solution of the compound Z-43-a (120 mg, 0.23 mmol) in EtOAc (EtOAc) Z-43, ESI-MS: 491 (M+H) + .
  • the compound Z-45 to Z-49 was prepared in the same manner as in Example 44 except that the compound ZB-8-c in the step was replaced with the compound ZB-10, 5-chloro-3-methyl-1H-carbazole, respectively.
  • the compound Z-99 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-15, and the compound Z-39-a was replaced with the compound Z-A-17.
  • the compound Z-102 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-42, and the reaction conditions were changed to 90 ° C and stirred for 8 hours.
  • the compound Z-109 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-17, and Z-39-a was replaced with Z-A-18.
  • the compound Z-110 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-17, and Z-39-a was replaced with Z-A-17.
  • the compound Z-111 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with a compound.
  • Z-B-13, Z-39-a is replaced by Z-A-17.
  • the compound Z-113 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-13, and Z-39-a was replaced with Z-A-18.
  • the compound Z-114 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-17, and Z-39-a was replaced with Z-A-20.
  • the compound Z-116 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-15, and Z-39-a was replaced with Z-A-18.
  • the compound Z-117 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-13, and Z-39-a was replaced with Z-A-20.
  • the compound Z-119 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-15, and Z-39-a was replaced with Z-A-20.
  • the compound Z-120 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-13, and Z-39-a was replaced with Z-A-21.
  • the compound Z-121 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-17, and Z-39-a was replaced with Z-A-21.
  • the compound Z-123 was prepared in the same manner as in Example 44 except that the compound Z-B-8-c in the step was replaced with the compound Z-B-15, and the Z-39-a was changed to Z-A-22, and the reaction conditions were changed to 60 ° C for 3 h.
  • Step 1 A mixture of compound ZB-20 (100 mg, 0.34 mmol), Compound ZA-7 (471 mg, 1.02 mmol), EtOAc (EtOAc (EtOAc) The organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated.
  • Step 2 compound Z-60-a starting material for the method of the embodiment with reference to the procedure of Example 7, to give a white solid Z-60, ESI-MS: 455.0 (M + H) +.
  • the compound Z-93 When the compound Z-93 is prepared, the compound ZB-20 in the step 1 of the embodiment 60 is replaced with the compound ZB-41, the compound ZA-7 is replaced with the compound ZA-2, and the trifluoroacetic acid is replaced with the hydrazine hydrate in the step 2, and the reaction conditions are as follows. It becomes reflux for 5 hours.
  • Step 1 compound ZB-21 and ZA-1 as starting material, prepared in Example 44 with reference to the embodiment, to give a yellow oil Z-67-a, ESI- MS: 632.1 (M + H) +.
  • Step 1 A mixture of the compound ZB-23 (100 mg, 0.373 mmol), compound ZA-7 (345 mg, 0.746 mmol), sodium hydride (30 mg, 0.746 mmol) and DMF (10 ml) was stirred at 60 ° C for 30 h. The mixture was poured into water and extracted with EtOAc. EtOAc EtOAc EtOAc. (M+H) + .
  • Step 2 A mixture of compound Z-80-a (165 mg, EtOAc (EtOAc) +H) + .
  • Step 1 To a solution of compound ZB-24 (20 mg, 0.126 mmol) The EA was extracted with EtOAc. EtOAc (EtOAc) ) + .
  • Step 1 Preparation method Refer to the preparation method of the compound Z-39-a.
  • Step 2 A mixture of compound Z-83-a (102 mg, 0.621 mmol), compound ZB-25 (194 mg, 0.621 mmol), potassium tert-butoxide (209 mg, 1.863 mmol) and DMF (10 ml) was stirred at 70 ° C After cooling to room temperature, it was poured into water, EtOAc was evaporated. EtOAcjjjjjjjjjjjjj M+H) + .
  • the compound Z-86 to Z-89 was prepared in the same manner as in Example 44 except that the compound ZB-8-c was replaced with ZB-26, 5-(trifluoromethyl)-1H-indole, 5- Chloro-1H-indole and ZB-7-b, the compound Z-39-a was replaced with ZA-4, ZA-1, ZA-1 and ZA-4, respectively.
  • Z-92 was prepared by the method of Example 83 using the compound Z-83-a and 4-(trifluoromethyl)-2,3-dihydro-1H-indol-1-ol as raw materials, and the reaction conditions were changed. Stir at room temperature for 2 h.
  • Step 1 Prepare the compound 1H-indol-5-alcohol as the starting material, and refer to the step 2 of the compound ZB-22, except that the methanesulfonyl chloride is replaced with t-butyl chloride to obtain the compound Z-94-a, ESI. -MS: 247 (MH) - .
  • Step 2 The compound Z-94-a was used as the starting material, and the compound Z-94-b, ESI-MS: 349 (M+H) + was obtained .
  • Step 3 To a stirred solution of the compound Z-94-b (50 mg, 0.143 mmol) in THF (2 ml). End of the reaction, concentrated under reduced pressure, water was added, extracted with ethyl acetate, washed with brine, dried and concentrated separated organic Xiangde compound Z-94-c (40mg) , ESI-MS: 233 (MH) -.
