WO2023131333A1 - Benzimidazole compound and medical use thereof - Google Patents

Benzimidazole compound and medical use thereof Download PDF

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WO2023131333A1
WO2023131333A1 PCT/CN2023/071429 CN2023071429W WO2023131333A1 WO 2023131333 A1 WO2023131333 A1 WO 2023131333A1 CN 2023071429 W CN2023071429 W CN 2023071429W WO 2023131333 A1 WO2023131333 A1 WO 2023131333A1
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substituted
alkyl
halogen
hydrogen
cyano
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PCT/CN2023/071429
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French (fr)
Chinese (zh)
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段文虎
耿美玉
张惠斌
谢作权
周金培
王玺渊
方林城
徐淋
张凯旋
刘帅达
丁健
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中国科学院上海药物研究所
中国药科大学
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Priority to CN202380014921.0A priority Critical patent/CN118401531A/en
Publication of WO2023131333A1 publication Critical patent/WO2023131333A1/en

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    • C07F5/02—Boron compounds
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems

Definitions

  • the invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to benzimidazole compounds and their medical applications.
  • ENPP1 outer nucleotide pyrophosphatase/phosphodiesterase I
  • cGAMP cyclic GMP-AMP synthetase
  • 2'3'-cGAMP activates STING, triggers an inflammatory response through the TANK-binding kinase 1 (TBK1)-interferon regulatory factor (IRF3) pathway, and produces type 1 interferon (IFN) and other cytokines.
  • TNK1 TANK-binding kinase 1
  • IRF3 interferon regulatory factor
  • ENPP1 catalyzes the hydrolysis of ATP or GTP to AMP or GMP
  • CD73 dephosphorylates AMP to adenosine
  • excess adenosine turns off innate and adaptive by stimulating G protein-coupled A2A and A2B adenosine receptors Therefore, after inhibiting ENPP1, it can reduce the production of adenosine and enhance the body's anti-tumor immunity.
  • the object of the present invention is to provide a compound with a novel structure or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition.
  • Another object of the present invention is to provide the preparation method of said compound and its pharmaceutically acceptable salt.
  • the last object of the present invention is to provide the use of said compound and its pharmaceutically acceptable salt, especially in the preparation of medicines for preventing and/or treating diseases related to ENPP1 dysfunction.
  • the first aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:
  • X is selected from: N or CR 1 ;
  • Y is selected from: N or CR 2 ;
  • Z is selected from: N or CR 3 ;
  • W is selected from: N or CR4 ;
  • R 1 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl or -OR f ;
  • R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
  • R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
  • R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
  • R 2 and R 3 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
  • L is selected from: C 1 ⁇ C 6 alkylene, -NH-, -NR a C(O)(CH 2 ) n -, -C(O)NR b (CH 2 ) n -;
  • A is selected from: hydrogen, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, C1 - C6 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, Substituted or unsubstituted 4-12 membered heterocyclic group, C 1 ⁇ C 6 alkylene group (substituted or unsubstituted 5-12 membered heteroaryl group); wherein, the substitution refers to 1-4 R n Substitution; each R n is independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g , -NR f C(O)R g ;
  • R t is selected from: -(CH 2 ) n R L' , -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N -(CH 2 ) m R s ;
  • R s is selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclic; wherein, the substitution refers to being substituted by 1-4 RL ;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i or 3-6 membered heterocycloalkane substituted by 0-4 R i base;
  • R j' are each independently selected from: hydrogen, halogen, C 1 ⁇ C 6 alkyl, halogenated C 1 ⁇ C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , 3-6 membered cycloalkyl group substituted by 0-4 R i or 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl or cyano;
  • R m is selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl, C 1 ⁇ C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ⁇ C 6 alkyl substituted 5 -6 membered heteroaryl;
  • R a , R b , R j , R k and R k' are each independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • X is selected from: N or CR 1 ;
  • Y is selected from: N or CR 2 ;
  • Z is selected from: N or CR 3 ;
  • W is selected from: N or CR4 ;
  • R 1 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl or -OR f ;
  • R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
  • R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
  • R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
  • L is selected from: C 1 ⁇ C 6 alkylene, -NH-, -NR a C(O)(CH 2 ) n -, -C(O)NR b (CH 2 ) n -;
  • A is selected from: hydrogen, substituted C5-C12 aryl, substituted 5-12 membered heteroaryl; wherein, the substitution refers to being substituted by 1-4 R n ; each R n is independently selected from: hydrogen, Halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O) NR f R g , -NR f C(O)R g ;
  • R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
  • R s is selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclic; wherein, the substitution refers to being substituted by 1-4 RL ;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i or 3-6 membered heterocycloalkane substituted by 0-4 R i base;
  • R j' are each independently selected from: hydrogen, halogen, C 1 ⁇ C 6 alkyl, halogenated C 1 ⁇ C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , 3-6 membered cycloalkyl group substituted by 0-4 R i or 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl or cyano;
  • R m is selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl, C 1 ⁇ C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ⁇ C 6 alkyl substituted 5 -6 membered heteroaryl;
  • R a , R b , R j , R k and R k' are each independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • each R n is independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • ring B is a saturated or unsaturated 4-6 membered carbocyclic ring or heterocyclic ring (such as furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, cyclohexyl, etc.), p is 0, 1 , 2, 3 or 4; R i and R t are as defined above.
  • R 1 , R 2 , R i and R t are as defined above.
  • R 1 , R 2 , R 3 , R 4 and R t are as above.
  • t is 1 or 2
  • R 1 , R 4 and R t are as defined above.
  • R s is selected from: substituted C5-C6 aryl, substituted 5-6 membered heteroaryl, substituted [5+6] aryl, substituted [5+6] heteroaryl , a substituted 6-7 membered heterocyclic ring or a substituted spirocyclic ring; wherein, the substitution refers to being substituted by 1-4 RL ; the definition of RL is as above.
  • the substituted 6-7 membered heterocycle or substituted spirocycle is a substituted 6-7 membered monocyclic heterocycle or substituted 8-11 membered bicyclic spirocycle, more preferably a substituted 6- 7 membered monocyclic heterocycle or substituted 9-10 membered bicyclic spiro ring, more preferably R u and R v have the same definitions as R L .
  • A is selected from: hydrogen, substituted C5-C6 aryl, substituted 5-6 membered heteroaryl, substituted [5+6] aryl, substituted [5+6] heteroaryl Base;
  • A is selected from the following group of substituted groups: phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazine Base, morpholinyl, piperazinyl, piperidinyl, benzimidazolyl, benzopyrazolyl, indolyl,
  • the substitution refers to substitution by 1-4 R n ; the definition of R n is as above.
  • A is selected from: hydrogen, R 5 and R 6 have the same definitions as R n .
  • R s is selected from: preferably Wherein, the definition of R u , R v and R w is the same as that of R L .
  • R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O) Rf , -CO2Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
  • R2 is selected from : hydrogen, cyano, -ORf , -NRfR g , -C(O) Rf , -CO2Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
  • R f and R g are each independently selected from: hydrogen, 0 to 4 C 1 to C 6 alkyl substituted by Rh, 0 to 4 C 2 to C 6 alkynyl substituted by Rh, 0 to 4 R C 2 -C 6 alkenyl substituted by h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkyl substituted by 0-4 R i ;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl, cyano;
  • R j and R k are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  • R 2 and R 3 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i , preferably 5-6 membered .
  • R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C (O) Rf , -CO2Rf , -C( O)NRfRg, or -NRfC ( O ) Rg ; preferably, R3 and R4 are each independently selected from: hydrogen, halogen, 0 to 4 C 1 to C 6 alkyl groups substituted by Rh, -OR f or -C(O)R f , -CO 2 R f ;
  • R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i , preferably 5-6 members;
  • R f and R g are each independently selected from: hydrogen, 0 to 4 C 1 to C 6 alkyl substituted by Rh, 0 to 4 C 2 to C 6 alkynyl substituted by Rh, 0 to 4 R C 2 -C 6 alkenyl substituted by h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkyl substituted by 0-4 R i ;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl, cyano;
  • R j and R k are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  • L is selected from: -NH-, -NR a C(O)(CH 2 ) n - or -C(O)NR b (CH 2 ) n -;
  • R a and R b are independently is selected from: hydrogen or C 1 -C 6 alkyl, n is 0, 1, 2, 3, 4, 5 or 6.
  • A is selected from: hydrogen, Preferably, A is selected from: hydrogen, Preferably, A is selected from: hydrogen, Preferably, A is selected from:
  • R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
  • R f and R g are each independently selected from: hydrogen, 0 to 4 C 1 to C 6 alkyl substituted by Rh, 0 to 4 C 2 to C 6 alkynyl substituted by Rh, 0 to 4 R C 2 -C 6 alkenyl substituted by h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkyl substituted by 0-4 R i ;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl, cyano;
  • R j and R k are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  • R s is selected from:
  • R s is selected from:
  • R v is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • R w is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • n and m' are independently 0, 1, 2, 3, 4, 5 or 6;
  • R f' and R g' are each independently selected from: hydrogen, 0-4 C 1 -C 6 alkyl substituted by Rh, 0-4 C 2 -C 6 alkynyl substituted by Rh , 0-4 C 2 -C 6 alkenyl substituted by R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6-membered heterocycloalkyl substituted by 0-4 R i ;
  • R j' are each independently selected from: hydrogen, halogen, C 1 ⁇ C 6 alkyl, halogenated C 1 ⁇ C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl, cyano;
  • R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  • the compound has the structure shown in (II):
  • R 1 is hydrogen
  • R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O) NRfRg or -NRfC (O) Rg ;
  • R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
  • R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
  • L is selected from: -NH-, -NR a C (O) (CH 2 ) n - or -C (O) NR b (CH 2 ) n -;
  • A is selected from: hydrogen,
  • R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
  • R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
  • R v is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • R w is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycle substituted by 0-4 R i alkyl;
  • R j' are each independently selected from: hydrogen, halogen, C 1 ⁇ C 6 alkyl, halogenated C 1 ⁇ C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl, cyano;
  • R a , R b , R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  • R 1 is hydrogen
  • R 2 is selected from: hydrogen, cyano, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O ) R g ;
  • R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f or -C(O)R f , -CO 2 R f ;
  • R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
  • L is selected from: -NH-, -NR a C (O) (CH 2 ) n - or -C (O) NR b (CH 2 ) n -;
  • A is selected from: hydrogen,
  • R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
  • R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
  • R v is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • R w is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkane substituted by 0-4 R i base;
  • R j' are each independently selected from: hydrogen, halogen, C 1 ⁇ C 6 alkyl, halogenated C 1 ⁇ C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
  • R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i , a 3-6-membered heterocycloalkyl group substituted by 0-4 R i ;
  • R i is selected from: C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl;
  • R a , R b , R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  • R 1 is hydrogen
  • L is selected from: -NH- or -NHC(O)-.
  • A is selected from: isopropyl, tert-butyl,
  • R 1 is hydrogen or C 1 -C 6 alkyl.
  • R 2 is selected from: hydrogen, halogen, cyano, -CO 2 R f , -C(O)NR f R g ; more preferably, R 2 is selected from: hydrogen, halogen, cyano , -CO 2 C 1 -C 6 alkyl, -C(O)NH 2 .
  • R 2 is selected from: hydrogen, halogen, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -CO 2 C 1 -C 6 alkyl, -C( O)NH 2 ; more preferably, R 2 is selected from: hydrogen, halogen, cyano, -COOCH 3 , -COOCH 2 CH 3 , -OCOCH 3 , -OCOCH 2 CH 3 , OCH 3 , -C(O)NH 2 .
  • R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 ⁇ C 6 alkyl, -OR f , -NR f R g ; more preferably, R 3 is selected from hydrogen, Halogen or C 1 -C 6 alkyl; R 4 is selected from: hydrogen, halogen, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl.
  • R 3 is selected from: hydrogen, halogen, C 1 -C 6 alkyl, -O C 1 -C 6 alkyl.
  • R 4 is selected from: hydrogen, halogen, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl.
  • the compound has the structure shown in formula IV
  • y and q are each independently 0, 1, 2, 3;
  • M is selected from: bond, O or CH2 ;
  • R v is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • R w is selected from: hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
  • R 1 , R 2 , R 3 , R 4 , L and A are as defined above.
  • the compound has the structure shown in formula V
  • R u , R v , R w , R 1 , R 2 , R 3 , R 4 , L and A are as defined above.
  • R v is selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, halogen, cyano, -OC 1 -C 6 alkyl.
  • R w is selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, halogen, cyano, -OC 1 -C 6 alkyl.
  • R t is selected from: -(CH 2 )-R s , -(CH 2 ) 2 -R s , -(CH 2 ) 3 -R s , -(CH 2 )-O-( CH 2 )R s , -(CH 2 ) 2 -O-(CH 2 )R s , -(CH 2 ) 3 -O-(CH 2 )R s , -(CH 2 )-O-(CH 2 ) 2 R s , -(CH 2 ) 2 -O-(CH 2 ) 2 R s , -(CH 2 ) 3 -O-(CH 2 ) 2 R s , R s is defined as above, preferably, R s for
  • R u , R v , R w are as defined above.
  • the prodrug of the compound has the structure shown in formula III or III'
  • E is selected from: O or NH
  • R x and R y are each independently selected from: -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' , C 1 ⁇ C 6 alkyl or halogenated C 1 ⁇ C 6 alkyl; or -ER x and -ER y together with the P atom they are connected to form a saturated or unsaturated 4-6 membered heterocyclic ring substituted by 0 to 4 R m ;
  • R m is selected from: halogen, hydroxyl, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylamino, halogen substituted C 1 ⁇ C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl (such as chlorobenzene), C 1 ⁇ C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ⁇ C 6 Alkyl substituted 5-6 membered heteroaryl.
  • X, Y, Z, W, R 1 , R 2 , R 3 , R 4 , R t , R x , R y , L and A are the groups corresponding to the specific compounds in the examples .
  • the compound is selected from the following compounds:
  • the second aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of one or more compounds as described in the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant or excipient.
  • a compound described in the first aspect or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition described in the second aspect in the preparation of an immune adjuvant or an ENPP1-inhibiting drug .
  • the disease associated with ENPP1 activity is one or more of the diseases associated with inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.
  • the fifth aspect of the present invention provides a method for treating diseases related to ENPP1 activity, the method comprising administering to a subject a therapeutically effective amount of the compound described in the first aspect, or a pharmaceutically acceptable salt or prodrug thereof Medicine or the pharmaceutical composition described in the second aspect.
  • the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.
  • the inventor After extensive and in-depth research, the inventor has designed and developed a compound with novel structure, and the experimental results show that the compound of the present invention has a good inhibitory effect on ENPP1, and can be used for the preparation of therapeutic and inhibitory ENPP1 or related to ENPP1 activity. medicines for diseases.
  • the present invention has been accomplished on this basis.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (i.e., C1-C6 means 1, 2, 3, 4, 5 or 6 carbon atoms).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • alkyl is also intended to include substituted alkyl, that is, one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkenyl denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms (or C2-C8).
  • C2-C6 alkenyl is an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms
  • C3-C6 alkenyl alkenyl groups include, but are not limited to, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • alkenyl includes substituted alkenyl.
  • alkynyl denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms (or C2-C8).
  • C2-C6 alkynyl refers to a straight or branched alkynyl group with 2, 3, 4, 5 or 6 carbon atoms, including but not limited to ethynyl, propynyl or similar groups .
  • the alkynyl group also includes a substituted alkynyl group, and the substituents may be halo, hydroxyl, cyano, nitro, etc.
  • alkylamino refers to an alkyl group linked to the rest of the molecule through an amino group.
  • C 1 -C 6 alkylamino has the formula C 1 -C 6 alkyl-NH-.
  • alkylene by itself or as part of another substituent refers to a divalent radical derived from an alkane, eg -CH2CH2CH2CH2- .
  • Alkyl (or alkylene) groups generally have 1 to 24 carbon atoms, with those groups having 3 or fewer carbon atoms (eg, C 1 -C 3 alkylene) being preferred in the present invention.
  • alkenylene or “alkynylene” refers to an unsaturated form of “alkylene” having double or triple bonds, respectively. Examples of “alkenylene” or “alkynylene” include, but are not limited to: ethenylene, propenylene, wait.
  • C1-C6 alkoxy (C1-C6 alkyl-O-) refers to a straight chain or branched chain or cyclic alkoxy group (such as C3-C6 cycloalkane) having 1 to 6 carbon atoms oxy), representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preference is given to C1-C3 alkoxy.
  • cycloalkyl refers to cyclic alkyl groups including saturated monocyclic or bicyclic (eg, fused bicyclic or spirobicyclic) or polycyclic rings.
  • 3-6 membered cycloalkyl refers to a cyclic alkyl group including 3, 4, 5, or 6 carbon atoms.
  • Representative cycloalkyl groups of the invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • substituted or unsubstituted cycloalkyl groups such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included within the definition of "cycloalkyl”.
  • heterocycloalkyl refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • Heterocycloalkyl groups can be monocyclic, bicyclic or polycyclic ring systems.
  • 3-6 membered heterocycloalkyl refers to a group in which 1 or 2 ring C atoms in a C3-6 cycloalkyl group are replaced by heteroatoms selected from N, O and S, heterocycloalkane
  • radicals include, but are not limited to: pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine , 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3- Pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc.
  • a heterocycloalkyl group can be attached
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S and O, which may be monocyclic or bicyclic, such as bridged ring or spiro ring.
  • the heterocyclic group is preferably a 3-10-membered heterocyclic group, more preferably a 5-8-membered heterocyclic group, more preferably a 4-6-membered heterocyclic group, and more preferably a 5-6-membered heterocyclic group.
  • heterocyclic groups include, but are not limited to: oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl, etc. .
  • the heterocyclic group can be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring (such as forming a [5+5], [6+5] or [6+6] fused ring system, etc. ), wherein the ring attached to the parent structure is a heterocyclyl.
  • aryl refers to an aromatic ring group that does not contain heteroatoms in the ring, and the aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the The rings joined together are aryl rings.
  • aryl that is, C6 aryl or six-membered aryl
  • naphthyl that is, C10 aryl or [6+6] aryl
  • the six-membered aryl is also intended to include six-membered aryl and 5-6 One-membered cycloalkyl and six-membered aryl and 5-6-membered heterocyclic group.
  • [5+6]aryl refers to a fused 6,5 bicyclic ring system.
  • the C5-C12 aryl group is preferably a C6-C12 aryl group, more preferably a C6-C10 aryl group.
  • Examples of aryl include phenyl, naphthyl.
  • Aryl groups can be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group with 1-3 atoms being heteroatoms selected from the group consisting of N, S and O, which may be a single ring or a condensed ring.
  • the heteroaryl group is preferably a 5-6 membered heteroaryl group.
  • heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • [5+6]heteroaryl refers to a fused 6,5 bicyclic ring system, such as benzothienyl, benzofuryl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiazolyl, Thiadiazolyl, benzoxazolyl, etc.
  • Carbocycle or heterocycle in the present invention alone or as part of another group refers to a monocyclic or bicyclic saturated, partially saturated or aromatic carbocycle (for example, cycloalkyl, ring alkenyl, phenyl, etc.), or a monocyclic or bicyclic saturated, partially saturated or aromatic heterocycle (for example, heteroalkyl, heterocyclyl, heteroaryl, etc. as described above), wherein , A 4-6 membered carbocyclic or heterocyclic ring refers to a carbocyclic or heterocyclic ring containing 4-6 ring atoms, preferably a 5-6 membered carbocyclic or heterocyclic ring.
  • carbocyclic or heterocyclic rings include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, Oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuryl, morpholinyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, Pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thiophene group, isoxazolyl, thiazolyl, oxazolyl,
  • amino refers to a -N(R)(R') structure
  • R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
  • R and R' can be the same or different in the dialkylamine moiety.
  • each group in the above-mentioned alkyl, alkoxy, cycloalkyl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, heterocyclyl, carbocyclyl, etc. may be substituted or not replaced.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • the typical substituents mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, carbocycle or heterocycle may be optionally substituted.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1 -C6 ureido group, etc.
  • halo or halogen includes fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to -OH.
  • compound of the present invention or “active ingredient of the present invention” are used interchangeably to refer to the compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
  • the compounds of the present invention are intended to include both E- and Z-geometric isomers.
  • Tautomer refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • salt refers to a salt (including zwitterions, etc.) that is biologically or otherwise (e.g., neither toxic nor deleterious to a subject) acceptable in an efficacy similar to that of the parent compound. Salt). Accordingly, embodiments of the present invention provide pharmaceutically acceptable salts of compounds of the present invention.
  • salt as used herein means any of the following acidic salts formed with inorganic and/or organic acids, and basic salts formed with inorganic and/or organic bases.
  • Salts of compounds of the present invention can be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the present invention with an amount of acid or base (e.g., an equivalent amount of acid or base) in a medium (e.g., such The medium can allow the salt to precipitate therein; or use water as the medium and then freeze-dry.) to obtain the reaction.
  • an amount of acid or base e.g., an equivalent amount of acid or base
  • a medium e.g., such
  • the medium can allow the salt to precipitate therein; or use water as the medium and then freeze-dry.
  • Exemplary acid salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate , hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, Phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, etc.
  • Suitable acid salts can be prepared by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid.
  • acids suitable for the formation of pharmaceutically acceptable salts are also selected from the following references: 1 P. Stahl et al, Camille G (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002); 2 Zurich, Wiley-VCH.
  • Exemplary base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts containing organic bases such as organic amines such as dicyclohexylamine , tert-butylamine, choline and salts containing amino acids (such as arginine, lysine), etc.
  • Basic nitrogen-containing groups can be combined with compounds such as lower alkyl halides (for example, methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (for example, dimethyl, diethyl and dibutyl sulfate), long-chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromide ) and others to form quaternary ammonium salts.
  • lower alkyl halides for example, methyl, ethyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates for example, dimethyl, diethyl and dibutyl sulfate
  • long-chain halides e.g., decyl, lauryl, and ste
  • Compounds carrying acidic groups can be mixed with appropriate pharmaceutically acceptable salts to prepare alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts) and formed by suitable organic ligands (such as quaternary ammonium salts). salt) formed salt. Additionally, in the presence of carboxy or hydroxyl groups, pharmaceutically acceptable esters can be used to improve the solubility or hydrolytic properties of the compounds.
  • alkali metal salts such as sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • suitable organic ligands such as quaternary ammonium salts
  • zwitterions inner salts
  • Certain compounds of the present invention may exist as zwitterions having anionic and cationic centers in the same compound and having a net neutral charge, and such zwitterions are also encompassed by the present invention.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent ENPP1 enzyme inhibitory activity
  • the compound of the present invention or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, and the compound containing the present invention are the main activity
  • the pharmaceutical composition of the ingredients can be used to prevent and/or treat (stabilize, alleviate or cure) ENPP1 enzyme-related diseases, for example, inflammatory diseases (acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation due to house dust mite, and interstitial cystitis), autoimmune disease, infectious disease (such as hepatitis B virus , human papillomavirus, nasopharyngeal carcinoma-associated Epstein-Barr virus, herpes simplex virus), cancers such as colon, breast, lung, mel
  • the pharmaceutical composition of the present invention comprises the compound of the present invention and pharmaceutically acceptable excipients or carriers in a safe and effective amount range.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as STING agonists.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, STING agonists).
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compound of the present invention for the prevention and/or treatment of STING Kinase activity or expression related diseases.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 20-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C).
  • the reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
  • the compound of formula I has a structure shown in formula vi, which can be prepared by the following method:
  • compound ii undergoes a reduction reaction with a reducing agent (such as sodium dithionite) to obtain compound iii;
  • a reducing agent such as sodium dithionite
  • compound iii is reacted with cyanide (such as cyanogen bromide) to obtain compound iv;
  • compound iv is combined with a carboxylic acid in the presence of a condensing agent (such as EDCI and HOBT) react to obtain compound v;
  • a condensing agent such as EDCI and HOBT
  • compound v is treated with n-butyllithium, triisopropyl borate, trimethylbromosilane, or phosphorus oxychloride to obtain compound vi.
  • the compound of the present invention has novel structure and excellent ENPP1 enzyme inhibitory effect
  • the compound of the present invention can effectively reduce the degradation of cGAMP, thereby promoting the secretion of type I interferon;
  • the compound of the present invention provides a new option for clinically screening and/or preparing drugs for diseases related to ENPP1 activity.
  • Step 6 N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole -5-Carboxamide (1-6)
  • Step 7 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) boronic acid (I-1)
  • Step 4 N-(1-(4-bromobenzyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole -5-formamide (2-4)
  • Step 5 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) boronic acid (I-2)
  • Step 4 3-amino-4-((4-bromophenethyl)amino)-5-methoxybenzonitrile (3-4)
  • Step 7 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[ d] imidazol-1-yl) ethyl) phenyl) boronic acid (I-3)
  • Step 4 N-(1-(4-bromobenzyl)-5-cyano-7-methoxy-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methanol Base-1H-pyrazole-5-carboxamide (4-4)
  • Step 5 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d] Imidazol-1-yl)methyl)phenyl)boronic acid (I-4)
  • Step 3 ethyl 4-((4-bromobenzyl)amino)-3-methoxy-5-nitrobenzoate (5-3)
  • Step 4 Methyl 3-amino-4-((4-bromobenzyl)amino)-5-methoxybenzoate (5-4)
  • Step 5 Ethyl 2-amino-1-(4-bromobenzyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (5-5)
  • Step 6 1-(4-bromobenzyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d ]Imidazole-5-ethyl carboxylate (5-6)
  • Step 7 (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) phenyl) boronic acid (I-5)
  • Step 5 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d ]imidazole-5-carboxamide (6-5)
  • Step 6 (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) phenyl) boronic acid (I-6)
  • Step 1 4-((4-bromophenethyl)amino)-3-methoxy-5-nitrobenzoic acid ethyl ester (7-1)
  • Step 4 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d ]imidazole-5-ethyl carboxylate (7-4)
  • Step 5 (4-(2-(5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H -Benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (I-7)
  • Step 1 Diethyl (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole -1-yl) ethyl) phenyl) phosphonate (8-1)
  • Step 2 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) phosphonic acid (I-8)
  • Step 1 1-(4-(diethoxyphosphoryl)phenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy -1H-Benzo[d]imidazole-5-carboxylic acid ethyl ester (14-1)
  • Step 2 (4-(2-(5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H- Benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-14)
  • Step 4 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-5-carba Amide (15-4)
  • Step 5 Diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d] imidazol-1-yl) ethyl) phenyl) phosphonate (15-5)
  • Step 6 Diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d] imidazol-1-yl) ethyl) phenyl) phosphonate (I-15)
  • Step 3 4-((4-((tert-butyldiphenylsilyl)oxy)phenethyl)amino)-3-methoxy-5-nitrobenzamide (16-3)
  • Step 4 3-amino-4-((4-((tert-butyldiphenylsilyl)oxy)phenethyl)amino)-5-methoxybenzamide (16-4)
  • Step 5 2-amino-1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (16-5)
  • Step 6 1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo[d]imidazole-5-carboxamide (16-6)
  • Step 7 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-(4-hydroxyphenethyl)-7-methoxy-1H-benzo[d ]imidazole-5-carboxamide (16-7)
  • Step 8 4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[ d] imidazol-1-yl) ethyl) phenyl dihydrogen phosphate (I-16)
  • step 1 The operating process and reaction conditions are the same as in Example 17, except that the raw material in step 1 is ethyl 4-chloro-3-nitrobenzoate, a white solid, and the yield is 65.3%.
  • step 1 The operation process and reaction conditions are the same as in Example 17, except that the raw materials in step 1 are I-18 and 4-(2-aminoethyl)benzenesulfonamide, a white solid, and the yield is 58.4%.
  • step 1 The operation process and reaction conditions are the same as in Example 17, except that the raw materials in step 1 are 6-1 and 4-(2-aminoethyl)benzenesulfonamide, white solid, and the yield is 49.5%.
  • Step 1 4-(((4-cyano-2-methoxy-6-nitrophenyl)amino)methyl)benzenesulfonamide (31-1)
  • Step 3 4-((2-amino-5-cyano-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzenesulfonamide (I-31)
  • step 1 The operation process and reaction conditions are the same as in Example 31, except that the raw material in step 1 is 4-(2-aminoethyl)benzenesulfonamide, a white solid, and the yield is 71.4%.
  • step 1 The operation process and reaction conditions are the same as in Example 31, except that the raw material in step 1 is 4-chloro-3-nitrobenzamide, a white solid, and the yield is 64.2%.
  • step 1 The operating process and reaction conditions are the same as in Example 31, except that the raw materials in step 1 are 4-chloro-3-nitrobenzamide and 4-(2-aminoethyl)benzenesulfonamide, white solid, yield 57.7 %.
  • Step 1 (E)-4-bromo-2,6-difluorobenzaldehyde oxime (35-1)
  • Step 3 4-((4-bromo-2,6-difluorobenzyl bromide)amino)-3-p-nitrobenzocyano (35-3)
  • Step 4 3-amino-4-((4-bromo-2,6-difluorobenzyl bromide)amino)benzonitrile (35-4)
  • Step 5 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H-benzo[d]imidazole-5-carbonitrile (35-5)
  • Step 6 N-(1-(4-bromo-2,6-difluorobenzyl bromide)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methanol Base-1H-pyrazole-5-carboxamide (35-6)
  • Step 7 Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)-3,5-fluorophenyl)phosphonate (I-35)
  • Step 1 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl) Methyl)-3,5-fluorophenyl)phosphonic acid (I-36)
  • Step 1 ethyl 4-((4-bromo-2,6-difluorobenzyl bromide) amino)-3-nitrobenzoate (37-1)
  • Step 2 ethyl 3-amino-4-((4-bromo-2,6-difluorobenzyl bromide)amino)benzoate (37-2)
  • Step 3 Ethyl 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H-benzo[d]imidazole-5-carboxylate (37-3)
  • Step 4 1-(4-bromo-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d ]Imidazole-5-ethyl carboxylate (37-4)
  • Step 5 1-(4-(diethoxyphosphoryl)-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-Benzo[d]imidazole-5-carboxylic acid ethyl ester (I-37)
  • Step 1 (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)-3,5-fluorophenyl)phosphonic acid (I-38)
  • Step 3 5-cyano-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-2-carboxamide (39-3)
  • Step 4 1-(4-bromophenethyl)-5-cyano-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole -2-Carboxamide (39-4)
  • Step 5 (4-(2-(5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole -1-yl) ethyl) phenyl) phosphonic acid diethyl ester (39-5)
  • Step 6 (4-(2-(5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole -1-yl) ethyl) phenyl) phosphonic acid (I-39)
  • Step 1 1-(4-bromophenyl)-5-cyano-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole- 2-Formamide (40-1)
  • Step 2 (4-((5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole-1 -yl) methyl) phenyl) phosphonic acid diethyl ester (40-2)
  • Step 3 (4-((5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole-1 -yl)methyl)phenyl)phosphonic acid (I-40)
  • Step 7 4-((4-bromophenyl)amino)-2-methyl-5-nitrobenzofuran-7-carboxamide (42-7)
  • Step 8 5-amino-4-((4-bromophenyl)amino)-2-methylbenzofuran-7-carboxamide (42-8)
  • Step 10 1-(4-bromophenyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran[4, 5-d] imidazole-5-carboxamide (42-10)
  • Step 4 N-(1-(4-bromophenyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole- 5-formamide (43-4)
  • Step 5 Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)phenyl)phosphonate (I-43)
  • Step 4 1-(4-bromophenyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran[4, 5-d] imidazole-5-carboxamide (44-4)
  • Step 5 Diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H- Benzofuro[4,5-d]imidazol-1-yl)ethyl)phenyl)phosphonate (44-5)
  • Step 6 (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran [4,5-d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-44)
  • Step 5 N-(1-(4-bromophenyl)-5-cyano-7-methyl-1H-benzofuro[4,5-d]imidazol-2-yl)-1-ethyl- 3-Methyl-1H-pyrazole-5-carboxamide (45-5)
  • Step 6 Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran [4,5-d] imidazol-1-yl) phenyl) phosphonate (45-6)
  • Step 7 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran[4, 5-d] imidazol-1-yl) methyl) phenyl) phosphonic acid (I-45)
  • Example 48 (((4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- base) methyl) phenyl) phosphoroguanidino) bis (oxo)) bis (methylene) bis (2,2-dimethylpropyl ester) (I-48)
  • Example 51 ((4-((2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H- Benzo[d]imidazol-1-yl)ethyl)phenyl)phosphoroguanidine)bis(oxo))bis(methylene)bis(2,2-dimethylpropyl ester)(I-51 )
  • Step 1 4-((4-bromophenethyl)amino)-3-p-nitrobenzocyano (53-1)
  • Step 4 N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)nicotinamide (53-4)
  • Step 5 Diethyl (4-(2-(5-cyano-2-(nicotinamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonate (53- 5)
  • Step 6 (4-(2-(5-cyano-2-(nicotinamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-53)
  • Step 1 N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)benzamide (54-1)
  • Step 2 Diethyl (4-(2-(2-benzamido-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonate (54-2 )
  • Step 3 (4-(2-(2-benzamido-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-54)
  • Step 1 N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-3,5-dimethylisoxazole-4-methanol Amide (55-1)
  • Step 2 (4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl Base) phenyl) diethyl phosphonate (55-2)
  • Step 3 (4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl Base) phenyl) phosphonic acid (I-55)
  • Step 1 N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)thiophene-2-carboxamide (56-1)
  • Step 2 Diethyl (4-(2-(5-cyano-2-(thiophene-2-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid Esters (56-2)
  • Step 3 (4-(2-(5-cyano-2-(thiophene-2-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I -56)
  • Step 1 N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-3-methylbutanamide (57-1)
  • Step 2 (4-(2-(5-cyano-2-(3-methylbutanylamino)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid diethyl Esters (57-2)
  • Step 3 (4-(2-(5-cyano-2-(3-methylbutanylamino)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I -57)
  • Step 1 (4-(2-((4-cyano-2-nitrophenyl)amino)ethyl)phenyl)phosphonic acid diethyl ester (58-1)
  • Step 6 N1-(4-bromobenzyl)-4,5-dimethoxybenzene-1,2-diamine (59-6)
  • Step 7 1-(4-bromobenzyl)-5,6-dimethoxy-1H-benzo[d]imidazol-2-amine (59-7)
  • Step 8 N-(1-(4-bromobenzyl)-5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H -pyrazole-5-carboxamide (59-8)
  • Step 9 4-((2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5,6-dimethoxy-1H-benzo[d]imidazole- 1-yl)methyl)phenyl)phosphonic acid diethyl ester (59-9)
  • Step 10 (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5,6-dimethoxy-1H-benzo[d ]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-59)
  • Step 2 7-nitro-2,3-dihydrobenzo[B][1,4]dioxin-6-amine (60-2)
  • Step 3 N-(4-bromobenzyl)-7-nitro-2,3-dihydrobenzo[B][1,4]dioxin-6-amine (60-3)
  • Step 4 N6-(4-bromobenzyl)-2,3-dihydrobenzo[B][1,4]dioxin-6,7-diamine (60-4)
  • Step 5 1-(4-bromobenzyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1, 2-d] imidazol-2-amine (60-5)
  • Step 6 N-(1-(4-bromobenzyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo [1,2-d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (60-6)
  • Step 7 (4-((2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-6,7-dihydro-1H-[1,4]dioxa Cyclohexeno[2',3':4,5]benzo[1,2-d]imidazol-1-yl)methyl)phenyl)phosphonic acid diethyl ester (60-7)
  • Step 8 (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-6,7-dihydro-1H-[1,4]di Oxine[2',3':4,5]benzo[1,2-d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-60)

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Abstract

The present invention provides a benzimidazole compound and a medical use thereof. Specifically, the compound has a structure shown in formula (I). The present invention also relates to a pharmaceutically acceptable salt or prodrug of the compound, a preparation method therefor and a use thereof, and further relates to a pharmaceutical composition containing the compound. The compound can be used in the preparation of a drug for treating diseases related to ENPP1 activity.

Description

苯并咪唑类化合物及其医药用途Benzimidazole compounds and their medicinal uses 技术领域technical field
本发明涉及药物化学和药物治疗学领域，具体涉及苯并咪唑类化合物及其医药用途。The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to benzimidazole compounds and their medical applications.
背景技术Background technique
近年来，免疫疗法的出现显示出改变癌症治疗方法的潜力。通过免疫检查点阻断释放抗肿瘤T细胞反应，在无法治疗的肿瘤中产生了显著的反应。扩大免疫治疗方法有效性的主要策略之一是要找到能够将免疫“冷”肿瘤转变到“热”肿瘤的方法，并因此克服局部免疫抑制机制，恢复机体的免疫监视功能。局部免疫刺激的一个策略是激活STING通路，这是一个关键的传感系统，它允许先天免疫系统对感染和肿瘤生长做出反应，协调免疫反应。In recent years, the advent of immunotherapy has shown the potential to transform cancer treatment. Unleashing antitumor T-cell responses through immune checkpoint blockade has produced dramatic responses in untreatable tumors. One of the main strategies to expand the effectiveness of immunotherapeutic approaches is to find ways to transform immune "cold" tumors into "hot" tumors, thereby overcoming local immunosuppressive mechanisms and restoring the body's immune surveillance functions. One strategy for local immune stimulation is to activate the STING pathway, a key sensing system that allows the innate immune system to coordinate immune responses in response to infection and tumor growth.
几十年前，外核苷酸焦磷酸酶/磷酸二酯酶I(ENPP1)被鉴定为具有核苷酸焦磷酸酶和磷酸二酯酶酶活性的II型跨膜糖蛋白，对嘌呤能传递信号至关重要。最近，ENPP1已成为一种重要的磷酸二酯酶，可降解STING的配体cGMP-AMP(cGAMP)。在细胞质中，环GMP-AMP合成酶(cGAS)与来自病原体或宿主受损细胞的dsDNA结合，催化GTP和ATP转化为环状GMP-AMP(cGAMP)。随后，2’3’-cGAMP激活STING，通过TANK结合激酶1(TBK1)-干扰素调节因子(IRF3)途径引发炎症反应，产生1型干扰素(IFN)和其他细胞因子。cGAS–STING途径与ENPP1之间的联系已经出现，即ENPP1对cGAMP的水解会减弱cGAS–STING信号传导，从而减弱机体抗肿瘤免疫能力。Decades ago, outer nucleotide pyrophosphatase/phosphodiesterase I (ENPP1) was identified as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activity, responsible for purinergic transmission Signals are crucial. Recently, ENPP1 has emerged as an important phosphodiesterase that degrades STING's ligand, cGMP-AMP (cGAMP). In the cytoplasm, cyclic GMP-AMP synthetase (cGAS) binds to dsDNA from pathogens or host damaged cells and catalyzes the conversion of GTP and ATP to cyclic GMP-AMP (cGAMP). Subsequently, 2'3'-cGAMP activates STING, triggers an inflammatory response through the TANK-binding kinase 1 (TBK1)-interferon regulatory factor (IRF3) pathway, and produces type 1 interferon (IFN) and other cytokines. The connection between the cGAS-STING pathway and ENPP1 has emerged, that is, the hydrolysis of cGAMP by ENPP1 will weaken the cGAS-STING signaling, thereby weakening the body's anti-tumor immunity.
据报道，在ENPP1基因敲除小鼠中表现出更长的cGAMP半衰期，说明其T 1/2在很大程度上取决于ENPP1。另一方面，ENPP1催化ATP或GTP水解为AMP或GMP，CD73将AMP脱磷酸化为腺苷，过量腺苷会通过刺激G蛋白偶联的A 2A和A 2B腺苷受体关闭先天性和适应性免疫反应，从而导致促炎细胞因子的产生减少和抗炎细胞因子的合成增加，因此抑制ENPP1后，可以减少腺苷生成，增强机体抗肿瘤免疫能力。 Longer cGAMP half-life was reported in ENPP1 knockout mice, suggesting that its T1 /2 is largely dependent on ENPP1. On the other hand, ENPP1 catalyzes the hydrolysis of ATP or GTP to AMP or GMP, CD73 dephosphorylates AMP to adenosine, and excess adenosine turns off innate and adaptive by stimulating G protein-coupled A2A and A2B adenosine receptors Therefore, after inhibiting ENPP1, it can reduce the production of adenosine and enhance the body's anti-tumor immunity.
综上所述，开发高效且安全的ENPP1抑制剂是十分有必要的。In summary, it is necessary to develop highly effective and safe ENPP1 inhibitors.
发明内容Contents of the invention
本发明目的是提供一种结构新颖的化合物、或其可药用的盐。The object of the present invention is to provide a compound with a novel structure or a pharmaceutically acceptable salt thereof.
本发明另一目的是提供一种药物组合物。Another object of the present invention is to provide a pharmaceutical composition.
本发明另一目的是提供所述化合物、其可药用的盐的制备方法。Another object of the present invention is to provide the preparation method of said compound and its pharmaceutically acceptable salt.
本发明最后一目的提供所述化合物、其可药用的盐的用途，特别是在制备预防和/或治疗ENPP1功能紊乱相关疾病的药物中的用途。The last object of the present invention is to provide the use of said compound and its pharmaceutically acceptable salt, especially in the preparation of medicines for preventing and/or treating diseases related to ENPP1 dysfunction.