  • Step 4-5 The compound Z-94-c is used as a raw material, and is prepared by the method of the step 1-2 of the compound Z-7, except that the ZA-1 in the step Z-7 is replaced by ZA-2, and the reaction conditions are changed. into stirred at room temperature 4h, to give a compound Z-94 (120mg), ESI -MS: 424 (MH) -.
  • Step 1 To a stirred solution of the compound furan-2-carboxylic acid (1 g, 8.93 mmol) in 2-fluorocyclohexane-1,3-diene (10 ml) was added EtOAc (1. Methyl), stirred in an ice bath for 1 h. The ice bath was removed, stirred at 75 ° C for 16 h, the reaction was completed, cooled to room temperature, poured into a hydrochloric acid solution (2N, 50 ml), extracted with ethyl acetate, washed with sodium hydrogen carbonate solution, and the organic phase was adjusted to pH 3-4.
  • Step 2 The compound Z-95-a is used as a starting material, and the compound Z-95-b is obtained by the method of the step 1 of the compound Z-B-22.
  • Step 3-4 The compound Z-95-b is used as a raw material, and is prepared by the method of the step 1-2 of the compound Z-7, except that the ZA-1 in the step Z-7 is replaced by ZA-2, and the reaction conditions are changed. to room temperature with stirring 1.5h, the compound Z-95 (2.2mg), ESI -MS: 468 (M + H) +.
  • Compound Z-96 was prepared according to Example 95 using Z-95-b as the starting material, except that Z-A-2 in step 3 was replaced with Z-A-16.
  • Step 1-3 Compound #-97 (4.56 mg), ESI-MS: 451.1 (Comp. M+H) + .
  • Step 1 Nitrogen protection, adding 8-methylquinoline (313 mg, 2.186 mmol), iodobenzene diacetic acid (700 mg, 2.173 mmol), palladium acetate (13 mg, 0.056 mmol), 10 ml acetic acid, 100 ° C to a 100 ml three-necked flask. Stir overnight. Completion of the reaction, cooled to room temperature, purified and concentrated to give compound Z-98-a (350mg) , ESI-MS: 202.1 (M + H) +.
  • Step 2 To a 100 ml three-necked flask was added Z-98-a (350 mg, 1.739 mmol), sodium hydroxide (220 mg, 5.5 mmol), 10 ml of ethanol, 10 ml of water, and stirred at 80 ° C for 2 h. Completion of the reaction, cooled to room temperature, concentrated under reduced pressure, 20ml of water was added, extracted with ethyl acetate, washed with brine, dried and concentrated Xiangde organic compound Z-98-b (240mg) , ESI-MS: 160.1 (M + H) +.
  • Step 3 The compound Z-98-b (80 mg) was used as a starting material, and the compound Z-81 was replaced by the method of the step 1 of the compound Z-81, and the compound Z-98 was replaced with Z-83-a to obtain the compound Z-98 (93.2 mg).
  • ESI-MS 451.1 (M+H) + .
  • Step 1 To a solution of the compound diethyl malonate (3.9 g, 24 mmol), a solution of sodium cyanide (2.4 g, 60 mmol) in THF (150 ml) was stirred at 0 ° C for 30 min and then added 1,2,3 -Trifluoro-4-nitrobenzene (3.5 g, 20 mmol), stirred at rt for 4 h. End of the reaction, poured into ice water, extracted with ethyl acetate, washed with brine, dried and concentrated to give purified compound Z-101-a (7.5g) , ESI-MS: 316.1 (MH) -.
  • Step 2 To a solution of compound Z-101-a (7.5 g, 23.6 mmol) in dimethyl sulfoxide (150 ml) and water (5 ml) was added lithium chloride (2.04 g, 47.3 mmol) and stirred at 150 ° C for 8 h. After completion of the reaction, the mixture was cooled to room temperature, extracted with ethyl acetate, washed with brine, dried and concentrated to afford compound Z-101-b (2 g), ESI-MS: N/A.
  • Step 3 compound Z-101-b as starting material, the compound prepared in Step 2 ZB-17 reference, to give a brown solid Z-101-c, ESI- MS: 168 (MH) -.
  • Step 4 The compound Z-101-c was used as a starting material, which was obtained by the procedure of Step 3 in the compound ZB-15 to give a yellow solid Z-101-d, ESI-MS: 195 (MH) - .
  • Step 5 compound Z-101-d as a raw material, preparation of reference compound Z-44, as a white solid Z-101, ESI-MS: 499 (MH) -.
  • Step 1 Using the compound 4-fluoroindole-2,3-dione as a starting material, the compound Z-103-a, ESI-MS: 150 (MH) -
  • Step 2 The compound Z-103-a was used as the starting material, and the compound ZB-15 was obtained by the procedure of the compound ZB-15, to give the compound Z-103-b, ESI-MS: 176 (MH) - .
  • Step 3 To a solution of the compound Z-103-b (70 mg, 0.395 mmol) of EtOAc (5 mL), chlorosuccinimide (53 mg, 0.395 mmol). End of the reaction, poured into ice water, extracted with ethyl acetate, purified and concentrated to give compound Z-103-c (35mg) , ESI-MS: 210 (MH) -.