本发明的第一方面，提供一种式(I)化合物、或其药学上可接受的盐或前药：The first aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:
Figure PCTCN2023071429-appb-000001
Figure PCTCN2023071429-appb-000001
其中，in,
X选自：N或C-R 1； X is selected from: N or CR 1 ;
Y选自：N或C-R 2； Y is selected from: N or CR 2 ;
Z选自：N或C-R 3； Z is selected from: N or CR 3 ;
W选自：N或C-R 4； W is selected from: N or CR4 ;
R 1选自：氢、卤素、氰基、C 1～C 6烷基或-OR f； R 1 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl or -OR f ;
R 2选自：氢、卤素、氰基、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
R 3、R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
或者，R 2和R 3与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 2 and R 3 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
L选自：C 1～C 6亚烷基、-NH-、-NR aC(O)(CH 2) n-、-C(O)NR b(CH 2) n-； L is selected from: C 1 ~ C 6 alkylene, -NH-, -NR a C(O)(CH 2 ) n -, -C(O)NR b (CH 2 ) n -;
A选自：氢、取代或未取代的C5～C12芳基、取代或未取代的5-12元杂芳基、C 1～C 6烷基、取代或未取代的C3-C12环烷基、取代或未取代的4-12元杂环基、C 1～C 6亚烷基(取代或未取代的5-12元杂芳基)；其中，所述取代是指被1-4个R n取代；各R n独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g、-NR fC(O)R g； A is selected from: hydrogen, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, C1 - C6 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, Substituted or unsubstituted 4-12 membered heterocyclic group, C 1 ~C 6 alkylene group (substituted or unsubstituted 5-12 membered heteroaryl group); wherein, the substitution refers to 1-4 R n Substitution; each R n is independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g , -NR f C(O)R g ;
R t选自：-(CH 2) nR L’、-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n R L' , -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N -(CH 2 ) m R s ;
R s选自：取代的C5～C12芳基、取代的5-12元杂芳基、取代的5-12元杂环基；其中，所述取代是指被1-4个R L取代； R s is selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclic; wherein, the substitution refers to being substituted by 1-4 RL ;
各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’、-(CH 2) m’NH 2SO 2NR f’R g’；或者在-(CH 2) m’P(＝O)(OR j’) 2和-(CH 2) m’OP(＝O)(OR j’) 2中两个OR j’与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； Each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen-substituted C 1 -C 6 alkyl, -OR f' , -NR f' R g' , -C( O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -(CH 2 ) m' OP(=O)( OR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m ' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' , -(CH 2 ) m' NH 2 SO 2 NR f' R g' ; or in -(CH 2 ) m' P(=O)(OR j' ) 2 and -(CH 2 ) m' OP In (=O)(OR j' ) 2, two OR j' and their connected P atoms together form 0-4 saturated or unsaturated 4-6 membered heterocyclic rings substituted by R m ;
R L’独立地选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、 -(CH 2) m’NHSO 2R f’、-(CH 2) m’NH 2SO 2NR f’R g’；或者在-(CH 2) m’P(＝O)(OR j’) 2和-(CH 2) m’OP(＝O)(OR j’) 2中两个OR j’与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； R L' is independently selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' , -(CH 2 ) m' NH 2 SO 2 NR f' R g' ; or in -(CH 2 ) m In ' P(=O)(OR j' ) 2 and -(CH 2 ) m' OP(=O)(OR j' ) 2, two OR j' and their connected P atoms together form 0 to 4 R m -substituted saturated or unsaturated 4-6 membered heterocyclic rings;
m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i or 3-6 membered heterocycloalkane substituted by 0-4 R i base;
R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , 3-6 membered cycloalkyl group substituted by 0-4 R i or 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基； R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl or cyano;
R m选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基、苯基、5-6元杂芳基、卤素取代的苯基、C 1～C 6烷基取代的苯基、卤素取代的5-6元杂芳基、C 1～C 6烷基取代的5-6元杂芳基； R m is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl, C 1 ~C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ~C 6 alkyl substituted 5 -6 membered heteroaryl;
R a、R b、R j、R k和R k’各自独立地选自：氢、卤素、C 1～C 6烷基或卤代C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
在另一优选例中，式(I)化合物、或其药学上可接受的盐或前药：In another preferred embodiment, the compound of formula (I) or its pharmaceutically acceptable salt or prodrug:
Figure PCTCN2023071429-appb-000002
Figure PCTCN2023071429-appb-000002
其中，in,
X选自：N或C-R 1； X is selected from: N or CR 1 ;
Y选自：N或C-R 2； Y is selected from: N or CR 2 ;
Z选自：N或C-R 3； Z is selected from: N or CR 3 ;
W选自：N或C-R 4； W is selected from: N or CR4 ;
R 1选自：氢、卤素、氰基、C 1～C 6烷基或-OR f； R 1 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl or -OR f ;
R 2选自：氢、卤素、氰基、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
R 3、R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
L选自：C 1～C 6亚烷基、-NH-、-NR aC(O)(CH 2) n-、-C(O)NR b(CH 2) n-； L is selected from: C 1 ~ C 6 alkylene, -NH-, -NR a C(O)(CH 2 ) n -, -C(O)NR b (CH 2 ) n -;
A选自：氢、取代的C5～C12芳基、取代的5-12元杂芳基；其中，所述取代是指被1-4个R n取代；各R n独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g、-NR fC(O)R g； A is selected from: hydrogen, substituted C5-C12 aryl, substituted 5-12 membered heteroaryl; wherein, the substitution refers to being substituted by 1-4 R n ; each R n is independently selected from: hydrogen, Halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O) NR f R g , -NR f C(O)R g ;
R t选自：-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
R s选自：取代的C5～C12芳基、取代的5-12元杂芳基、取代的5-12元杂环基；其中，所述取代是指被1-4个R L取代； R s is selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclic; wherein, the substitution refers to being substituted by 1-4 RL ;
各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’、-(CH 2) m’NH 2SO 2NR f’R g’；或者在-(CH 2) m’P(＝O)(OR j’) 2和-(CH 2) m’OP(＝O)(OR j’) 2中两个OR j’与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； Each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen-substituted C 1 -C 6 alkyl, -OR f' , -NR f' R g' , -C( O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -(CH 2 ) m' OP(=O)( OR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m ' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' , -(CH 2 ) m' NH 2 SO 2 NR f' R g' ; or in -(CH 2 ) m' P(=O)(OR j' ) 2 and -(CH 2 ) m' OP In (=O)(OR j' ) 2, two OR j' and their connected P atoms together form 0-4 saturated or unsaturated 4-6 membered heterocyclic rings substituted by R m ;
m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i or 3-6 membered heterocycloalkane substituted by 0-4 R i base;
R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , 3-6 membered cycloalkyl group substituted by 0-4 R i or 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基； R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl or cyano;
R m选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基、苯基、5-6元杂芳基、卤素取代的苯基、C 1～C 6烷基取代的苯基、卤素取代的5-6元杂芳基、C 1～C 6烷基取代的5-6元杂芳基； R m is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl, C 1 ~C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ~C 6 alkyl substituted 5 -6 membered heteroaryl;
R a、R b、R j、R k和R k’各自独立地选自：氢、卤素、C 1～C 6烷基或卤代C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
在另一优选例中，各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’、-(CH 2) m’NH 2SO 2NR f’R g’；或者在-(CH 2) m’P(＝O)(OR j’) 2中两个OR j’与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环。 In another preferred example, each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen-substituted C 1 -C 6 alkyl, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -(CH 2 ) m ' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' , -(CH 2 ) m' NH 2 SO 2 NR f' R g' ; or in -(CH 2 ) m' P(=O)(OR j' ) 2 , two OR j' and their connected P atoms together form 0 to 4 R m substitutions Saturated or unsaturated 4-6 membered heterocyclic rings.
在另一优选例中，各R n独立地选自：氢、卤素、C 1～C 6烷基或卤代C 1～C 6烷基。 In another preferred example, each R n is independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
在另一优选例中，
Figure PCTCN2023071429-appb-000003
为
Figure PCTCN2023071429-appb-000004
其中，环B为饱和或不饱和的4～6元碳环或杂环(如呋喃基、噻吩基、咪唑基、吡咯基、恶唑基、噻唑基、环己基等)，p为0、1、2、3或4；R i和R t的定义如上所述。 In another preferred example,
Figure PCTCN2023071429-appb-000003
for
Figure PCTCN2023071429-appb-000004
Among them, ring B is a saturated or unsaturated 4-6 membered carbocyclic ring or heterocyclic ring (such as furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, cyclohexyl, etc.), p is 0, 1 , 2, 3 or 4; R i and R t are as defined above.
在另一优选例中，
Figure PCTCN2023071429-appb-000005
为
Figure PCTCN2023071429-appb-000006
p、R 1、R 2、R i和R t的定义如上所述。 In another preferred example,
Figure PCTCN2023071429-appb-000005
for
Figure PCTCN2023071429-appb-000006
p, R 1 , R 2 , R i and R t are as defined above.
在另一优选例中，
Figure PCTCN2023071429-appb-000007
为
Figure PCTCN2023071429-appb-000008
其中，R 1、R 2、R 3、R 4和R t的定义如上所述。 In another preferred example,
Figure PCTCN2023071429-appb-000007
for
Figure PCTCN2023071429-appb-000008
Wherein, the definitions of R 1 , R 2 , R 3 , R 4 and R t are as above.
在另一优选例中，
Figure PCTCN2023071429-appb-000009
为
Figure PCTCN2023071429-appb-000010
t为1或2，R 1、R 4和R t的定义如上所述。 In another preferred example,
Figure PCTCN2023071429-appb-000009
for
Figure PCTCN2023071429-appb-000010
t is 1 or 2, and R 1 , R 4 and R t are as defined above.
在另一优选例中，R s选自：取代的C5～C6芳基、取代的5～6元杂芳基、取代的[5+6]芳基、取代的[5+6]杂芳基、取代的6-7元杂环或取代的螺环；其中，所述取代是指被1-4个R L取代；R L的定义如上所述。 In another preferred example, R s is selected from: substituted C5-C6 aryl, substituted 5-6 membered heteroaryl, substituted [5+6] aryl, substituted [5+6] heteroaryl , a substituted 6-7 membered heterocyclic ring or a substituted spirocyclic ring; wherein, the substitution refers to being substituted by 1-4 RL ; the definition of RL is as above.
在另一优选例中，取代的6-7元杂环或取代的螺环为取代的6-7元单环杂环或取代的8-11元双环螺环，更优选地为取代的6-7元单环杂环或取代的9-10元双环螺环，更优选地为
Figure PCTCN2023071429-appb-000011
R u和R v的定义同R L。 In another preference, the substituted 6-7 membered heterocycle or substituted spirocycle is a substituted 6-7 membered monocyclic heterocycle or substituted 8-11 membered bicyclic spirocycle, more preferably a substituted 6- 7 membered monocyclic heterocycle or substituted 9-10 membered bicyclic spiro ring, more preferably
Figure PCTCN2023071429-appb-000011
R u and R v have the same definitions as R L .
在另一优选例中，A选自：氢、取代的C5～C6芳基、取代的5～6元杂芳基、取代的[5+6]芳基、取代的[5+6]杂芳基；优选地，A选自取代的下组基团：苯基、吡咯基、咪唑基、吡唑基、呋喃基、噻吩基、噻唑基、恶唑基、吡啶基、吡嗪基、哒嗪基、吗啉基、哌嗪基、哌啶基、苯并咪唑基、苯并吡唑基、吲哚基、
Figure PCTCN2023071429-appb-000012
所述取代是指被1-4个R n取代；R n的定义如上所述。 In another preferred example, A is selected from: hydrogen, substituted C5-C6 aryl, substituted 5-6 membered heteroaryl, substituted [5+6] aryl, substituted [5+6] heteroaryl Base; Preferably, A is selected from the following group of substituted groups: phenyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazine Base, morpholinyl, piperazinyl, piperidinyl, benzimidazolyl, benzopyrazolyl, indolyl,
Figure PCTCN2023071429-appb-000012
The substitution refers to substitution by 1-4 R n ; the definition of R n is as above.
在另一优选例中，A选自：氢、
Figure PCTCN2023071429-appb-000013
Figure PCTCN2023071429-appb-000014
R 5和R 6的定义同R n。 In another preference, A is selected from: hydrogen,
Figure PCTCN2023071429-appb-000013
Figure PCTCN2023071429-appb-000014
R 5 and R 6 have the same definitions as R n .
在另一优选例中，R s选自：
Figure PCTCN2023071429-appb-000015
Figure PCTCN2023071429-appb-000016
优选地为
Figure PCTCN2023071429-appb-000017
Figure PCTCN2023071429-appb-000018
其中，R u、R v和R w的定义同R L。 In another preference, R s is selected from:
Figure PCTCN2023071429-appb-000015
Figure PCTCN2023071429-appb-000016
preferably
Figure PCTCN2023071429-appb-000017
Figure PCTCN2023071429-appb-000018
Wherein, the definition of R u , R v and R w is the same as that of R L .
在另一优选例中，R 2选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g；优选地，R 2选自：氢、氰基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； In another preferred example, R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O) Rf , -CO2Rf , -C(O) NRfRg , or -NRfC (O) Rg ; preferably, R2 is selected from : hydrogen, cyano, -ORf , -NRfR g , -C(O) Rf , -CO2Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
R f、R g各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、被0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f and R g are each independently selected from: hydrogen, 0 to 4 C 1 to C 6 alkyl substituted by Rh, 0 to 4 C 2 to C 6 alkynyl substituted by Rh, 0 to 4 R C 2 -C 6 alkenyl substituted by h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkyl substituted by 0-4 R i ;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基或被0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基； R i is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl, cyano;
R j、R k各自独立地选自：氢或C 1～C 6烷基。 R j and R k are each independently selected from: hydrogen or C 1 -C 6 alkyl.
在另一优选例中，或者，R 2和R 3与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环，优选5-6元。 In another preferred example, or, R 2 and R 3 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i , preferably 5-6 membered .
在另一优选例中，R 3和R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g；优选地，R 3和R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f或-C(O)R f、-CO 2R f； In another preferred example, R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C (O) Rf , -CO2Rf , -C( O)NRfRg, or -NRfC ( O ) Rg ; preferably, R3 and R4 are each independently selected from: hydrogen, halogen, 0 to 4 C 1 to C 6 alkyl groups substituted by Rh, -OR f or -C(O)R f , -CO 2 R f ;
或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环，优选5-6元； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i , preferably 5-6 members;
R f、R g各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、被0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f and R g are each independently selected from: hydrogen, 0 to 4 C 1 to C 6 alkyl substituted by Rh, 0 to 4 C 2 to C 6 alkynyl substituted by Rh, 0 to 4 R C 2 -C 6 alkenyl substituted by h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkyl substituted by 0-4 R i ;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基或被0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基； R i is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl, cyano;
R j、R k各自独立地选自：氢或C 1～C 6烷基。 R j and R k are each independently selected from: hydrogen or C 1 -C 6 alkyl.
在另一优选例中，L选自：-NH-、-NR aC(O)(CH 2) n-或-C(O)NR b(CH 2) n-；R a、R b各自独立地选自：氢或C 1～C 6烷基，n为0、1、2、3、4、5或6。 In another preferred example, L is selected from: -NH-, -NR a C(O)(CH 2 ) n - or -C(O)NR b (CH 2 ) n -; R a and R b are independently is selected from: hydrogen or C 1 -C 6 alkyl, n is 0, 1, 2, 3, 4, 5 or 6.
在另一优选例中，A选自：氢、
Figure PCTCN2023071429-appb-000019
Figure PCTCN2023071429-appb-000020
优选地，A选自：氢、
Figure PCTCN2023071429-appb-000021
优选地，A选自：
Figure PCTCN2023071429-appb-000022
In another preference, A is selected from: hydrogen,
Figure PCTCN2023071429-appb-000019
Figure PCTCN2023071429-appb-000020
Preferably, A is selected from: hydrogen,
Figure PCTCN2023071429-appb-000021
Preferably, A is selected from:
Figure PCTCN2023071429-appb-000022
R 5和R 6各自独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
R f、R g各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、被0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f and R g are each independently selected from: hydrogen, 0 to 4 C 1 to C 6 alkyl substituted by Rh, 0 to 4 C 2 to C 6 alkynyl substituted by Rh, 0 to 4 R C 2 -C 6 alkenyl substituted by h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkyl substituted by 0-4 R i ;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基或被0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基； R i is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl, cyano;
R j、R k各自独立地选自：氢或C 1～C 6烷基。 R j and R k are each independently selected from: hydrogen or C 1 -C 6 alkyl.
在另一优选例中，R s选自：
Figure PCTCN2023071429-appb-000023
Figure PCTCN2023071429-appb-000024
优选地，R s选自：
Figure PCTCN2023071429-appb-000025
Figure PCTCN2023071429-appb-000026
In another preference, R s is selected from:
Figure PCTCN2023071429-appb-000023
Figure PCTCN2023071429-appb-000024
Preferably, R s is selected from:
Figure PCTCN2023071429-appb-000025
Figure PCTCN2023071429-appb-000026
R u选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’或-(CH 2) m’NH 2SO 2NR f’R g’； R u is selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' or -(CH 2 ) m' NH 2 SO 2 NR f' R g' ;
R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R v is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R w is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
m、m’分别独立地为0、1、2、3、4、5或6；m and m' are independently 0, 1, 2, 3, 4, 5 or 6;
R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、被0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f' and R g' are each independently selected from: hydrogen, 0-4 C 1 -C 6 alkyl substituted by Rh, 0-4 C 2 -C 6 alkynyl substituted by Rh , 0-4 C 2 -C 6 alkenyl substituted by R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6-membered heterocycloalkyl substituted by 0-4 R i ;
R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基或被0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基； R i is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl, cyano;
R j、R k和R k’各自独立地选自：氢或C 1～C 6烷基。 R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
在另一优选例中，所述化合物具有(II)所示的结构：In another preferred example, the compound has the structure shown in (II):
Figure PCTCN2023071429-appb-000027
Figure PCTCN2023071429-appb-000027
其中，in,
R 1为氢； R 1 is hydrogen;
R 2选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O) NRfRg or -NRfC (O) Rg ;
R 3和R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
L选自：-NH-、-NR aC(O)(CH 2) n-或-C(O)NR b(CH 2) n-； L is selected from: -NH-, -NR a C (O) (CH 2 ) n - or -C (O) NR b (CH 2 ) n -;
A选自：氢、
Figure PCTCN2023071429-appb-000028
Figure PCTCN2023071429-appb-000029
A is selected from: hydrogen,
Figure PCTCN2023071429-appb-000028
Figure PCTCN2023071429-appb-000029
R 5和R 6各自独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
R t选自：-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
R s选自：
Figure PCTCN2023071429-appb-000030
Figure PCTCN2023071429-appb-000031
Rs are selected from:
Figure PCTCN2023071429-appb-000030
Figure PCTCN2023071429-appb-000031
R u选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’或-(CH 2) m’NH 2SO 2NR f’R g’； R u is selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' or -(CH 2 ) m' NH 2 SO 2 NR f' R g' ;
R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R v is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R w is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、被0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycle substituted by 0-4 R i alkyl;
R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基或被0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基； R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl, cyano;
R a、R b、R j、R k和R k’各自独立地选自：氢或C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
在另一优选例中，R 1为氢； In another preferred embodiment, R 1 is hydrogen;
R 2选自：氢、氰基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, cyano, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O ) R g ;
R 3和R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f或-C(O)R f、-CO 2R f； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f or -C(O)R f , -CO 2 R f ;
或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
L选自：-NH-、-NR aC(O)(CH 2) n-或-C(O)NR b(CH 2) n-； L is selected from: -NH-, -NR a C (O) (CH 2 ) n - or -C (O) NR b (CH 2 ) n -;
A选自：氢、
Figure PCTCN2023071429-appb-000032
A is selected from: hydrogen,
Figure PCTCN2023071429-appb-000032
R 5和R 6各自独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
R t选自：-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
R s选自：
Figure PCTCN2023071429-appb-000033
Rs are selected from:
Figure PCTCN2023071429-appb-000033
R u选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’； R u is selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' ;
R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R v is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R w is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkane substituted by 0-4 R i base;
R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i , a 3-6-membered heterocycloalkyl group substituted by 0-4 R i ;
R i选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基； R i is selected from: C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl;
R a、R b、R j、R k和R k’各自独立地选自：氢或C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
在另一优选例中，R 1为氢。 In another preferred embodiment, R 1 is hydrogen.
在另一优选例中，各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的 C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2或-(CH 2) m’SO 2NR f’R g’；m’、m”、R f’、R g’和R j’的定义如上所述，优选地各R L独立地选自：-B(OH) 2、P(＝O)(OH) 2、P(＝O)(OCH 2CH 3) 2、P(＝O)(OCH 2CF 3) 2、P(＝O)(OCH 2COOCH 3) 2、P(＝O)(OCH 2COOCH 2CH 3) 2、P(＝O)(OCH 2COOCH 2CH 2CH 3) 2、P(＝O)(OCH 2COOC(CH 3) 3) 2、P(＝O)(OCH 2OCOCH 3) 2、P(＝O)(OCH 2OCOCH 2CH 3) 2、P(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、P(＝O)(OCH 2OCOC(CH 3) 3) 2、P(＝O)(NHCH 2COOCH 3) 2、P(＝O)(NHCH 2COOCH 2CH 3) 2、P(＝O)(NHCH 2COOCH 2CH 2CH 3) 2、SO 2NH 2。 In another preferred example, each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen-substituted C 1 -C 6 alkyl, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -(CH 2 ) m ' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 or -(CH 2 ) m' SO 2 NR f' R g' ; m', m", R f' , R g' and R j' are as defined above , preferably each R L is independently selected from: -B(OH) 2 , P(=O)(OH) 2 , P(=O)(OCH 2 CH 3 ) 2 , P(=O)(OCH 2 CF 3 ) 2 , P(=O)(OCH 2 COOCH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , P (=O)(OCH 2 COOC(CH 3 ) 3 ) 2 , P(=O)(OCH 2 OCOCH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 3 ) 2 , P(=O)( OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOC(CH 3 ) 3 ) 2 , P(=O)(NHCH 2 COOCH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 , SO 2 NH 2 .
在另一优选例中，各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-OP(＝O)(OR j’) 2、-P(＝O)(OR j’) 2、-P(＝O)(NHR j’) 2、-P(OR j’) 2、-B(OR j’) 2或-SO 2NR f’R g’；优选地，各R L独立地选自：H、卤素(如F)、-B(OH) 2、P(＝O)(OH) 2、P(＝O)(OCH 2CH 3) 2、P(＝O)(OCH 2CF 3) 2、P(＝O)(OCH 2COOCH 3) 2、P(＝O)(OCH 2COOCH 2CH 3) 2、P(＝O)(OCH 2COOCH 2CH 2CH 3) 2、P(＝O)(OCH 2COOC(CH 3) 3) 2、P(＝O)(OCH 2OCOCH 3) 2、P(＝O)(OCH 2OCOCH 2CH 3) 2、P(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、P(＝O)(OCH 2OCOC(CH 3) 3) 2、P(＝O)(NHCH 2COOCH 3) 2、P(＝O)(NHCH 2COOCH 2CH 3) 2、P(＝O)(NHCH 2COOCH 2CH 2CH 3) 2、SO 2NH 2、OP(＝O)(OH) 2、OP(＝O)(OCH 2CH 3) 2、OP(＝O)(OCH 2CF 3) 2、OP(＝O)(OCH 2COOCH 3) 2、OP(＝O)(OCH 2COOCH 2CH 3) 2、OP(＝O)(OCH 2COOCH 2CH 2CH 3) 2、OP(＝O)(OCH 2COOC(CH 3) 3) 2、OP(＝O)(OCH 2OCOCH 3) 2、OP(＝O)(OCH 2OCOCH 2CH 3) 2、OP(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、OP(＝O)(OCH 2OCOC(CH 3) 3) 2、OP(＝O)(NHCH 2COOCH 3) 2、OP(＝O)(NHCH 2COOCH 2CH 3) 2、OP(＝O)(NHCH 2COOCH 2CH 2CH 3) 2。 In another preferred example, each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen-substituted C 1 -C 6 alkyl, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -OP(=O) (OR j' ) 2 , -P(=O)(OR j' ) 2 , -P(=O)(NHR j' ) 2 , -P(OR j' ) 2 , -B(OR j' ) 2 or -SO 2 NR f' R g' ; preferably, each R L is independently selected from: H, halogen (such as F), -B(OH) 2 , P(=O)(OH) 2 , P(= O)(OCH 2 CH 3 ) 2 , P(=O)(OCH 2 CF 3 ) 2 , P(=O)(OCH 2 COOCH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , P(=O)(OCH 2 COOC(CH 3 ) 3 ) 2 , P(=O)(OCH 2 OCOCH 3 ) 2 , P( =O)(OCH 2 OCOCH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOC(CH 3 ) 3 ) 2 , P(= O)(NHCH 2 COOCH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 , SO 2 NH 2 , OP(= O)(OH) 2 , OP(=O)(OCH 2 CH 3 ) 2 , OP(=O)(OCH 2 CF 3 ) 2 , OP(=O)(OCH 2 COOCH 3 ) 2 , OP(=O )(OCH 2 COOCH 2 CH 3 ) 2 , OP(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , OP(=O)(OCH 2 COOC(CH 3 ) 3 ) 2 , OP(=O) (OCH 2 OCOCH 3 ) 2 , OP(=O)(OCH 2 OCOCH 2 CH 3 ) 2 , OP(=O)(OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , OP(=O)(OCH 2 OCOC( CH 3 ) 3 ) 2 , OP(=O)(NHCH 2 COOCH 3 ) 2 , OP(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , OP(=O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 .
在另一优选例中，L选自：-NH-或-NHC(O)-。In another preferred example, L is selected from: -NH- or -NHC(O)-.
在另一优选例中，
Figure PCTCN2023071429-appb-000034
选自：NH 2、
Figure PCTCN2023071429-appb-000035
Figure PCTCN2023071429-appb-000036
In another preferred example,
Figure PCTCN2023071429-appb-000034
selected from: NH 2 ,
Figure PCTCN2023071429-appb-000035
Figure PCTCN2023071429-appb-000036
在另一优选例中，
Figure PCTCN2023071429-appb-000037
为
Figure PCTCN2023071429-appb-000038
In another preferred example,
Figure PCTCN2023071429-appb-000037
for
Figure PCTCN2023071429-appb-000038
在另一优选例中，A选自：异丙基、叔丁基、
Figure PCTCN2023071429-appb-000039
Figure PCTCN2023071429-appb-000040
In another preference, A is selected from: isopropyl, tert-butyl,
Figure PCTCN2023071429-appb-000039
Figure PCTCN2023071429-appb-000040
在另一优选例中，R 1为氢或C 1～C 6烷基。 In another preferred example, R 1 is hydrogen or C 1 -C 6 alkyl.
在另一优选例中，R 2选自：氢、卤素、氰基、-CO 2R f、-C(O)NR fR g；更优选地，R 2选自：氢、卤素、氰基、-CO 2C 1～C 6烷基、-C(O)NH 2。 In another preferred example, R 2 is selected from: hydrogen, halogen, cyano, -CO 2 R f , -C(O)NR f R g ; more preferably, R 2 is selected from: hydrogen, halogen, cyano , -CO 2 C 1 -C 6 alkyl, -C(O)NH 2 .
在另一优选例中，R 2选自：氢、卤素、氰基、C 1～C 6烷基、-OC 1～C 6烷基、-CO 2C 1～C 6烷基、-C(O)NH 2；更优选地，R 2选自：氢、卤素、氰基、-COOCH 3、-COOCH 2CH 3、-OCOCH 3、-OCOCH 2CH 3、OCH 3、-C(O)NH 2。 In another preferred example, R 2 is selected from: hydrogen, halogen, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -CO 2 C 1 -C 6 alkyl, -C( O)NH 2 ; more preferably, R 2 is selected from: hydrogen, halogen, cyano, -COOCH 3 , -COOCH 2 CH 3 , -OCOCH 3 , -OCOCH 2 CH 3 , OCH 3 , -C(O)NH 2 .
在另一优选例中，R 3和R 4各自独立地选自：氢、卤素、C 1～C 6烷基、-OR f、-NR fR g；更优选地，R 3选自氢、卤素或C 1～C 6烷基；R 4选自：氢、卤素、C 1～C 6烷基、-OC 1～C 6烷基。 In another preferred example, R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, -OR f , -NR f R g ; more preferably, R 3 is selected from hydrogen, Halogen or C 1 -C 6 alkyl; R 4 is selected from: hydrogen, halogen, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl.
在另一优选例中，R 3选自：氢、卤素、C 1～C 6烷基、-O C 1～C 6烷基。 In another preferred example, R 3 is selected from: hydrogen, halogen, C 1 -C 6 alkyl, -O C 1 -C 6 alkyl.
在另一优选例中，R 4选自：氢、卤素、C 1～C 6烷基、-OC 1～C 6烷基。 In another preferred example, R 4 is selected from: hydrogen, halogen, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl.
在另一优选例中，所述化合物具有式IV所示的结构In another preferred example, the compound has the structure shown in formula IV
Figure PCTCN2023071429-appb-000041
Figure PCTCN2023071429-appb-000041
y和q各自独立地为0、1、2、3；y and q are each independently 0, 1, 2, 3;
M选自：键、O或CH 2； M is selected from: bond, O or CH2 ;
R u选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’或-(CH 2) m’NH 2SO 2NR f’R g’； R u is selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' or -(CH 2 ) m' NH 2 SO 2 NR f' R g' ;
R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R v is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R w is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
R 1、R 2、R 3、R 4、L和A的定义如上所述。 R 1 , R 2 , R 3 , R 4 , L and A are as defined above.
在另一优选例中，当M为键时，
Figure PCTCN2023071429-appb-000042
为
Figure PCTCN2023071429-appb-000043
In another preferred example, when M is a bond,
Figure PCTCN2023071429-appb-000042
for
Figure PCTCN2023071429-appb-000043
在另一优选例中，所述化合物具有式V所示的结构In another preferred example, the compound has the structure shown in formula V
Figure PCTCN2023071429-appb-000044
Figure PCTCN2023071429-appb-000044
q、R u、R v、R w、R 1、R 2、R 3、R 4、L和A的定义如上所述。 q, R u , R v , R w , R 1 , R 2 , R 3 , R 4 , L and A are as defined above.
在另一优选例中，R u选自：-OP(＝O)(OR j’) 2、-P(＝O)(NHR j’) 2、-P(＝O)(OR j’) 2、-B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-NHSO 2R f’或-NH 2SO 2NR f’R g’；优选地，R u选自：-B(OH) 2、P(＝O)(OH) 2、P(＝O)(OCH 2CH 3) 2、P(＝O)(OCH 2CF 3) 2、P(＝O)(OCH 2COOCH 3) 2、P(＝O)(OCH 2COOCH 2CH 3) 2、P(＝O)(OCH 2COOCH 2CH 2CH 3) 2、P(＝O)(OCH 2COOC(CH 3) 3) 2、P(＝O)(OCH 2OCOCH 3) 2、P(＝O)(OCH 2OCOCH 2CH 3) 2、P(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、P(＝O)(OCH 2OCOC(CH 3) 3) 2、P(＝O)(NHCH 2COOCH 3) 2、P(＝O)(NHCH 2COOCH 2CH 3) 2、P(＝O)(NHCH 2COOCH 2CH 2CH 3) 2、SO 2NH 2、OP(＝O)(OH) 2、OP(＝O)(OCH 2CH 3) 2、OP(＝O)(OCH 2CF 3) 2、OP(＝O)(OCH 2COOCH 3) 2、OP(＝O)(OCH 2COOCH 2CH 3) 2、OP(＝O)(OCH 2COOCH 2CH 2CH 3) 2、OP(＝O)(OCH 2COOC(CH 3) 3) 2、OP(＝O)(OCH 2OCOCH 3) 2、OP(＝O)(OCH 2OCOCH 2CH 3) 2、OP(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、OP(＝O)(OCH 2OCOC(CH 3) 3) 2、OP(＝O)(NHCH 2COOCH 3) 2、OP(＝O)(NHCH 2COOCH 2CH 3) 2、OP(＝O)(NHCH 2COOCH 2CH 2CH 3) 2。 In another preferred example, R u is selected from: -OP(=O)(OR j' ) 2 , -P(=O)(NHR j' ) 2 , -P(=O)(OR j' ) 2 , -B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -NHSO 2 R f' or -NH 2 SO 2 NR f' R g' ; preferably, R u selected from: -B(OH) 2 , P(=O)(OH) 2 , P(=O)(OCH 2 CH 3 ) 2 , P(=O)(OCH 2 CF 3 ) 2 , P(=O )(OCH 2 COOCH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , P(=O)(OCH 2 COOC (CH 3 ) 3 ) 2 , P(=O)(OCH 2 OCOCH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOC(CH 3 ) 3 ) 2 , P(=O)(NHCH 2 COOCH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , P( =O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 , SO 2 NH 2 , OP(=O)(OH) 2 , OP(=O)(OCH 2 CH 3 ) 2 , OP(=O)(OCH 2 CF 3 ) 2 , OP(=O)(OCH 2 COOCH 3 ) 2 , OP(=O)(OCH 2 COOCH 2 CH 3 ) 2 , OP(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , OP(=O)(OCH 2 COOC(CH 3 ) 3 ) 2 , OP(=O)(OCH 2 OCOCH 3 ) 2 , OP(=O)(OCH 2 OCOCH 2 CH 3 ) 2 , OP(=O )(OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , OP(=O)(OCH 2 OCOC(CH 3 ) 3 ) 2 , OP(=O)(NHCH 2 COOCH 3 ) 2 , OP(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , OP(=O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 .
在另一优选例中，R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OC 1～C 6烷基。 In another preferred example, R v is selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, halogen, cyano, -OC 1 -C 6 alkyl.
在另一优选例中，R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OC 1～C 6烷基。 In another preferred example, R w is selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by halogen, halogen, cyano, -OC 1 -C 6 alkyl.
在另一优选例中，R t选自：-(CH 2)-R s、-(CH 2) 2-R s、-(CH 2) 3-R s、-(CH 2)-O-(CH 2)R s、-(CH 2) 2-O-(CH 2)R s、-(CH 2) 3-O-(CH 2)R s、-(CH 2)-O-(CH 2) 2R s、-(CH 2) 2-O-(CH 2) 2R s、-(CH 2) 3-O-(CH 2) 2R s，R s的定义如上所述，优选地，R s为
Figure PCTCN2023071429-appb-000045
In another preferred example, R t is selected from: -(CH 2 )-R s , -(CH 2 ) 2 -R s , -(CH 2 ) 3 -R s , -(CH 2 )-O-( CH 2 )R s , -(CH 2 ) 2 -O-(CH 2 )R s , -(CH 2 ) 3 -O-(CH 2 )R s , -(CH 2 )-O-(CH 2 ) 2 R s , -(CH 2 ) 2 -O-(CH 2 ) 2 R s , -(CH 2 ) 3 -O-(CH 2 ) 2 R s , R s is defined as above, preferably, R s for
Figure PCTCN2023071429-appb-000045
在另一优选例中，
Figure PCTCN2023071429-appb-000046
为
Figure PCTCN2023071429-appb-000047
R u、R v、R w的定义如上所述。 In another preferred example,
Figure PCTCN2023071429-appb-000046
for
Figure PCTCN2023071429-appb-000047
R u , R v , R w are as defined above.
在另一优选例中，
Figure PCTCN2023071429-appb-000048
选自：
Figure PCTCN2023071429-appb-000049
Figure PCTCN2023071429-appb-000050
In another preferred example,
Figure PCTCN2023071429-appb-000048
selected from:
Figure PCTCN2023071429-appb-000049
Figure PCTCN2023071429-appb-000050
在另一优选例中，所述化合物的前药具有式III或III’所示的结构In another preferred example, the prodrug of the compound has the structure shown in formula III or III'
Figure PCTCN2023071429-appb-000051
Figure PCTCN2023071429-appb-000051
式中，In the formula,
E选自：O或NH；E is selected from: O or NH;
R x和R y各自独立地选自：-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’、C 1～C 6烷基或卤代C 1～C 6烷基；或者-ER x和-ER y与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； R x and R y are each independently selected from: -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' , C 1 ～C 6 alkyl or halogenated C 1 ～ C 6 alkyl; or -ER x and -ER y together with the P atom they are connected to form a saturated or unsaturated 4-6 membered heterocyclic ring substituted by 0 to 4 R m ;
m”、X、Y、Z、W、R m、R k’、L和A的定义如上所述。 m", X, Y, Z, W, Rm , Rk ' , L and A are as defined above.
在另一优选例中，-ER x和-ER y与它们连接的P原子共同形成0～4个R m取代
Figure PCTCN2023071429-appb-000052
R m选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基、苯基、5-6元杂芳基、卤素取代的苯基(如氯苯)、C 1～C 6烷基取代的苯基、卤素取代的5-6元杂芳基、C 1～C 6烷基取代的5-6元杂芳基。 In another preferred example, -ER x and -ER y together form 0 to 4 R m substitutions with their connected P atoms
Figure PCTCN2023071429-appb-000052
R m is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl (such as chlorobenzene), C 1 ~C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ~C 6 Alkyl substituted 5-6 membered heteroaryl.
在另一优选例中，X、Y、Z、W、R 1、R 2、R 3、R 4、R t、R x、R y、L和A为实施例中各具体化合物所对应基团。 In another preferred example, X, Y, Z, W, R 1 , R 2 , R 3 , R 4 , R t , R x , R y , L and A are the groups corresponding to the specific compounds in the examples .
在另一优选例中，所述化合物选自以下化合物：In another preferred embodiment, the compound is selected from the following compounds:
Figure PCTCN2023071429-appb-000053
Figure PCTCN2023071429-appb-000053
Figure PCTCN2023071429-appb-000054
Figure PCTCN2023071429-appb-000054
Figure PCTCN2023071429-appb-000055
Figure PCTCN2023071429-appb-000055
Figure PCTCN2023071429-appb-000056
Figure PCTCN2023071429-appb-000056
Figure PCTCN2023071429-appb-000057
Figure PCTCN2023071429-appb-000057
本发明第二方面，提供一种药物组合物，其含有治疗有效量的一种或多种如第一方面所述的化合物、或其药学上可接受的盐或前药，和药学上可接受的载体、辅料或赋形剂。The second aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of one or more compounds as described in the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant or excipient.
本发明第三方面，提供一种第一方面所述的化合物、或其药学上可接受的盐或前药或第二方面所述的药物组合物在制备免疫佐剂或抑制ENPP1药物中的用途。In the third aspect of the present invention, there is provided a compound described in the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition described in the second aspect in the preparation of an immune adjuvant or an ENPP1-inhibiting drug .
本发明第四方面，提供一种第一方面所述的化合物、或其药学上可接受的盐或前药或第二所述的药物组合物在制备治疗与ENPP1活性相关的疾病的药物中的用途，所述与ENPP1活性相关的疾病是与炎性、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。In the fourth aspect of the present invention, there is provided a compound described in the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition described in the second aspect in the preparation of a drug for treating diseases related to ENPP1 activity purposes, the disease associated with ENPP1 activity is one or more of the diseases associated with inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.
本发明第五方面，提供一种治疗与ENPP1活性相关的疾病的方法，所述方法包括向受试者施用治疗有效量的第一方面所述的化合物、或其药学上可接受的盐或前药或第二方面所述的药物组合物。The fifth aspect of the present invention provides a method for treating diseases related to ENPP1 activity, the method comprising administering to a subject a therapeutically effective amount of the compound described in the first aspect, or a pharmaceutically acceptable salt or prodrug thereof Medicine or the pharmaceutical composition described in the second aspect.
在另一优选例中，本发明化合物可以制备成散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂等。In another preferred example, the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
具体实施方式Detailed ways
本发明人经过广泛而深入的研究，设计开发了一种结构新颖的化合物，并且实验结果表明，本发明化合物对ENPP1具有较好的抑制作用，能够用于制备治疗与抑制ENPP1或与ENPP1活性相关的疾病的药物。在此基础上完成了本发明。After extensive and in-depth research, the inventor has designed and developed a compound with novel structure, and the experimental results show that the compound of the present invention has a good inhibitory effect on ENPP1, and can be used for the preparation of therapeutic and inhibitory ENPP1 or related to ENPP1 activity. medicines for diseases. The present invention has been accomplished on this basis.
术语the term
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the usual meanings known to those skilled in the art.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
术语“烷基”本身或作为另一取代基的一部分，是指具有指定的碳原子数的直链或支链烃基(即，C1-C6是指包含1、2、3、4、5或6个碳原子)。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。本申请中，烷基还意在包含取代烷基，即烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (i.e., C1-C6 means 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like. In the present application, alkyl is also intended to include substituted alkyl, that is, one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position.
术语“烯基”表示含一个或多个双键且通常长度为2至20个碳原子(或C2-C8)的直链或支链的烃基。例如，本发明中，“C2-C6烯基”含有2、3、4、5或6个碳原子的烯基，“C3-C6烯基”。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。本发明中，烯基包括取代的烯基。The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms (or C2-C8). For example, in the present invention, "C2-C6 alkenyl" is an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms, and "C3-C6 alkenyl". Alkenyl groups include, but are not limited to, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl includes substituted alkenyl.
术语“炔基”表示含一个或多个三键且通常长度为2至20个碳原子(或C2-C8)的直链或支链的烃基。本发明中，“C2-C6炔基”是指具有2、3、4、5或6个碳原子的直链或支链 的炔基，包括但不限于乙炔基、丙炔基或类似基团。本发明中，炔基还包括取代炔基，取代基可以为卤代、羟基、氰基、硝基等。The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms (or C2-C8). In the present invention, "C2-C6 alkynyl" refers to a straight or branched alkynyl group with 2, 3, 4, 5 or 6 carbon atoms, including but not limited to ethynyl, propynyl or similar groups . In the present invention, the alkynyl group also includes a substituted alkynyl group, and the substituents may be halo, hydroxyl, cyano, nitro, etc.
术语"烷氨基"指通过氨基连接于分子的其余部分的烷基，本发明中，“C 1～C 6烷氨基”具有式C 1～C 6烷基-NH-。 The term "alkylamino" refers to an alkyl group linked to the rest of the molecule through an amino group. In the present invention, "C 1 -C 6 alkylamino" has the formula C 1 -C 6 alkyl-NH-.
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团，例如-CH 2CH 2CH 2CH 2-。烷基(或亚烷基)通常具有1-24个碳原子，其中本发明优选具有3个或更少碳原子的那些基团(如C 1～C 3亚烷基)。类似地，“亚烯基”或“亚炔基”分别指具有双键或三键的不饱和形式的“亚烷基”。“亚烯基”或“亚炔基”的实例包括但不限于：亚乙烯基、亚丙烯基、
Figure PCTCN2023071429-appb-000058
Figure PCTCN2023071429-appb-000059
等。 The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkane, eg -CH2CH2CH2CH2- . Alkyl (or alkylene) groups generally have 1 to 24 carbon atoms, with those groups having 3 or fewer carbon atoms (eg, C 1 -C 3 alkylene) being preferred in the present invention. Similarly, "alkenylene" or "alkynylene" refers to an unsaturated form of "alkylene" having double or triple bonds, respectively. Examples of "alkenylene" or "alkynylene" include, but are not limited to: ethenylene, propenylene,
Figure PCTCN2023071429-appb-000058
Figure PCTCN2023071429-appb-000059
wait.
本发明中，“C1-C6烷氧基(C1-C6烷基-O-)”是指具有1至6个碳原子的直链或支链或环状烷氧基(如C3-C6环烷氧基)，代表性的例子包括(但并不限于)：甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C3烷氧基。In the present invention, "C1-C6 alkoxy (C1-C6 alkyl-O-)" refers to a straight chain or branched chain or cyclic alkoxy group (such as C3-C6 cycloalkane) having 1 to 6 carbon atoms oxy), representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preference is given to C1-C3 alkoxy.
术语“环烷基”是指包括饱和单环或双环(如，稠合双环或螺双环)或多环的环状烷基。本发明中，“3～6元环烷基”指包括3、4、5、6个碳原子的环状烷基。本发明的代表性的环烷基包括但不限于：环丙基、环丁基、环戊基、环己基等。应理解，取代或未取代的环烷基，例如支化环烷基(如1-甲基环丙基和2-甲基环丙基)，均包括在“环烷基”的定义中。The term "cycloalkyl" refers to cyclic alkyl groups including saturated monocyclic or bicyclic (eg, fused bicyclic or spirobicyclic) or polycyclic rings. In the present invention, "3-6 membered cycloalkyl" refers to a cyclic alkyl group including 3, 4, 5, or 6 carbon atoms. Representative cycloalkyl groups of the invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. It is to be understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included within the definition of "cycloalkyl".
术语“杂环烷基”是指是指含有一至五个选自N、O和S的杂原子的环烷基，其中氮和硫原子任选被氧化，且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。本发明中，“3～6元杂环烷基”是指C3～6环烷基中的1或2个环C原子被选自N、O和S的杂原子取代的基团，杂环烷基的例子包括但不限于：吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、苯邻二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以经环碳或杂原子连接于分子的其余部分。The term "heterocycloalkyl" refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heterocycloalkyl groups can be monocyclic, bicyclic or polycyclic ring systems. In the present invention, "3-6 membered heterocycloalkyl" refers to a group in which 1 or 2 ring C atoms in a C3-6 cycloalkyl group are replaced by heteroatoms selected from N, O and S, heterocycloalkane Examples of radicals include, but are not limited to: pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine , 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3- Pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. A heterocycloalkyl group can be attached to the remainder of the molecule via a ring carbon or a heteroatom.
术语“杂环基”是指具有选自N、S和O的杂原子的饱和或部分饱和的环状基团，其可以是单环，也可以是双环形式，例如桥环或螺环形式。杂环基优选3-10元杂环基，更优选5-8元，更优选地为4-6元杂环基，更优选地为5-6元杂环基。杂环基的实例包括但不限于：氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基和吡咯烷基等。所述杂环基可以稠合于芳基、杂芳基、杂环基或环烷基环上(如形成[5+5]、[6+5]或[6+6]稠合环系等)，其中与母体结构连接在一起的环为杂环基。The term "heterocyclyl" refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S and O, which may be monocyclic or bicyclic, such as bridged ring or spiro ring. The heterocyclic group is preferably a 3-10-membered heterocyclic group, more preferably a 5-8-membered heterocyclic group, more preferably a 4-6-membered heterocyclic group, and more preferably a 5-6-membered heterocyclic group. Examples of heterocyclic groups include, but are not limited to: oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl, etc. . The heterocyclic group can be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring (such as forming a [5+5], [6+5] or [6+6] fused ring system, etc. ), wherein the ring attached to the parent structure is a heterocyclyl.
本发明中，术语“芳基”是指在环上不含杂原子的芳香族环基，所述芳基可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。如苯基(即C6芳基或六元芳基)、萘基(即C10芳基或[6+6]芳基)等，其中六元芳基还意在包含六元芳基并5-6元环烷基和六元芳基并5-6元杂环基。术语“[5+6]芳基”是指稠合的6、5双环 体系。本发明中，C5～C12芳基优选为C6-C12芳基，更优选地为C6-C10芳基。芳基的实例包括苯基、萘基。芳基可以是任选取代的或未取代的。In the present invention, the term "aryl" refers to an aromatic ring group that does not contain heteroatoms in the ring, and the aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the The rings joined together are aryl rings. Such as phenyl (that is, C6 aryl or six-membered aryl), naphthyl (that is, C10 aryl or [6+6] aryl), etc., wherein the six-membered aryl is also intended to include six-membered aryl and 5-6 One-membered cycloalkyl and six-membered aryl and 5-6-membered heterocyclic group. The term "[5+6]aryl" refers to a fused 6,5 bicyclic ring system. In the present invention, the C5-C12 aryl group is preferably a C6-C12 aryl group, more preferably a C6-C10 aryl group. Examples of aryl include phenyl, naphthyl. Aryl groups can be optionally substituted or unsubstituted.
术语“杂芳基”指具有1-3个原子为选自下组N、S和O的杂原子的环状芳香基，其可以是单环，也可以是稠环形式。本发明中，杂芳基优选地为5-6元杂芳基。杂芳基的实例包括但不限于：吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。术语“[5+6]杂芳基”是指稠合的6、5双环体系，如苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并三唑基、苯并噻唑基、苯并噻二唑基、苯并噁唑基等。The term "heteroaryl" refers to a cyclic aromatic group with 1-3 atoms being heteroatoms selected from the group consisting of N, S and O, which may be a single ring or a condensed ring. In the present invention, the heteroaryl group is preferably a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring. The term "[5+6]heteroaryl" refers to a fused 6,5 bicyclic ring system, such as benzothienyl, benzofuryl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiazolyl, Thiadiazolyl, benzoxazolyl, etc.
本发明中“碳环或杂环”单独或作为其他基团的一部分是指单环的或双环的饱和的、部分饱和的或芳族的碳环(例如，如上所述的环烷基、环烯基、苯基等)，或者单环的或双环的的饱和的、部分饱和的或芳族的杂环(例如，如上所述的杂烷基、杂环基、杂芳基等)，其中，4～6元碳环或杂环是指包含4-6个环原子的碳环或杂环，优选地为5-6元碳环或杂环。碳环或杂环的实例包括，但不限于：环丙基、环丁基、环戊基、环己基、环戊烯基、环己烯基、环戊二烯基、环己二烯基、氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基、吡咯烷基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。"Carbocycle or heterocycle" in the present invention alone or as part of another group refers to a monocyclic or bicyclic saturated, partially saturated or aromatic carbocycle (for example, cycloalkyl, ring alkenyl, phenyl, etc.), or a monocyclic or bicyclic saturated, partially saturated or aromatic heterocycle (for example, heteroalkyl, heterocyclyl, heteroaryl, etc. as described above), wherein , A 4-6 membered carbocyclic or heterocyclic ring refers to a carbocyclic or heterocyclic ring containing 4-6 ring atoms, preferably a 5-6 membered carbocyclic or heterocyclic ring. Examples of carbocyclic or heterocyclic rings include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, Oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuryl, morpholinyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, Pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thiophene group, isoxazolyl, thiazolyl, oxazolyl, etc.
在本发明中，“氨基”是指具有-N(R)(R')结构，R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。In the present invention, "amino" refers to a -N(R)(R') structure, R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.
在本发明中，上述的烷基、烷氧基、环烷基、杂芳基、杂环烷基、烯基、炔基、杂环基、碳环基等中各基团可以是取代的或未取代的。In the present invention, each group in the above-mentioned alkyl, alkoxy, cycloalkyl, heteroaryl, heterocycloalkyl, alkenyl, alkynyl, heterocyclyl, carbocyclyl, etc. may be substituted or not replaced.
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom with a dissatisfied valence has sufficient hydrogen atoms to fill its valence.
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、氰基、硝基、氧代(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e，P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e、NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中，R a可以独立表示氢、氘、烷基、 环烷基、烯基、炔基、碳环或杂环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、碳环或杂环，或者R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、碳环或杂环可以任选取代。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。 In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by this invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aromatic ring, OR a , SR a , S (= O)Re e , S(=O) 2 R e , P(=O) 2 Re , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S ( =O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C( =O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O ) NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 R e , wherein, R a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, carbocycle or heterocycle, R b , R c and R d can independently represent hydrogen, deuterium, alkane Base, cycloalkyl, carbocycle or heterocycle, or R b and R c together with N atoms can form a heterocycle; Re can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring. The typical substituents mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, carbocycle or heterocycle may be optionally substituted. The substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1 -C6 ureido group, etc.
术语“卤代”或“卤素”包括氟、氯、溴和碘。The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.
术语“羟基”指-OH。The term "hydroxyl" refers to -OH.
本发明中的-C(O)NR aR b、-C(O)OR、-C(O)R、-NRC(O)R的-C(O)-表示由碳和氧两种原子通过双键链接而成的羰基(-C＝O-)，-CO 2-可以为-C(＝O)O-或-OC(＝O)-，例如，-CO 2R可以为-C(＝O)OR或-OC(＝O)R。 The -C(O)- of -C(O)NR a R b , -C(O)OR, -C(O)R, -NRC(O)R in the present invention means that the carbon and oxygen atoms pass through Carbonyl (-C=O-) formed by double bonds, -CO 2 - can be -C(=O)O- or -OC(=O)-, for example, -CO 2 R can be -C(= O)OR or -OC(=O)R.
活性成分active ingredient
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式(I)化合物、或其药学上可接受的盐或前药。As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to the compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。"Tautomer" refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography. ), see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; A.M.Stalcup, Chiral Separations, Annu.Rev.Anal.Chem.3 :341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc.Chem . Res. 1990, 23, 128.
药学上可接受的盐pharmaceutically acceptable salt
术语“药物上可接受的盐”是指具有类似于母体化合物的功效且在生物学上或其他 方面(例如，对受试者既无毒也无害)可接受的盐(包括两性离子等内盐)。因此，本发明的实施例提供了本发明化合物的药学上可接受盐。此处所用术语“盐”表示以下任何由无机和/或有机酸形成的酸式盐，以及由无机和/或有机碱形成的碱式盐。本发明化合物的盐可以由本领域普通技术人员已知的方法形成，例如，通过将本发明化合物与一定量的酸或碱(例如等当量的酸或碱)，在一种介质(例如，这种介质可以使得盐在其中沉淀；或者以水为介质，然后冻干。)中反应获得。The term "pharmaceutically acceptable salt" refers to a salt (including zwitterions, etc.) that is biologically or otherwise (e.g., neither toxic nor deleterious to a subject) acceptable in an efficacy similar to that of the parent compound. Salt). Accordingly, embodiments of the present invention provide pharmaceutically acceptable salts of compounds of the present invention. The term "salt" as used herein means any of the following acidic salts formed with inorganic and/or organic acids, and basic salts formed with inorganic and/or organic bases. Salts of compounds of the present invention can be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the present invention with an amount of acid or base (e.g., an equivalent amount of acid or base) in a medium (e.g., such The medium can allow the salt to precipitate therein; or use water as the medium and then freeze-dry.) to obtain the reaction.
示例性酸式盐包括乙酸酯、抗坏血酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、延胡索酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳酸盐、马来酸盐、甲基磺酸盐(“甲磺酸盐”)、萘磺酸盐、硝酸盐、草酸盐、磷酸盐、丙酸盐、水杨酸盐，琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐等。合适的酸式盐可通过将化合物的溶液与药学上可接受的酸(例如盐酸、硫酸、乙酸、三氟乙酸或苯甲酸)的溶液混合而制得。此外，适用于形成药用盐的酸还选自以下参考文献：①P.Stahl et al,Camille G(eds.)Handbook of Pharmaceutical Salts.Properties,Selection and Use.(2002)；②Zurich,Wiley-VCH.S.Berge el al,Journal of Pharmaceutical Sciences(1977)66(1),1-19；③P.Gould,International J.of Pharmaceutics(1986)33,201-217；④Anderson el al,The Practice of Medicinal Chemistry(1996),Academic Press,New York；⑤The Orange Book(Food&Drug Administration,Washing,D.C.on their website).Exemplary acid salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate , hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, Phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, etc. Suitable acid salts can be prepared by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid. In addition, acids suitable for the formation of pharmaceutically acceptable salts are also selected from the following references: ① P. Stahl et al, Camille G (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002); ② Zurich, Wiley-VCH. S.Berge el al, Journal of Pharmaceutical Sciences(1977)66(1),1-19; ③P.Gould, International J.of Pharmaceuticals(1986)33,201-217; ④Anderson el al, The Practice of Medicinal Chemistry(1996) , Academic Press, New York; ⑤ The Orange Book (Food & Drug Administration, Washing, D.C. on their website).
示例性碱式盐包括铵盐、碱金属盐(例如钠、锂和钾盐)、碱土金属盐(例如钙和镁盐)、含有机碱(例如有机胺)的盐(例如二环己胺)、叔丁胺、胆碱和含氨基酸(例如精氨酸、赖氨酸)的盐等。碱性含氮基团可与诸如低烷基卤化物(例如，甲基、乙基和丁基氯化物、溴化物和碘化物)、二烷基硫酸盐(例如，二甲基、二乙基和二丁基硫酸盐)、长链卤化物(例如，癸基、月桂基和硬脂基氯化物、溴化物和碘化物)、芳烷基卤化物(例如，苄基和苯乙基溴化物)和其他等形成季铵盐。携带酸性基团的化合物可与适当的药学上可接受的盐混合制备碱金属盐(例如钠或钾盐)、碱土金属盐(例如钙或镁盐)和由适当的有机配体(例如季铵盐)形成的盐。此外，在存在羧基或羟基的情况下，药学上可接受的酯可用于改善化合物的溶解度或水解特性。Exemplary base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts containing organic bases such as organic amines such as dicyclohexylamine , tert-butylamine, choline and salts containing amino acids (such as arginine, lysine), etc. Basic nitrogen-containing groups can be combined with compounds such as lower alkyl halides (for example, methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (for example, dimethyl, diethyl and dibutyl sulfate), long-chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromide ) and others to form quaternary ammonium salts. Compounds carrying acidic groups can be mixed with appropriate pharmaceutically acceptable salts to prepare alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as calcium or magnesium salts) and formed by suitable organic ligands (such as quaternary ammonium salts). salt) formed salt. Additionally, in the presence of carboxy or hydroxyl groups, pharmaceutically acceptable esters can be used to improve the solubility or hydrolytic properties of the compounds.
所有这些酸式盐和碱式盐都是本发明范围内的药学上可接受的盐，并且为了本发明的目的，所有酸式盐和碱式盐都被认为等同于本发明的相应的母化合物。All such acid salts and base salts are pharmaceutically acceptable salts within the scope of the present invention, and all acid salts and base salts are considered equivalent to the corresponding parent compounds of the present invention for purposes of the present invention .
此外，当本发明化合物同时含有碱性基团(例如但不限于一级、二级、三级脂肪胺或环胺、芳香胺或杂芳基胺、吡啶或咪唑)和酸性基团(例如但不限于四唑或羧酸)时，可形成的两性离子(“内盐”)也包含在本发明专利的术语“盐”中。本发明的某些化合物可能以两性离子形式存在，在同一化合物中具有阴离子和阳离子中心，并且具有净中性电荷，这种两性离子也包含在本发明中。In addition, when the compounds of the present invention contain basic groups (such as but not limited to primary, secondary, tertiary aliphatic amines or cyclic amines, aromatic amines or heteroaryl (not limited to tetrazole or carboxylic acid), zwitterions ("inner salts") that can be formed are also included in the term "salt" in the patent of the present invention. Certain compounds of the present invention may exist as zwitterions having anionic and cationic centers in the same compound and having a net neutral charge, and such zwitterions are also encompassed by the present invention.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
由于本发明化合物具有优异的ENPP1酶的抑制活性，因此本发明化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)ENPP1酶相关疾病例如，炎性疾病(寻常性痤疮、哮喘、腹腔疾病、慢性前列腺炎、肾小球肾炎、炎症性肠病、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症和间质性膀胱炎)、自身免疫性疾病、感染性疾病(如乙肝病毒，人乳头瘤病毒，鼻咽癌相关EB病毒、单纯疱疹病毒)、癌症(如结肠癌、乳腺癌、肺癌、黑素瘤、肝癌、胃癌、宫颈癌、卵巢癌、纤维肉瘤和鳞状细胞癌、脑癌等癌症)、癌前期综合征相关的疾病。Since the compound of the present invention has excellent ENPP1 enzyme inhibitory activity, the compound of the present invention or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, and the compound containing the present invention are the main activity The pharmaceutical composition of the ingredients can be used to prevent and/or treat (stabilize, alleviate or cure) ENPP1 enzyme-related diseases, for example, inflammatory diseases (acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation due to house dust mite, and interstitial cystitis), autoimmune disease, infectious disease (such as hepatitis B virus , human papillomavirus, nasopharyngeal carcinoma-associated Epstein-Barr virus, herpes simplex virus), cancers such as colon, breast, lung, melanoma, liver, stomach, cervix, ovary, fibrosarcoma, and squamous cell carcinoma , brain cancer and other cancers), precancerous syndrome-related diseases.
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises the compound of the present invention and pharmaceutically acceptable excipients or carriers in a safe and effective amount range. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2023071429-appb-000060
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween
Figure PCTCN2023071429-appb-000060
), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如STING激动剂)联合给药。The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as STING agonists.
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如STING激动剂)。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗STING激酶的活性或表达量相关的疾病。When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, STING agonists). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compound of the present invention for the prevention and/or treatment of STING Kinase activity or expression related diseases.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 20-500 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
化合物的制备方法Compound preparation method
以下方案中描述了制备式I所示化合物的方法。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。Methods for preparing compounds of formula I are described in the following schemes. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate a reaction or to avoid undesired side reaction products. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃-150℃，优选10℃-100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
优选地，所述式I化合物具有式vi所示的结构，其可通过如下方法制备：Preferably, the compound of formula I has a structure shown in formula vi, which can be prepared by the following method:
Figure PCTCN2023071429-appb-000061
Figure PCTCN2023071429-appb-000061
其中，以上n、A、B＝R u、R 1、R 2、R 3、R 4、R u、R v和R w的定义如上所述； Wherein, the above n, A, B=R u , R 1 , R 2 , R 3 , R 4 , R u , R v and R w are as defined above;
s1)在有机溶剂(如正丁醇)中，碱(如碳酸钾、三乙胺)存在下，化合物i与化合物i'反应，得到化合物ii；s1) In an organic solvent (such as n-butanol), in the presence of a base (such as potassium carbonate, triethylamine), react compound i with compound i' to obtain compound ii;
s2)在有机溶剂中，化合物ii与还原剂(如连二亚硫酸钠)发生还原反应，得到化合物iii；s2) In an organic solvent, compound ii undergoes a reduction reaction with a reducing agent (such as sodium dithionite) to obtain compound iii;
s3)在有机溶剂中，化合物iii与氰化物(如溴化氰)反应，得到化合物iv；s3) In an organic solvent, compound iii is reacted with cyanide (such as cyanogen bromide) to obtain compound iv;
s4)在有机溶剂中，化合物iv在缩合剂(如EDCI和HOBT)存在下与羧酸
Figure PCTCN2023071429-appb-000062
反应，得到化合物v； s4) In an organic solvent, compound iv is combined with a carboxylic acid in the presence of a condensing agent (such as EDCI and HOBT)
Figure PCTCN2023071429-appb-000062
react to obtain compound v;
s5)在有机溶剂中，化合物v经正丁基锂、硼酸三异丙酯处理，或经三甲基溴硅烷处理，或经三氯氧磷处理后得到化合物vi。s5) In an organic solvent, compound v is treated with n-butyllithium, triisopropyl borate, trimethylbromosilane, or phosphorus oxychloride to obtain compound vi.
本发明的主要优点在于：The main advantages of the present invention are:
1.本发明的化合物结构新颖且具有优异的ENPP1酶抑制作用；1. The compound of the present invention has novel structure and excellent ENPP1 enzyme inhibitory effect;
2.本发明的化合物作为ENPP1抑制剂，能有效减少cGAMP的降解，进而促进I型干扰素的分泌；2. As an ENPP1 inhibitor, the compound of the present invention can effectively reduce the degradation of cGAMP, thereby promoting the secretion of type I interferon;
3.本发明化合物为临床上筛选和/或制备与ENPP1活性相关的疾病的药物提供了一种新的选择。3. The compound of the present invention provides a new option for clinically screening and/or preparing drugs for diseases related to ENPP1 activity.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。The experimental materials and reagents used in the following examples can be obtained from commercially available channels unless otherwise specified.
实施例Example
以下的实施例中的详细实验步骤将进一步具体阐述本发明。这些示例化合物在下面的实施例中以中性形式绘制。在某些情况下，根据用于最终纯化的方法和/或内在分子性质，化合物被分离为盐。这些示例仅用于说明本发明，并不打算以任何方式限制本专利的范围。除另有定义或说明，本文中所使用的所有专业与科学用语均与本领域技术人员所熟悉的意义相同。The detailed experimental steps in the following examples will further specifically illustrate the present invention. These exemplified compounds are drawn in neutral form in the Examples below. In some cases, compounds were isolated as salts depending on the methods used for final purification and/or intrinsic molecular properties. These examples are for illustration of the invention only and are not intended to limit the scope of this patent in any way. Unless otherwise defined or stated, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art.
实施例1(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-1)Example 1 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) boronic acid (I-1)
Figure PCTCN2023071429-appb-000063
Figure PCTCN2023071429-appb-000063
步骤①：1-乙基-3-甲基-1H-吡唑-5-甲酸乙酯(1-1)Step ①: Ethyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (1-1)
Figure PCTCN2023071429-appb-000064
Figure PCTCN2023071429-appb-000064
2克3-甲基吡唑-5-甲酸乙酯溶于20毫升N,N-二甲基甲酰胺，冰浴下加入2.7克碳酸钾和1.25毫升碘乙烷，室温搅拌过夜。反应液加水，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝100：1柱层析纯化，得1-乙基-3-甲基-1H-吡唑-5-甲酸乙酯(1-1)无色透明液体1.1克，收率46.5％。ESI-MS(m/z):183.1[M+H] +. 2 g of ethyl 3-methylpyrazole-5-carboxylate was dissolved in 20 ml of N,N-dimethylformamide, 2.7 g of potassium carbonate and 1.25 ml of ethyl iodide were added under ice cooling, and stirred overnight at room temperature. The reaction solution was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=100:1 to obtain 1-ethyl-3-methyl-1H-pyrazole- 5-Ethyl carboxylate (1-1) 1.1 g of colorless transparent liquid, yield 46.5%. ESI-MS(m/z):183.1[M+H] + .
步骤②：1-乙基-3-甲基-1H-吡唑-5-羧酸(1-2)Step ②: 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1-2)
Figure PCTCN2023071429-appb-000065
Figure PCTCN2023071429-appb-000065
1.1克1-1、263毫克氢氧化锂、2毫升水和4毫升甲醇混合物在室温搅拌2小时。反应液旋干，残余物加水稀释，加入1M HCl，析出白色固体，抽滤得1-乙基-3-甲基-1H-吡唑-5-羧酸(1-2)白色固体506毫克，收率59.8％。ESI-MS(m/z):155.1[M+H] +. A mixture of 1.1 g of 1-1, 263 mg of lithium hydroxide, 2 ml of water and 4 ml of methanol was stirred at room temperature for 2 hours. The reaction solution was spin-dried, the residue was diluted with water, 1M HCl was added, a white solid was precipitated, and 506 mg of a white solid of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1-2) was obtained by suction filtration. Yield 59.8%. ESI-MS(m/z):155.1[M+H] + .
步骤③：4-((4-溴苯乙基)氨基)-3-硝基苯甲腈(1-3)Step ③: 4-((4-bromophenethyl)amino)-3-nitrobenzonitrile (1-3)
Figure PCTCN2023071429-appb-000066
Figure PCTCN2023071429-appb-000066
1克4-氯-3-硝基苯甲腈、2.2克4-溴苯乙胺、1.5克碳酸钾和554毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴苯乙基)氨基)-3-硝基苯甲腈(1-3)黄色固体1.1克，收率58％。ESI-MS(m/z):346.0[M+H] +. 1 g of 4-chloro-3-nitrobenzonitrile, 2.2 g of 4-bromophenethylamine, 1.5 g of potassium carbonate and 554 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 1.1 g of a yellow solid of 4-((4-bromophenethyl)amino)-3-nitrobenzonitrile (1-3), with a yield of 58%. ESI-MS(m/z):346.0[M+H] + .
步骤④：3-氨基-4-((4-溴苯乙基)氨基)苯甲腈(1-4)Step ④: 3-amino-4-((4-bromophenethyl)amino)benzonitrile (1-4)
Figure PCTCN2023071429-appb-000067
Figure PCTCN2023071429-appb-000067
将1.8克1-3、6.3克连二亚硫酸钠、4毫升氨水和20毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得3-氨基-4-((4-溴苯乙基)氨基)苯甲腈(1-4)白色固体1克，收率60％。ESI-MS(m/z):316.1[M+H] +. A mixture of 1.8 g of 1-3, 6.3 g of sodium dithionite, 4 ml of aqueous ammonia and 20 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromophenethyl)amino)benzonitrile (1 -4) 1 g of white solid, yield 60%. ESI-MS(m/z):316.1[M+H] + .
步骤⑤：2-氨基-1-(4-溴苯乙基)-1H-苯并[d]咪唑-5-甲腈(1-5)Step ⑤: 2-amino-1-(4-bromophenethyl)-1H-benzo[d]imidazole-5-carbonitrile (1-5)
Figure PCTCN2023071429-appb-000068
Figure PCTCN2023071429-appb-000068
将100毫克1-4和40毫克溴化氰溶于2毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得2-氨基-1-(4-溴苯乙基)-1H-苯并[d]咪唑-5-甲腈(1-5)白色固体95毫克，收率88％。ESI-MS(m/z):341.1[M+H] +. 100 mg of 1-4 and 40 mg of cyanogen bromide were dissolved in 2 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromophenethyl)-1H-benzo[d]imidazole-5- Formaldehyde (1-5) 95 mg white solid, yield 88%. ESI-MS(m/z):341.1[M+H] + .
步骤⑥：N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(1-6)Step ⑥: N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole -5-Carboxamide (1-6)
Figure PCTCN2023071429-appb-000069
Figure PCTCN2023071429-appb-000069
将100毫克1-5、52毫克化合物1-2、91毫克EDCI、13.5毫克HOBT、59毫克三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(1-6)白色固体102毫克，收率72.9％。 1H NMR(300MHz,DMSO-d 6)δ12.90(s,1H),7.78(s,1H),7.70–7.55(m,2H),7.41(d,J＝8.2Hz,2H),7.19(d,J＝8.2Hz,2H),6.66(s,1H),4.60(q,J＝7.1Hz,2H),4.44(t,J＝7.2Hz,2H),3.07(t,J＝7.1Hz,2H),2.20(s,3H),1.35(t,J＝7.1Hz,3H). A mixture of 100 mg of 1-5, 52 mg of compound 1-2, 91 mg of EDCI, 13.5 mg of HOBT, 59 mg of triethylamine, and 2 mL of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d] Imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (1-6) 102 mg white solid, yield 72.9%. 1 H NMR (300MHz, DMSO-d 6 ) δ12.90(s, 1H), 7.78(s, 1H), 7.70–7.55(m, 2H), 7.41(d, J=8.2Hz, 2H), 7.19( d, J=8.2Hz, 2H), 6.66(s, 1H), 4.60(q, J=7.1Hz, 2H), 4.44(t, J=7.2Hz, 2H), 3.07(t, J=7.1Hz, 2H), 2.20(s, 3H), 1.35(t, J=7.1Hz, 3H).
步骤⑦：(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-1)Step ⑦: (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) boronic acid (I-1)
Figure PCTCN2023071429-appb-000070
Figure PCTCN2023071429-appb-000070
氮气保护下，将100毫克化合物1-6溶于2毫升四氢呋喃中，在-78℃下搅拌20分钟后，加入409毫克正丁基锂，在-78℃下搅拌1小时后，加入157毫克硼酸三异丙酯，室温搅拌1小时后，加入3M HCl淬灭。以二氯甲烷萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-1)淡黄色固体25毫克，收率26.9％。ESI-MS(m/z):443.10[M+H] +. Under nitrogen protection, 100 mg of compound 1-6 was dissolved in 2 ml of tetrahydrofuran, stirred at -78°C for 20 minutes, added 409 mg of n-butyllithium, stirred at -78°C for 1 hour, added 157 mg of boric acid Triisopropyl ester was stirred at room temperature for 1 hour, then quenched by adding 3M HCl. Extracted with dichloromethane, the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-cyano-2-(1-ethyl- 3-Methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (I-1) light yellow solid 25 mg, yield 26.9 %. ESI-MS(m/z):443.10[M+H] + .
实施例2(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-2)Example 2 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) boronic acid (I-2)
Figure PCTCN2023071429-appb-000071
Figure PCTCN2023071429-appb-000071
步骤①：4-((4-溴代苄基)氨基)-3-硝基苯甲腈(2-1)Step ①: 4-((4-bromobenzyl)amino)-3-nitrobenzonitrile (2-1)
Figure PCTCN2023071429-appb-000072
Figure PCTCN2023071429-appb-000072
1克4-氯-3-硝基苯甲腈、2克4-溴苄胺、1.5克碳酸钾和1毫克三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴代苄基)氨基)-3-硝基苯甲腈(2-1)黄色固体1.5克，收率82.4％。 1H NMR(300MHz,CDCl 3)δ8.78(s,1H),8.56(d,J＝2.0Hz,1H),7.59(ddd,J＝9.0,2.0,0.7Hz,1H),7.56–7.52(m,2H),7.25–7.21(m,2H),6.85(d,J＝9.0Hz,1H),4.58(d,J＝5.7Hz,2H). 1 g of 4-chloro-3-nitrobenzonitrile, 2 g of 4-bromobenzylamine, 1.5 g of potassium carbonate and 1 mg of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 1.5 g of 4-((4-bromobenzyl)amino)-3-nitrobenzonitrile (2-1) as a yellow solid, with a yield of 82.4%. 1 H NMR (300MHz, CDCl 3 ) δ8.78 (s, 1H), 8.56 (d, J = 2.0Hz, 1H), 7.59 (ddd, J = 9.0, 2.0, 0.7Hz, 1H), 7.56–7.52 ( m,2H),7.25–7.21(m,2H),6.85(d,J=9.0Hz,1H),4.58(d,J=5.7Hz,2H).
步骤②：3-氨基-4-((4-溴代苄基)氨基)苯甲腈(2-2)Step ②: 3-amino-4-((4-bromobenzyl)amino)benzonitrile (2-2)
Figure PCTCN2023071429-appb-000073
Figure PCTCN2023071429-appb-000073
将1.8克2-1、6.6克连二亚硫酸钠、4毫升氨水和20毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得3-氨基-4-((4-溴代苄基)氨基)苯甲腈(2-2)白色固体1.1克，收率67.1％。ESI-MS(m/z):302.0[M+H] +. A mixture of 1.8 g of 2-1, 6.6 g of sodium dithionite, 4 ml of aqueous ammonia and 20 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromobenzyl)amino)benzonitrile (2- 2) 1.1 g of white solid, yield 67.1%. ESI-MS(m/z):302.0[M+H] + .
步骤③：2-氨基-1-(4-溴代苄基)-1H-苯并[d]咪唑-5-甲腈(2-3)Step ③: 2-amino-1-(4-bromobenzyl)-1H-benzo[d]imidazole-5-carbonitrile (2-3)
Figure PCTCN2023071429-appb-000074
Figure PCTCN2023071429-appb-000074
将1.2克2-2和504毫克溴化氰溶于10毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得2-氨基-1-(4-溴代苄基)-1H-苯并[d]咪唑-5-甲腈(2-3)白色固体1.1克，收率84.6％。ESI-MS(m/z):327.1[M+H] +. 1.2 g of 2-2 and 504 mg of cyanogen bromide were dissolved in 10 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromobenzyl)-1H-benzo[d]imidazole-5-methanol Nitrile (2-3) white solid 1.1 g, yield 84.6%. ESI-MS(m/z):327.1[M+H] + .
步骤④：N-(1-(4-溴代苄基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(2-4)Step ④: N-(1-(4-bromobenzyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole -5-formamide (2-4)
Figure PCTCN2023071429-appb-000075
Figure PCTCN2023071429-appb-000075
将750毫克2-3、424毫克化合物1-2、710毫克EDCI、105毫克HOBT、611微升三乙胺和4毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴代苄基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(2-4)白色固体610毫克，收率57.4％。 1H NMR(300MHz,DMSO-d 6)δ13.03(s,1H),7.83(s,1H),7.71–7.62(m,2H),7.58–7.51(m,2H),7.36(d,J＝8.2Hz,2H),6.71(s,1H),5.45(s,2H),4.57(q,J＝7.1Hz,2H),2.17(s,3H),1.31(t,J＝7.1Hz,3H). A mixture of 750 mg 2-3, 424 mg compound 1-2, 710 mg EDCI, 105 mg HOBT, 611 μl triethylamine and 4 ml N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromobenzyl)-5-cyano-1H-benzo[d]imidazole -2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (2-4) 610 mg of white solid, yield 57.4%. 1 H NMR (300MHz,DMSO-d 6 )δ13.03(s,1H),7.83(s,1H),7.71–7.62(m,2H),7.58–7.51(m,2H),7.36(d,J =8.2Hz,2H),6.71(s,1H),5.45(s,2H),4.57(q,J=7.1Hz,2H),2.17(s,3H),1.31(t,J=7.1Hz,3H ).
步骤⑤：(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-2)Step ⑤: (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) boronic acid (I-2)
Figure PCTCN2023071429-appb-000076
Figure PCTCN2023071429-appb-000076
氮气保护下,将200毫克化合物2-4溶于2毫升四氢呋喃中，在-78℃下搅拌20分钟后，加入1毫升正丁基锂，在-78℃下搅拌1小时后，加入398毫克硼酸三异丙酯，室温搅拌1小时后，加入3M HCl淬灭。以二氯甲烷萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-2)淡黄色固体42毫克，收率22.7％。 1H NMR(300MHz,DMSO-d 6)δ8.24–7.68(m,6H),7.42(dd,J＝53.4,8.1Hz,3H),6.69(s,1H),5.48(s,2H),2.19(d,J＝12.9Hz,3H),1.32(q,J＝7.6Hz,3H). Under the protection of nitrogen, dissolve 200 mg of compound 2-4 in 2 ml of tetrahydrofuran, stir at -78°C for 20 minutes, add 1 ml of n-butyl lithium, stir at -78°C for 1 hour, add 398 mg of boric acid Triisopropyl ester was stirred at room temperature for 1 hour, then quenched by adding 3M HCl. Extracted with dichloromethane, the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-cyano-2-(1-ethyl- 3-Methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (I-2) light yellow solid 42 mg, yield 22.7 %. 1 H NMR (300MHz, DMSO-d 6 )δ8.24–7.68 (m, 6H), 7.42 (dd, J=53.4, 8.1Hz, 3H), 6.69 (s, 1H), 5.48 (s, 2H), 2.19(d,J=12.9Hz,3H),1.32(q,J=7.6Hz,3H).
实施例3(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基) 乙基)苯基)硼酸(Ⅰ-3)Example 3 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- base) ethyl) phenyl) boronic acid (I-3)
Figure PCTCN2023071429-appb-000077
Figure PCTCN2023071429-appb-000077
步骤①：4-羟基-3-甲氧基-5-硝基苯甲腈(3-1)Step ①: 4-Hydroxy-3-methoxy-5-nitrobenzonitrile (3-1)
Figure PCTCN2023071429-appb-000078
Figure PCTCN2023071429-appb-000078
2克3-甲氧基-4-羟基苯甲腈溶于20毫升乙酸，冰浴下缓慢加入714微升硝酸，滴加完毕移去冰浴，室温搅拌1小时。反应液加水，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得4-羟基-3-甲氧基-5-硝基苯甲腈(3-1)黄色固体1.5克，收率56.7％。ESI-MS(m/z):193.0[M-H] -. 2 g of 3-methoxy-4-hydroxybenzonitrile was dissolved in 20 ml of acetic acid, and 714 μl of nitric acid was slowly added in ice bath. After the addition was complete, the ice bath was removed, and stirred at room temperature for 1 hour. The reaction solution was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 4-hydroxy-3-methoxy-5-nitrobenzene Mesonitrile (3-1) yellow solid 1.5 g, yield 56.7%. ESI-MS(m/z):193.0[MH] - .
步骤②：4-氯-3-甲氧基-5-硝基苯甲腈(3-2)Step ②: 4-chloro-3-methoxy-5-nitrobenzonitrile (3-2)
Figure PCTCN2023071429-appb-000079
Figure PCTCN2023071429-appb-000079
1克3-1溶于10毫升N,N-二甲基甲酰胺，冰浴下缓慢加入1.1毫升草酰氯，滴加完毕移去冰浴，80℃搅拌1小时。反应液加水，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得4-氯-3-甲氧基-5-硝基苯甲腈(3-2)淡黄色固体0.71克，收率64.8％。 1H NMR(400MHz,CDCl 3)δ11.13–11.10(m,1H),8.10(d,J＝1.9Hz,1H),7.30(d,J＝1.9Hz,1H),4.02(s,3H). 1 g of 3-1 was dissolved in 10 ml of N,N-dimethylformamide, and 1.1 ml of oxalyl chloride was slowly added under ice-cooling. After the addition was complete, the ice bath was removed, and stirred at 80°C for 1 hour. The reaction solution was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 4-chloro-3-methoxy-5-nitrobenzene Mesonitrile (3-2) 0.71 g of pale yellow solid, yield 64.8%. 1 H NMR (400MHz, CDCl 3 ) δ11.13–11.10 (m, 1H), 8.10 (d, J = 1.9Hz, 1H), 7.30 (d, J = 1.9Hz, 1H), 4.02 (s, 3H) .
步骤③：4-((4-溴苯乙基)氨基)-3-甲氧基-5-硝基苯甲腈(3-3)Step ③: 4-((4-bromophenethyl)amino)-3-methoxy-5-nitrobenzonitrile (3-3)
Figure PCTCN2023071429-appb-000080
Figure PCTCN2023071429-appb-000080
1克3-2、1.9克4-溴苯乙胺、1.3克碳酸钾和1毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴苯乙基)氨基)-3-甲氧基-5-硝基苯甲腈(3-3)黄色固体1.2克，收率67.8％。ESI-MS(m/z):376.1[M+H] +. 1 g of 3-2, 1.9 g of 4-bromophenethylamine, 1.3 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 1.2 g of 4-((4-bromophenethyl)amino)-3-methoxy-5-nitrobenzonitrile (3-3) yellow solid, yield 67.8 %. ESI-MS(m/z):376.1[M+H] + .
步骤④：3-氨基-4-((4-溴苯乙基)氨基)-5-甲氧基苯甲腈(3-4)Step ④: 3-amino-4-((4-bromophenethyl)amino)-5-methoxybenzonitrile (3-4)
Figure PCTCN2023071429-appb-000081
Figure PCTCN2023071429-appb-000081
将1克3-3、3.2克连二亚硫酸钠、2毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得3-氨基-4-((4-溴苯乙基)氨基)-5-甲氧基苯甲腈(3-4)白色固体740毫克，收率80.4％。 1H NMR(300MHz,CDCl 3)δ7.47–7.41(m,2H),7.15–7.09(m,2H),6.65(d,J＝1.7Hz,1H),6.57(d,J＝1.7Hz,1H),3.78(s,5H),3.26(t,J＝6.9Hz,2H),2.77(t,J＝6.9Hz,2H). A mixture of 1 g of 3-3, 3.2 g of sodium dithionite, 2 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromophenethyl)amino)-5-methoxy Benzonitrile (3-4) was 740 mg of white solid, and the yield was 80.4%. 1 H NMR (300MHz, CDCl 3 )δ7.47–7.41(m,2H),7.15–7.09(m,2H),6.65(d,J=1.7Hz,1H),6.57(d,J=1.7Hz, 1H), 3.78(s, 5H), 3.26(t, J=6.9Hz, 2H), 2.77(t, J=6.9Hz, 2H).