  • Step 4 Compound Z-103, ESI-MS: 515 (MH) - was obtained from the compound Z-103-c.
  • Steps 1 to 2 The compound 2-chloro-5-nitropyridine was used as a starting material, and the compound 6B5 of Steps 1 to 2 in the compound ZB-17 was used to obtain a yellow solid Z-104-b, ESI-MS: 167 (MH) ) - .
  • Step 3 Prepare the compound Z-104-b as the starting material, and refer to the method of the step 3 in the compound ZB-13.
  • the reaction conditions are changed to minus 78 ° C to obtain a yellow solid Z-104-c, ESI-MS: 197.1 (M+ H) + .
  • Step 4 The compound Z-104-c was used as the starting material, and the compound Z-44 was obtained by the method of the compound Z-44 to obtain a yellow solid Z-104, ESI-MS: 500 (MH) - .
  • Compound Z-105 was prepared according to Example 101 using Z-101-c as a starting material, except that the 1-bromo-2-chloroethane in Step 4 was changed to methyl iodide.
  • Comparative Compound 1 was the same as Compound Z-B-43 except that the compound Z-A-6 and benzyl alcohol were used as the starting materials, and the reaction conditions in Step 1 were changed to room temperature and stirred for 4 hours.
  • 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 mL? 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.sub.5-5 (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 the combination of inactivation states Reflects the inhibitory or activating effects of the compound (Hille, B., Journal of General Physiology (1977), 69: 497-515).
  • Representative compounds of the invention were tested using a manual patch clamp experiment.
  • the purpose of this study was to test the effect of compounds on the ion channel current on a stable cell line transfected with a particular ion channel using a manual patch clamp method.
  • the stable cell lines CHO-hNav1.7 and HEK-hNav1.5 used were from Genionics and WuXi Apptec (Shanghai), respectively.
  • the manual patch clamp experimental protocol is as follows:
  • the positive control drug and the test compound were first dissolved in 100% DMSO (Sigma-Aldrich, D2650, and stored in a certain concentration (100 nM, 1000 nM) stock solution.
  • DMSO Sigma-Aldrich, D2650
  • the above stock solution was serially diluted with DMSO before the experiment, and then used outside the cell.
  • the solution is further diluted to give the test solution at the desired concentration.
  • the final concentration of DMSO in the extracellular fluid does not exceed 0.30%.
  • This stimulation procedure can also be referred to as a channel state dependent voltage stimulation procedure.
  • the other is a non-inactivation stimulation program that maintains the clamp potential at -120 mV, gives a voltage stimulus to -10 mV, continues for 20 ms to draw sodium current, and finally returns to the clamp potential. That is to say, under the conditions of the stimulation program, all the channels have not experienced the inactivation state, but are directly activated from the resting state.
  • the time interval of the above two voltage stimulation programs is 10s.
  • the inhibitory effect of the compound was calculated by the change in current before and after dosing, and the IC 50 value was fitted by the Hill equation.
  • a compound is state dependent on the channel if it exhibits a multiple of the channel effect under the two different voltage stimuli described above. The results are shown in Table 1, Table 2 and Table 3, respectively.
  • 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.
  • Vehicle control 5% dimethylacetamide (National Medicine), 5% solutol (Sigma) and 90% saline
  • Drugs to be tested compounds Z-47, Z-49, Z-54, Z-56, Z-99, Z-100;
  • 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 h at a dose of 100 mg/kg, respectively, as shown in Table 4.
  • Surgical instruments (scissors, tweezers, scalpels, surgical cotton, sutures, spreaders) have been sterilized prior to surgery.
  • 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.
  • 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.
  • compound Z-47 inhibits cold-stimulated hyperalgesia in a rat model of spinal nerve ligation, ***p ⁇ 0.001.
  • a Dunnett multiple comparison test was added using one-way ANOVA compared to the solvent group.
  • Oral compound Z-47 and positive control 100 mg/kg for 2 h inhibited cold allodynia induced by spinal nerve ligation, respectively.
  • compound Z-54 inhibits cold-stimulated hyperalgesia in a rat model of spinal nerve ligation, ***p ⁇ 0.001.
  • a Dunnett multiple comparison test was added using one-way ANOVA compared to the solvent group.
  • Oral compound Z-54 and positive control 100 mg/kg for 2 h inhibited cold allodynia induced by spinal nerve ligation, respectively.

Abstract

La présente invention concerne un dérivé de benzènesulfonamide substitué bicyclique, et le procédé de préparation et une utilisation pharmaceutique de celui-ci. En particulier, la présente invention concerne le composé de formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère, un solvate ou un promédicament de celui-ci, et le procédé de préparation et une utilisation de celui-ci. Les définitions détaillées de chaque groupe dans la formule (I) sont présentées dans la description et les revendications.
PCT/CN2016/081183 2015-05-05 2016-05-05 Dérivé de benzènesulfonamide substitué bicyclique, et procédé de préparation et utilisation pharmaceutique de celui-ci WO2016177340A1 (fr)

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US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
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