步骤⑤：2-氨基-1-(4-溴苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲腈(3-5)Step ⑤: 2-amino-1-(4-bromophenethyl)-7-methoxy-1H-benzo[d]imidazole-5-carbonitrile (3-5)
Figure PCTCN2023071429-appb-000082
Figure PCTCN2023071429-appb-000082
将220毫克3-4和74毫克溴化氰溶于2毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得2-氨基-1-(4-溴苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲腈(3-5)白色固体206毫克，收率87.3％。ESI-MS(m/z):371.1[M+H] +. 220 mg of 3-4 and 74 mg of cyanogen bromide were dissolved in 2 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromophenethyl)-7-methoxy-1H-benzo[ d] Imidazole-5-carbonitrile (3-5) 206 mg of white solid, yield 87.3%. ESI-MS(m/z):371.1[M+H] + .
步骤⑥：N-(1-(4-溴苯乙基)-5-氰基-7-甲氧基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(3-6)Step ⑥: N-(1-(4-bromophenethyl)-5-cyano-7-methoxy-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methanol Base-1H-pyrazole-5-carboxamide (3-6)
Figure PCTCN2023071429-appb-000083
Figure PCTCN2023071429-appb-000083
将1.18克3-5、588毫克化合物1-2、1.48克EDCI、147毫克HOBT、846微升三乙胺和10毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得N-(1-(4-溴苯乙基)-5-氰基-7-甲氧基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(3-6)白色固体920毫克，收率57％。 1H NMR(300MHz,DMSO-d 6)δ12.92(s,1H),7.48(d,J＝1.3Hz,1H),7.46–7.40(m,2H),7.33(d,J＝1.4Hz,1H),7.16–7.08(m,2H),6.63(s,1H),4.63–4.46(m,4H),3.95(s,3H),3.01(t,J＝7.3Hz,2H),2.20(s,3H),1.34(t,J＝7.1Hz,3H). A mixture of 1.18 g of 3-5, 588 mg of compound 1-2, 1.48 g of EDCI, 147 mg of HOBT, 846 μl of triethylamine and 10 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromophenethyl)-5-cyano-7-methoxy-1H -Benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (3-6) 920 mg white solid, yield 57%. 1 H NMR (300MHz, DMSO-d 6 )δ12.92(s,1H),7.48(d,J=1.3Hz,1H),7.46–7.40(m,2H),7.33(d,J=1.4Hz, 1H),7.16–7.08(m,2H),6.63(s,1H),4.63–4.46(m,4H),3.95(s,3H),3.01(t,J＝7.3Hz,2H),2.20(s ,3H),1.34(t,J=7.1Hz,3H).
步骤⑦：(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-3)Step ⑦: (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[ d] imidazol-1-yl) ethyl) phenyl) boronic acid (Ⅰ-3)
Figure PCTCN2023071429-appb-000084
Figure PCTCN2023071429-appb-000084
氮气保护下，将100毫克化合物3-6溶于2毫升四氢呋喃中，在-78℃下搅拌20分钟后，加入473微升正丁基锂，在-78℃下搅拌1小时后，加入788微升硼酸三异丙酯，室温搅拌1小时后，加入3M HCl淬灭。以二氯甲烷萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-3)淡黄色固体20毫克，收率21.5％。 1H NMR(300MHz,DMSO-d 6)δ12.86(s,1H),7.99(d,J＝6.2Hz,2H),7.81–7.71(m,2H),7.40(s,1H),7.22–7.17(m,1H),6.67(d,J＝11.3Hz,1H),4.69–4.48(m,4H),4.02(d,J＝6.3Hz,3H),3.06–2.99(m,2H),2.20(s,3H),1.35(dd,J＝9.1,4.9Hz,3H). Under the protection of nitrogen, 100 mg of compound 3-6 was dissolved in 2 ml of tetrahydrofuran, stirred at -78°C for 20 minutes, added 473 µl of n-butyllithium, stirred at -78°C for 1 hour, then added 788 µl Triisopropyl borate was added, stirred at room temperature for 1 hour, then quenched by adding 3M HCl. Extracted with dichloromethane, the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-cyano-2-(1-ethyl- 3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (I-3) pale yellow solid 20 mg, yield 21.5%. 1 H NMR (300MHz,DMSO-d 6 )δ12.86(s,1H),7.99(d,J＝6.2Hz,2H),7.81–7.71(m,2H),7.40(s,1H),7.22– 7.17(m,1H),6.67(d,J=11.3Hz,1H),4.69–4.48(m,4H),4.02(d,J=6.3Hz,3H),3.06–2.99(m,2H),2.20 (s,3H),1.35(dd,J=9.1,4.9Hz,3H).
实施例4(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)硼酸(Ⅰ-4)Example 4 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d] Imidazol-1-yl)methyl)phenyl)boronic acid (I-4)
Figure PCTCN2023071429-appb-000085
Figure PCTCN2023071429-appb-000085
步骤①：4-((4-溴代苄基)氨基)-3-甲氧基-5-硝基苯甲腈(4-1)Step ①: 4-((4-bromobenzyl)amino)-3-methoxy-5-nitrobenzonitrile (4-1)
Figure PCTCN2023071429-appb-000086
Figure PCTCN2023071429-appb-000086
1克3-2、1.75克4-溴苄胺、1.3克碳酸钾和1毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴代苄基)氨基)-3-甲氧基-5-硝基苯甲腈(4-1)黄色固体1.5克，收率88％。 1H NMR(300MHz,DMSO-d 6)δ8.47(t,J＝6.7Hz,1H),8.03(d,J＝1.9Hz,1H),7.55–7.45(m,2H),7.40(d,J＝1.9Hz,1H),7.19(d,J＝8.1Hz,2H),4.70(d,J＝6.6Hz,2H),3.79(s,3H). 1 g of 3-2, 1.75 g of 4-bromobenzylamine, 1.3 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 1.5 g of a yellow solid of 4-((4-bromobenzyl)amino)-3-methoxy-5-nitrobenzonitrile (4-1) in a yield of 88 %. 1 H NMR (300MHz, DMSO-d 6 )δ8.47(t, J=6.7Hz, 1H), 8.03(d, J=1.9Hz, 1H), 7.55–7.45(m, 2H), 7.40(d, J=1.9Hz, 1H), 7.19(d, J=8.1Hz, 2H), 4.70(d, J=6.6Hz, 2H), 3.79(s, 3H).
步骤②：3-氨基-4-((4-溴代苄基)氨基)-5-甲氧基苯甲腈(4-2)Step ②: 3-amino-4-((4-bromobenzyl)amino)-5-methoxybenzonitrile (4-2)
Figure PCTCN2023071429-appb-000087
Figure PCTCN2023071429-appb-000087
将1.6克4-1、5.3克连二亚硫酸钠、2毫升氨水和15毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得3-氨基-4-((4-溴代苄基)氨基)-5-甲氧基苯甲腈(4-2)白色固体1克，收率68％。 1H NMR(300MHz,CDCl 3)δ7.49–7.43(m,2H),7.22–7.16(m,2H),6.69(d,J＝1.7Hz,1H),6.56(d,J＝1.7Hz,1H),4.12(s,2H),3.92(d,J＝25.4Hz,2H),3.73(s,3H). A mixture of 1.6 g of 4-1, 5.3 g of sodium dithionite, 2 ml of aqueous ammonia and 15 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromobenzyl)amino)-5-methoxy 1 gram of white solid of benzonitrile (4-2), yield 68%. 1 H NMR (300MHz, CDCl 3 )δ7.49–7.43(m,2H),7.22–7.16(m,2H),6.69(d,J=1.7Hz,1H),6.56(d,J=1.7Hz, 1H), 4.12(s, 2H), 3.92(d, J=25.4Hz, 2H), 3.73(s, 3H).
步骤③：2-氨基-1-(4-溴代苄基)-7-甲氧基-1H-苯并[d]咪唑-5-甲腈(4-3)Step ③: 2-amino-1-(4-bromobenzyl)-7-methoxy-1H-benzo[d]imidazole-5-carbonitrile (4-3)
Figure PCTCN2023071429-appb-000088
Figure PCTCN2023071429-appb-000088
将940毫克4-2和360毫克溴化氰溶于5毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得2-氨基-1-(4-溴代苄基)-7-甲氧基-1H-苯并[d]咪唑-5-甲腈(4-3)白色固体900毫克，收率89％。ESI-MS(m/z):357.1[M+H] +. Dissolve 940 mg of 4-2 and 360 mg of cyanogen bromide in 5 ml of methanol and stir overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromobenzyl)-7-methoxy-1H-benzo[ d] Imidazole-5-carbonitrile (4-3) 900 mg white solid, yield 89%. ESI-MS(m/z):357.1[M+H] + .
步骤④：N-(1-(4-溴代苄基)-5-氰基-7-甲氧基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(4-4)Step ④: N-(1-(4-bromobenzyl)-5-cyano-7-methoxy-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methanol Base-1H-pyrazole-5-carboxamide (4-4)
Figure PCTCN2023071429-appb-000089
Figure PCTCN2023071429-appb-000089
将936毫克4-3、485毫克化合物1-2、1.22毫克EDCI、121毫克HOBT、698微升三乙胺和6毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得N-(1-(4-溴代苄基)-5-氰基-7-甲氧基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(4-4)白色固体720毫克，收率55.7％。 1H NMR(300MHz,DMSO-d 6)δ13.06(s,1H),7.55–7.49(m,3H),7.35(d,J＝1.3Hz,1H),7.31–7.25(m,2H),6.66(s,1H),5.52(s,2H),4.55(q,J＝7.1Hz,2H),3.90(s,3H),2.16(s,3H),1.29(t,J＝7.1Hz,3H). A mixture of 936 mg of 4-3, 485 mg of compound 1-2, 1.22 mg of EDCI, 121 mg of HOBT, 698 μl of triethylamine and 6 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromobenzyl)-5-cyano-7-methoxy-1H -Benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (4-4) 720 mg of white solid, yield 55.7%. 1 H NMR (300MHz,DMSO-d 6 )δ13.06(s,1H),7.55–7.49(m,3H),7.35(d,J=1.3Hz,1H),7.31–7.25(m,2H), 6.66(s,1H),5.52(s,2H),4.55(q,J=7.1Hz,2H),3.90(s,3H),2.16(s,3H),1.29(t,J=7.1Hz,3H ).
步骤⑤：(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)硼酸(Ⅰ-4)Step ⑤: (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d] Imidazol-1-yl)methyl)phenyl)boronic acid (I-4)
Figure PCTCN2023071429-appb-000090
Figure PCTCN2023071429-appb-000090
氮气保护下，将100毫克化合物4-4溶于2毫升四氢呋喃中，在-78℃下搅拌20分钟 后，加入486微升正丁基锂，在-78℃下搅拌1小时后，加入187微升硼酸三异丙酯，室温搅拌1小时后，加入3M HCl淬灭。以二氯甲烷萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)硼酸(Ⅰ-4)淡黄色固体16毫克，收率17.2％。 1H NMR(300MHz,DMSO-d 6)δ8.01(s,2H),7.83(s,1H),7.72(d,J＝7.5Hz,1H),7.40(s,1H),7.26(d,J＝7.7Hz,2H),6.65(s,1H),5.57(s,2H),3.91(s,3H),1.29(t,J＝7.1Hz,3H). Under the protection of nitrogen, 100 mg of compound 4-4 was dissolved in 2 ml of tetrahydrofuran. After stirring at -78 ° C for 20 minutes, 486 μl of n-butyllithium was added. After stirring at -78 ° C for 1 hour, 187 μl of Triisopropyl borate was added, stirred at room temperature for 1 hour, then quenched by adding 3M HCl. Extracted with dichloromethane, the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain (4-((5-cyano-2-(1-ethyl-3- Methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (I-4) light yellow solid 16 mg , yield 17.2%. 1 H NMR (300MHz, DMSO-d 6 )δ8.01(s, 2H), 7.83(s, 1H), 7.72(d, J=7.5Hz, 1H), 7.40(s, 1H), 7.26(d, J＝7.7Hz, 2H), 6.65(s, 1H), 5.57(s, 2H), 3.91(s, 3H), 1.29(t, J＝7.1Hz, 3H).
实施例5(4-((5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)硼酸(Ⅰ-5)Example 5 (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) phenyl) boronic acid (I-5)
Figure PCTCN2023071429-appb-000091
Figure PCTCN2023071429-appb-000091
步骤①：4-羟基-3-甲氧基-5-硝基苯甲酸乙酯(5-1)Step ①: Ethyl 4-hydroxy-3-methoxy-5-nitrobenzoate (5-1)
Figure PCTCN2023071429-appb-000092
Figure PCTCN2023071429-appb-000092
5克香草酸乙酯溶于42毫升乙酸，冰浴下缓慢加入4.2毫升硝酸，滴加完毕移去冰浴，室温搅拌1小时。反应液加水，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得4-羟基-3-甲氧基-5-硝基苯甲酸乙酯(5-1)棕色固体3.2克，收率52.1％。ESI-MS(m/z):264.1[M+Na] +. 5 g of ethyl vanillic acid was dissolved in 42 ml of acetic acid, and 4.2 ml of nitric acid was slowly added in an ice bath. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 4-hydroxy-3-methoxy-5-nitrobenzene Ethyl formate (5-1) brown solid 3.2 g, yield 52.1%. ESI-MS(m/z):264.1[M+Na] + .
步骤②：4-氯-3-甲氧基-5-硝基苯甲酸乙酯(5-2)Step ②: Ethyl 4-chloro-3-methoxy-5-nitrobenzoate (5-2)
Figure PCTCN2023071429-appb-000093
Figure PCTCN2023071429-appb-000093
5克5-1溶于45毫升N,N-二甲基甲酰胺，冰浴下缓慢加入5.3毫升草酰氯，滴加完毕移去冰浴，80℃搅拌1小时。反应液加水，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得4-氯-3-甲氧基-5-硝基苯甲酸乙酯(5-2)灰白色固体3.5克，收率65％。ESI-MS(m/z):282.0[M+Na] +. 5 g of 5-1 was dissolved in 45 ml of N,N-dimethylformamide, and 5.3 ml of oxalyl chloride was slowly added under ice-cooling. After the addition was complete, the ice bath was removed, and stirred at 80°C for 1 hour. The reaction solution was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 4-chloro-3-methoxy-5-nitrobenzene Ethyl formate (5-2) was 3.5 grams of off-white solid, and the yield was 65%. ESI-MS(m/z):282.0[M+Na] + .
步骤③：4-((4-溴代苄基)氨基)-3-甲氧基-5-硝基苯甲酸乙酯(5-3)Step ③: ethyl 4-((4-bromobenzyl)amino)-3-methoxy-5-nitrobenzoate (5-3)
Figure PCTCN2023071429-appb-000094
Figure PCTCN2023071429-appb-000094
1克5-2、1.43克4-溴苯乙胺、1克碳酸钾和1毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴代苄基)氨基)-3-甲氧基-5-硝基苯甲酸乙酯(5-3)黄色固体1.2克，收率76％。ESI-MS(m/z):409.1[M+H] +. 1 g of 5-2, 1.43 g of 4-bromophenethylamine, 1 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution, a solid was precipitated, and suction filtration gave 1.2 g of a yellow solid of ethyl 4-((4-bromobenzyl)amino)-3-methoxy-5-nitrobenzoate (5-3). 76%. ESI-MS(m/z):409.1[M+H] + .
步骤④：3-氨基-4-((4-溴代苄基)氨基)-5-甲氧基苯甲酸甲酯(5-4)Step ④: Methyl 3-amino-4-((4-bromobenzyl)amino)-5-methoxybenzoate (5-4)
Figure PCTCN2023071429-appb-000095
Figure PCTCN2023071429-appb-000095
将200毫克5-3、595毫克连二亚硫酸钠、0.5毫升氨水和2毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得3-氨基-4-((4-溴代苄基)氨基)-5-甲氧基苯甲酸甲酯(5-4)白色固体130毫克，收率70.1％。 1H NMR(300MHz,CDCl 3)δ7.46(d,J＝2.5Hz,1H),7.43(d,J＝1.9Hz,1H),7.24–7.18(m,2H),7.14(d,J＝1.8Hz,1H),7.02(d,J＝1.7Hz,1H),4.36(q,J＝7.1Hz,2H),4.15(s,2H),3.89(d,J＝16.7Hz,2H),3.76(s,3H),1.40(t,J＝7.1Hz,3H). A mixture of 200 mg of 5-3, 595 mg of sodium dithionite, 0.5 ml of aqueous ammonia and 2 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromobenzyl)amino)-5-methoxy 130 mg of methyl benzoate (5-4) as a white solid, with a yield of 70.1%. 1 H NMR (300MHz, CDCl 3 ) δ7.46(d, J=2.5Hz, 1H), 7.43(d, J=1.9Hz, 1H), 7.24–7.18(m, 2H), 7.14(d, J= 1.8Hz, 1H), 7.02(d, J=1.7Hz, 1H), 4.36(q, J=7.1Hz, 2H), 4.15(s, 2H), 3.89(d, J=16.7Hz, 2H), 3.76 (s,3H),1.40(t,J=7.1Hz,3H).
步骤⑤：2-氨基-1-(4-溴代苄基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(5-5)Step ⑤: Ethyl 2-amino-1-(4-bromobenzyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (5-5)
Figure PCTCN2023071429-appb-000096
Figure PCTCN2023071429-appb-000096
将510毫克5-4和170毫克溴化氰溶于4毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得2-氨基-1-(4-溴代苄基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(5-5)白色固体470毫克，收率86.5％。ESI-MS(m/z):404.1[M+H] +. 510 mg of 5-4 and 170 mg of cyanogen bromide were dissolved in 4 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromobenzyl)-7-methoxy-1H-benzo[ d] Ethyl imidazole-5-carboxylate (5-5) 470 mg of white solid, yield 86.5%. ESI-MS(m/z):404.1[M+H] + .
步骤⑥：1-(4-溴代苄基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(5-6)Step ⑥: 1-(4-bromobenzyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d ]Imidazole-5-ethyl carboxylate (5-6)
Figure PCTCN2023071429-appb-000097
Figure PCTCN2023071429-appb-000097
将530毫克5-5、222毫克化合物1-2、611毫克EDCI、61毫克HOBT、350微升三乙 胺和5毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得1-(4-溴代苄基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(5-6)白色固体370毫克，收率52％。 1H NMR(300MHz,DMSO-d 6)δ13.00(s,1H),7.83(dd,J＝5.8,1.3Hz,1H),7.57–7.48(m,2H),7.36(dd,J＝2.7,1.4Hz,1H),7.29(d,J＝8.4Hz,2H),6.65(s,1H),5.53(s,2H),4.56(q,J＝7.1Hz,2H),4.38–4.24(m,2H),3.90(d,J＝1.1Hz,3H),2.16(s,3H),1.31(dt,J＝9.7,7.1Hz,5H). A mixture of 530 mg of 5-5, 222 mg of compound 1-2, 611 mg of EDCI, 61 mg of HOBT, 350 μl of triethylamine and 5 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 1-(4-bromobenzyl)-2-(1-ethyl-3-methyl-1H- Ethyl pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (5-6) 370 mg white solid, yield 52%. 1 H NMR (300MHz, DMSO-d 6 ) δ13.00(s, 1H), 7.83(dd, J=5.8, 1.3Hz, 1H), 7.57–7.48(m, 2H), 7.36(dd, J=2.7 ,1.4Hz,1H),7.29(d,J=8.4Hz,2H),6.65(s,1H),5.53(s,2H),4.56(q,J=7.1Hz,2H),4.38–4.24(m ,2H),3.90(d,J=1.1Hz,3H),2.16(s,3H),1.31(dt,J=9.7,7.1Hz,5H).
步骤⑦：(4-((5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)硼酸(Ⅰ-5)Step ⑦: (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) phenyl) boronic acid (I-5)
Figure PCTCN2023071429-appb-000098
Figure PCTCN2023071429-appb-000098
氮气保护下，将100毫克化合物5-6溶于2毫升四氢呋喃中，在-78℃下搅拌20分钟后，加入473微升正丁基锂，在-78℃下搅拌1小时后，加入788微升硼酸三异丙酯，室温搅拌1小时后，加入3M HCl淬灭。以二氯甲烷萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得(4-((5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)硼酸(Ⅰ-5)淡黄色固体23毫克，收率24.6％。 1H NMR(300MHz,CDCl 3)δ12.16(s,1H),7.37(d,J＝8.0Hz,2H),7.02–6.66(m,5H),5.53(s,2H),4.70(q,J＝7.2Hz,2H),3.96(s,3H),2.30(s,3H),1.41(t,J＝7.0Hz,3H),0.86(q,J＝7.4,6.9Hz,6H). Under the protection of nitrogen, 100 mg of compound 5-6 was dissolved in 2 ml of tetrahydrofuran, stirred at -78°C for 20 minutes, added 473 µl of n-butyllithium, stirred at -78°C for 1 hour, then added 788 µl Triisopropyl borate was added, stirred at room temperature for 1 hour, then quenched by adding 3M HCl. Extracted with dichloromethane, the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain (4-((5-(ethoxycarbonyl)-2-(1-ethyl -3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyl)boronic acid (I-5) light yellow The solid was 23 mg, and the yield was 24.6%. 1 H NMR (300MHz, CDCl 3 ) δ12.16(s, 1H), 7.37(d, J=8.0Hz, 2H), 7.02–6.66(m, 5H), 5.53(s, 2H), 4.70(q, J＝7.2Hz, 2H), 3.96(s, 3H), 2.30(s, 3H), 1.41(t, J＝7.0Hz, 3H), 0.86(q, J＝7.4, 6.9Hz, 6H).
实施例6(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-6)Example 6 (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) phenyl) boronic acid (I-6)
Figure PCTCN2023071429-appb-000099
Figure PCTCN2023071429-appb-000099
步骤①：4-氯-3-甲氧基-5-硝基苯甲酰胺(6-1)Step ①: 4-chloro-3-methoxy-5-nitrobenzamide (6-1)
Figure PCTCN2023071429-appb-000100
Figure PCTCN2023071429-appb-000100
将5克4-氯-3-甲氧基-5-硝基苯甲酸甲酯和70毫升氨水放入封管中，于50℃加热搅 拌5小时。反应液倒入水中搅拌1小时，过滤干燥得黄色固体(6-1)3.77克，收率80.4％。LCMS(ESI)m/z[M+H] +:231.5. Put 5 g of methyl 4-chloro-3-methoxy-5-nitrobenzoate and 70 ml of ammonia water into a sealed tube, heat and stir at 50°C for 5 hours. The reaction solution was poured into water and stirred for 1 hour, filtered and dried to obtain 3.77 g of a yellow solid (6-1), with a yield of 80.4%. LCMS(ESI)m/z[M+H] + :231.5.
步骤②：4-((4-溴苯乙基)氨基)-3-甲氧基-5-硝基苯甲酰胺(6-2)Step ②: 4-((4-bromophenethyl)amino)-3-methoxy-5-nitrobenzamide (6-2)
Figure PCTCN2023071429-appb-000101
Figure PCTCN2023071429-appb-000101
1克6-1、2.6克4-溴苯乙胺、1.3克碳酸钾和1毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴苯乙基)氨基)-3-甲氧基-5-硝基苯甲酰胺(6-2)黄色固体1.3克，收率60.1％。LCMS(ESI)m/z[M+Na] +:418.0. 1 g of 6-1, 2.6 g of 4-bromophenethylamine, 1.3 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 1.3 g of 4-((4-bromophenethyl)amino)-3-methoxy-5-nitrobenzamide (6-2) as a yellow solid, yield 60.1 %. LCMS (ESI) m/z [M+Na] + : 418.0.
步骤③：3-氨基-4-((4-溴苯乙基)氨基)-5-甲氧基苯甲酰胺(6-3)Step ③: 3-amino-4-((4-bromophenethyl)amino)-5-methoxybenzamide (6-3)
Figure PCTCN2023071429-appb-000102
Figure PCTCN2023071429-appb-000102
将1.4克6-2、5克连二亚硫酸钠、2毫升氨水和15毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得3-氨基-4-((4-溴苯乙基)氨基)-5-甲氧基苯甲酰胺(6-3)白色固体850毫克，收率65.5％。LCMS(ESI)m/z:364.1[M+H] +. A mixture of 1.4 g of 6-2, 5 g of sodium dithionite, 2 ml of aqueous ammonia and 15 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromophenethyl)amino)-5-methoxy Benzyl benzamide (6-3) was 850 mg of white solid, and the yield was 65.5%. LCMS(ESI)m/z:364.1[M+H] + .
步骤④：2-氨基-1-(4-溴苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(6-4)Step ④: 2-amino-1-(4-bromophenethyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (6-4)
Figure PCTCN2023071429-appb-000103
Figure PCTCN2023071429-appb-000103
将850毫克6-3和247毫克溴化氰溶于2毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得2-氨基-1-(4-溴苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(6-4)白色固体560毫克，收率95.8％。LCMS(ESI)m/z[M+Na] +:389.1. Dissolve 850 mg of 6-3 and 247 mg of cyanogen bromide in 2 ml of methanol and stir overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromophenethyl)-7-methoxy-1H-benzo[ d] Imidazole-5-carboxamide (6-4) 560 mg of white solid, yield 95.8%. LCMS(ESI) m/z[M+Na] + :389.1.
步骤⑤：1-(4-溴苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(6-5)Step ⑤: 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d ]imidazole-5-carboxamide (6-5)
Figure PCTCN2023071429-appb-000104
Figure PCTCN2023071429-appb-000104
将300毫克6-4、220毫克化合物1-2、370毫克EDCI、37毫克HOBT、210微升三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得1-(4-溴苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(6-5)白色固体240毫克，收率58.8％。 1H NMR(300MHz,DMSO-d 6)δ12.83(s,1H),8.02(s,1H),7.66(d,J＝1.3Hz,1H),7.46(d,J＝1.8Hz,1H),7.44(d,J＝1.9Hz,1H),7.42–7.34(m,2H),7.17–7.12(m,2H),6.62(s,1H),4.66–4.50(m,4H),3.97(s,3H),3.08–3.00(m,2H),2.20(s,3H),1.34(t,J＝7.1Hz,3H). A mixture of 300 mg of 6-4, 220 mg of compound 1-2, 370 mg of EDCI, 37 mg of HOBT, 210 μl of triethylamine and 2 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H- Pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (6-5) 240 mg white solid, yield 58.8%. 1 H NMR (300MHz,DMSO-d 6 )δ12.83(s,1H),8.02(s,1H),7.66(d,J=1.3Hz,1H),7.46(d,J=1.8Hz,1H) ,7.44(d,J＝1.9Hz,1H),7.42–7.34(m,2H),7.17–7.12(m,2H),6.62(s,1H),4.66–4.50(m,4H),3.97(s ,3H),3.08–3.00(m,2H),2.20(s,3H),1.34(t,J＝7.1Hz,3H).
步骤⑥：(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-6)Step ⑥: (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) phenyl) boronic acid (I-6)
Figure PCTCN2023071429-appb-000105
Figure PCTCN2023071429-appb-000105
氮气保护下，将100毫克化合物Ⅰ-6溶于2毫升四氢呋喃中，在-78℃下搅拌20分钟后，加入473微升正丁基锂，在-78℃下搅拌1小时后，加入788微升硼酸三异丙酯，室温搅拌1小时后，加入3M HCl淬灭。以二氯甲烷萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-6)淡黄色固体15毫克，收率16.1％。 1H NMR(300MHz,DMSO-d 6)δ12.83(d,J＝5.1Hz,1H),8.01(s,1H),7.67(d,J＝1.5Hz,1H),7.49–7.42(m,1H),7.41–7.11(m,5H),6.63(d,J＝8.0Hz,1H),4.61(td,J＝16.3,15.0,8.1Hz,4H),3.99(d,J＝6.2Hz,3H),3.04(q,J＝6.0,3.6Hz,2H),2.20(s,3H),1.38–1.31(m,3H). Under nitrogen protection, 100 mg of compound Ⅰ-6 was dissolved in 2 ml of tetrahydrofuran, stirred at -78°C for 20 minutes, added 473 µl of n-butyllithium, stirred at -78°C for 1 hour, added 788 µl Triisopropyl borate was added, stirred at room temperature for 1 hour, then quenched by adding 3M HCl. Extracted with dichloromethane, the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-carbamoyl-2-(1-ethyl -3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (I-6) light yellow 15 mg of solid, yield 16.1%. 1 H NMR (300MHz, DMSO-d 6 )δ12.83(d, J=5.1Hz, 1H), 8.01(s, 1H), 7.67(d, J=1.5Hz, 1H), 7.49–7.42(m, 1H), 7.41–7.11(m, 5H), 6.63(d, J=8.0Hz, 1H), 4.61(td, J=16.3, 15.0, 8.1Hz, 4H), 3.99(d, J=6.2Hz, 3H ),3.04(q,J＝6.0,3.6Hz,2H),2.20(s,3H),1.38–1.31(m,3H).
实施例7(4-(2-(5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-7)Example 7 (4-(2-(5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H- Benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (I-7)
Figure PCTCN2023071429-appb-000106
Figure PCTCN2023071429-appb-000106
步骤①：4-((4-溴苯乙基)氨基)-3-甲氧基-5-硝基苯甲酸乙酯(7-1)Step ①: 4-((4-bromophenethyl)amino)-3-methoxy-5-nitrobenzoic acid ethyl ester (7-1)
Figure PCTCN2023071429-appb-000107
Figure PCTCN2023071429-appb-000107
1克5-2、1.5克4-溴苯乙胺、1.0克碳酸钾和1毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴苯乙基)氨基)-3-甲氧基-5-硝基苯甲酸乙酯(7-1)黄色固体1.15克，收率70.5％。LCMS(ESI)m/z:423.1[M+H] +. 1 g of 5-2, 1.5 g of 4-bromophenethylamine, 1.0 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 1.15 g of yellow solid 4-((4-bromophenethyl)amino)-3-methoxy-5-nitrobenzoic acid ethyl ester (7-1). 70.5%. LCMS(ESI)m/z:423.1[M+H] + .
步骤②：3-氨基-4-((4-溴苯乙基)氨基)-5-甲氧基苯甲酸乙酯(7-2)Step ②: Ethyl 3-amino-4-((4-bromophenethyl)amino)-5-methoxybenzoate (7-2)
Figure PCTCN2023071429-appb-000108
Figure PCTCN2023071429-appb-000108
将1.6克3-3、4.6克连二亚硫酸钠、3毫升氨水和20毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得3-氨基-4-((4-溴苯乙基)氨基)-5-甲氧基苯甲酸乙酯(7-2)白色固体950毫克，收率63.9％。LCMS(ESI)m/z:339.1[M+H] +. A mixture of 1.6 g of 3-3, 4.6 g of sodium dithionite, 3 ml of aqueous ammonia and 20 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromophenethyl)amino)-5-methoxy Ethyl benzoate (7-2) was 950 mg of white solid, and the yield was 63.9%. LCMS(ESI)m/z:339.1[M+H] + .
步骤③：2-氨基-1-(4-溴苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(7-3)Step ③: Ethyl 2-amino-1-(4-bromophenethyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxylate (7-3)
Figure PCTCN2023071429-appb-000109
Figure PCTCN2023071429-appb-000109
将860毫克7-2和278毫克溴化氰溶于8毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得2-氨基-1-(4-溴苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(7-3)白色固体800毫克，收率87.5％。LCMS(ESI)m/z:418.1[M+H] +. Dissolve 860 mg of 7-2 and 278 mg of cyanogen bromide in 8 ml of methanol and stir overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromophenethyl)-7-methoxy-1H-benzo[ d] Ethyl imidazole-5-carboxylate (7-3) 800 mg of white solid, yield 87.5%. LCMS(ESI)m/z:418.1[M+H] + .
步骤④：1-(4-溴苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(7-4)Step ④: 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d ]imidazole-5-ethyl carboxylate (7-4)
Figure PCTCN2023071429-appb-000110
Figure PCTCN2023071429-appb-000110
将1克3-5、481毫克化合物1-2、1.2克EDCI、120毫克HOBT、536微升三乙胺和10毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷： 甲醇＝200：1柱层析纯化，得1-(4-溴苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(7-4)白色固体870毫克，收率61.8％。 1H NMR(300MHz,DMSO-d 6)δ12.87(s,1H),7.79(d,J＝1.3Hz,1H),7.47–7.40(m,2H),7.36(d,J＝1.4Hz,1H),7.17–7.08(m,2H),6.62(s,1H),4.66–4.47(m,4H),4.33(q,J＝7.1Hz,2H),3.96(s,3H),3.08–2.97(m,2H),2.20(s,3H),1.34(td,J＝7.0,1.7Hz,6H). A mixture of 1 g of 3-5, 481 mg of compound 1-2, 1.2 g of EDCI, 120 mg of HOBT, 536 μl of triethylamine, and 10 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H- Pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole-5-carboxylic acid ethyl ester (7-4) 870 mg white solid, yield 61.8%. 1 H NMR (300MHz, DMSO-d 6 )δ12.87(s, 1H), 7.79(d, J=1.3Hz, 1H), 7.47–7.40(m, 2H), 7.36(d, J=1.4Hz, 1H),7.17–7.08(m,2H),6.62(s,1H),4.66–4.47(m,4H),4.33(q,J＝7.1Hz,2H),3.96(s,3H),3.08–2.97 (m,2H),2.20(s,3H),1.34(td,J=7.0,1.7Hz,6H).
步骤⑤：(4-(2-(5-(乙氧基羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-7)Step ⑤: (4-(2-(5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H -Benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (I-7)
Figure PCTCN2023071429-appb-000111
Figure PCTCN2023071429-appb-000111
氮气保护下，将100毫克化合物7-4溶于2毫升四氢呋喃中，在-78℃下搅拌20分钟后，加入433微升正丁基锂，在-78℃下搅拌1小时后，加入166微升硼酸三异丙酯，室温搅拌1小时后，加入3M HCl淬灭。以二氯甲烷萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得(4-(2-(5-(乙氧基羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)硼酸(Ⅰ-7)淡黄色固体17毫克，收率18.1％。 1H NMR(300MHz,CDCl 3)δ12.16(s,1H),7.74(d,J＝7.6Hz,1H),7.54–7.39(m,1H),7.24–7.07(m,1H),7.06–6.64(m,3H),4.88–4.48(m,4H),4.04(d,J＝14.5Hz,3H),3.35–2.99(m,2H),2.34(d,J＝5.7Hz,2H),1.48(d,J＝15.0Hz,3H),0.86(d,J＝7.1Hz,6H). Under the protection of nitrogen, 100 mg of compound 7-4 was dissolved in 2 ml of tetrahydrofuran. After stirring at -78 ° C for 20 minutes, 433 μl of n-butyllithium was added. After stirring at -78 ° C for 1 hour, 166 μl of Triisopropyl borate was added, stirred at room temperature for 1 hour, then quenched by adding 3M HCl. Extracted with dichloromethane, the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-(ethoxycarbonyl)-2-(1 -Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)boronic acid (Ⅰ-7 ) 17 mg of light yellow solid, yield 18.1%. 1 H NMR (300MHz, CDCl 3 )δ12.16(s,1H),7.74(d,J=7.6Hz,1H),7.54–7.39(m,1H),7.24–7.07(m,1H),7.06– 6.64(m,3H),4.88–4.48(m,4H),4.04(d,J＝14.5Hz,3H),3.35–2.99(m,2H),2.34(d,J＝5.7Hz,2H),1.48 (d,J=15.0Hz,3H),0.86(d,J=7.1Hz,6H).
实施例8(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-8)Example 8 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) phosphonic acid (I-8)
Figure PCTCN2023071429-appb-000112
Figure PCTCN2023071429-appb-000112
步骤①：二乙基(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸酯(8-1)Step ①: Diethyl (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole -1-yl) ethyl) phenyl) phosphonate (8-1)
Figure PCTCN2023071429-appb-000113
Figure PCTCN2023071429-appb-000113
200毫克1-6、204毫克碳酸铯、48毫克四三苯基膦钯和115微升亚磷酸二乙酯和2毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得二乙基(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸酯(8-1)白色固体120毫克，收率53.6％。ESI-MS(m/z):535.3[M+H] +. Mix 200 mg of 1-6, 204 mg of cesium carbonate, 48 mg of tetrakistriphenylphosphine palladium, 115 microliters of diethyl phosphite and 2 milliliters of tetrahydrofuran, and stir at 100°C overnight under reflux. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain diethyl (4-(2-(5-cyano-2-(1-ethyl-3-methyl (8-1) white solid 120 mg, yield 53.6%. ESI-MS(m/z):535.3[M+H] + .
步骤②：(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-8)Step ②: (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) phosphonic acid (I-8)
Figure PCTCN2023071429-appb-000114
Figure PCTCN2023071429-appb-000114
50毫克8-1溶于2毫升二氯甲烷，冰浴，加入62微升三甲基溴硅烷，滴加完毕移去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析纯化，得(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-8)白色固体21毫克，收率29.3％。 1H NMR(300MHz,DMSO-d 6)δ12.92(s,1H),7.56(t,J＝63.5Hz,7H),6.70(s,1H),4.53(d,J＝38.3Hz,4H),2.21(s,3H),1.35(s,3H). Dissolve 50mg of 8-1 in 2ml of dichloromethane, put in ice bath, add 62μl of bromotrimethylsilane, remove the ice bath after the dropwise addition, and stir at room temperature overnight; the reaction solution is concentrated to dryness, add methanol, and reflux at 80°C overnight. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H -pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-8) white solid 21 mg, yield 29.3%. 1 H NMR (300MHz, DMSO-d 6 )δ12.92(s, 1H), 7.56(t, J=63.5Hz, 7H), 6.70(s, 1H), 4.53(d, J=38.3Hz, 4H) ,2.21(s,3H),1.35(s,3H).
实施例9(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸(Ⅰ-9)Example 9 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl) Methyl)phenyl)phosphonic acid (Ⅰ-9)
Figure PCTCN2023071429-appb-000115
Figure PCTCN2023071429-appb-000115
操作过程和反应条件同实施例8相同，不同的是步骤①中原料为2-4，白色固体，收率56.3％。 1H NMR(300MHz,DMSO-d 6)δ13.05(s,1H),7.84(s,1H),7.64(dq,J＝19.5,8.0,6.6Hz,4H),7.50–7.39(m,2H),6.70(s,1H),5.52(s,2H),4.56(q,J＝7.1Hz,2H),2.17(s,3H),1.31(t,J＝7.1Hz,3H). The operating process and reaction conditions are the same as in Example 8, except that the raw material in step ① is 2-4, white solid, and the yield is 56.3%. 1 H NMR (300MHz,DMSO-d 6 )δ13.05(s,1H),7.84(s,1H),7.64(dq,J=19.5,8.0,6.6Hz,4H),7.50–7.39(m,2H ),6.70(s,1H),5.52(s,2H),4.56(q,J=7.1Hz,2H),2.17(s,3H),1.31(t,J=7.1Hz,3H).
实施例10(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d] 咪唑-1-基)乙基)苯基)膦酸(Ⅰ-10)Example 10 (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[ d] imidazol-1-yl) ethyl) phenyl) phosphonic acid (Ⅰ-10)
Figure PCTCN2023071429-appb-000116
Figure PCTCN2023071429-appb-000116
操作过程和反应条件同实施例8相同，不同的是步骤①中原料为3-6，白色固体，收率43.2％。 1H NMR(300MHz,DMSO-d 6)δ12.95(s,1H),7.71–7.15(m,7H),4.49(d,J＝47.5Hz,4H),3.91(d,J＝19.5Hz,3H),2.19(s,3H),1.33(t,J＝6.9Hz,3H). The operating process and reaction conditions are the same as in Example 8, except that the raw material in step ① is 3-6, white solid, and the yield is 43.2%. 1 H NMR (300MHz, DMSO-d 6 )δ12.95(s,1H),7.71–7.15(m,7H),4.49(d,J=47.5Hz,4H),3.91(d,J=19.5Hz, 3H), 2.19(s, 3H), 1.33(t, J=6.9Hz, 3H).
实施例11(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸(Ⅰ-11)Example 11 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d] Imidazol-1-yl)methyl)phenyl)phosphonic acid (I-11)
Figure PCTCN2023071429-appb-000117
Figure PCTCN2023071429-appb-000117
操作过程和反应条件同实施例8相同，不同的是步骤①中原料为Ⅰ-8，白色固体，收率36.1％。 1H NMR(300MHz,DMSO-d 6)δ13.08(s,1H),7.67–7.52(m,3H),7.35(dd,J＝9.0,2.4Hz,3H),6.65(s,1H),5.58(s,2H),4.54(q,J＝7.1Hz,2H),3.88(s,3H),2.15(s,3H),1.29(t,J＝7.1Hz,3H). The operation process and reaction conditions are the same as in Example 8, except that the raw material in step ① is I-8, a white solid, and the yield is 36.1%. 1 H NMR (300MHz, DMSO-d 6 )δ13.08(s,1H),7.67–7.52(m,3H),7.35(dd,J=9.0,2.4Hz,3H),6.65(s,1H), 5.58(s,2H),4.54(q,J=7.1Hz,2H),3.88(s,3H),2.15(s,3H),1.29(t,J=7.1Hz,3H).
实施例12(4-((5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸(Ⅰ-12)Example 12 (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) methyl) phenyl) phosphonic acid (I-12)
Figure PCTCN2023071429-appb-000118
Figure PCTCN2023071429-appb-000118
操作过程和反应条件同实施例8相同，不同的是步骤①中原料为5-6，白色固体，收率29.3％。 1H NMR(300MHz,DMSO-d 6)δ13.04(s,1H),8.00–7.26(m,6H),6.67(d,J＝24.1Hz,1H),5.60(s,2H),4.55(s,2H),4.30(s,2H),2.14(s,3H),1.28(s,6H). The operating process and reaction conditions are the same as in Example 8, except that the raw material in step ① is 5-6, white solid, and the yield is 29.3%. 1 H NMR (300MHz, DMSO-d 6 ) δ13.04(s, 1H), 8.00–7.26(m, 6H), 6.67(d, J=24.1Hz, 1H), 5.60(s, 2H), 4.55( s,2H),4.30(s,2H),2.14(s,3H),1.28(s,6H).
实施例13(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-13)Example 13 (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo [d] imidazol-1-yl) ethyl) phenyl) phosphonic acid (I-13)
Figure PCTCN2023071429-appb-000119
Figure PCTCN2023071429-appb-000119
操作过程和反应条件同实施例8相同，不同的是步骤①中原料为6-5，白色固体，收率28.5％。ESI-MS(m/z):527.3[M+H] +. The operating process and reaction conditions are the same as in Example 8, except that the raw material in step ① is 6-5, white solid, and the yield is 28.5%. ESI-MS(m/z):527.3[M+H] + .
实施例14(4-(2-(5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-14)Example 14 (4-(2-(5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H- Benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-14)
Figure PCTCN2023071429-appb-000120
Figure PCTCN2023071429-appb-000120
步骤①：1-(4-(二乙氧基磷酰基)苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(14-1)Step ①: 1-(4-(diethoxyphosphoryl)phenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy -1H-Benzo[d]imidazole-5-carboxylic acid ethyl ester (14-1)
Figure PCTCN2023071429-appb-000121
Figure PCTCN2023071429-appb-000121
氮气气氛下，将200毫克7-4、176毫克碳酸铯、42毫克四(三苯基膦)钯、100微升亚磷酸二乙脂和5毫升无水四氢呋喃的混合物于110℃加热搅拌36小时。反应液浓缩至干，残余物加水以乙酸乙酯萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝20:1柱层析纯化，得类白色类固体1-(4-(二乙氧基磷酰基)苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酸乙酯(14-1)95毫克，收率43％。ESI-MS(m/z):612.4[M+H] +. Under a nitrogen atmosphere, a mixture of 200 mg of 7-4, 176 mg of cesium carbonate, 42 mg of tetrakis(triphenylphosphine)palladium, 100 μl of diethyl phosphite and 5 ml of anhydrous tetrahydrofuran was heated and stirred at 110°C for 36 hours . The reaction solution was concentrated to dryness, the residue was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain off-white solid 1-(4-(di Ethoxyphosphoryl)phenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole- 95 mg of ethyl 5-carboxylate (14-1), yield 43%. ESI-MS(m/z):612.4[M+H] + .
步骤②：(4-(2-(5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-14)Step ②: (4-(2-(5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H- Benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-14)
Figure PCTCN2023071429-appb-000122
Figure PCTCN2023071429-appb-000122
在氮气氛围下，将95毫克化合物14-1、103微升三甲基溴硅烷和2毫升无水二氯甲烷的混合物室温搅拌过夜。反应液浓缩至干，残余物加2毫升甲醇，混合物于80℃加热搅拌16小时。反应液浓缩至干，残余物以二氯甲烷：甲醇＝60：6制备薄层，得白色固体(4-(2-(5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-14)37毫克，收率43％。ESI-MS(m/z):555.3[M+H] +. Under a nitrogen atmosphere, a mixture of 95 mg of compound 14-1, 103 μl of bromotrimethylsilane and 2 ml of anhydrous dichloromethane was stirred overnight at room temperature. The reaction solution was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was heated and stirred at 80°C for 16 hours. The reaction solution was concentrated to dryness, and the residue was prepared into a thin layer with dichloromethane:methanol=60:6 to obtain a white solid (4-(2-(5-(ethoxycarbonyl)-2-(1-ethyl-3- Methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-14) 37 mg, received rate 43%. ESI-MS(m/z):555.3[M+H] + .
实施例15(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-15)Example 15 (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl) ethyl) phenyl) phosphonic acid (I-15)
Figure PCTCN2023071429-appb-000123
Figure PCTCN2023071429-appb-000123
步骤①：3-硝基-4-((4-溴苯乙基)氨基)苯甲酰胺(15-1)Step ①: 3-nitro-4-((4-bromophenethyl)amino)benzamide (15-1)
Figure PCTCN2023071429-appb-000124
Figure PCTCN2023071429-appb-000124
将700毫克4-氯-3-硝基苯甲酰胺、1.4克4-溴苯乙胺、965毫克碳酸钾、1毫升的三乙胺和3毫升正丁醇的混合物于100℃搅拌过夜。加水，析出固体，残余物以石油醚：乙酸乙酯＝5:1柱层析纯化，得黄色固体3-硝基-4-((4-溴苯乙基)氨基)苯甲酰胺(15-1)920毫克，收率72％。ESI-MS(m/z):364.1[M+H] +. A mixture of 700 mg of 4-chloro-3-nitrobenzamide, 1.4 g of 4-bromophenethylamine, 965 mg of potassium carbonate, 1 ml of triethylamine and 3 ml of n-butanol was stirred overnight at 100°C. Water was added to precipitate a solid, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 5:1 to obtain a yellow solid 3-nitro-4-((4-bromophenethyl)amino)benzamide (15- 1) 920 mg, yield 72%. ESI-MS(m/z):364.1[M+H] + .
步骤②：3-氨基-4-((4-溴苯乙基)氨基)苯甲酰胺(15-2)Step ②: 3-amino-4-((4-bromophenethyl)amino)benzamide (15-2)
Figure PCTCN2023071429-appb-000125
Figure PCTCN2023071429-appb-000125
将920毫克3-硝基-4-((4-溴苯乙基)氨基)苯甲酰胺、3.08克连二亚硫酸钠、2毫升氨水和10毫升甲醇的混合物于45℃加热搅拌0.5小时。反应液浓缩至干，残余物以石油醚：乙酸乙酯＝2：1柱层析纯化，得类黄色类固体3-氨基-4-((4-溴苯乙基)氨基)苯甲酰胺(15-2)500毫克，收率59％。ESI-MS(m/z):334.1[M+H] +. A mixture of 920 mg of 3-nitro-4-((4-bromophenethyl)amino)benzamide, 3.08 g of sodium dithionite, 2 ml of ammonia water and 10 ml of methanol was heated and stirred at 45°C for 0.5 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=2:1 to obtain a yellowish solid 3-amino-4-((4-bromophenethyl)amino)benzamide ( 15-2) 500 mg, yield 59%. ESI-MS(m/z):334.1[M+H] + .
步骤③：2-氨基-1-(4-溴苯乙基)-1H-苯并[d]咪唑-5-甲酰胺(15-3)Step ③: 2-amino-1-(4-bromophenethyl)-1H-benzo[d]imidazole-5-carboxamide (15-3)
Figure PCTCN2023071429-appb-000126
Figure PCTCN2023071429-appb-000126
将500毫克3-氨基-4-((4-溴苯乙基)氨基)苯甲酰胺、191毫克溴化氰和5毫升甲醇于 室温下搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝20：1柱层析纯化，得白色固体2-氨基-1-(4-溴苯乙基)-1H-苯并[d]咪唑-5-甲酰胺(15-3)450毫克，收率84％。LCMS(ESI)m/z:359.1[M+H] +. 500 mg of 3-amino-4-((4-bromophenethyl)amino)benzamide, 191 mg of cyanogen bromide and 5 ml of methanol were stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain a white solid 2-amino-1-(4-bromophenethyl)-1H-benzo[d]imidazole- 450 mg of 5-formamide (15-3), yield 84%. LCMS(ESI)m/z:359.1[M+H] + .
步骤④：1-(4-溴苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酰胺(15-4)Step ④: 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-5-carba Amide (15-4)
Figure PCTCN2023071429-appb-000127
Figure PCTCN2023071429-appb-000127
在冰浴下，将322毫克1-乙基-3-甲基-1H-吡唑-5-羧酸、539毫克EDCI、81毫克HOBT、482微升三乙胺和5毫升N,N-二甲基甲酰胺的混合物搅拌0.5小时。将624毫克2-氨基-1-(4-溴苯乙基)-1H-苯并[d]咪唑-5-甲酰胺加入混合物中室温搅拌过夜。加水，析出固体，残余物以二氯甲烷：甲醇＝20:1柱层析纯化，得1-(4-溴苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酰胺(15-4)白色固体720毫克，收率84％。 1H NMR(300MHz,DMSO-d 6)δ12.81(s,1H),8.08–7.86(m,2H),7.75(dd,J＝8.4,1.7Hz,1H),7.51–7.30(m,4H),7.21(d,J＝8.1Hz,2H),6.64(s,1H),4.61(q,J＝7.1Hz,2H),4.44(t,J＝7.2Hz,2H),3.09(t,J＝7.1Hz,2H),2.20(s,3H),1.35(t,J＝7.1Hz,3H). Under an ice bath, mix 322 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 539 mg of EDCI, 81 mg of HOBT, 482 μl of triethylamine and 5 ml of N,N-di The mixture of methylformamide was stirred for 0.5 hours. 624 mg of 2-amino-1-(4-bromophenethyl)-1H-benzo[d]imidazole-5-carboxamide was added to the mixture and stirred overnight at room temperature. Water was added to precipitate a solid, and the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyridine Azole-5-carboxamide)-1H-benzo[d]imidazole-5-carboxamide (15-4) 720 mg white solid, yield 84%. 1 H NMR (300MHz,DMSO-d 6 )δ12.81(s,1H),8.08–7.86(m,2H),7.75(dd,J=8.4,1.7Hz,1H),7.51–7.30(m,4H ), 7.21(d, J=8.1Hz, 2H), 6.64(s, 1H), 4.61(q, J=7.1Hz, 2H), 4.44(t, J=7.2Hz, 2H), 3.09(t, J =7.1Hz, 2H), 2.20(s, 3H), 1.35(t, J=7.1Hz, 3H).
步骤⑤：二乙基(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸酯(15-5)Step ⑤: Diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d] imidazol-1-yl) ethyl) phenyl) phosphonate (15-5)
Figure PCTCN2023071429-appb-000128
Figure PCTCN2023071429-appb-000128
氮气气氛下，将200毫克1-(4-溴苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酰胺、197毫克碳酸铯、47毫克四(三苯基膦)钯、112微升亚磷酸二乙脂和5毫升无水四氢呋喃的混合物于110℃加热搅拌36小时。反应液浓缩至干，残余物加水以乙酸乙酯萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝20:1柱层析纯化，得类白色类固体二乙基(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸酯(15-5)85毫克，收率38％。LCMS(ESI)m/z:553.4[M+H] +. Under a nitrogen atmosphere, 200 mg of 1-(4-bromophenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole - A mixture of 5-carboxamide, 197 mg of cesium carbonate, 47 mg of tetrakis(triphenylphosphine) palladium, 112 μl of diethyl phosphite and 5 ml of anhydrous tetrahydrofuran was heated and stirred at 110° C. for 36 hours. The reaction solution was concentrated to dryness, the residue was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain off-white solid diethyl(4-( 2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)ethyl)benzene Base) phosphonate (15-5) 85 mg, yield 38%. LCMS(ESI)m/z:553.4[M+H] + .
步骤⑥：二乙基(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸酯(I-15)Step ⑥: Diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d] imidazol-1-yl) ethyl) phenyl) phosphonate (I-15)
Figure PCTCN2023071429-appb-000129
Figure PCTCN2023071429-appb-000129
在氮气氛围下，将85毫克二乙基(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸酯、142微升三甲基溴硅烷和2毫升无水二氯甲烷的混合物室温搅拌过夜。反应液浓缩至干，残余物加2毫升甲醇，混合物于80℃加热搅拌16小时。反应液浓缩至干，残余物以二氯甲烷：甲醇＝60：6制备薄层，得白色固体二乙基(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸酯(I-15)32毫克，收率42％。 1H NMR(300MHz,DMSO-d 6)δ7.99(d,J＝5.1Hz,1H),7.84–7.22(m,8H),6.71(d,J＝6.7Hz,1H),3.94–3.52(m,4H),3.15(d,J＝7.3Hz,2H),2.21(s,3H),1.35(t,J＝7.0Hz,3H). Under a nitrogen atmosphere, 85 mg of diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H- A mixture of benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonate, 142 microliters of bromotrimethylsilane and 2 mL of anhydrous dichloromethane was stirred overnight at room temperature. The reaction solution was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was heated and stirred at 80°C for 16 hours. The reaction solution was concentrated to dryness, and the residue was prepared into a thin layer with dichloromethane:methanol=60:6 to obtain a white solid diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3 -Methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonate (I-15) 32 mg, yield 42%. 1 H NMR (300MHz, DMSO-d 6 ) δ7.99 (d, J=5.1Hz, 1H), 7.84–7.22 (m, 8H), 6.71 (d, J=6.7Hz, 1H), 3.94–3.52( m,4H),3.15(d,J=7.3Hz,2H),2.21(s,3H),1.35(t,J=7.0Hz,3H).
实施例16 4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-16)Example 16 4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[ d] imidazol-1-yl) ethyl) phenyl dihydrogen phosphate (Ⅰ-16)
Figure PCTCN2023071429-appb-000130
Figure PCTCN2023071429-appb-000130
步骤①：(4-((叔丁基二苯基硅基)氧基)苯乙基)氨基甲酸叔丁酯(16-1)Step ①: tert-butyl (4-((tert-butyldiphenylsilyl)oxy)phenethyl)carbamate (16-1)
Figure PCTCN2023071429-appb-000131
Figure PCTCN2023071429-appb-000131
将1克叔丁基(4-羟基苯乙基)氨基甲酸酯溶于10毫升无水二氯甲烷中，加入670毫克咪唑，冰浴搅拌十分钟后，加入2.31克稀释一倍的叔丁基二苯基氯硅烷，室温下搅拌1小时。向反应液中加水，然后用二氯甲烷萃取，有机相用饱和食盐水洗涤，浓缩至干，得淡黄色油状物(16-1)2克，收率100％。LCMS(ESI)m/z[M+Na] +:498.8. Dissolve 1 gram of tert-butyl (4-hydroxyphenethyl) carbamate in 10 milliliters of anhydrous dichloromethane, add 670 mg of imidazole, stir in ice bath for ten minutes, add 2.31 grams of tert-butyl diphenylchlorosilane and stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with dichloromethane, the organic phase was washed with saturated brine, and concentrated to dryness to obtain 2 g of light yellow oil (16-1), with a yield of 100%. LCMS(ESI) m/z[M+Na] + :498.8.
步骤②：2-(4-((叔丁基二苯基硅基)氧基)苯基)乙-1-胺(16-2)Step ②: 2-(4-((tert-butyldiphenylsilyl)oxy)phenyl)ethan-1-amine (16-2)
Figure PCTCN2023071429-appb-000132
Figure PCTCN2023071429-appb-000132
将2克16-1溶于25毫升二氯甲烷中，加入10毫升三氟乙酸，室温搅拌1小时。将反应液浓缩后加入少量二氯甲烷和大量正己烷，浓缩至干。加入少量二氯甲烷和大量石油醚，旋蒸除去二氯甲烷，产物析出。过滤干燥得白色固体(16-2)1.03克，收率50.2％。LCMS(ESI)m/z[M+H] +:376.2. Dissolve 2 g of 16-1 in 25 ml of dichloromethane, add 10 ml of trifluoroacetic acid, and stir at room temperature for 1 hour. After the reaction solution was concentrated, a small amount of dichloromethane and a large amount of n-hexane were added, and concentrated to dryness. A small amount of dichloromethane and a large amount of petroleum ether were added, the dichloromethane was removed by rotary evaporation, and the product was precipitated. After filtration and drying, 1.03 g of white solid (16-2) was obtained, with a yield of 50.2%. LCMS(ESI)m/z[M+H] + :376.2.
步骤③：4-((4-((叔丁基二苯基硅基)氧基)苯乙基)氨基)-3-甲氧基-5-硝基苯甲酰胺(16-3)Step ③: 4-((4-((tert-butyldiphenylsilyl)oxy)phenethyl)amino)-3-methoxy-5-nitrobenzamide (16-3)
Figure PCTCN2023071429-appb-000133
Figure PCTCN2023071429-appb-000133
在氩气氛下，将840毫克的6-1溶于15毫升无水N,N-二甲基甲酰胺中，加入2毫升N,N-二异丙基乙胺，室温搅拌20分钟后加入430毫克的16-2，于110℃加热搅拌过夜。反应完成后向反应液中加水，析出橙黄色固体，过滤干燥得橙黄色固体(16-3)860毫克，收率88.8％。LCMS(ESI)m/z[M+Na] +:592.6. Under an argon atmosphere, dissolve 840 mg of 6-1 in 15 ml of anhydrous N,N-dimethylformamide, add 2 ml of N,N-diisopropylethylamine, stir at room temperature for 20 minutes and then add 430 mg of 16-2, heated and stirred overnight at 110°C. After the reaction was completed, water was added to the reaction solution to precipitate an orange-yellow solid, which was filtered and dried to obtain 860 mg of an orange-yellow solid (16-3), with a yield of 88.8%. LCMS(ESI) m/z[M+Na] + :592.6.
步骤④：3-氨基-4-((4-((叔丁基二苯基硅基)氧基)苯乙基)氨基)-5-甲氧基苯甲酰胺(16-4)Step ④: 3-amino-4-((4-((tert-butyldiphenylsilyl)oxy)phenethyl)amino)-5-methoxybenzamide (16-4)
Figure PCTCN2023071429-appb-000134
Figure PCTCN2023071429-appb-000134
将113毫克16-3溶于10毫升甲醇中，加入173毫克连二亚硫酸钠，1.5毫升氨水，于55℃加热搅拌3小时。反应液抽滤，滤液浓缩至干，残余物以二氯甲烷：甲醇＝99:1柱层析纯化，得黄色油状物(16-4)60毫克，收率56％。LCMS(ESI)m/z[M+H] +:540.7. Dissolve 113 mg of 16-3 in 10 ml of methanol, add 173 mg of sodium dithionite and 1.5 ml of ammonia water, and heat and stir at 55°C for 3 hours. The reaction solution was suction-filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=99:1 to obtain 60 mg of yellow oil (16-4) with a yield of 56%. LCMS(ESI)m/z[M+H] + :540.7.
步骤⑤：2-氨基-1-(4-((叔丁基二苯基硅基)氧基)苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(16-5)Step ⑤: 2-amino-1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (16-5)
Figure PCTCN2023071429-appb-000135
Figure PCTCN2023071429-appb-000135
氩气氛下，将850毫克的16-4溶于15毫升无水甲醇中，超声溶解后加入800毫克的溴化氰，室温搅拌2小时。析出白色固体。向反应液中加入乙酸乙酯，继续搅拌1小时，将反应液过滤，浓缩干燥得白色固体(16-5)518毫克，收率58.5％。LCMS(ESI)m/z[M+H] +:565.4. Under an argon atmosphere, 850 mg of 16-4 was dissolved in 15 ml of anhydrous methanol. After ultrasonic dissolution, 800 mg of cyanogen bromide was added and stirred at room temperature for 2 hours. A white solid precipitated out. Ethyl acetate was added to the reaction solution, and the stirring was continued for 1 hour. The reaction solution was filtered, concentrated and dried to obtain 518 mg of white solid (16-5), with a yield of 58.5%. LCMS(ESI)m/z[M+H] + :565.4.
步骤⑥：1-(4-((叔丁基二苯基硅基)氧基)苯乙基)-2-(1-乙基-3-甲基-1H-吡唑 -5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(16-6)Step ⑥: 1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo[d]imidazole-5-carboxamide (16-6)
Figure PCTCN2023071429-appb-000136
Figure PCTCN2023071429-appb-000136
氩气氛下，将5.64克16-5溶于80毫升无水N,N-二甲基甲酰胺中，加入2.16克1-乙基-3-甲基-1H-吡唑-5-羧酸、4.56克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)和8.3毫升N,N-二异丙基乙胺，室温搅拌过夜。反应完成后将反应液倒入水中，析出白色固体，搅拌30分钟，过滤干燥得白色固体(16-6)5.7克，收率81.4％。LCMS(ESI)m/z[M+H] +:701.8. Under an argon atmosphere, 5.64 g of 16-5 was dissolved in 80 ml of anhydrous N,N-dimethylformamide, and 2.16 g of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 4.56 g of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (HATU) and 8.3 mL of N,N-diisopropyl Ethylamine, stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into water, and a white solid was precipitated, stirred for 30 minutes, filtered and dried to obtain 5.7 g of a white solid (16-6), with a yield of 81.4%. LCMS(ESI)m/z[M+H] + :701.8.
步骤⑦：2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1-(4-羟基苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(16-7)Step ⑦: 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-(4-hydroxyphenethyl)-7-methoxy-1H-benzo[d ]imidazole-5-carboxamide (16-7)
Figure PCTCN2023071429-appb-000137
Figure PCTCN2023071429-appb-000137
氩气氛下，将5.7克16-6溶于100毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将15毫升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得灰白色固体(16-7)3.76克，收率100％。LCMS(ESI)m/z[M+H] +:463.5. 1H NMR(400MHz,DMSO-d 6)δ9.29(s,1H),8.05(s,1H),7.66(s,1H),7.38(d,J＝9.5Hz,2H),7.00(d,J＝8.0Hz,2H),6.78–6.55(m,3H),4.62(q,J＝7.1Hz,2H),4.47(t,J＝7.6Hz,2H),4.00(s,3H),2.92(t,J＝7.9Hz,2H),2.19(s,3H),1.35(t,J＝7.1Hz,3H). Under an argon atmosphere, dissolve 5.7 g of 16-6 in 100 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 15 ml of tetrabutylammonium fluoride three times, slowly drop into the reaction solution, and stir at room temperature 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 3.76 g of off-white solid (16-7) was obtained, with a yield of 100%. LCMS (ESI) m/z [M+H] + :463.5. 1 H NMR (400MHz, DMSO-d 6 ) δ9.29 (s, 1H), 8.05 (s, 1H), 7.66 (s, 1H), 7.38(d, J=9.5Hz, 2H), 7.00(d, J=8.0Hz, 2H), 6.78–6.55(m, 3H), 4.62(q, J=7.1Hz, 2H), 4.47(t, J =7.6Hz, 2H), 4.00(s, 3H), 2.92(t, J=7.9Hz, 2H), 2.19(s, 3H), 1.35(t, J=7.1Hz, 3H).
步骤⑧：4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-16)Step ⑧: 4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[ d] imidazol-1-yl) ethyl) phenyl dihydrogen phosphate (Ⅰ-16)
Figure PCTCN2023071429-appb-000138
Figure PCTCN2023071429-appb-000138
氮气保护下，将100毫克16-7溶于1毫升无水吡啶，混合物冷却至-15℃搅拌10分钟，滴加100微升三氯氧磷，滴加完毕后室温搅拌30分钟，将混合物倒入碳酸氢钠水溶液。以二氯甲烷萃取，有机相浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析纯化，得4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑 -1-基)乙基)苯基磷酸二氢(Ⅰ-16)淡黄色固体12毫克，收率10.23％。LCMS(ESI)m/z[M+K] +:581.2. Under nitrogen protection, dissolve 100 mg of 16-7 in 1 ml of anhydrous pyridine, cool the mixture to -15°C and stir for 10 minutes, add 100 μl of phosphorus oxychloride dropwise, stir at room temperature for 30 minutes after the addition, pour the mixture into into aqueous sodium bicarbonate solution. Extracted with dichloromethane, the organic phase was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=10:1 to obtain 4-(2-(5-carbamoyl-2-(1-ethyl- 3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl dihydrogen phosphate (Ⅰ-16) light yellow The solid is 12 mg, and the yield is 10.23%. LCMS(ESI)m/z[M+K] + :581.2.
实施例17 4-((2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)甲基)苯磺酰胺(Ⅰ-17)Example 17 4-((2-amino-5-cyano-1H-benzo[d]imidazol-1-yl)methyl)benzenesulfonamide (I-17)
Figure PCTCN2023071429-appb-000139
Figure PCTCN2023071429-appb-000139
步骤①：4-(((4-氰基-2-硝基苯基)氨基)甲基)苯磺酰胺(17-1)Step ①: 4-(((4-cyano-2-nitrophenyl)amino)methyl)benzenesulfonamide (17-1)
Figure PCTCN2023071429-appb-000140
Figure PCTCN2023071429-appb-000140
500毫克4-氯-3-硝基苯甲腈、1克磺胺米隆、758毫克碳酸钾和1毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-(((4-氰基-2-硝基苯基)氨基)甲基)苯磺酰胺(17-1)黄色固体400毫克，收率43.9％。LCMS(ESI)m/z[M-H] -:331.0. 500 mg of 4-chloro-3-nitrobenzonitrile, 1 g of sulfamethorone, 758 mg of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol, and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 400 mg of 4-(((4-cyano-2-nitrophenyl)amino)methyl)benzenesulfonamide (17-1) as a yellow solid, with a yield of 43.9%. LCMS(ESI)m/z[MH] - :331.0.
步骤②：4-(((2-氨基-4-氰基苯基)氨基)甲基)苯磺酰胺(17-2)Step ②: 4-(((2-amino-4-cyanophenyl)amino)methyl)benzenesulfonamide (17-2)
Figure PCTCN2023071429-appb-000141
Figure PCTCN2023071429-appb-000141
将1克17-1、3.67克连二亚硫酸钠、3毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得4-(((2-氨基-4-氰基苯基)氨基)甲基)苯磺酰胺(17-2)白色固体630毫克，收率69.2％。LCMS(ESI)m/z[M+H] +:303.1. A mixture of 1 g of 17-1, 3.67 g of sodium dithionite, 3 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 4-(((2-amino-4-cyanophenyl)amino)methyl)benzene Sulfonamide (17-2) white solid 630 mg, yield 69.2%. LCMS(ESI)m/z[M+H] + :303.1.
步骤③：4-((2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)甲基)苯磺酰胺(Ⅰ-17)Step ③: 4-((2-amino-5-cyano-1H-benzo[d]imidazol-1-yl)methyl)benzenesulfonamide (Ⅰ-17)
Figure PCTCN2023071429-appb-000142
Figure PCTCN2023071429-appb-000142
将100毫克17-2和42毫克溴化氰溶于2毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得4-((2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)甲基)苯磺酰胺(Ⅰ-17)白色固体75毫克，收率69.3％。 1H NMR(300MHz,DMSO-d 6)δ9.15(s,2H),7.89(d,J＝1.5Hz,1H),7.84–7.78(m,2H),7.71(dd,J＝8.4,1.5Hz,1H),7.57(d,J＝8.4Hz,1H),7.47(d,J＝8.3Hz,2H),7.40(s,2H),5.58(s,2H). 100 mg of 17-2 and 42 mg of cyanogen bromide were dissolved in 2 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 4-((2-amino-5-cyano-1H-benzo[d]imidazol-1-yl) Methyl)benzenesulfonamide (I-17) was 75 mg of white solid, and the yield was 69.3%. 1 H NMR (300MHz, DMSO-d 6 ) δ9.15(s, 2H), 7.89(d, J=1.5Hz, 1H), 7.84–7.78(m, 2H), 7.71(dd, J=8.4, 1.5 Hz,1H),7.57(d,J=8.4Hz,1H),7.47(d,J=8.3Hz,2H),7.40(s,2H),5.58(s,2H).
实施例18 2-氨基-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-18)Example 18 2-Amino-1-(4-sulfamoylbenzyl)-1H-benzo[d]imidazole-5-carboxylic acid ethyl ester (I-18)
Figure PCTCN2023071429-appb-000143
Figure PCTCN2023071429-appb-000143
操作过程和反应条件同实施例17相同，不同的是步骤①中原料为4-氯-3-硝基苯甲酸乙酯，白色固体，收率65.3％。 1H NMR(300MHz,DMSO-d 6)δ9.16(s,2H),7.98(d,J＝1.5Hz,1H),7.88–7.79(m,3H),7.53–7.44(m,3H),7.40(s,2H),5.60(s,2H),4.33(q,J＝7.1Hz,2H),1.33(t,J＝7.1Hz,3H). The operating process and reaction conditions are the same as in Example 17, except that the raw material in step ① is ethyl 4-chloro-3-nitrobenzoate, a white solid, and the yield is 65.3%. 1 H NMR (300MHz,DMSO-d 6 )δ9.16(s,2H),7.98(d,J＝1.5Hz,1H),7.88–7.79(m,3H),7.53–7.44(m,3H), 7.40(s,2H),5.60(s,2H),4.33(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).
实施例19 2-氨基-7-甲氧基-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-5-甲酰胺(Ⅰ-19)Example 19 2-Amino-7-methoxy-1-(4-sulfamoylbenzyl)-1H-benzo[d]imidazole-5-carboxamide (I-19)
Figure PCTCN2023071429-appb-000144
Figure PCTCN2023071429-appb-000144
操作过程和反应条件同实施例17相同，不同的是步骤①中原料为6-1，白色固体，收率53.6％。 1H NMR(300MHz,DMSO-d 6)δ8.95(s,2H),8.14(s,1H),7.80(d,J＝8.1Hz,2H),7.60–7.55(m,1H),7.40(dt,J＝8.6,4.8Hz,6H),5.64(s,2H),3.82(s,3H). The operation process and reaction conditions are the same as in Example 17, except that the raw material in step ① is 6-1, a white solid, and the yield is 53.6%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.95(s, 2H), 8.14(s, 1H), 7.80(d, J=8.1Hz, 2H), 7.60–7.55(m, 1H), 7.40( dt,J＝8.6,4.8Hz,6H),5.64(s,2H),3.82(s,3H).
实施例20 2-氨基-7-甲氧基-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-20)Example 20 2-Amino-7-methoxy-1-(4-sulfamoylbenzyl)-1H-benzo[d]imidazole-5-carboxylic acid ethyl ester (I-20)
Figure PCTCN2023071429-appb-000145
Figure PCTCN2023071429-appb-000145
操作过程和反应条件同实施例17相同，不同的是步骤①中原料为5-2，白色固体，收率58.4％。 1H NMR(300MHz,DMSO-d 6)δ8.98(s,2H),7.89–7.73(m,2H),7.64(d,J＝1.3Hz,1H),7.40(d,J＝8.4Hz,5H),5.61(s,2H),4.34(q,J＝7.1Hz,2H),3.84(s,3H),1.33(t,J＝7.1Hz,3H). The operating process and reaction conditions are the same as in Example 17, except that the raw material in step ① is 5-2, a white solid, and the yield is 58.4%. 1 H NMR (300MHz, DMSO-d 6 )δ8.98(s, 2H), 7.89–7.73(m, 2H), 7.64(d, J=1.3Hz, 1H), 7.40(d, J=8.4Hz, 5H), 5.61(s, 2H), 4.34(q, J=7.1Hz, 2H), 3.84(s, 3H), 1.33(t, J=7.1Hz, 3H).
实施例21 N-(5-氰基-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(Ⅰ-21)Example 21 N-(5-cyano-1-(4-sulfamoylbenzyl)-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole -5-Carboxamide (Ⅰ-21)
Figure PCTCN2023071429-appb-000146
Figure PCTCN2023071429-appb-000146
将100毫克Ⅰ-17、56毫克化合物1-2、142毫克EDCI、14毫克HOBT、81微升三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得N-(5-氰基-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(Ⅰ-21)白色固体74毫克，收率52.3％。 1H NMR(300 MHz,DMSO-d 6)δ13.06(s,1H),7.87–7.75(m,3H),7.69(dd,J＝8.3,1.6Hz,1H),7.62(d,J＝8.4Hz,1H),7.55(d,J＝8.1Hz,2H),7.34(s,2H),6.70(s,1H),5.56(s,2H),4.56(q,J＝7.1Hz,2H),2.17(s,3H),1.30(t,J＝7.0Hz,3H). A mixture of 100 mg I-17, 56 mg compound 1-2, 142 mg EDCI, 14 mg HOBT, 81 μl triethylamine and 2 ml N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain N-(5-cyano-1-(4-sulfamoylbenzyl)-1H-benzo[d] Imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (I-21) 74 mg of white solid, yield 52.3%. 1 H NMR (300 MHz, DMSO-d 6 ) δ13.06(s, 1H), 7.87–7.75(m, 3H), 7.69(dd, J=8.3, 1.6Hz, 1H), 7.62(d, J= 8.4Hz, 1H), 7.55(d, J=8.1Hz, 2H), 7.34(s, 2H), 6.70(s, 1H), 5.56(s, 2H), 4.56(q, J=7.1Hz, 2H) ,2.17(s,3H),1.30(t,J=7.0Hz,3H).
实施例22 2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-22)Example 22 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-(4-sulfamoylbenzyl)-1H-benzo[d]imidazole-5-carboxylic acid Ethyl ester (Ⅰ-22)
Figure PCTCN2023071429-appb-000147
Figure PCTCN2023071429-appb-000147
操作过程和反应条件同实施例21相同，不同的是步骤中原料为Ⅰ-18，白色固体，收率60.3％。 1H NMR(300MHz,DMSO-d 6)δ13.00(s,1H),8.14(d,J＝1.6Hz,1H),7.88–7.76(m,3H),7.53(dd,J＝8.5,2.0Hz,3H),7.34(s,2H),6.69(s,1H),5.56(s,2H),4.57(q,J＝7.0Hz,2H),4.33(q,J＝7.1Hz,2H),2.16(s,3H),1.32(q,J＝7.1Hz,6H). The operation process and reaction conditions are the same as in Example 21, except that the raw material in the step is I-18, a white solid, and the yield is 60.3%. 1 H NMR (300MHz, DMSO-d 6 ) δ13.00(s, 1H), 8.14(d, J=1.6Hz, 1H), 7.88–7.76(m, 3H), 7.53(dd, J=8.5, 2.0 Hz,3H),7.34(s,2H),6.69(s,1H),5.56(s,2H),4.57(q,J=7.0Hz,2H),4.33(q,J=7.1Hz,2H), 2.16(s,3H),1.32(q,J=7.1Hz,6H).
实施例23 2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-23)Example 23 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1-(4-sulfamoylbenzyl)-1H-benzo[d ]Imidazole-5-carboxylic acid ethyl ester (Ⅰ-23)
Figure PCTCN2023071429-appb-000148
Figure PCTCN2023071429-appb-000148
操作过程和反应条件同实施例21相同，不同的是步骤中原料为Ⅰ-20，白色固体，收率60.3％。 1H NMR(300MHz,DMSO-d 6)δ13.02(s,1H),7.87–7.73(m,3H),7.48(d,J＝8.1Hz,2H),7.35(d,J＝14.8Hz,3H),6.64(s,1H),5.63(s,2H),4.55(q,J＝7.1Hz,2H),4.33(q,J＝7.1Hz,2H),3.89(s,3H),2.16(s,3H),1.31(dt,J＝13.8,7.2Hz,6H). The operation process and reaction conditions are the same as in Example 21, except that the raw material in the step is I-20, a white solid, and the yield is 60.3%. 1 H NMR (300MHz, DMSO-d 6 )δ13.02(s, 1H), 7.87–7.73(m, 3H), 7.48(d, J=8.1Hz, 2H), 7.35(d, J=14.8Hz, 3H),6.64(s,1H),5.63(s,2H),4.55(q,J=7.1Hz,2H),4.33(q,J=7.1Hz,2H),3.89(s,3H),2.16( s,3H),1.31(dt,J=13.8,7.2Hz,6H).
实施例24 4-(2-(2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯磺酰胺(Ⅰ-24)Example 24 4-(2-(2-amino-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)benzenesulfonamide (I-24)
Figure PCTCN2023071429-appb-000149
Figure PCTCN2023071429-appb-000149
操作过程和反应条件同实施例17相同，不同的是步骤中原料为4-(2-氨乙基)苯磺酰胺，白色固体，收率64.6％。 1H NMR(300MHz,DMSO-d 6)δ13.77(s,2H),12.58(d,J＝1.4Hz,1H),12.54–12.36(m,4H),12.26(d,J＝8.1Hz,2H),12.09(s,2H),9.19(t,J＝7.6Hz,2H),7.83(t,J＝7.7Hz,2H). The operation process and reaction conditions are the same as in Example 17, except that the raw material in the step is 4-(2-aminoethyl)benzenesulfonamide, a white solid, and the yield is 64.6%. 1 H NMR (300MHz, DMSO-d 6 )δ13.77(s, 2H), 12.58(d, J=1.4Hz, 1H), 12.54–12.36(m, 4H), 12.26(d, J=8.1Hz, 2H), 12.09(s, 2H), 9.19(t, J=7.6Hz, 2H), 7.83(t, J=7.7Hz, 2H).
实施例25 2-氨基-1-(4-氨磺酰苯乙基)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-25)Example 25 2-Amino-1-(4-sulfamoylphenethyl)-1H-benzo[d]imidazole-5-carboxylic acid ethyl ester (I-25)
Figure PCTCN2023071429-appb-000150
Figure PCTCN2023071429-appb-000150
操作过程和反应条件同实施例17相同，不同的是步骤①中原料为Ⅰ-18和4-(2-氨乙基)苯磺酰胺，白色固体，收率58.4％。 1H NMR(300MHz,DMSO-d 6)δ9.12(d,J＝3.9Hz,2H),7.93(d,J＝1.5Hz,1H),7.84(dd,J＝8.4,1.6Hz,1H),7.73(d,J＝7.9Hz,2H),7.61(d,J＝8.5Hz,1H),7.53(d,J＝8.0Hz,2H),7.35(s,2H),4.47(t,J＝7.6Hz,2H),4.38–4.24(m,2H),3.09(t,J＝7.7Hz,2H),1.41–1.09(m,2H). The operation process and reaction conditions are the same as in Example 17, except that the raw materials in step ① are I-18 and 4-(2-aminoethyl)benzenesulfonamide, a white solid, and the yield is 58.4%. 1 H NMR (300MHz, DMSO-d 6 ) δ9.12(d, J=3.9Hz, 2H), 7.93(d, J=1.5Hz, 1H), 7.84(dd, J=8.4, 1.6Hz, 1H) ,7.73(d,J=7.9Hz,2H),7.61(d,J=8.5Hz,1H),7.53(d,J=8.0Hz,2H),7.35(s,2H),4.47(t,J= 7.6Hz, 2H), 4.38–4.24(m, 2H), 3.09(t, J=7.7Hz, 2H), 1.41–1.09(m, 2H).
实施例26 2-氨基-7-甲氧基-1-(4-氨磺酰苯乙基)-1H-苯并[d]咪唑-5-甲酰胺(Ⅰ-26)Example 26 2-Amino-7-methoxy-1-(4-sulfamoylphenethyl)-1H-benzo[d]imidazole-5-carboxamide (I-26)
Figure PCTCN2023071429-appb-000151
Figure PCTCN2023071429-appb-000151
操作过程和反应条件同实施例17相同，不同的是步骤①中原料为6-1和4-(2-氨乙基)苯磺酰胺，白色固体，收率49.5％。 1H NMR(300MHz,DMSO-d 6)δ8.73(s,2H),8.12(s,1H),7.84–7.71(m,2H),7.56–7.41(m,5H),7.35(s,2H),4.46(t,J＝7.6Hz,2H),3.97(s,3H),3.09(t,J＝7.7Hz,2H). The operation process and reaction conditions are the same as in Example 17, except that the raw materials in step ① are 6-1 and 4-(2-aminoethyl)benzenesulfonamide, white solid, and the yield is 49.5%. 1 H NMR (300MHz,DMSO-d 6 )δ8.73(s,2H),8.12(s,1H),7.84–7.71(m,2H),7.56–7.41(m,5H),7.35(s,2H ), 4.46(t, J=7.6Hz, 2H), 3.97(s, 3H), 3.09(t, J=7.7Hz, 2H).
实施例27 2-氨基-7-甲氧基-1-(4-氨磺酰苯乙基)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-27)Example 27 2-Amino-7-methoxy-1-(4-sulfamoylphenethyl)-1H-benzo[d]imidazole-5-carboxylic acid ethyl ester (I-27)
Figure PCTCN2023071429-appb-000152
Figure PCTCN2023071429-appb-000152
操作过程和反应条件同实施例17相同，不同的是步骤①中原料为5-2和4-(2-氨乙基)苯磺酰胺，白色固体，收率54.6％。 1H NMR(300MHz,DMSO-d 6)δ8.84(d,J＝3.6Hz,2H),7.76(d,J＝8.1Hz,2H),7.59(d,J＝1.3Hz,1H),7.51–7.27(m,5H),4.46(t,J＝7.5Hz,2H),4.33(dt,J＝15.5,6.9Hz,2H),3.96(s,3H),3.09(t,J＝7.7Hz,2H),1.34(t,J＝7.1Hz,1H). The operation process and reaction conditions are the same as in Example 17, except that the raw materials in step ① are 5-2 and 4-(2-aminoethyl)benzenesulfonamide, white solid, and the yield is 54.6%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.84(d, J=3.6Hz, 2H), 7.76(d, J=8.1Hz, 2H), 7.59(d, J=1.3Hz, 1H), 7.51 –7.27(m,5H),4.46(t,J=7.5Hz,2H),4.33(dt,J=15.5,6.9Hz,2H),3.96(s,3H),3.09(t,J=7.7Hz, 2H), 1.34(t, J=7.1Hz, 1H).
实施例28 N-(5-氰基-1-(4-氨磺酰苯乙基)-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(Ⅰ-28)Example 28 N-(5-cyano-1-(4-sulfamoylphenethyl)-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H- Pyrazole-5-carboxamide (Ⅰ-28)
Figure PCTCN2023071429-appb-000153
Figure PCTCN2023071429-appb-000153
操作过程和反应条件同实施例21相同，不同的是步骤中原料为Ⅰ-24，白色固体，收率63.5％。 1H NMR(300MHz,DMSO-d 6)δ12.94(s,1H),7.78(d,J＝1.4Hz,1H),7.71(d,J＝8.2Hz,2H),7.67–7.58(m,2H),7.48(d,J＝8.3Hz,2H),7.31(s,2H),6.72(s,1H),4.61(q,J＝7.1Hz,2H),4.48(t,J＝7.3Hz,2H),3.23–3.12(m,2H),2.21(s,3H),1.35(t,J＝7.1Hz,3H). The operation process and reaction conditions are the same as in Example 21, except that the raw material in the step is I-24, a white solid, and the yield is 63.5%. 1 H NMR (300MHz, DMSO-d 6 )δ12.94(s, 1H), 7.78(d, J=1.4Hz, 1H), 7.71(d, J=8.2Hz, 2H), 7.67–7.58(m, 2H), 7.48(d, J=8.3Hz, 2H), 7.31(s, 2H), 6.72(s, 1H), 4.61(q, J=7.1Hz, 2H), 4.48(t, J=7.3Hz, 2H), 3.23–3.12(m, 2H), 2.21(s, 3H), 1.35(t, J＝7.1Hz, 3H).
实施例29 2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1-(4-氨磺酰苯乙基)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-29)Example 29 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-(4-sulfamoylphenethyl)-1H-benzo[d]imidazole-5 - Ethyl formate (Ⅰ-29)
Figure PCTCN2023071429-appb-000154
Figure PCTCN2023071429-appb-000154
操作过程和反应条件同实施例21相同，不同的是步骤中原料为Ⅰ-25，白色固体，收率55.3％。 1H NMR(300MHz,DMSO-d 6)δ12.87(s,1H),8.13–8.07(m,1H),7.82(d,J＝8.4Hz,1H),7.72(d,J＝8.0Hz,2H),7.53(dd,J＝18.8,8.2Hz,3H),7.30(s,2H),6.70(s,1H),4.62(q,J＝7.1Hz,2H),4.48(t,J＝7.4Hz,2H),4.31(dt,J＝16.1,6.9Hz,2H),2.21(s,3H),1.35(q,J＝6.9Hz,6H). The operation process and reaction conditions are the same as in Example 21, except that the raw material in the step is I-25, a white solid, and the yield is 55.3%. 1 H NMR (300MHz,DMSO-d 6 )δ12.87(s,1H),8.13–8.07(m,1H),7.82(d,J=8.4Hz,1H),7.72(d,J=8.0Hz, 2H), 7.53(dd, J=18.8, 8.2Hz, 3H), 7.30(s, 2H), 6.70(s, 1H), 4.62(q, J=7.1Hz, 2H), 4.48(t, J=7.4 Hz, 2H), 4.31(dt, J=16.1, 6.9Hz, 2H), 2.21(s, 3H), 1.35(q, J=6.9Hz, 6H).
实施例30 2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1-(4-氨磺酰苯乙基)-1H-苯并[d]咪唑-5-甲酸乙酯(Ⅰ-30)Example 30 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1-(4-sulfamoylphenethyl)-1H-benzo [d] Ethyl imidazole-5-carboxylate (Ⅰ-30)
Figure PCTCN2023071429-appb-000155
Figure PCTCN2023071429-appb-000155
操作过程和反应条件同实施例21相同，不同的是步骤中原料为Ⅰ-27，白色固体，收率57.6％。 1H NMR(300MHz,DMSO-d 6)δ12.90(s,1H),7.81(t,J＝3.5Hz,1H),7.75(d,J＝7.9Hz,2H),7.41(d,J＝8.0Hz,2H),7.33(d,J＝5.5Hz,3H),6.68(s,1H),4.61(dt,J＝15.6,7.7Hz,4H),4.31(dt,J＝17.5,6.7Hz,2H),3.94(s,3H),2.20(s,3H),1.39–1.19(m,6H). The operation process and reaction conditions are the same as in Example 21, except that the raw material in the step is I-27, a white solid, and the yield is 57.6%. 1 H NMR (300MHz, DMSO-d 6 )δ12.90(s, 1H), 7.81(t, J=3.5Hz, 1H), 7.75(d, J=7.9Hz, 2H), 7.41(d, J= 8.0Hz, 2H), 7.33(d, J=5.5Hz, 3H), 6.68(s, 1H), 4.61(dt, J=15.6, 7.7Hz, 4H), 4.31(dt, J=17.5, 6.7Hz, 2H), 3.94(s,3H), 2.20(s,3H), 1.39–1.19(m,6H).
实施例31 4-((2-氨基-5-氰基-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯磺酰胺(Ⅰ-31)Example 31 4-((2-Amino-5-cyano-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzenesulfonamide (I-31)
Figure PCTCN2023071429-appb-000156
Figure PCTCN2023071429-appb-000156
步骤①：4-(((4-氰基-2-甲氧基-6-硝基苯基)氨基)甲基)苯磺酰胺(31-1)Step ①: 4-(((4-cyano-2-methoxy-6-nitrophenyl)amino)methyl)benzenesulfonamide (31-1)
Figure PCTCN2023071429-appb-000157
Figure PCTCN2023071429-appb-000157
1克3-2、1.75克磺胺米隆、1.3克碳酸钾和1毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-(((4-氰基-2-甲氧基-6-硝基苯基)氨基)甲基)苯磺酰胺(31-1)黄色固体0.9克，收率52.8％。 1H NMR(300MHz,DMSO-d 6)δ8.97(s,2H),7.84–7.75(m,2H),7.54(d,J＝1.2Hz,1H),7.44–7.34(m,5H),5.59(s,2H),3.82(s,3H). 1 g of 3-2, 1.75 g of sulfamethione, 1.3 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution, a solid precipitated out, and suction filtration gave 0.9 g of a yellow solid of 4-(((4-cyano-2-methoxy-6-nitrophenyl)amino)methyl)benzenesulfonamide (31-1) , yield 52.8%. 1 H NMR (300MHz,DMSO-d 6 )δ8.97(s,2H),7.84–7.75(m,2H),7.54(d,J=1.2Hz,1H),7.44–7.34(m,5H), 5.59(s,2H),3.82(s,3H).
步骤②：4-(((2-氨基-4-氰基-6-甲氧基苯基)氨基)甲基)苯磺酰胺(31-2)Step ②: 4-(((2-amino-4-cyano-6-methoxyphenyl)amino)methyl)benzenesulfonamide (31-2)
Figure PCTCN2023071429-appb-000158
Figure PCTCN2023071429-appb-000158
将955毫克31-1、3.21克连二亚硫酸钠、2毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析纯化，得4-(((2-氨基-4-氰基-6-甲氧基苯基)氨基)甲基)苯磺酰胺(31-2)白色固体580毫克，收率66.2％。ESI-MS(m/z):333.0[M+H] +. A mixture of 955 mg of 31-1, 3.21 g of sodium dithionite, 2 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 4-(((2-amino-4-cyano-6-methoxyphenyl) Amino)methyl)benzenesulfonamide (31-2) 580 mg white solid, yield 66.2%. ESI-MS(m/z):333.0[M+H] + .
步骤③：4-((2-氨基-5-氰基-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯磺酰胺(Ⅰ-31)Step ③: 4-((2-amino-5-cyano-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzenesulfonamide (Ⅰ-31)
Figure PCTCN2023071429-appb-000159
Figure PCTCN2023071429-appb-000159
将500毫克31-2和191毫克溴化氰溶于5毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析纯化，得4-((2-氨基-5-氰基-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯磺酰胺(Ⅰ-31)白色固体420毫克，收率78.1％。 1H NMR(300MHz,DMSO-d 6)δ8.97(s,2H),7.84–7.75(m,2H),7.54(d,J＝1.2Hz,1H),7.44–7.34(m,5H),5.59(s,2H),3.82(s,3H). 500 mg of 31-2 and 191 mg of cyanogen bromide were dissolved in 5 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=200:1 to obtain 4-((2-amino-5-cyano-7-methoxy-1H-benzo[d] Imidazol-1-yl)methyl)benzenesulfonamide (I-31) was 420 mg of white solid, and the yield was 78.1%. 1 H NMR (300MHz,DMSO-d 6 )δ8.97(s,2H),7.84–7.75(m,2H),7.54(d,J=1.2Hz,1H),7.44–7.34(m,5H), 5.59(s,2H),3.82(s,3H).
实施例32 4-(2-(2-氨基-5-氰基-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯磺酰胺(Ⅰ-32)Example 32 4-(2-(2-Amino-5-cyano-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)benzenesulfonamide (I-32)
Figure PCTCN2023071429-appb-000160
Figure PCTCN2023071429-appb-000160
操作过程和反应条件同实施例31相同，不同的是步骤①中原料为4-(2-氨乙基)苯磺酰胺，白色固体，收率71.4％。 1H NMR(300MHz,DMSO-d 6)δ8.90(s,2H),7.80–7.71(m,2H),7.51–7.31(m,6H),4.45(t,J＝7.5Hz,2H),3.94(s,3H),3.08(t,J＝7.6Hz,2H). The operation process and reaction conditions are the same as in Example 31, except that the raw material in step ① is 4-(2-aminoethyl)benzenesulfonamide, a white solid, and the yield is 71.4%. 1 H NMR (300MHz,DMSO-d 6 )δ8.90(s,2H),7.80–7.71(m,2H),7.51–7.31(m,6H),4.45(t,J＝7.5Hz,2H), 3.94(s,3H),3.08(t,J=7.6Hz,2H).
实施例33 2-氨基-1-(4-氨磺酰苄)-1H-苯并[d]咪唑-5-甲酰胺(Ⅰ-33)Example 33 2-Amino-1-(4-sulfamoylbenzyl)-1H-benzo[d]imidazole-5-carboxamide (Ⅰ-33)
Figure PCTCN2023071429-appb-000161
Figure PCTCN2023071429-appb-000161
操作过程和反应条件同实施例31相同，不同的是步骤①中原料为4-氯-3-硝基苯甲酰胺，白色固体，收率64.2％。 1H NMR(300MHz,DMSO-d 6)δ7.98(d,J＝23.2Hz,3H),7.84–7.77(m,3H),7.64(dd,J＝8.3,1.6Hz,1H),7.42–7.25(m,6H). The operation process and reaction conditions are the same as in Example 31, except that the raw material in step ① is 4-chloro-3-nitrobenzamide, a white solid, and the yield is 64.2%. 1 H NMR (300MHz, DMSO-d 6 ) δ7.98 (d, J=23.2Hz, 3H), 7.84–7.77 (m, 3H), 7.64 (dd, J=8.3, 1.6Hz, 1H), 7.42– 7.25(m,6H).
实施例34 2-氨基-1-(4-氨磺酰苯乙基)-1H-苯并[d]咪唑-5-甲酰胺(Ⅰ-34)Example 34 2-Amino-1-(4-sulfamoylphenethyl)-1H-benzo[d]imidazole-5-carboxamide (I-34)
Figure PCTCN2023071429-appb-000162
Figure PCTCN2023071429-appb-000162
操作过程和反应条件同实施例31相同，不同的是步骤①中原料为4-氯-3-硝基苯甲酰胺和4-(2-氨乙基)苯磺酰胺，白色固体，收率57.7％。 1H NMR(300MHz,DMSO-d 6)δ8.91(s,2H),8.09(s,1H),7.87(d,J＝1.5Hz,1H),7.81(dd,J＝8.4,1.6Hz,1H),7.76–7.71(m,2H),7.60–7.52(m,3H),7.43(s,1H),7.35(s,2H),4.45(t,J＝7.7Hz,2H),3.09(t,J＝7.6Hz,2H). The operating process and reaction conditions are the same as in Example 31, except that the raw materials in step ① are 4-chloro-3-nitrobenzamide and 4-(2-aminoethyl)benzenesulfonamide, white solid, yield 57.7 %. 1 H NMR (300MHz, DMSO-d 6 )δ8.91(s, 2H), 8.09(s, 1H), 7.87(d, J=1.5Hz, 1H), 7.81(dd, J=8.4, 1.6Hz, 1H),7.76–7.71(m,2H),7.60–7.52(m,3H),7.43(s,1H),7.35(s,2H),4.45(t,J＝7.7Hz,2H),3.09(t ,J＝7.6Hz,2H).
实施例35二乙基(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸酯(I-35)Example 35 Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)-3,5-fluorophenyl)phosphonate (I-35)
Figure PCTCN2023071429-appb-000163
Figure PCTCN2023071429-appb-000163
步骤①：(E)-4-溴-2,6-二氟苯甲醛肟(35-1)Step ①: (E)-4-bromo-2,6-difluorobenzaldehyde oxime (35-1)
Figure PCTCN2023071429-appb-000164
Figure PCTCN2023071429-appb-000164
室温下，将2克4-溴-2，6-二氟苯甲醛溶于30毫升乙醇中，加入880毫克盐酸羟胺和1.04克醋酸钾,22℃下反应30分钟。反应完成后，冰浴下加冰水，搅拌一小时，抽滤，滤饼以乙醇：水＝1:1冷过滤和洗涤，残余物以石油醚：乙酸乙酯＝10：1柱层析纯化，得类白色固体(E)-4-溴-2,6-二氟苯甲醛肟(35-1)1.4克，收率66％。 1H NMR(300MHz,DMSO-d 6)δ11.96(s,1H),8.10(s,1H),7.65–7.52(m,2H). Dissolve 2 g of 4-bromo-2,6-difluorobenzaldehyde in 30 ml of ethanol at room temperature, add 880 mg of hydroxylamine hydrochloride and 1.04 g of potassium acetate, and react at 22°C for 30 minutes. After the reaction is completed, add ice water under ice bath, stir for one hour, and filter with suction. The filter cake is cold filtered and washed with ethanol: water = 1:1, and the residue is purified by column chromatography with petroleum ether: ethyl acetate = 10:1 1.4 g of off-white solid (E)-4-bromo-2,6-difluorobenzaldehyde oxime (35-1) was obtained, with a yield of 66%. 1 H NMR (300MHz,DMSO-d 6 )δ11.96(s,1H),8.10(s,1H),7.65–7.52(m,2H).
步骤②：(4-溴-2,6-氟代苯基)甲胺(35-2)Step ②: (4-bromo-2,6-fluorophenyl)methanamine (35-2)
Figure PCTCN2023071429-appb-000165
Figure PCTCN2023071429-appb-000165
将1.4克(E)-4-溴-2,6-二氟苯甲醛肟溶于10毫升乙酸，与65℃下加入2.9克锌粉，加热搅拌两小时。反应液浓缩至干，残余物加水，以乙酸乙酯萃取；水相用碳酸氢钠固体处理，调节PH至8-9。抽滤，滤液以乙酸乙酯萃取，有机相浓缩至干，得黄色油状物(4-溴-2,6-氟代苯基)甲胺(35-2)680毫克，收率56％。ESI-MS(m/z):222.0[M+H] +. Dissolve 1.4 g of (E)-4-bromo-2,6-difluorobenzaldehyde oxime in 10 ml of acetic acid, add 2.9 g of zinc powder at 65° C., and heat and stir for two hours. The reaction solution was concentrated to dryness, the residue was added with water, and extracted with ethyl acetate; the aqueous phase was treated with solid sodium bicarbonate, and the pH was adjusted to 8-9. After suction filtration, the filtrate was extracted with ethyl acetate, and the organic phase was concentrated to dryness to obtain 680 mg of (4-bromo-2,6-fluorophenyl)methanamine (35-2) as a yellow oil, with a yield of 56%. ESI-MS(m/z):222.0[M+H] + .
步骤③：4-((4-溴-2,6-二氟苄溴)氨基)-3-对硝基苯氰基(35-3)Step ③: 4-((4-bromo-2,6-difluorobenzyl bromide)amino)-3-p-nitrobenzocyano (35-3)
Figure PCTCN2023071429-appb-000166
Figure PCTCN2023071429-appb-000166
将1克4-氯-3-硝基苯甲腈、1.28克(4-溴-2,6-氟代苯基)甲胺、1.51克碳酸钾、1毫升的三乙胺和3毫升正丁醇的混合物于100℃搅拌过夜。加水，析出固体，残余物以石油醚：乙酸乙酯＝2:1柱层析纯化，得黄色固体4-((4-溴-2,6-二氟苄溴)氨基)-3-对硝基苯氰基(35-3)1.1克，收率55％。1 g of 4-chloro-3-nitrobenzonitrile, 1.28 g of (4-bromo-2,6-fluorophenyl)methylamine, 1.51 g of potassium carbonate, 1 ml of triethylamine and 3 ml of n-butyl The alcohol mixture was stirred overnight at 100°C. Water was added to precipitate a solid, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 2:1 to obtain a yellow solid 4-((4-bromo-2,6-difluorobenzyl bromide)amino)-3-p-nitrogen Benzene cyano (35-3) 1.1 g, yield 55%.
步骤④：3-氨基-4-((4-溴-2,6-二氟苄溴)氨基)苯甲腈(35-4)Step ④: 3-amino-4-((4-bromo-2,6-difluorobenzyl bromide)amino)benzonitrile (35-4)
Figure PCTCN2023071429-appb-000167
Figure PCTCN2023071429-appb-000167
将1.1克4-((4-溴-2,6-二氟苄溴)氨基)-3-对硝基苯氰基、3.9克连二亚硫酸钠和10毫升甲醇的混合物于45℃加热搅拌0.5小时。反应液浓缩至干，残余物以石油醚：乙酸 乙酯＝1：1柱层析纯化，得浅黄色类固体3-氨基-4-((4-溴-2,6-二氟苄溴)氨基)苯甲腈(35-4)560毫克，收率56％。ESI-MS(m/z):338.0[M+H] +. A mixture of 1.1 g of 4-((4-bromo-2,6-difluorobenzyl bromide) amino)-3-p-nitrobenzocyano, 3.9 g of sodium dithionite and 10 ml of methanol was heated and stirred at 45°C for 0.5 hours . The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain light yellow solid 3-amino-4-((4-bromo-2,6-difluorobenzyl bromide) Amino)benzonitrile (35-4) 560 mg, yield 56%. ESI-MS(m/z):338.0[M+H] + .
步骤⑤：2-氨基-1-(4-溴-2,6-二氟苄溴)-1H-苯并[d]咪唑-5-甲腈(35-5)Step ⑤: 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H-benzo[d]imidazole-5-carbonitrile (35-5)
Figure PCTCN2023071429-appb-000168
Figure PCTCN2023071429-appb-000168
将560毫克3-氨基-4-((4-溴-2,6-二氟苄溴)氨基)苯甲腈、211毫克溴化氰和5毫升甲醇于室温下搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝20：1柱层析纯化，得类白色固体2-氨基-1-(4-溴-2,6-二氟苄溴)-1H-苯并[d]咪唑-5-甲腈(35-5)490毫克，收率81％。 1H NMR(300MHz,DMSO-d 6)δ9.16(d,J＝9.3Hz,2H),7.85(s,1H),7.70(d,J＝8.4Hz,1H),7.60(d,J＝7.9Hz,1H),7.54–7.10(m,2H),5.55(d,J＝11.2Hz,2H). 560 mg of 3-amino-4-((4-bromo-2,6-difluorobenzylbromo)amino)benzonitrile, 211 mg of cyanogen bromide and 5 ml of methanol were stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain off-white solid 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H- Benzo[d]imidazole-5-carbonitrile (35-5) 490 mg, yield 81%. 1 H NMR (300MHz, DMSO-d 6 )δ9.16(d, J=9.3Hz, 2H), 7.85(s, 1H), 7.70(d, J=8.4Hz, 1H), 7.60(d, J= 7.9Hz, 1H), 7.54–7.10(m, 2H), 5.55(d, J=11.2Hz, 2H).
步骤⑥：N-(1-(4-溴-2,6-二氟苄溴)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(35-6)Step ⑥: N-(1-(4-bromo-2,6-difluorobenzyl bromide)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methanol Base-1H-pyrazole-5-carboxamide (35-6)
Figure PCTCN2023071429-appb-000169
Figure PCTCN2023071429-appb-000169
在冰浴下将221毫克1-乙基-3-甲基-1H-吡唑-5-羧酸、371毫克EDCI、56毫克HOBT、332微升三乙胺和4毫升N,N-二甲基甲酰胺的混合物搅拌0.5小时。将490毫克2-氨基-1-(4-溴-2,6-二氟苄溴)-1H-苯并[d]咪唑-5-甲腈加入混合物中室温搅拌过夜。加水，析出固体，残余物以二氯甲烷：甲醇＝20:1柱层析纯化，得白色固体N-(1-(4-溴-2,6-二氟苄溴)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(35-6)450毫克，收率67％。 1H NMR(300MHz,DMSO-d 6)δ12.95(s,1H),7.86–7.64(m,3H),7.54(d,J＝7.5Hz,2H),6.63(s,1H),5.47(s,2H),4.54(q,J＝7.0Hz,2H),2.19(s,3H),1.31(t,J＝7.1Hz,3H). Mix 221 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 371 mg of EDCI, 56 mg of HOBT, 332 μl of triethylamine, and 4 ml of N,N-dimethyl The mixture of methyl formamide was stirred for 0.5 hours. 490 mg of 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H-benzo[d]imidazole-5-carbonitrile was added to the mixture and stirred overnight at room temperature. Water was added to precipitate a solid, and the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain white solid N-(1-(4-bromo-2,6-difluorobenzyl bromide)-5-cyano- 1H-Benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (35-6) 450 mg, yield 67%. 1 H NMR (300MHz, DMSO-d 6 ) δ12.95(s, 1H), 7.86–7.64(m, 3H), 7.54(d, J=7.5Hz, 2H), 6.63(s, 1H), 5.47( s,2H),4.54(q,J=7.0Hz,2H),2.19(s,3H),1.31(t,J=7.1Hz,3H).
步骤⑦：二乙基(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸酯(I-35)Step ⑦: Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)-3,5-fluorophenyl)phosphonate (I-35)
Figure PCTCN2023071429-appb-000170
Figure PCTCN2023071429-appb-000170
氮气气氛下，将200毫克N-(1-(4-溴-2,6-二氟苄溴)-5-氰基-1H-苯并[d]咪唑-2-基)-1- 乙基-3-甲基-1H-吡唑-5-甲酰胺、196毫克碳酸铯、47毫克四(三苯基膦)钯、111微升亚磷酸二乙脂和5毫升无水四氢呋喃的混合物于110℃加热搅拌36小时。反应液浓缩至干，残余物加水以乙酸乙酯萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝20:1柱层析纯化，得类白色类固体二乙基(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸酯(I-35)54毫克，收率24％。 1H NMR(300MHz,DMSO-d 6)δ12.96(s,1H),7.82(t,J＝1.1Hz,1H),7.76(d,J＝1.1Hz,2H),7.43(dd,J＝14.1,7.0Hz,2H),6.57(d,J＝0.6Hz,1H),5.57(s,2H),4.52(q,J＝7.1Hz,2H),4.07–3.97(m,4H),2.18(s,3H),1.25–1.16(m,9H). Under a nitrogen atmosphere, 200 mg of N-(1-(4-bromo-2,6-difluorobenzyl bromide)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl -3-methyl-1H-pyrazole-5-carboxamide, 196 mg of cesium carbonate, 47 mg of tetrakis (triphenylphosphine) palladium, 111 microliters of diethyl phosphite and 5 milliliters of anhydrous tetrahydrofuran at 110 It was heated and stirred at ℃ for 36 hours. The reaction solution was concentrated to dryness, the residue was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain off-white solid diethyl(4-( (5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)methyl)-3,5 -Fluorophenyl) phosphonate (I-35) 54 mg, yield 24%. 1 H NMR (300MHz, DMSO-d 6 )δ12.96(s, 1H), 7.82(t, J=1.1Hz, 1H), 7.76(d, J=1.1Hz, 2H), 7.43(dd, J= 14.1,7.0Hz,2H),6.57(d,J＝0.6Hz,1H),5.57(s,2H),4.52(q,J＝7.1Hz,2H),4.07–3.97(m,4H),2.18( s,3H),1.25–1.16(m,9H).
实施例36(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸(I-36)Example 36 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl) Methyl)-3,5-fluorophenyl)phosphonic acid (I-36)
Figure PCTCN2023071429-appb-000171
Figure PCTCN2023071429-appb-000171
步骤①：(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸(I-36)Step ①: (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl) Methyl)-3,5-fluorophenyl)phosphonic acid (I-36)
Figure PCTCN2023071429-appb-000172
Figure PCTCN2023071429-appb-000172
在氮气氛围下，将54毫克二乙基(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸酯、101微升三甲基溴硅烷和2毫升无水二氯甲烷的混合物室温搅拌过夜。反应液浓缩至干，残余物加2毫升甲醇，混合物于80℃加热搅拌16小时。反应液浓缩至干，残余物以二氯甲烷：甲醇＝60：6制备薄层，得白色固体(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸(I-36)24毫克，收率50％。 1H NMR(300MHz,DMSO-d 6)δ12.95(s,1H),7.75(d,J＝30.6Hz,3H),7.27(s,2H),6.63(d,J＝7.2Hz,1H),5.50(s,2H),4.51(s,2H),2.16(d,J＝5.1Hz,3H),1.27(q,J＝9.4,8.1Hz,3H). Under nitrogen atmosphere, 54 mg of diethyl(4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[ d] A mixture of imidazol-1-yl)methyl)-3,5-fluorophenyl)phosphonate, 101 μl trimethylbromosilane and 2 ml anhydrous dichloromethane was stirred overnight at room temperature. The reaction solution was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was heated and stirred at 80°C for 16 hours. The reaction solution was concentrated to dryness, and the residue was prepared into a thin layer with dichloromethane:methanol=60:6 to obtain a white solid (4-((5-cyano-2-(1-ethyl-3-methyl-1H- Pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)methyl)-3,5-fluorophenyl)phosphonic acid (I-36) 24 mg, yield 50%. 1 H NMR (300MHz,DMSO-d 6 )δ12.95(s,1H),7.75(d,J=30.6Hz,3H),7.27(s,2H),6.63(d,J=7.2Hz,1H) ,5.50(s,2H),4.51(s,2H),2.16(d,J=5.1Hz,3H),1.27(q,J=9.4,8.1Hz,3H).
实施例37 1-(4-(二乙氧基磷酰基)-2,6-二氟苄溴)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酸乙酯(I-37)Example 37 1-(4-(diethoxyphosphoryl)-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-Benzo[d]imidazole-5-carboxylic acid ethyl ester (I-37)
Figure PCTCN2023071429-appb-000173
Figure PCTCN2023071429-appb-000173
步骤①：4-((4-溴-2,6-二氟苄溴)氨基)-3-硝基苯甲酸乙酯(37-1)Step ①: ethyl 4-((4-bromo-2,6-difluorobenzyl bromide) amino)-3-nitrobenzoate (37-1)
Figure PCTCN2023071429-appb-000174
Figure PCTCN2023071429-appb-000174
将1克4-氯-3-硝基苯甲酸乙酯、1.2克化合物6-4、1.25克碳酸钾、1毫升的三乙胺和3毫升正丁醇的混合物于100℃搅拌过夜。加水，析出固体，残余物以石油醚：乙酸乙酯＝5:1柱层析纯化，得黄色固体4-((4-溴-2,6-二氟苄溴)氨基)-3-硝基苯甲酸乙酯(37-1)1.03克，收率57％。LCMS(ESI)m/z:295.2[M+H] +. A mixture of 1 g of ethyl 4-chloro-3-nitrobenzoate, 1.2 g of compound 6-4, 1.25 g of potassium carbonate, 1 ml of triethylamine and 3 ml of n-butanol was stirred overnight at 100°C. Water was added to precipitate a solid, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 5:1 to obtain a yellow solid 4-((4-bromo-2,6-difluorobenzyl bromide)amino)-3-nitro Ethyl benzoate (37-1) 1.03 g, yield 57%. LCMS(ESI)m/z:295.2[M+H] + .
步骤②：3-氨基-4-((4-溴-2,6-二氟苄溴)氨基)苯甲酸乙酯(37-2)Step ②: ethyl 3-amino-4-((4-bromo-2,6-difluorobenzyl bromide)amino)benzoate (37-2)
Figure PCTCN2023071429-appb-000175
Figure PCTCN2023071429-appb-000175
将1.03克4-((4-溴-2,6-二氟苄溴)氨基)-3-硝基苯甲酸乙酯、3.1克连二亚硫酸钠和10毫升甲醇的混合物于45℃加热搅拌0.5小时。反应液浓缩至干，残余物以石油醚：乙酸乙酯＝3：1柱层析纯化，得浅黄色类固体3-氨基-4-((4-溴-2,6-二氟苄溴)氨基)苯甲酸乙酯(37-2)520毫克，收率54％。 1H NMR(300MHz,CDCl 3-d)δ7.61(dd,J＝8.3,1.9Hz,1H),7.43(d,J＝1.9Hz,1H),7.16–7.10(m,2H),6.76(d,J＝8.4Hz,1H),4.46(s,2H),4.27(t,J＝6.6Hz,2H),1.36(s,3H). A mixture of 1.03 g of 4-((4-bromo-2,6-difluorobenzyl bromide) amino)-3-nitrobenzoic acid ethyl ester, 3.1 g of sodium dithionite and 10 ml of methanol was heated and stirred at 45°C for 0.5 hours . The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 3:1 to obtain light yellow solid 3-amino-4-((4-bromo-2,6-difluorobenzyl bromide) Amino) ethyl benzoate (37-2) 520 mg, yield 54%. 1 H NMR (300MHz, CDCl 3 -d) δ7.61 (dd, J = 8.3, 1.9Hz, 1H), 7.43 (d, J = 1.9Hz, 1H), 7.16–7.10 (m, 2H), 6.76 ( d, J=8.4Hz, 1H), 4.46(s, 2H), 4.27(t, J=6.6Hz, 2H), 1.36(s, 3H).
步骤③：2-氨基-1-(4-溴-2,6-二氟苄溴)-1H-苯并[d]咪唑-5-甲酸乙酯(37-3)Step ③: Ethyl 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H-benzo[d]imidazole-5-carboxylate (37-3)
Figure PCTCN2023071429-appb-000176
Figure PCTCN2023071429-appb-000176
将520毫克3-氨基-4-((4-溴-2,6-二氟苄溴)氨基)苯甲酸乙酯、171.6毫克溴化氰和5毫升甲醇于室温下搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝20：1柱层析纯化，得类白色固体2-氨基-1-(4-溴-2,6-二氟苄溴)-1H-苯并[d]咪唑-5-甲酸乙酯(37-3)460毫克，收率83％。 1H NMR(300MHz,DMSO-d 6)δ9.13(s,2H),7.93(d,J＝1.5Hz,1H),7.87(dd,J＝8.4,1.6Hz,1H),7.69–7.51(m,2H),7.29(d,J＝8.5Hz,1H),5.53(s, 2H),4.28(t,J＝6.4Hz,2H),0.93(t,J＝7.4Hz,3H). 520 mg of ethyl 3-amino-4-((4-bromo-2,6-difluorobenzyl bromide)amino)benzoate, 171.6 mg of cyanogen bromide and 5 ml of methanol were stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain off-white solid 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H- Benzo[d]imidazole-5-carboxylic acid ethyl ester (37-3) 460 mg, yield 83%. 1 H NMR (300MHz, DMSO-d 6 ) δ9.13(s, 2H), 7.93(d, J=1.5Hz, 1H), 7.87(dd, J=8.4, 1.6Hz, 1H), 7.69–7.51( m, 2H), 7.29(d, J=8.5Hz, 1H), 5.53(s, 2H), 4.28(t, J=6.4Hz, 2H), 0.93(t, J=7.4Hz, 3H).
步骤④：1-(4-溴-2,6-二氟苄溴)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酸乙酯(37-4)Step ④: 1-(4-bromo-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d ]Imidazole-5-ethyl carboxylate (37-4)
Figure PCTCN2023071429-appb-000177
Figure PCTCN2023071429-appb-000177
在冰浴下，将208毫克1-乙基-3-甲基-1H-吡唑-5-羧酸、348毫克EDCI、52毫克HOBT、311微升三乙胺和4毫升N,N-二甲基甲酰胺的混合物搅拌0.5小时。将460毫克2-氨基-1-(4-溴-2,6-二氟苄溴)-1H-苯并[d]咪唑-5-甲酸乙酯加入混合物中室温搅拌过夜。加水，析出固体，残余物以二氯甲烷：甲醇＝20:1柱层析纯化，得白色固体1-(4-溴-2,6-二氟苄溴)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酸乙酯(37-4)467毫克，收率76％。 1H NMR(300MHz,DMSO-d 6)δ12.91(s,1H),8.15(d,J＝1.6Hz,1H),7.92(dd,J＝1.7,8.4Hz,1H),7.62(d,J＝8.5Hz,1H),7.55(d,J＝7.5Hz,2H),6.65(s,1H),5.49(s,2H),4.58(q,J＝7.1Hz,2H),4.31(t,J＝6.4Hz,2H),2.21(s,3H),1.40–1.19(m,6H). In an ice bath, mix 208 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 348 mg of EDCI, 52 mg of HOBT, 311 μl of triethylamine and 4 ml of N,N-di The mixture of methylformamide was stirred for 0.5 hours. 460 mg of ethyl 2-amino-1-(4-bromo-2,6-difluorobenzyl bromide)-1H-benzo[d]imidazole-5-carboxylate was added to the mixture and stirred overnight at room temperature. Water was added to precipitate a solid, and the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain a white solid 1-(4-bromo-2,6-difluorobenzyl bromide)-2-(1-ethyl- 3-Methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-5-carboxylic acid ethyl ester (37-4) 467 mg, yield 76%. 1 H NMR (300MHz, DMSO-d 6 )δ12.91(s, 1H), 8.15(d, J=1.6Hz, 1H), 7.92(dd, J=1.7, 8.4Hz, 1H), 7.62(d, J＝8.5Hz, 1H), 7.55(d, J＝7.5Hz, 2H), 6.65(s, 1H), 5.49(s, 2H), 4.58(q, J＝7.1Hz, 2H), 4.31(t, J＝6.4Hz, 2H), 2.21(s, 3H), 1.40–1.19(m, 6H).
步骤⑤:1-(4-(二乙氧基磷酰基)-2,6-二氟苄溴)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酸乙酯(I-37)Step ⑤: 1-(4-(diethoxyphosphoryl)-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-Benzo[d]imidazole-5-carboxylic acid ethyl ester (I-37)
Figure PCTCN2023071429-appb-000178
Figure PCTCN2023071429-appb-000178
氮气气氛下，将200毫克1-(4-溴-2,6-二氟苄溴)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酸乙酯、179毫克碳酸铯、43毫克四(三苯基膦)钯、101微升亚磷酸二乙脂和5毫升无水四氢呋喃的混合物于110℃加热搅拌36小时。反应液浓缩至干，残余物加水以乙酸乙酯萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝20:1柱层析纯化，得类白色类固体1-(4-(二乙氧基磷酰基)-2,6-二氟苄溴)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酸乙酯(I-37)96毫克，收率43％。 1H NMR(300MHz,DMSO-d 6)δ12.18(s,1H),8.06–7.94(m,2H),7.44–7.34(m,2H),7.30(d,J＝8.4Hz,1H),6.82(s,1H),5.52(s,2H),4.69(q,J＝7.2Hz,2H),4.36(t,J＝6.6Hz,2H),4.30–4.02(m,4H),2.33(s,3H),1.83–1.71(m,3H),1.52–1.47(m,3H),1.32–1.23(m,6H). Under nitrogen atmosphere, 200 mg of 1-(4-bromo-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H- A mixture of ethyl benzo[d]imidazole-5-carboxylate, 179 mg of cesium carbonate, 43 mg of tetrakis(triphenylphosphine)palladium, 101 microliters of diethyl phosphite and 5 milliliters of anhydrous tetrahydrofuran was heated and stirred at 110°C 36 hours. The reaction solution was concentrated to dryness, the residue was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness; the residue was purified by column chromatography with dichloromethane:methanol=20:1 to obtain off-white solid 1-(4-(di Ethoxyphosphoryl)-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole- 96 mg of ethyl 5-carboxylate (I-37), yield 43%. 1 H NMR (300MHz,DMSO-d 6 )δ12.18(s,1H),8.06–7.94(m,2H),7.44–7.34(m,2H),7.30(d,J＝8.4Hz,1H), 6.82(s,1H),5.52(s,2H),4.69(q,J=7.2Hz,2H),4.36(t,J=6.6Hz,2H),4.30–4.02(m,4H),2.33(s ,3H),1.83–1.71(m,3H),1.52–1.47(m,3H),1.32–1.23(m,6H).
实施例38(4-((5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸(I-38)Example 38 (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)-3,5-fluorophenyl)phosphonic acid (I-38)
Figure PCTCN2023071429-appb-000179
Figure PCTCN2023071429-appb-000179
步骤①：(4-((5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸(I-38)Step ①: (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)-3,5-fluorophenyl)phosphonic acid (I-38)
Figure PCTCN2023071429-appb-000180
Figure PCTCN2023071429-appb-000180
在氮气氛围下，将54毫克1-(4-(二乙氧基磷酰基)-2,6-二氟苄溴)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-5-甲酸乙酯、97微升三甲基溴硅烷和2毫升无水二氯甲烷的混合物室温搅拌过夜。反应液浓缩至干，残余物加2毫升甲醇，混合物于80℃加热搅拌16小时。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1制备薄层，得白色固体(4-((5-(乙氧羰基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)-3,5-氟代苯基)膦酸(I-38)27毫克，收率55％。 1H NMR(300MHz,DMSO-d 6)δ13.14–12.61(m,1H),8.11(s,1H),7.97–7.76(m,1H),7.57(s,1H),7.27(s,2H),6.63(s,1H),5.51(s,2H),4.53(s,2H),4.26(s,2H),2.16(s,3H),1.37(d,J＝42.8Hz,6H). Under nitrogen atmosphere, 54 mg of 1-(4-(diethoxyphosphoryl)-2,6-difluorobenzyl bromide)-2-(1-ethyl-3-methyl-1H-pyrazole- A mixture of ethyl 5-formamide)-1H-benzo[d]imidazole-5-carboxylate, 97 μl trimethylbromosilane and 2 ml anhydrous dichloromethane was stirred overnight at room temperature. The reaction solution was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was heated and stirred at 80°C for 16 hours. The reaction solution was concentrated to dryness, and the residue was prepared into a thin layer with dichloromethane:methanol=10:1 to obtain a white solid (4-((5-(ethoxycarbonyl)-2-(1-ethyl-3-methyl -1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl)methyl)-3,5-fluorophenyl)phosphonic acid (I-38) 27 mg, yield 55%. 1 H NMR (300MHz,DMSO-d 6 )δ13.14–12.61(m,1H),8.11(s,1H),7.97–7.76(m,1H),7.57(s,1H),7.27(s,2H ),6.63(s,1H),5.51(s,2H),4.53(s,2H),4.26(s,2H),2.16(s,3H),1.37(d,J=42.8Hz,6H).
实施例39(4-(2-(5-氰基-2-((1-乙基-3-甲基-1H-吡唑-5-基)氨甲酰)-1H苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-39)Example 39 (4-(2-(5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1H benzo[d]imidazole -1-yl) ethyl) phenyl) phosphonic acid (I-39)
Figure PCTCN2023071429-appb-000181
Figure PCTCN2023071429-appb-000181
步骤①：5-氰基-1H-苯并[d]咪唑-2-羧酸(39-1)Step ①: 5-cyano-1H-benzo[d]imidazole-2-carboxylic acid (39-1)
Figure PCTCN2023071429-appb-000182
Figure PCTCN2023071429-appb-000182
氩气氛下，将1克3,4-二氨基苯腈分散于10毫升无水二氯甲烷中，加入1.25毫升2,2,2-三氯乙酸甲酯，冰浴下加入1.5毫升三氟乙酸，搅拌1小时。反应液过滤，向滤液中加入15毫升1.5M的氢氧化钠，浓缩除去二氯甲烷。向残余物中加入15毫升的甲醇，搅拌4小时。向反应液中缓慢滴加1M的盐酸，逐渐析出固体，干燥得淡黄色固体(39-1)800毫克，收率57.1％。LCMS(ESI)m/z[M+H] +:188.1. Under argon atmosphere, disperse 1 g of 3,4-diaminobenzonitrile in 10 ml of anhydrous dichloromethane, add 1.25 ml of methyl 2,2,2-trichloroacetate, add 1.5 ml of trifluoroacetic acid under ice-cooling , and stirred for 1 hour. The reaction solution was filtered, 15 ml of 1.5M sodium hydroxide was added to the filtrate, and the dichloromethane was removed by concentration. 15 ml of methanol was added to the residue, followed by stirring for 4 hours. 1M hydrochloric acid was slowly added dropwise to the reaction solution, the solid was gradually precipitated, and dried to obtain 800 mg of light yellow solid (39-1), with a yield of 57.1%. LCMS(ESI)m/z[M+H] + :188.1.
步骤②：1-乙基-3-甲基-1H-吡唑-5-胺(39-2)Step ②: 1-Ethyl-3-methyl-1H-pyrazol-5-amine (39-2)
Figure PCTCN2023071429-appb-000183
Figure PCTCN2023071429-appb-000183
氩气氛下，将2克(Z)-3-氨基-2-烯腈溶于40毫升无水乙醇中，加入4.8克乙肼草酸盐和8.5毫升三乙胺，于80℃加热搅拌4小时。反应液过滤，滤液浓缩至干得淡黄色液体。残余物以二氯甲烷：甲醇＝50:1柱层析纯化，得淡黄色固体(39-2)2.7克，收率88.5％。LCMS(ESI)m/z[M+H] +:126.1. 1H NMR(400MHz,DMSO-d6)δ5.04(s,1H),5.00(s,2H),3.75(q,J＝7.1Hz,2H),1.95(s,3H),1.17(t,J＝7.1Hz,3H). Under an argon atmosphere, dissolve 2 g of (Z)-3-amino-2-enenitrile in 40 ml of absolute ethanol, add 4.8 g of dihydrazine oxalate and 8.5 ml of triethylamine, and heat and stir at 80°C for 4 hours . The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain a pale yellow liquid. The residue was purified by column chromatography with dichloromethane:methanol=50:1 to obtain 2.7 g of light yellow solid (39-2) with a yield of 88.5%. LCMS (ESI) m/z [M+H] + : 126.1. 1 H NMR (400MHz, DMSO-d6) δ5.04 (s, 1H), 5.00 (s, 2H), 3.75 (q, J = 7.1Hz ,2H),1.95(s,3H),1.17(t,J=7.1Hz,3H).
步骤③：5-氰基-N-(1-乙基-3-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2-甲酰胺(39-3)Step ③: 5-cyano-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole-2-carboxamide (39-3)
Figure PCTCN2023071429-appb-000184
Figure PCTCN2023071429-appb-000184
氩气氛下，将400毫克39-1溶于15毫升N,N-二甲基甲酰胺中，加入450毫克39-2、1.2克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)和2毫升N,N-二异丙基乙胺，室温搅拌过夜。反应液加水稀释，用二氯甲烷萃取，有机相用水和饱和食盐水充分洗涤，水相用乙酸乙酯反萃，合并有机相。有机相浓缩至干，残余物以石油醚：乙酸乙酯＝3:2柱层析纯化，得淡黄色固体(39-3)330毫克，收率48.5％。LCMS(ESI)m/z[M+H] +:295.2. Under argon atmosphere, dissolve 400 mg of 39-1 in 15 ml of N,N-dimethylformamide, add 450 mg of 39-2, 1.2 g of N,N,N',N'-tetramethyl-O- (7-Azabenzotriazol-1-yl)urea hexafluorophosphate (HATU) and 2 ml of N,N-diisopropylethylamine were stirred overnight at room temperature. The reaction solution was diluted with water, extracted with dichloromethane, the organic phase was fully washed with water and saturated brine, the aqueous phase was back-extracted with ethyl acetate, and the organic phases were combined. The organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 3:2 to obtain 330 mg of light yellow solid (39-3) with a yield of 48.5%. LCMS(ESI)m/z[M+H] + :295.2.
步骤④：1-(4-溴苯乙基)-5-氰基-N-(1-乙基-3-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2-甲酰胺(39-4)Step ④: 1-(4-bromophenethyl)-5-cyano-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole -2-Carboxamide (39-4)
Figure PCTCN2023071429-appb-000185
Figure PCTCN2023071429-appb-000185
将180毫克39-3溶于10毫升二甲基亚砜中，加入50毫克氢氧化钾，250毫克对溴苯乙基溴，室温下搅拌过夜。向反应液中加入乙酸乙酯，用水和饱和食盐水充分洗涤，除去二甲基亚砜。有机相浓缩至干，残余物以石油醚：乙酸乙酯＝7:3柱层析纯化，得淡黄色固体(39-4)150毫克，收率51.5％。LCMS(ESI)m/z[M+H]+:477.1，479.1. 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.42(d,J＝9.3Hz,1H),7.97(d,J＝8.6Hz,1H),7.77(dd,J＝9.0,8.5Hz,1H),7.41(dd,J＝8.2,4.1Hz,2H),7.09(dd,J＝9.7,8.0Hz,2H),6.00(d,J＝3.7Hz,1H),4.92(s,2H),4.03–3.82(m,2H),3.08(s,2H),2.15(s,3H),1.28(t,J＝7.2Hz,3H). Dissolve 180 mg of 39-3 in 10 ml of dimethyl sulfoxide, add 50 mg of potassium hydroxide and 250 mg of p-bromophenethyl bromide, and stir overnight at room temperature. Ethyl acetate was added to the reaction liquid, and the mixture was washed well with water and saturated brine to remove dimethyl sulfoxide. The organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 7:3 to obtain 150 mg of light yellow solid (39-4) with a yield of 51.5%. LCMS (ESI) m/z [M+H]+: 477.1, 479.1. 1 H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 8.42 (d, J = 9.3Hz, 1H), 7.97 (d,J=8.6Hz,1H),7.77(dd,J=9.0,8.5Hz,1H),7.41(dd,J=8.2,4.1Hz,2H),7.09(dd,J=9.7,8.0Hz, 2H), 6.00(d, J=3.7Hz, 1H), 4.92(s, 2H), 4.03–3.82(m, 2H), 3.08(s, 2H), 2.15(s, 3H), 1.28(t, J =7.2Hz,3H).
步骤⑤：(4-(2-(5-氰基-2-((1-乙基-3-甲基-1H-吡唑-5-基)氨甲酰)-1H苯 并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(39-5)Step ⑤: (4-(2-(5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole -1-yl) ethyl) phenyl) phosphonic acid diethyl ester (39-5)
Figure PCTCN2023071429-appb-000186
Figure PCTCN2023071429-appb-000186
氩气氛下，将50毫克39-4溶于6毫升无水四氢呋喃中，加入15毫克四(三苯基膦)钯、85微升三乙胺、34微升亚磷酸二乙酯，于100℃加热搅拌12小时。反应液过滤，滤液浓缩。残余物加水后用乙酸乙酯萃取，有机相浓缩至干。残余物以二氯甲烷：甲醇＝50:1制备薄层，得白色固体(39-5)30毫克，收率53.6％。LCMS(ESI)m/z[M+H] +:535,2. Under an argon atmosphere, dissolve 50 mg of 39-4 in 6 ml of anhydrous tetrahydrofuran, add 15 mg of tetrakis(triphenylphosphine)palladium, 85 μl of triethylamine, and 34 μl of diethyl phosphite, at 100°C Heat and stir for 12 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was added with water and extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was prepared into a thin layer with dichloromethane:methanol=50:1 to obtain 30 mg of white solid (39-5), with a yield of 53.6%. LCMS(ESI)m/z[M+H] + :535,2.
步骤⑥：(4-(2-(5-氰基-2-((1-乙基-3-甲基-1H-吡唑-5-基)氨甲酰)-1H苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-39)Step ⑥: (4-(2-(5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole -1-yl) ethyl) phenyl) phosphonic acid (I-39)
Figure PCTCN2023071429-appb-000187
Figure PCTCN2023071429-appb-000187
氩气氛下，将30毫克39-5溶于5毫升无水二氯甲烷中，冰浴下搅拌10分钟后缓慢加入70微升三甲基碘硅烷，随后室温搅拌过夜。向反应液中加入3毫升甲醇和3毫升的水，搅拌至析出固体后，继续搅拌3个小时。反应液过滤，得灰白色固体(I-39)10毫克，收率37.3％。LCMS(ESI)m/z[M+H] +:479.1. 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.39(d,J＝1.5Hz,1H),7.96(d,J＝8.5Hz,1H),7.78(dd,J＝8.6,1.5Hz,1H),7.56(d,J＝7.9Hz,1H),7.53(d,J＝7.8Hz,1H),7.29(d,J＝3.4Hz,1H),7.27(d,J＝3.4Hz,1H),6.04(s,1H),4.92(t,J＝7.6Hz,2H),3.94(q,J＝7.2Hz,2H),3.14(t,J＝7.7Hz,2H),2.16(s,3H),1.29(t,J＝7.1Hz,3H). Under an argon atmosphere, 30 mg of 39-5 was dissolved in 5 ml of anhydrous dichloromethane, stirred in an ice bath for 10 minutes, and then 70 μl of iodotrimethylsilane was slowly added, followed by stirring overnight at room temperature. Add 3 milliliters of methanol and 3 milliliters of water to the reaction solution, stir until solid precipitates, and then continue to stir for 3 hours. The reaction solution was filtered to obtain 10 mg of off-white solid (I-39), with a yield of 37.3%. LCMS (ESI) m/z [M+H] + : 479.1. 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 8.39 (d, J = 1.5Hz, 1H), 7.96 (d ,J=8.5Hz,1H),7.78(dd,J=8.6,1.5Hz,1H),7.56(d,J=7.9Hz,1H),7.53(d,J=7.8Hz,1H),7.29(d ,J=3.4Hz,1H),7.27(d,J=3.4Hz,1H),6.04(s,1H),4.92(t,J=7.6Hz,2H),3.94(q,J=7.2Hz,2H ), 3.14(t, J=7.7Hz, 2H), 2.16(s, 3H), 1.29(t, J=7.1Hz, 3H).
实施例40(4-((5-氰基-2-((1-乙基-3-甲基-1H-吡唑-5-基)氨甲酰)-1H苯并[d]咪唑-1-基)甲基)苯基)膦酸(I-40)Example 40 (4-((5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole-1 -yl)methyl)phenyl)phosphonic acid (I-40)
Figure PCTCN2023071429-appb-000188
Figure PCTCN2023071429-appb-000188
步骤①：1-(4-溴苯基)-5-氰基-N-(1-乙基-3-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2-甲酰胺(40-1)Step ①: 1-(4-bromophenyl)-5-cyano-N-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazole- 2-Formamide (40-1)
Figure PCTCN2023071429-appb-000189
Figure PCTCN2023071429-appb-000189
将200毫克39-3溶于10毫升二甲基亚砜中，加入60毫克氢氧化钾，250毫克化合物对溴苄溴，室温下搅拌16小时。向反应液中加入乙酸乙酯，用水和饱和食盐水充分洗涤，除去二甲基亚砜。有机相浓缩至干，残余物以石油醚：乙酸乙酯＝7：3柱层析纯化，得淡黄色固体(40-1)80毫克，收率25.5％。LCMS(ESI)m/z[M+H] +:463，465. 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.46(d,J＝9.3Hz,1H),8.02(d,J＝8.6Hz,1H),7.78(dd,J＝9.0,8.5Hz,1H),7.45(dd,J＝8.2,4.1Hz,2H),7.06(dd,J＝9.7,8.0Hz,2H),6.04(d,J＝3.7Hz,1H),4.88(s,2H),4.03–3.82(m,2H),2.18(s,3H),1.32(t,J＝7.2Hz,3H). Dissolve 200 mg of 39-3 in 10 ml of dimethyl sulfoxide, add 60 mg of potassium hydroxide and 250 mg of compound p-bromobenzyl bromide, and stir at room temperature for 16 hours. Ethyl acetate was added to the reaction liquid, and the mixture was washed well with water and saturated brine to remove dimethyl sulfoxide. The organic phase was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether:ethyl acetate=7:3 to obtain 80 mg of light yellow solid (40-1) with a yield of 25.5%. LCMS (ESI) m/z [M+H] + : 463, 465. 1 H NMR (400MHz, DMSO-d6) δ10.78 (s, 1H), 8.46 (d, J = 9.3Hz, 1H), 8.02 (d,J=8.6Hz,1H),7.78(dd,J=9.0,8.5Hz,1H),7.45(dd,J=8.2,4.1Hz,2H),7.06(dd,J=9.7,8.0Hz, 2H), 6.04(d, J=3.7Hz, 1H), 4.88(s, 2H), 4.03–3.82(m, 2H), 2.18(s, 3H), 1.32(t, J=7.2Hz, 3H).
步骤②：(4-((5-氰基-2-((1-乙基-3-甲基-1H-吡唑-5-基)氨甲酰)-1H苯并[d]咪唑-1-基)甲基)苯基)膦酸二乙酯(40-2)Step ②: (4-((5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole-1 -yl) methyl) phenyl) phosphonic acid diethyl ester (40-2)
Figure PCTCN2023071429-appb-000190
Figure PCTCN2023071429-appb-000190
氩气氛下将40毫克40-1溶于5毫升无水四氢呋喃中，加入15毫克四(三苯基膦)钯、85微升三乙胺、50微升亚磷酸二乙酯，于100℃加热搅拌12小时。反应液过滤，滤液浓缩。残余物加水后用乙酸乙酯萃取，有机相浓缩至干。残余物以二氯甲烷：甲醇＝50:1制备薄层，得淡黄色油状物(40-2)20毫克，收率44.4％。LCMS(ESI)m/z[M+H] +:521.2. Dissolve 40 mg of 40-1 in 5 ml of anhydrous tetrahydrofuran under an argon atmosphere, add 15 mg of tetrakis(triphenylphosphine)palladium, 85 μl of triethylamine, and 50 μl of diethyl phosphite, and heat at 100°C Stir for 12 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was added with water and extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was prepared into a thin layer with dichloromethane:methanol=50:1 to obtain 20 mg of light yellow oil (40-2) with a yield of 44.4%. LCMS(ESI)m/z[M+H] + :521.2.
步骤③：(4-((5-氰基-2-((1-乙基-3-甲基-1H-吡唑-5-基)氨甲酰)-1H苯并[d]咪唑-1-基)甲基)苯基)膦酸(I-40)Step ③: (4-((5-cyano-2-((1-ethyl-3-methyl-1H-pyrazol-5-yl)carbamoyl)-1Hbenzo[d]imidazole-1 -yl)methyl)phenyl)phosphonic acid (I-40)
Figure PCTCN2023071429-appb-000191
Figure PCTCN2023071429-appb-000191
氩气氛下，将20毫克40-2溶于4毫升无水二氯甲烷中，冰浴下搅拌10分钟后缓慢滴加60微升三甲基碘硅烷，随后室温搅拌过夜。向反应液中加入3毫升甲醇和3毫升的水，搅拌至析出固体后，继续搅拌3个小时。反应液过滤，得灰白色固体(I-40)7毫克，收率39.3％。LCMS(ESI)m/z[M-H] +:463.1. 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.45(s,1H),7.96–7.93(m,1H),7.92(d,J＝8.6Hz,1H),7.64–7.55(m,2H), 7.25(dt,J＝8.5,4.5Hz,2H),6.07(s,1H),6.02(t,J＝2.3Hz,2H),3.98–3.82(m,2H),2.13(s,3H),1.24(t,J＝7.2Hz,3H). Under an argon atmosphere, 20 mg of 40-2 was dissolved in 4 ml of anhydrous dichloromethane, stirred in an ice bath for 10 minutes, and then 60 μl of iodotrimethylsilane was slowly added dropwise, followed by stirring overnight at room temperature. Add 3 milliliters of methanol and 3 milliliters of water to the reaction solution, stir until solid precipitates, and then continue to stir for 3 hours. The reaction solution was filtered to obtain 7 mg of off-white solid (I-40), with a yield of 39.3%. LCMS (ESI) m/z [MH] + :463.1. 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 8.45 (s, 1H), 7.96–7.93 (m, 1H), 7.92 (d,J=8.6Hz,1H),7.64–7.55(m,2H), 7.25(dt,J=8.5,4.5Hz,2H),6.07(s,1H),6.02(t,J=2.3Hz, 2H), 3.98–3.82(m, 2H), 2.13(s, 3H), 1.24(t, J＝7.2Hz, 3H).
实施例41 4-(2-(5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基二乙基磷酸酯(I-41)Example 41 4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[ d] imidazol-1-yl) ethyl) phenyl diethyl phosphate (I-41)
Figure PCTCN2023071429-appb-000192
Figure PCTCN2023071429-appb-000192
在氩气氛下，将4克16-7溶于40毫升干燥二氯甲烷和40毫升干燥二甲基亚砜的混合液中，于冰浴下搅拌10分钟后，加入1.7克氰基磷酸二乙酯，随后缓慢加入2.4毫升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和二氯甲烷萃取，有机相用水充分洗涤后，浓缩至干。依次用乙醚和乙酸乙酯打浆，干燥得棕黄色固体(I-41)3.9克，收率为75.4％。LCMS(ESI)m/z[M+H] +:599.3. 1H NMR(400MHz,CD 3OD)δ7.54(s,1H),7.27(s,1H),7.10–6.97(m,4H),6.60(s,1H),4.60(d,J＝7.3Hz,2H),4.49(d,J＝8.6Hz,2H),4.15(ddt,J＝12.0,7.1,3.5Hz,4H),3.92(s,3H),3.31(s,1H),3.05–2.95(m,2H),2.66(s,1H),2.21(s,3H),1.42–1.27(m,9H). Under an argon atmosphere, 4 g of 16-7 was dissolved in a mixture of 40 ml of dry dichloromethane and 40 ml of dry dimethyl sulfoxide, stirred in an ice bath for 10 minutes, and then 1.7 g of diethyl cyanophosphate was added. ester, and then slowly added 2.4 ml of triethylamine, stirred in an ice bath for 30 minutes, and stirred overnight at room temperature. The reaction solution was extracted with water and dichloromethane, and the organic phase was fully washed with water and then concentrated to dryness. Slurry with diethyl ether and ethyl acetate in turn, and dry to obtain 3.9 g of brown-yellow solid (I-41), with a yield of 75.4%. LCMS (ESI) m/z [M+H] + :599.3. 1 H NMR (400MHz, CD 3 OD) δ7.54 (s, 1H), 7.27 (s, 1H), 7.10–6.97 (m, 4H) ,6.60(s,1H),4.60(d,J=7.3Hz,2H),4.49(d,J=8.6Hz,2H),4.15(ddt,J=12.0,7.1,3.5Hz,4H),3.92( s,3H),3.31(s,1H),3.05–2.95(m,2H),2.66(s,1H),2.21(s,3H),1.42–1.27(m,9H).
实施例42(4-((5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)甲基)苯基)膦酸(I-42)Example 42 (4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran [4 ,5-d]imidazol-1-yl)methyl)phenyl)phosphonic acid (I-42)
Figure PCTCN2023071429-appb-000193
Figure PCTCN2023071429-appb-000193
步骤①：4-乙酰氨基-2-羟基-5-硝基苯甲酸甲酯(42-1)Step ①: Methyl 4-acetylamino-2-hydroxy-5-nitrobenzoate (42-1)
Figure PCTCN2023071429-appb-000194
Figure PCTCN2023071429-appb-000194
将30克对乙酰氨基-邻甲氧基苯甲酸甲酯溶于300毫升三氟乙酸，冰浴下加入16.6克硝酸钾于室温搅拌4小时。反应液过滤，滤饼水洗至中性，干燥得橘黄色固体(42-1)27克，收率74％。LCMS(ESI)m/z[M+H] +:255.0. Dissolve 30 g of methyl p-acetamido-o-methoxybenzoate in 300 ml of trifluoroacetic acid, add 16.6 g of potassium nitrate under ice-cooling and stir at room temperature for 4 hours. The reaction solution was filtered, the filter cake was washed with water until neutral, and dried to obtain 27 g of an orange solid (42-1), with a yield of 74%. LCMS(ESI)m/z[M+H] + :255.0.
步骤②：4-乙酰胺基-5-硝基-2-(丙-2-炔-1-基氧)苯甲酸甲酯(42-2)Step ②: Methyl 4-acetamido-5-nitro-2-(prop-2-yn-1-yloxy)benzoate (42-2)
Figure PCTCN2023071429-appb-000195
Figure PCTCN2023071429-appb-000195
氩气氛下，将27克42-1、19.98克碳酸钾、13.5毫升3-溴丙炔和200毫升N,N-二甲基甲酰胺的混合物80度搅拌2小时。反应液加水搅拌1小时，过滤干燥得黄色固体(42-2)28克，收率98％。LCMS(ESI)m/z[M+H] +:293.0. Under an argon atmosphere, a mixture of 27 g of 42-1, 19.98 g of potassium carbonate, 13.5 ml of 3-bromopropyne and 200 ml of N,N-dimethylformamide was stirred at 80°C for 2 hours. The reaction solution was stirred with water for 1 hour, filtered and dried to obtain 28 g of yellow solid (42-2), with a yield of 98%. LCMS(ESI)m/z[M+H] + :293.0.
步骤③：4-乙酰氨基-2-甲基-5-硝基苯并呋喃-7-甲酸甲酯(42-3)Step ③: Methyl 4-acetylamino-2-methyl-5-nitrobenzofuran-7-carboxylate (42-3)
Figure PCTCN2023071429-appb-000196
Figure PCTCN2023071429-appb-000196
氩气氛下，将28克42-2和150毫升N-甲基吡咯烷酮的混合物210℃搅拌2小时。反应液搅水搅拌1小时，过滤干燥得棕黄色固体(42-3)14克，收率50％。LCMS(ESI)m/z[M+H] +:293.0. Under an argon atmosphere, a mixture of 28 g of 42-2 and 150 ml of N-methylpyrrolidone was stirred at 210°C for 2 hours. The reaction liquid was stirred with water and stirred for 1 hour, filtered and dried to obtain 14 g of brown-yellow solid (42-3), with a yield of 50%. LCMS(ESI)m/z[M+H] + :293.0.
步骤④：4-氨基-2-甲基-5-硝基苯并呋喃-7-甲酸甲酯(42-4)Step ④: 4-Amino-2-methyl-5-nitrobenzofuran-7-carboxylic acid methyl ester (42-4)
Figure PCTCN2023071429-appb-000197
Figure PCTCN2023071429-appb-000197
将14克42-3、33克碳酸钾和180毫升甲醇的混合物室温搅拌过夜。反应液加水搅拌30分钟，过滤干燥得橘黄色固体(42-4)7.6克，收率63％。LCMS(ESI)m/z[M+H] +:251.0. A mixture of 14 g of 42-3, 33 g of potassium carbonate and 180 ml of methanol was stirred overnight at room temperature. The reaction solution was stirred with water for 30 minutes, filtered and dried to obtain 7.6 g of orange solid (42-4), with a yield of 63%. LCMS(ESI)m/z[M+H] + :251.0.
步骤⑤：4-氯-2-甲基-5-硝基苯并呋喃-7-甲酸甲酯(42-5)Step ⑤: Methyl 4-chloro-2-methyl-5-nitrobenzofuran-7-carboxylate (42-5)
Figure PCTCN2023071429-appb-000198
Figure PCTCN2023071429-appb-000198
氩气氛下，将7.6克42-4、5.34克氯化亚铜、6.5毫升亚硝酸叔丁酯和70毫升乙腈的混合物搅拌1小时。反应液抽滤，滤饼用50毫升乙酸乙酯洗3次，滤液浓缩，残余物以乙酸乙酯和水萃取，有机相用无水硫酸钠干燥，过滤浓缩干燥得类黄色固体(42-5)6.7克，收率82％。LCMS(ESI)m/z[M+H] +:270.0. Under an argon atmosphere, a mixture of 7.6 g of 42-4, 5.34 g of cuprous chloride, 6.5 mL of tert-butyl nitrite and 70 mL of acetonitrile was stirred for 1 hour. The reaction solution was suction-filtered, the filter cake was washed 3 times with 50 ml of ethyl acetate, the filtrate was concentrated, the residue was extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated and dried to obtain a yellowish solid (42-5 )6.7 grams, yield 82%. LCMS(ESI)m/z[M+H] + :270.0.
步骤⑥：4-氯-2-甲基-5-硝基-1-苯并呋喃-7-甲酰胺(42-6)Step ⑥: 4-chloro-2-methyl-5-nitro-1-benzofuran-7-carboxamide (42-6)
Figure PCTCN2023071429-appb-000199
Figure PCTCN2023071429-appb-000199
将6.7克42-5和80毫升氨水的混合物于50度搅拌过夜。反应液过滤，干燥得土黄色固体(42-6)5.3克，收率84％。LCMS(ESI)m/z[M+H] +:255.0. 1H NMR(400MHz, DMSO-d 6)δ8.30(s,1H),8.11-8.05(m,1H),7.97(s,1H)6.99(s,1H),2.58(d,J＝1.1Hz,3H). A mixture of 6.7 g of 42-5 and 80 ml of ammonia was stirred overnight at 50°C. The reaction liquid was filtered and dried to obtain 5.3 g of khaki solid (42-6), with a yield of 84%. LCMS(ESI)m/z[M+H] + :255.0. 1 H NMR(400MHz, DMSO-d 6 )δ8.30(s,1H),8.11-8.05(m,1H),7.97(s,1H )6.99(s,1H),2.58(d,J=1.1Hz,3H).
步骤⑦：4-((4-溴苯基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺(42-7)Step ⑦: 4-((4-bromophenyl)amino)-2-methyl-5-nitrobenzofuran-7-carboxamide (42-7)
Figure PCTCN2023071429-appb-000200
Figure PCTCN2023071429-appb-000200
将1克42-6、1.1克对溴苄胺、3毫升N,N-二异丙基乙胺和10毫升N,N-二甲基甲酰胺混合物于100℃加热搅拌1小时。反应液加水搅拌1小时，过滤干燥得黄色固体(42-7)1.4克，收率89％。LCMS(ESI)m/z[M+H] +:404.0. A mixture of 1 g of 42-6, 1.1 g of p-bromobenzylamine, 3 ml of N,N-diisopropylethylamine and 10 ml of N,N-dimethylformamide was heated and stirred at 100°C for 1 hour. The reaction solution was stirred with water for 1 hour, filtered and dried to obtain 1.4 g of yellow solid (42-7), with a yield of 89%. LCMS(ESI)m/z[M+H] + :404.0.
步骤⑧：5-氨基-4-((4-溴苯基)氨基)-2-甲基苯并呋喃-7-甲酰胺(42-8)Step ⑧: 5-amino-4-((4-bromophenyl)amino)-2-methylbenzofuran-7-carboxamide (42-8)
Figure PCTCN2023071429-appb-000201
Figure PCTCN2023071429-appb-000201
将1.4克42-7、5克连二亚硫酸钠、6毫升氨水和25毫升甲醇的混合溶液于室温搅拌3小时。反应液抽滤，滤液浓缩，残余物以乙酸乙酯：石油醚＝1:1柱层析纯化，得淡黄色固体(42-8)600毫克，收率47％。LCMS(ESI)m/z[M+H] +:374.0. A mixed solution of 1.4 g of 42-7, 5 g of sodium dithionite, 6 ml of aqueous ammonia and 25 ml of methanol was stirred at room temperature for 3 hours. The reaction solution was suction-filtered, the filtrate was concentrated, and the residue was purified by column chromatography with ethyl acetate:petroleum ether=1:1 to obtain 600 mg of light yellow solid (42-8) with a yield of 47%. LCMS(ESI)m/z[M+H] + :374.0.
步骤⑨：2-氨基-1-(4-溴苯基)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-5-甲酰胺(42-9)Step ⑨: 2-amino-1-(4-bromophenyl)-7-methyl-1H-benzofuro[4,5-d]imidazole-5-carboxamide (42-9)
Figure PCTCN2023071429-appb-000202
Figure PCTCN2023071429-appb-000202
将600毫克42-8、700毫克溴化氰和10毫升甲醇混合物于室温搅拌4小时。反应液加石油醚：乙酸乙酯＝1:1溶液200毫升搅拌1小时，过滤干燥得白色固体(42-9)517毫克，收率81％。LCMS(ESI)m/z[M+H] +:399.0. A mixture of 600 mg of 42-8, 700 mg of cyanogen bromide and 10 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was added petroleum ether: ethyl acetate = 1:1 solution 200 ml, stirred for 1 hour, filtered and dried to obtain 517 mg of white solid (42-9), yield 81%. LCMS(ESI)m/z[M+H] + :399.0.
步骤⑩：1-(4-溴苯基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-5-甲酰胺(42-10)Step ⑩: 1-(4-bromophenyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran[4, 5-d] imidazole-5-carboxamide (42-10)
Figure PCTCN2023071429-appb-000203
Figure PCTCN2023071429-appb-000203
将517毫克42-9、301毫克1-乙基-3-甲基-1H-吡唑-5-羧酸、743毫克2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、570微升N,N-二异丙基乙胺和6毫升N,N-二甲基甲酰胺混合物于室温搅拌4小时。反应液加水搅拌后过滤，干燥得棕色固体(42-10)395毫克，收率57％。LCMS(ESI)m/z[M+H] +:535.0. 517 mg 42-9, 301 mg 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 743 mg 2-(7-azabenzotriazole)-N,N,N A mixture of ',N'-tetramethylurea hexafluorophosphate, 570 μl N,N-diisopropylethylamine and 6 ml N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was stirred with water, filtered, and dried to obtain 395 mg of brown solid (42-10), with a yield of 57%. LCMS(ESI)m/z[M+H] + :535.0.
步骤
Figure PCTCN2023071429-appb-000204
二乙基(4-((5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)苯基)膦酸酯(42-11) step
Figure PCTCN2023071429-appb-000204
Diethyl(4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran[4 ,5-d] imidazol-1-yl) phenyl) phosphonate (42-11)
Figure PCTCN2023071429-appb-000205
Figure PCTCN2023071429-appb-000205
氩气氛下，将395毫克42-10、86毫克四三苯基膦钯、204毫克亚磷酸二乙酯、374毫克三乙胺和5毫升无水四氢呋喃混合物于110℃搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1:1柱层析纯化，得白色固体(42-11)320毫克，收率73％。LCMS(ESI)m/z[M+H] +:593.0. Under an argon atmosphere, a mixture of 395 mg of 42-10, 86 mg of tetrakistriphenylphosphine palladium, 204 mg of diethyl phosphite, 374 mg of triethylamine and 5 ml of anhydrous tetrahydrofuran was stirred at 110°C for 4 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 320 mg of white solid (42-11) with a yield of 73%. LCMS(ESI)m/z[M+H] + :593.0.
步骤
Figure PCTCN2023071429-appb-000206
(4-((5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)甲基)苯基)膦酸(I-42) step
Figure PCTCN2023071429-appb-000206
(4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuro[4,5- d] imidazol-1-yl) methyl) phenyl) phosphonic acid (I-42)
Figure PCTCN2023071429-appb-000207
Figure PCTCN2023071429-appb-000207
将50毫克42-11溶于二氯甲烷，氩气氛冰浴条件下，缓慢滴加85毫克碘代三甲基硅烷，滴加完毕于室温搅拌2小时。反应液中加入甲醇和水，搅拌4小时过滤得淡黄色固体(I-42)13毫克，收率29％。LCMS(ESI)m/z[M+H] +:537.0. 1H NMR(400MHz,DMSO-d 6)δ13.06(s,1H),7.95(s,1H),7.80(s,1H),7.66-7.55(m,3H),7.33(s,2H),6.79(s,1H),6.63(s,1H),5.68(s,2H),4.57(q,J＝7.3Hz,2H),2.48(s,3H),2.14(s,3H),1.29(t,J＝7.1Hz,3H). Dissolve 50 mg of 42-11 in dichloromethane, and slowly add 85 mg of iodotrimethylsilane dropwise under an argon atmosphere ice bath, and stir at room temperature for 2 hours after the addition is complete. Methanol and water were added to the reaction solution, stirred for 4 hours and filtered to obtain 13 mg of light yellow solid (I-42), with a yield of 29%. LCMS (ESI) m/z [M+H] + :537.0. 1 H NMR (400MHz, DMSO-d 6 ) δ13.06 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 7.66-7.55(m,3H),7.33(s,2H),6.79(s,1H),6.63(s,1H),5.68(s,2H),4.57(q,J＝7.3Hz,2H),2.48 (s,3H),2.14(s,3H),1.29(t,J=7.1Hz,3H).
实施例43二乙基(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸酯(I-43)Example 43 Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)phenyl)phosphonate (I-43)
Figure PCTCN2023071429-appb-000208
Figure PCTCN2023071429-appb-000208
步骤①：4-((4-溴苄基)氨基)-3-硝基苄腈(43-1)Step ①: 4-((4-bromobenzyl)amino)-3-nitrobenzonitrile (43-1)
Figure PCTCN2023071429-appb-000209
Figure PCTCN2023071429-appb-000209
将10克4-氯-3-硝基苯腈、12毫升4-溴苄胺、48毫升N,N-二异丙基乙胺和100毫升N.N-二甲基甲酰胺于100度搅拌1小时。反应液加水搅拌一小时，过滤干燥得黄色固体(43-1)15克，收率82％。LCMS(ESI)m/z[M+H] +:332.0. Stir 10 g of 4-chloro-3-nitrobenzonitrile, 12 ml of 4-bromobenzylamine, 48 ml of N,N-diisopropylethylamine and 100 ml of NN-dimethylformamide at 100°C for 1 hour . The reaction solution was stirred with water for one hour, filtered and dried to obtain 15 g of yellow solid (43-1), with a yield of 82%. LCMS(ESI)m/z[M+H] + :332.0.
步骤②：3-氨基-4-((4-溴苄基)氨基)苯腈(43-2)Step ②: 3-amino-4-((4-bromobenzyl)amino)benzonitrile (43-2)
Figure PCTCN2023071429-appb-000210
Figure PCTCN2023071429-appb-000210
将15克43-1、43克连二亚硫酸钠、40毫升氨水和150毫升甲醇混合物于室温搅拌2小时。反应液抽滤，滤液浓缩，残余物以乙酸乙酯：石油醚＝1:1柱层析纯化，得淡黄色固体(43-2)7克，收率51％。LCMS(ESI)m/z[M+H] +:302.0. A mixture of 15 g of 43-1, 43 g of sodium dithionite, 40 ml of aqueous ammonia and 150 ml of methanol was stirred at room temperature for 2 hours. The reaction solution was suction-filtered, the filtrate was concentrated, and the residue was purified by column chromatography with ethyl acetate:petroleum ether=1:1 to obtain 7 g of light yellow solid (43-2), with a yield of 51%. LCMS(ESI)m/z[M+H] + :302.0.
步骤③：2-氨基-1-(4-溴苄基)-1H-苯并[d]咪唑-5-甲腈(43-3)Step ③: 2-amino-1-(4-bromobenzyl)-1H-benzo[d]imidazole-5-carbonitrile (43-3)
Figure PCTCN2023071429-appb-000211
Figure PCTCN2023071429-appb-000211
将7克43-2、12.5克溴化氰和70毫升甲醇混合物于室温搅拌4小时。反应液加石油醚：乙酸乙酯＝1:1溶液200毫升搅拌1小时，过滤干燥得白色固体(43-3)6.5克，收率86％。LCMS(ESI)m/z[M+H] +:327.0. A mixture of 7 g of 43-2, 12.5 g of cyanogen bromide and 70 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was added petroleum ether: ethyl acetate = 1:1 solution 200 ml, stirred for 1 hour, filtered and dried to obtain 6.5 g of white solid (43-3), yield 86%. LCMS(ESI)m/z[M+H] + :327.0.
步骤④：N-(1-(4-溴苯基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(43-4)Step ④: N-(1-(4-bromophenyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole- 5-formamide (43-4)
Figure PCTCN2023071429-appb-000212
Figure PCTCN2023071429-appb-000212
将6.6克43-3、3.7克1-乙基-3-甲基-1H-吡唑-5-羧酸、9.2克2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、7.2毫升N,N-二异丙基乙胺和60毫升N,N-二甲基甲酰胺的混合物于室温搅拌4小时。反应液加水搅拌，过滤干燥得棕色固体(43-4)5.3克,收率57％。LCMS(ESI)m/z[M+H] +:463.1. 6.6 grams of 43-3, 3.7 grams of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 9.2 grams of 2-(7-azabenzotriazole)-N,N,N A mixture of ',N'-tetramethylurea hexafluorophosphate, 7.2 ml of N,N-diisopropylethylamine and 60 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was stirred with water, filtered and dried to obtain 5.3 g of brown solid (43-4), with a yield of 57%. LCMS(ESI)m/z[M+H] + :463.1.
步骤⑤：二乙基(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸酯(I-43)Step ⑤: Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1 -yl)methyl)phenyl)phosphonate (I-43)
Figure PCTCN2023071429-appb-000213
Figure PCTCN2023071429-appb-000213
氩气氛下，将5.3克43-4、1.4克四三苯基膦钯、2.4毫升亚磷酸二乙酯、6毫升三乙 胺和50毫升无水四氢呋喃混合物于110度搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1:1柱层析纯化，得白色固体(I-43)3.5克，收率56％。LCMS(ESI)m/z[M+H] +:521.0. 1H NMR(400MHz,DMSO-d 6)δ13.06(s,1H),7.84(d,J＝1.5Hz,1H),7.75–7.60(m,4H),7.51(dd,J＝8.1,3.7Hz,2H),6.68(s,1H),5.56(s,2H),4.55(q,J＝7.1Hz,2H),4.09–3.87(m,4H),2.16(s,3H),1.28(t,J＝7.1Hz,3H),1.19(t,J＝7.0Hz,6H). Under an argon atmosphere, a mixture of 5.3 g of 43-4, 1.4 g of tetrakistriphenylphosphine palladium, 2.4 ml of diethyl phosphite, 6 ml of triethylamine and 50 ml of anhydrous tetrahydrofuran was stirred at 110°C for 4 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 3.5 g of white solid (I-43), with a yield of 56%. LCMS (ESI) m/z [M+H] + :521.0. 1 H NMR (400MHz, DMSO-d 6 ) δ13.06 (s, 1H), 7.84 (d, J=1.5Hz, 1H), 7.75– 7.60(m,4H),7.51(dd,J=8.1,3.7Hz,2H),6.68(s,1H),5.56(s,2H),4.55(q,J=7.1Hz,2H),4.09–3.87 (m,4H),2.16(s,3H),1.28(t,J=7.1Hz,3H),1.19(t,J=7.0Hz,6H).
实施例44(4-(2-(5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)乙基)苯基)膦酸(I-44)Example 44 (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran [4,5-d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-44)
Figure PCTCN2023071429-appb-000214
Figure PCTCN2023071429-appb-000214
步骤①：4-((4-溴苯基)氨基)-2-甲基-5-硝基苯并呋喃-7-甲酰胺(44-1)Step ①: 4-((4-bromophenyl)amino)-2-methyl-5-nitrobenzofuran-7-carboxamide (44-1)
Figure PCTCN2023071429-appb-000215
Figure PCTCN2023071429-appb-000215
将1.5克化合物42-6、1.76克对溴苯乙胺、3.8克N,N-二异丙基乙胺和20毫升N,N-二甲基甲酰胺混合溶液于100℃搅拌1小时。反应液加水搅拌，过滤干燥得黄色固体(44-1)1.83克，收率74％。LCMS(ESI)m/z[M+H] +:418.0. A mixed solution of 1.5 g of compound 42-6, 1.76 g of p-bromophenethylamine, 3.8 g of N,N-diisopropylethylamine and 20 ml of N,N-dimethylformamide was stirred at 100° C. for 1 hour. The reaction solution was stirred with water, filtered and dried to obtain 1.83 g of yellow solid (44-1), with a yield of 74%. LCMS(ESI)m/z[M+H] + :418.0.
步骤②：5-氨基-4-((4-溴苯基)氨基)-2-甲基苯并呋喃-7-甲酰胺(44-2)Step ②: 5-amino-4-((4-bromophenyl)amino)-2-methylbenzofuran-7-carboxamide (44-2)
Figure PCTCN2023071429-appb-000216
Figure PCTCN2023071429-appb-000216
将1.83克44-1、5克连二亚硫酸钠、4毫升氨水和20毫升甲醇混合物于室温搅拌2小时。反应液抽滤，滤液浓缩，残余物以乙酸乙酯：石油醚＝1:1柱层析纯化，得淡黄色固体(44-2)1.03克，收率61％。LCMS(ESI)m/z[M+H] +:388.0. A mixture of 1.83 g of 44-1, 5 g of sodium dithionite, 4 ml of aqueous ammonia and 20 ml of methanol was stirred at room temperature for 2 hours. The reaction solution was suction-filtered, the filtrate was concentrated, and the residue was purified by column chromatography with ethyl acetate:petroleum ether=1:1 to obtain 1.03 g of light yellow solid (44-2), with a yield of 61%. LCMS(ESI)m/z[M+H] + :388.0.
步骤③：2-氨基-1-(4-溴苯基)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-5-甲酰胺(44-3)Step ③: 2-amino-1-(4-bromophenyl)-7-methyl-1H-benzofuro[4,5-d]imidazole-5-carboxamide (44-3)
Figure PCTCN2023071429-appb-000217
Figure PCTCN2023071429-appb-000217
将1.03克44-2、2.3克溴化氰和10毫升甲醇混合物于室温搅拌4小时。反应液加石 油醚：乙酸乙酯＝1:1溶液80毫升搅拌1小时，抽滤得白色固体(44-3)0.85克，收率80％。LCMS(ESI)m/z[M+H] +:413.0. A mixture of 1.03 g of 44-2, 2.3 g of cyanogen bromide and 10 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was added petroleum ether: ethyl acetate = 1:1 solution 80 ml and stirred for 1 hour, and suction filtered to obtain 0.85 g of white solid (44-3), yield 80%. LCMS(ESI)m/z[M+H] + :413.0.
步骤④：1-(4-溴苯基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-5-甲酰胺(44-4)Step ④: 1-(4-bromophenyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran[4, 5-d] imidazole-5-carboxamide (44-4)
Figure PCTCN2023071429-appb-000218
Figure PCTCN2023071429-appb-000218
将0.85克44-3、0.47克1-乙基-3-甲基-1H-吡唑-5-羧酸、1.55克2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、1.32克N,N-二异丙基乙胺和10毫升N,N-二甲基甲酰胺的混合物于室温搅拌4小时。反应液加水搅拌，过滤干燥得棕色固体(44-4)820毫克,收率72％。LCMS(ESI)m/z[M+H] +:551.0. 0.85 g of 44-3, 0.47 g of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 1.55 g of 2-(7-azabenzotriazole)-N,N,N A mixture of ',N'-tetramethylurea hexafluorophosphate, 1.32 g of N,N-diisopropylethylamine and 10 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was stirred with water, filtered and dried to obtain 820 mg of brown solid (44-4), with a yield of 72%. LCMS(ESI)m/z[M+H] + :551.0.
步骤⑤：二乙基(4-(2-(5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)乙基)苯基)膦酸酯(44-5)Step ⑤: Diethyl (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H- Benzofuro[4,5-d]imidazol-1-yl)ethyl)phenyl)phosphonate (44-5)
Figure PCTCN2023071429-appb-000219
Figure PCTCN2023071429-appb-000219
氩气氛下，将380毫克44-4、73毫克四三苯基膦钯、173毫克亚磷酸二乙酯、190毫克三乙胺和5毫升无水四氢呋喃混合溶液110℃下搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1:1柱层析纯化，得白色固体(44-5)320毫克，收率76％。LCMS(ESI)m/z[M+H] +:607.0. Under an argon atmosphere, a mixed solution of 380 mg of 44-4, 73 mg of tetrakistriphenylphosphine palladium, 173 mg of diethyl phosphite, 190 mg of triethylamine and 5 ml of anhydrous tetrahydrofuran was stirred at 110°C for 4 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 320 mg of white solid (44-5) with a yield of 76%. LCMS(ESI)m/z[M+H] + :607.0.
步骤⑥：(4-(2-(5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)乙基)苯基)膦酸(I-44)Step ⑥: (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran [4,5-d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-44)
Figure PCTCN2023071429-appb-000220
Figure PCTCN2023071429-appb-000220
将100毫克44-5溶于二氯甲烷，氩气氛冰浴条件下滴加330毫克碘代三甲基硅烷于室温搅拌2小时。反应液依次加入甲醇和水，搅拌2小时，过滤，得灰白色固体(I-44)55毫克，收率60％。LCMS(ESI)m/z[M+H] +:551.0. 1H NMR(400MHz,DMSO-d 6)δ12.91(s,1H),7.91(s,1H),7.81(s,1H),7.64(s,1H),7.62–7.52(m,2H),7.39(dd,J＝8.1, 3.3Hz,2H),7.03(d,J＝1.3Hz,1H),6.68(s,1H),4.62(m,4H),3.17(t,J＝7.4Hz,2H),2.61–2.55(m,3H),2.21(s,3H),1.35(t,J＝7.1Hz,3H). 100 mg of 44-5 was dissolved in dichloromethane, and 330 mg of iodotrimethylsilane was added dropwise under an argon atmosphere ice bath, and stirred at room temperature for 2 hours. Methanol and water were added to the reaction solution in turn, stirred for 2 hours, and filtered to obtain 55 mg of off-white solid (I-44), with a yield of 60%. LCMS (ESI) m/z [M+H] + :551.0. 1 H NMR (400MHz, DMSO-d 6 ) δ12.91 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.64(s,1H),7.62–7.52(m,2H),7.39(dd,J=8.1,3.3Hz,2H),7.03(d,J=1.3Hz,1H),6.68(s,1H),4.62 (m,4H),3.17(t,J=7.4Hz,2H),2.61–2.55(m,3H),2.21(s,3H),1.35(t,J=7.1Hz,3H).
实施例45(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)甲基)苯基)膦酸(I-45)Example 45 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran [4, 5-d] imidazol-1-yl) methyl) phenyl) phosphonic acid (I-45)
Figure PCTCN2023071429-appb-000221
Figure PCTCN2023071429-appb-000221
步骤①：4-氯-2-甲基-5-硝基苯并呋喃-7-腈(45-1)Step ①: 4-chloro-2-methyl-5-nitrobenzofuran-7-carbonitrile (45-1)
Figure PCTCN2023071429-appb-000222
Figure PCTCN2023071429-appb-000222
将450毫克42-6、645微升二氯亚砜和5毫升的N,N-二甲基甲酰胺混合于封管加热至120℃搅拌3小时。反应液加水搅拌，过滤干燥，得棕黄色固体(45-1)180毫克，收率43％。 1H NMR(400MHz,DMSO-d 6)δ8.69(d,J＝1.2Hz,1H),7.13–7.07(m,1H),2.60(s,3H). Mix 450 mg of 42-6, 645 μl of thionyl chloride and 5 ml of N,N-dimethylformamide in a sealed tube and heat to 120°C for 3 hours. The reaction solution was stirred with water, filtered and dried to obtain 180 mg of brown-yellow solid (45-1), with a yield of 43%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.69 (d, J=1.2Hz, 1H), 7.13–7.07 (m, 1H), 2.60 (s, 3H).
步骤②：4-((4-溴苯基)氨基)-2-甲基-5-硝基苯并呋喃-7-碳腈(45-2)Step ②: 4-((4-bromophenyl)amino)-2-methyl-5-nitrobenzofuran-7-carbonitrile (45-2)
Figure PCTCN2023071429-appb-000223
Figure PCTCN2023071429-appb-000223
将180毫克45-1、284毫克对溴苄胺、1.2毫升N,N-二异丙基乙胺和3毫升N,N-二甲基甲酰胺混合溶液于110℃搅拌30分钟。反应液加水搅拌1小时，过滤干燥得黄色固体(45-2)270毫克，收率91％。LCMS(ESI)m/z[M+H] +:386.0. A mixed solution of 180 mg of 45-1, 284 mg of p-bromobenzylamine, 1.2 ml of N,N-diisopropylethylamine and 3 ml of N,N-dimethylformamide was stirred at 110°C for 30 minutes. The reaction solution was stirred with water for 1 hour, filtered and dried to obtain 270 mg of yellow solid (45-2), with a yield of 91%. LCMS(ESI)m/z[M+H] + :386.0.
步骤③：5-氨基-4-((4-溴苯基)氨基)-2-甲基苯并呋喃-7-碳腈(45-3)Step ③: 5-amino-4-((4-bromophenyl)amino)-2-methylbenzofuran-7-carbonitrile (45-3)
Figure PCTCN2023071429-appb-000224
Figure PCTCN2023071429-appb-000224
将270毫克45-2、1克连二亚硫酸钠、2毫升氨水和10毫升甲醇的混合液室温搅拌4小时。反应液抽滤，滤液浓缩，残余物以乙酸乙酯：石油醚＝1:1柱层析纯化，得淡黄色固体(45-3)136毫克，收率55％。LCMS(ESI)m/z[M+H] +:356.0. A mixture of 270 mg of 45-2, 1 g of sodium dithionite, 2 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was suction-filtered, the filtrate was concentrated, and the residue was purified by column chromatography with ethyl acetate:petroleum ether=1:1 to obtain 136 mg of light yellow solid (45-3) with a yield of 55%. LCMS(ESI)m/z[M+H] + :356.0.
步骤④：2-氨基-1-(4-溴苯基)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-5-碳腈(45-4)Step ④: 2-amino-1-(4-bromophenyl)-7-methyl-1H-benzofuro[4,5-d]imidazole-5-carbonitrile (45-4)
Figure PCTCN2023071429-appb-000225
Figure PCTCN2023071429-appb-000225
将80毫克45-3、100毫克溴化氰和800微升甲醇的混合溶液室温搅拌2小时。反应液加石油醚：乙酸乙酯＝1:1溶液80毫升搅拌1小时，抽滤得白色固体(45-4)50毫克，收率58％。LCMS(ESI)m/z[M+H] +:381.0. A mixed solution of 80 mg of 45-3, 100 mg of cyanogen bromide and 800 µl of methanol was stirred at room temperature for 2 hours. The reaction solution was added petroleum ether: ethyl acetate = 1:1 solution 80 ml and stirred for 1 hour, then suction filtered to obtain 50 mg of white solid (45-4) with a yield of 58%. LCMS(ESI)m/z[M+H] + :381.0.
步骤⑤：N-(1-(4-溴苯基)-5-氰基-7-甲基-1H-苯并呋喃[4,5-d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(45-5)Step ⑤: N-(1-(4-bromophenyl)-5-cyano-7-methyl-1H-benzofuro[4,5-d]imidazol-2-yl)-1-ethyl- 3-Methyl-1H-pyrazole-5-carboxamide (45-5)
Figure PCTCN2023071429-appb-000226
Figure PCTCN2023071429-appb-000226
将50毫克45-4、41毫克1-乙基-3-甲基-1H-吡唑-5-羧酸、100毫克2-(7-氮杂苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯、35毫克N,N-二异丙基乙胺和500微升N,N-二甲基甲酰胺的混合物于室温搅拌4小时。反应液加水搅拌，过滤干燥得棕色固体(45-5)37毫克，收率55％。LCMS(ESI)m/z[M+H] +:517.0. 50 mg of 45-4, 41 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 100 mg of 2-(7-azabenzotriazole)-N,N,N , a mixture of N-tetramethyluronium hexafluorophosphate, 35 mg of N,N-diisopropylethylamine and 500 μl of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was stirred with water, filtered and dried to obtain 37 mg of brown solid (45-5), with a yield of 55%. LCMS(ESI)m/z[M+H] + :517.0.
步骤⑥：二乙基(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)苯基)膦酸酯(45-6)Step ⑥: Diethyl (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran [4,5-d] imidazol-1-yl) phenyl) phosphonate (45-6)
Figure PCTCN2023071429-appb-000227
Figure PCTCN2023071429-appb-000227
氩气氛下，将37毫克45-5、8.3毫克四三苯基膦钯、20毫克亚磷酸二乙酯、14.5毫克三乙胺和1毫升无水四氢呋喃混合溶液110℃下搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1:1柱层析纯化，得白色固体(45-6)27毫克，收率66％。LCMS(ESI)m/z[M+H] +:575.0. Under an argon atmosphere, a mixed solution of 37 mg of 45-5, 8.3 mg of tetrakistriphenylphosphine palladium, 20 mg of diethyl phosphite, 14.5 mg of triethylamine and 1 ml of anhydrous tetrahydrofuran was stirred at 110°C for 4 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 27 mg of white solid (45-6), with a yield of 66%. LCMS(ESI)m/z[M+H] + :575.0.
步骤⑦：(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲基-1H-苯并呋喃[4,5-d]咪唑-1-基)甲基)苯基)膦酸(I-45)Step ⑦: (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methyl-1H-benzofuran[4, 5-d] imidazol-1-yl) methyl) phenyl) phosphonic acid (I-45)
Figure PCTCN2023071429-appb-000228
Figure PCTCN2023071429-appb-000228
将10毫克45-6溶于二氯甲烷，氩气氛冰浴条件下缓慢滴加35毫克碘代三甲基硅烷，滴加完毕于室温搅拌2小时。反应液中加入甲醇和水，敞口搅拌4小时过滤，得灰色固体(I-45)6毫克，收率66％。LCMS(ESI)m/z[M+H] +:519.0. 1H NMR(400MHz,DMSO-d 6)δ13.12(s,1H),7.79(s,1H),7.64–7.53(m,2H),7.32(s,2H),6.85(s,1H),6.63(s,1H),5.64(s,2H),4.53(s,2H),2.46(s,3H),2.12(s,3H).1.27(t,J＝7.1Hz,3H) Dissolve 10 mg of 45-6 in dichloromethane, slowly add 35 mg of iodotrimethylsilane dropwise under an argon atmosphere ice bath, and stir at room temperature for 2 hours after the addition is completed. Methanol and water were added to the reaction solution, and the mixture was stirred open for 4 hours and filtered to obtain 6 mg of gray solid (I-45) with a yield of 66%. LCMS (ESI) m/z [M+H] + :519.0. 1 H NMR (400MHz, DMSO-d 6 ) δ13.12 (s, 1H), 7.79 (s, 1H), 7.64–7.53 (m, 2H ),7.32(s,2H),6.85(s,1H),6.63(s,1H),5.64(s,2H),4.53(s,2H),2.46(s,3H),2.12(s,3H) .1.27(t,J=7.1Hz,3H)
实施例46前药的制备The preparation of embodiment 46 prodrug
N-(1-(4-(4-(3-氯苯基)-2-氧化-1,3,2-二氧膦杂环己烷-2-基)苄基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(I-46)N-(1-(4-(4-(3-chlorophenyl)-2-oxide-1,3,2-dioxaphosphinin-2-yl)benzyl)-5-cyano- 1H-Benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (I-46)
Figure PCTCN2023071429-appb-000229
Figure PCTCN2023071429-appb-000229
氩气氛下，将30毫克I-9、37毫克(S)-1-(3-氯苯基)-1,3-丙二醇、117微升吡啶、40毫克N,N'-二环己基碳二亚胺和1毫升N,N-二甲基甲酰胺的混合物于封管中，加热至80℃搅拌10小时。反应液制备薄层(二氯甲烷：甲醇＝15:1)，得类白色固体(I-46)13毫克，收率34％。LCMS(ESI)m/z[M+H] +:615.3. 1H NMR(400MHz,CD 3OD)δ7.82(d,J＝49.4Hz,3H),7.48(d,J＝46.2Hz,2H),7.30(d,J＝15.5Hz,6H),6.67(d,J＝7.6Hz,1H),5.74(s,1H),5.56(s,2H),4.52(d,J＝50.5Hz,4H),2.18(s,3H),1.30(dt,J＝15.0,7.2Hz,3H). Under an argon atmosphere, 30 mg of I-9, 37 mg of (S)-1-(3-chlorophenyl)-1,3-propanediol, 117 μl of pyridine, 40 mg of N,N'-dicyclohexylcarbodiol A mixture of imine and 1 ml of N,N-dimethylformamide was heated to 80°C in a sealed tube and stirred for 10 hours. Thin layers of the reaction solution were prepared (dichloromethane:methanol=15:1) to obtain 13 mg of off-white solid (I-46), with a yield of 34%. LCMS (ESI) m/z [M+H] + :615.3. 1 H NMR (400MHz, CD 3 OD) δ7.82 (d, J = 49.4Hz, 3H), 7.48 (d, J = 46.2Hz, 2H ),7.30(d,J=15.5Hz,6H),6.67(d,J=7.6Hz,1H),5.74(s,1H),5.56(s,2H),4.52(d,J=50.5Hz,4H ),2.18(s,3H),1.30(dt,J=15.0,7.2Hz,3H).
实施例47(4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)苯基)双(2,2,2-三氟乙基)膦酸酯(I-47)Example 47 (4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazol-1-yl) Methyl)phenyl)bis(2,2,2-trifluoroethyl)phosphonate (I-47)
Figure PCTCN2023071429-appb-000230
Figure PCTCN2023071429-appb-000230
氩气氛下，将50毫克I-9、87毫克2,2,2-三氟乙醇、222微升吡啶、133毫克N,N'-二环己基碳二亚胺和1毫升N,N-二甲基甲酰胺的混合物于封管中，加热至80℃搅拌10小时。反应液制备薄层(二氯甲烷：甲醇＝15:1)，得类白色固体(I-47)20毫克，收率30％。LCMS(ESI)m/z[M+H] +:629.3. 1H NMR(400MHz,CD 3OD)δ7.90–7.77(m,3H),7.58(t,J＝8.0Hz,3H),7.47(d,J＝8.3Hz,1H),6.68(s,1H),5.60(s,2H),4.59(q,J＝8.3Hz,6H),2.21(s,3H),1.30(t,J＝7.1Hz,3H). Under argon atmosphere, 50 mg of I-9, 87 mg of 2,2,2-trifluoroethanol, 222 μl of pyridine, 133 mg of N,N'-dicyclohexylcarbodiimide and 1 ml of N,N-dicyclodiimide The mixture of methylformamide was heated to 80°C in a sealed tube and stirred for 10 hours. Thin layers of the reaction solution were prepared (dichloromethane:methanol=15:1) to obtain 20 mg of off-white solid (I-47), with a yield of 30%. LCMS (ESI) m/z [M+H] + :629.3. 1 H NMR (400MHz, CD 3 OD) δ7.90–7.77 (m, 3H), 7.58 (t, J = 8.0Hz, 3H), 7.47 (d,J=8.3Hz,1H),6.68(s,1H),5.60(s,2H),4.59(q,J=8.3Hz,6H),2.21(s,3H),1.30(t,J= 7.1Hz, 3H).
实施例48(((4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)苯基)磷酰胍基)二(氧代))二(亚甲基)二(2,2-二甲基丙酯)(I-48)Example 48 (((4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzo[d]imidazole-1- base) methyl) phenyl) phosphoroguanidino) bis (oxo)) bis (methylene) bis (2,2-dimethylpropyl ester) (I-48)
Figure PCTCN2023071429-appb-000231
Figure PCTCN2023071429-appb-000231
氩气氛下，将50毫克I-9、113微升N,N-二异丙基乙胺和1毫升乙腈混合物于冰浴条件下搅拌10分钟，缓慢加入156毫克特戊酸碘甲酯，恢复至室温反应6小时，反应液浓缩至干后制备薄层(二氯甲烷：甲醇＝20:1)，得到类白色固体(I-48)14毫克， 收率19％。LCMS(ESI)m/z[M+H] +:693.4. 1H NMR(400MHz,CD 3OD)δ7.81(s,1H),7.76(dd,J＝13.9,7.9Hz,2H),7.64–7.49(m,4H),6.74(s,1H),5.71(d,J＝1.9Hz,2H),5.68(s,2H),5.58(s,2H),4.64(q,J＝7.2Hz,2H),2.24(s,3H),1.37(t,J＝7.1Hz,3H),0.97(s,19H). Under an argon atmosphere, a mixture of 50 mg of I-9, 113 μl of N,N-diisopropylethylamine and 1 ml of acetonitrile was stirred in an ice bath for 10 minutes, and 156 mg of iodomethyl pivalate was slowly added to recover After reacting at room temperature for 6 hours, the reaction solution was concentrated to dryness and then prepared a thin layer (dichloromethane:methanol=20:1) to obtain 14 mg of off-white solid (I-48), with a yield of 19%. LCMS (ESI) m/z [M+H] + :693.4. 1 H NMR (400MHz, CD 3 OD) δ7.81 (s, 1H), 7.76 (dd, J = 13.9, 7.9Hz, 2H), 7.64 –7.49(m,4H),6.74(s,1H),5.71(d,J=1.9Hz,2H),5.68(s,2H),5.58(s,2H),4.64(q,J=7.2Hz, 2H),2.24(s,3H),1.37(t,J=7.1Hz,3H),0.97(s,19H).
实施例49二乙基2,2'-(((4-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1H-苯并[d]咪唑-1-基)甲基)苯基)磷酰胍基)双(氮杂二烷基))二乙酸酯(I-49)Example 49 Diethyl 2,2'-(((4-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1H-benzene [d]imidazol-1-yl)methyl)phenyl)phosphoroguanidine)bis(azadialkyl))diacetate (I-49)
Figure PCTCN2023071429-appb-000232
Figure PCTCN2023071429-appb-000232
氩气氛下，将20毫克I-9、16毫克2-胺基乙酸乙酯、68毫克1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐、60微升N,N-二异丙基乙胺和1毫升N,N-二甲基甲酰胺的混合物于室温条件下搅拌5小时。反应液制备薄层(二氯甲烷：甲醇＝12:1)得类白色固体(I-49)5毫克，收率19％。LCMS(ESI)m/z[M+H] +:635.3. Under argon atmosphere, 20 mg of I-9, 16 mg of ethyl 2-aminoacetate, 68 mg of 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 60 μl of N,N- A mixture of diisopropylethylamine and 1 ml of N,N-dimethylformamide was stirred at room temperature for 5 hours. The reaction liquid was prepared into a thin layer (dichloromethane:methanol=12:1) to obtain 5 mg of off-white solid (I-49), with a yield of 19%. LCMS(ESI)m/z[M+H] + :635.3.
实施例50 1-(4-((4-(3-氯苯基)-2-氧化-1,3,2-二氧膦杂环己烷-2-基)氧代)苯乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(I-50)Example 50 1-(4-((4-(3-chlorophenyl)-2-oxidation-1,3,2-dioxaphosphinin-2-yl)oxo)phenethyl)- 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (I-50)
Figure PCTCN2023071429-appb-000233
Figure PCTCN2023071429-appb-000233
氩气氛下，将20毫克I-16、21毫克(S)-1-(3-氯苯基)-1,3-丙二醇、67微升吡啶、23毫克N,N'-二环己基碳二亚胺和1毫升N,N-二甲基甲酰胺的混合物于封管中，加热至80℃搅拌10小时。反应液制备薄层(二氯甲烷：甲醇＝15:1)，得白色固体(I-50)8毫克，收率32％。LCMS(ESI)m/z[M+H] +:693.3. 1H NMR(400MHz,CD 3OD)δ7.59(s,1H),7.38–7.33(m,3H),7.27(s,1H),7.23(d,J＝4.6Hz,1H),7.18(d,J＝8.2Hz,2H),7.06(d,J＝7.9Hz,2H),6.69(s,1H),5.80–5.66(m,1H),4.68(q,J＝7.6,7.1Hz,6H),4.00(s,3H),3.15(t,J＝7.2Hz,2H),2.25(s,3H),2.17(s,2H),1.40(t,J＝7.0Hz,3H). Under an argon atmosphere, 20 mg of I-16, 21 mg of (S)-1-(3-chlorophenyl)-1,3-propanediol, 67 μl of pyridine, 23 mg of N,N'-dicyclohexylcarbodiol A mixture of imine and 1 ml of N,N-dimethylformamide was heated to 80°C in a sealed tube and stirred for 10 hours. The reaction solution was prepared into a thin layer (dichloromethane:methanol=15:1) to obtain 8 mg of white solid (I-50), with a yield of 32%. LCMS (ESI) m/z [M+H] + :693.3. 1 H NMR (400MHz, CD 3 OD) δ7.59 (s, 1H), 7.38–7.33 (m, 3H), 7.27 (s, 1H) ,7.23(d,J=4.6Hz,1H),7.18(d,J=8.2Hz,2H),7.06(d,J=7.9Hz,2H),6.69(s,1H),5.80–5.66(m, 1H), 4.68(q, J=7.6, 7.1Hz, 6H), 4.00(s, 3H), 3.15(t, J=7.2Hz, 2H), 2.25(s, 3H), 2.17(s, 2H), 1.40(t,J=7.0Hz,3H).
实施例51((4-((2-(5-氨甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)磷酰胍基)二(氧代))二(亚甲基)二(2,2-二甲基丙酯)(I-51)Example 51 ((4-((2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H- Benzo[d]imidazol-1-yl)ethyl)phenyl)phosphoroguanidine)bis(oxo))bis(methylene)bis(2,2-dimethylpropyl ester)(I-51 )
Figure PCTCN2023071429-appb-000234
Figure PCTCN2023071429-appb-000234
氩气氛下，将100毫克I-16、195微升N,N-二异丙基乙胺和2毫升乙腈混合物于冰浴条件下搅拌10分钟，缓慢加入166毫克特戊酸碘甲酯，恢复至室温反应6小时，反应液浓缩至干后制备薄层(二氯甲烷：甲醇＝20:1)，得到类白色固体(I-51)28毫克，收率20％。LCMS(ESI)m/z[M+H] +:771.5. Under an argon atmosphere, a mixture of 100 mg of I-16, 195 μl of N,N-diisopropylethylamine and 2 ml of acetonitrile was stirred in an ice bath for 10 minutes, and 166 mg of iodomethyl pivalate was slowly added to recover After reacting at room temperature for 6 hours, the reaction solution was concentrated to dryness and then prepared a thin layer (dichloromethane:methanol=20:1) to obtain 28 mg of off-white solid (I-51), with a yield of 20%. LCMS(ESI)m/z[M+H] + :771.5.
实施例52二乙基2,2'-((4-((2-(5-氨甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)磷酰胍基)二(氨叉基))二乙酸酯(I-52)Example 52 Diethyl 2,2'-((4-((2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)- 7-Methoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphoroguanidine)bis(aminoidene)diacetate (I-52)
Figure PCTCN2023071429-appb-000235
Figure PCTCN2023071429-appb-000235
氩气氛下，将20毫克I-16、13毫克2-胺基乙酸乙酯、58毫克1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐、52微升N,N-二异丙基乙胺和1毫升N,N-二甲基甲酰胺的混合物于室温条件下搅拌5小时。反应液制备薄层(二氯甲烷：甲醇＝12:1)，得类白色固体(I-52)5毫克，收率19％。LCMS(ESI)m/z[M+H] +:713.3. Under argon atmosphere, 20 mg of I-16, 13 mg of ethyl 2-aminoacetate, 58 mg of 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 52 μl of N,N- A mixture of diisopropylethylamine and 1 ml of N,N-dimethylformamide was stirred at room temperature for 5 hours. Thin layers of the reaction solution were prepared (dichloromethane:methanol=12:1) to obtain 5 mg of off-white solid (I-52), with a yield of 19%. LCMS(ESI)m/z[M+H] + :713.3.
实施例53(4-(2-(5-氰基-2-(烟酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-53)Example 53 (4-(2-(5-cyano-2-(nicotinamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-53)
Figure PCTCN2023071429-appb-000236
Figure PCTCN2023071429-appb-000236
步骤①：4-((4-溴苯乙基)氨基)-3-对硝基苯氰基(53-1)Step ①: 4-((4-bromophenethyl)amino)-3-p-nitrobenzocyano (53-1)
Figure PCTCN2023071429-appb-000237
Figure PCTCN2023071429-appb-000237
1克4-氯-3-硝基苯甲腈，2.2克4-溴苯乙胺，1.5克碳酸钾和554毫升三乙胺溶于4毫升正丁醇，在100℃下搅拌2小时。反应液加水，析出固体，抽滤得4-((4-溴苯乙基)氨基)-3-对硝基苯氰基(53-1)黄色固体1.1克，收率58％。ESI-MS(m/z):346.0[M+H] +. 1 g of 4-chloro-3-nitrobenzonitrile, 2.2 g of 4-bromophenethylamine, 1.5 g of potassium carbonate and 554 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100°C for 2 hours. Water was added to the reaction solution to precipitate a solid, which was filtered by suction to obtain 1.1 g of a yellow solid of 4-((4-bromophenethyl)amino)-3-p-nitrophenylcyano (53-1), with a yield of 58%. ESI-MS(m/z):346.0[M+H] + .
步骤②：3-氨基-4-((4-溴苯乙基)氨基)苯甲腈(53-2)Step ②: 3-amino-4-((4-bromophenethyl)amino)benzonitrile (53-2)
Figure PCTCN2023071429-appb-000238
Figure PCTCN2023071429-appb-000238
将1.8克53-1、6.3克化连二亚硫酸钠、4毫升氨水和20毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得3-氨基-4-((4-溴苯乙基)氨基)苯甲腈(53-2)白色固体1克，收率60％。ESI-MS(m/z):316.1[M+H] +. A mixture of 1.8 g of 53-1, 6.3 g of sodium dithionite, 4 ml of aqueous ammonia and 20 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-((4-bromophenethyl)amino)benzonitrile (53- 2) 1 gram of white solid, yield 60%. ESI-MS(m/z):316.1[M+H] + .
步骤③：2-氨基-1-(4-溴苯乙基)-1H-苯并[d]咪唑-5-甲腈(53-3)Step ③: 2-amino-1-(4-bromophenethyl)-1H-benzo[d]imidazole-5-carbonitrile (53-3)
Figure PCTCN2023071429-appb-000239
Figure PCTCN2023071429-appb-000239
将100毫克53-2和40毫克溴化氢溶于2毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得2-氨基-1-(4-溴苯乙基)-1H-苯并[d]咪唑-5-甲腈(53-3)白色固体95毫克，收率88％。ESI-MS(m/z):341.1[M+H] +. 100 mg of 53-2 and 40 mg of hydrogen bromide were dissolved in 2 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain 2-amino-1-(4-bromophenethyl)-1H-benzo[d]imidazole-5-methanol Nitrile (53-3) white solid 95 mg, yield 88%. ESI-MS(m/z):341.1[M+H] + .
步骤④：N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)烟酰胺(53-4)Step ④: N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)nicotinamide (53-4)
Figure PCTCN2023071429-appb-000240
Figure PCTCN2023071429-appb-000240
将100毫克53-3、52毫克烟酸、91毫克EDCI、13.5毫克HOBT、59毫克三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)烟酰胺(53-4)白色固体105毫克，收率80.8％。 1H NMR(300MHz,DMSO-d 6)δ13.00(s,1H),9.35(dd,J＝2.2,0.9Hz,1H),8.73(dd,J＝4.8,1.7Hz,1H),8.45(dt,J＝7.9,1.9Hz,1H),7.82(t,J＝1.0Hz,1H),7.71–7.63(m,2H),7.54(ddd,J＝7.9,4.8,0.9Hz,1H),7.42–7.35(m,2H),7.23–7.17(m,2H),4.54(t,J＝7.0Hz,2H),3.12(t,J＝7.0Hz,2H). A mixture of 100 mg 53-3, 52 mg niacin, 91 mg EDCI, 13.5 mg HOBT, 59 mg triethylamine, and 2 mL N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazole -2-yl) Nicotinamide (53-4) White solid 105 mg, yield 80.8%. 1 H NMR (300MHz, DMSO-d 6 ) δ13.00(s, 1H), 9.35(dd, J=2.2, 0.9Hz, 1H), 8.73(dd, J=4.8, 1.7Hz, 1H), 8.45( dt,J=7.9,1.9Hz,1H),7.82(t,J=1.0Hz,1H),7.71–7.63(m,2H),7.54(ddd,J=7.9,4.8,0.9Hz,1H),7.42 –7.35(m,2H),7.23–7.17(m,2H),4.54(t,J=7.0Hz,2H),3.12(t,J=7.0Hz,2H).
步骤⑤：(4-(2-(5-氰基-2-(烟酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(53-5)Step ⑤: Diethyl (4-(2-(5-cyano-2-(nicotinamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonate (53- 5)
Figure PCTCN2023071429-appb-000241
Figure PCTCN2023071429-appb-000241
氩气氛围下，将200毫克53-4、204毫克碳酸铯、48毫克四三苯基膦钯和115微升亚磷酸二乙酯和2毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物 以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-(5-氰基-2-(烟酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(53-5)白色固体87毫克，收率38.7％。 1H NMR(300MHz,CDCl 3)δ12.46(s,1H),9.55(dd,J＝2.1,0.9Hz,1H),8.76(dd,J＝4.8,1.8Hz,1H),8.52(dt,J＝7.9,1.9Hz,1H),7.77–7.66(m,2H),7.62(d,J＝1.3Hz,1H),7.51–7.40(m,2H),7.30(d,J＝3.8Hz,2H),7.07(d,J＝8.4Hz,1H),4.53(t,J＝7.1Hz,2H),4.15–3.93(m,4H),3.28(t,J＝7.1Hz,2H),1.28(d,J＝7.2Hz,6H). Under an argon atmosphere, 200 mg of 53-4, 204 mg of cesium carbonate, 48 mg of tetrakistriphenylphosphine palladium, 115 μl of diethyl phosphite and 2 ml of tetrahydrofuran were mixed, and stirred at reflux at 100° C. overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-cyano-2-(nicotinylamino)-1H-benzo[d] Imidazol-1-yl)ethyl)phenyl)phosphonic acid diethyl ester (53-5) 87mg white solid, yield 38.7%. 1 H NMR (300MHz, CDCl 3 ) δ12.46(s, 1H), 9.55(dd, J=2.1, 0.9Hz, 1H), 8.76(dd, J=4.8, 1.8Hz, 1H), 8.52(dt, J=7.9,1.9Hz,1H),7.77–7.66(m,2H),7.62(d,J=1.3Hz,1H),7.51–7.40(m,2H),7.30(d,J=3.8Hz,2H ), 7.07(d, J=8.4Hz, 1H), 4.53(t, J=7.1Hz, 2H), 4.15–3.93(m, 4H), 3.28(t, J=7.1Hz, 2H), 1.28(d ,J＝7.2Hz,6H).
步骤⑥：(4-(2-(5-氰基-2-(烟酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-53)Step ⑥: (4-(2-(5-cyano-2-(nicotinamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-53)
Figure PCTCN2023071429-appb-000242
Figure PCTCN2023071429-appb-000242
50毫克53-5溶于2毫升二氯甲烷，冰浴，加入62微升三甲基碘硅烷，滴加完毕移去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(5-氰基-2-(烟酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-53)白色固体21毫克，收率47.3％。 1H NMR(300MHz,DMSO-d 6)δ13.08(s,1H),9.39(d,J＝2.0Hz,1H),8.85(dd,J＝5.0,1.6Hz,1H),8.72(dt,J＝7.9,1.8Hz,1H),7.85(s,1H),7.78(dd,J＝8.0,5.1Hz,1H),7.69(s,2H),7.55(dd,J＝12.8,7.8Hz,2H),7.38(dd,J＝8.0,3.4Hz,2H),4.58(t,J＝7.2Hz,2H),3.22–3.14(m,2H). Dissolve 50mg of 53-5 in 2ml of dichloromethane, put in an ice bath, add 62μl of iodotrimethylsilane, remove the ice bath after the dropwise addition, and stir at room temperature overnight; concentrate the reaction solution to dryness, add methanol, and reflux at 80°C overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(5-cyano-2-(nicotinylamino)-1H-benzo[d] Imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-53) white solid 21 mg, yield 47.3%. 1 H NMR (300MHz, DMSO-d 6 )δ13.08(s, 1H), 9.39(d, J=2.0Hz, 1H), 8.85(dd, J=5.0, 1.6Hz, 1H), 8.72(dt, J=7.9,1.8Hz,1H),7.85(s,1H),7.78(dd,J=8.0,5.1Hz,1H),7.69(s,2H),7.55(dd,J=12.8,7.8Hz,2H ),7.38(dd,J=8.0,3.4Hz,2H),4.58(t,J=7.2Hz,2H),3.22–3.14(m,2H).
实施例54(4-(2-(2-苯甲酰氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-54)Example 54 (4-(2-(2-benzamido-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-54)
Figure PCTCN2023071429-appb-000243
Figure PCTCN2023071429-appb-000243
步骤①：N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)苯甲酰胺(54-1)Step ①: N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)benzamide (54-1)
Figure PCTCN2023071429-appb-000244
Figure PCTCN2023071429-appb-000244
将300毫克53-3、129毫克苯甲酸、280毫克EDCI、205毫克HOBT、245毫克三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二 氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)苯甲酰胺(54-1)白色固体290毫克，收率74.2％。 1H NMR(300MHz,DMSO-d 6)δ12.95(s,1H),8.31–8.14(m,2H),7.79(d,J＝1.5Hz,1H),7.68–7.59(m,2H),7.52(qd,J＝8.6,7.6,2.5Hz,3H),7.44–7.37(m,2H),7.22(d,J＝8.1Hz,2H),4.51(t,J＝7.2Hz,2H),3.12(t,J＝7.1Hz,2H). A mixture of 300 mg 53-3, 129 mg benzoic acid, 280 mg EDCI, 205 mg HOBT, 245 mg triethylamine, and 2 mL N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazole -2-yl)benzamide (54-1) 290 mg of white solid, yield 74.2%. 1 H NMR (300MHz,DMSO-d 6 )δ12.95(s,1H),8.31–8.14(m,2H),7.79(d,J=1.5Hz,1H),7.68–7.59(m,2H), 7.52(qd, J=8.6,7.6,2.5Hz,3H),7.44–7.37(m,2H),7.22(d,J=8.1Hz,2H),4.51(t,J=7.2Hz,2H),3.12 (t,J=7.1Hz,2H).
步骤②：(4-(2-(2-苯甲酰氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(54-2)Step ②: Diethyl (4-(2-(2-benzamido-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonate (54-2 )
Figure PCTCN2023071429-appb-000245
Figure PCTCN2023071429-appb-000245
氩气氛围下，将200毫克54-1、209毫克碳酸铯、50毫克四三苯基膦钯和118微升亚磷酸二乙酯和2毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-(2-苯甲酰氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(54-2)白色固体110毫克，收率48.9％。1H NMR(300MHz,CDCl 3)δ12.49(s,1H),8.33(dt,J＝7.0,1.5Hz,2H),7.79–7.66(m,2H),7.61–7.43(m,5H),7.35–7.29(m,2H),7.03(d,J＝8.4Hz,1H),4.52(t,J＝7.1Hz,2H),4.14–3.93(m,4H),3.28(t,J＝7.1Hz,2H),1.28(d,J＝6.7Hz,7H). Under an argon atmosphere, mix 200 mg of 54-1, 209 mg of cesium carbonate, 50 mg of tetrakistriphenylphosphine palladium, 118 μl of diethyl phosphite and 2 ml of tetrahydrofuran, and stir at reflux at 100°C overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(2-benzamido-5-cyano-1H-benzo[d]imidazole -1-yl)ethyl)phenyl)phosphonic acid diethyl ester (54-2) white solid 110 mg, yield 48.9%. 1H NMR (300MHz, CDCl 3 )δ12.49(s,1H),8.33(dt,J=7.0,1.5Hz,2H),7.79–7.66(m,2H),7.61–7.43(m,5H),7.35 –7.29(m,2H),7.03(d,J=8.4Hz,1H),4.52(t,J=7.1Hz,2H),4.14–3.93(m,4H),3.28(t,J=7.1Hz, 2H), 1.28(d, J=6.7Hz, 7H).
步骤③：(4-(2-(2-苯甲酰氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-54)Step ③: (4-(2-(2-benzamido-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-54)
Figure PCTCN2023071429-appb-000246
Figure PCTCN2023071429-appb-000246
将60毫克54-2溶于2毫升二氯甲烷，冰浴，加入62微升三甲基碘硅烷，滴加完毕移去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(2-苯甲酰氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-54)白色固体21毫克，收率39.3％。 1H NMR(300MHz,DMSO-d 6)δ8.26(d,J＝7.1Hz,2H),7.82(s,1H),7.57(dd,J＝21.0,12.6Hz,7H),7.47–7.27(m,2H),4.53(t,J＝7.2Hz,2H),3.19(t,J＝7.0Hz,2H). Dissolve 60 mg of 54-2 in 2 ml of dichloromethane, put in an ice bath, add 62 µl of iodotrimethylsilane, remove the ice bath after the dropwise addition, and stir overnight at room temperature; Reflux overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(2-benzamido-5-cyano-1H-benzo[d]imidazole -1-yl)ethyl)phenyl)phosphonic acid (I-54) 21 mg of white solid, yield 39.3%. 1 H NMR (300MHz, DMSO-d 6 ) δ8.26 (d, J=7.1Hz, 2H), 7.82(s, 1H), 7.57 (dd, J=21.0, 12.6Hz, 7H), 7.47–7.27( m, 2H), 4.53(t, J=7.2Hz, 2H), 3.19(t, J=7.0Hz, 2H).
实施例55(4-(2-(5-氰基-2-(3，5-二甲基异恶唑-4-甲酰氨基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-55)Example 55 (4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl Base) phenyl) phosphonic acid (I-55)
Figure PCTCN2023071429-appb-000247
Figure PCTCN2023071429-appb-000247
步骤①：N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-3，5-二甲基异恶唑-4-甲酰胺(55-1)Step ①: N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-3,5-dimethylisoxazole-4-methanol Amide (55-1)
Figure PCTCN2023071429-appb-000248
Figure PCTCN2023071429-appb-000248
将200毫克53-3、84毫克3,5-二甲基异噁唑-4-羧酸、136毫克EDCI、28毫克HOBT、164毫克三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-3，5-二甲基异恶唑-4-甲酰胺(55-1)白色固体202毫克，收率73.5％。 1H NMR(400MHz,DMSO-d 6)δ12.91(s,1H),7.78(d,J＝1.5Hz,1H),7.68–7.59(m,2H),7.46–7.40(m,2H),7.22–7.16(m,2H),4.41(t,J＝7.4Hz,2H),3.05(t,J＝7.4Hz,2H),2.76(s,3H). Mix 200 mg of 53-3, 84 mg of 3,5-dimethylisoxazole-4-carboxylic acid, 136 mg of EDCI, 28 mg of HOBT, 164 mg of triethylamine and 2 mL of N,N-dimethylformamide The mixture was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazole -2-yl)-3,5-dimethylisoxazole-4-carboxamide (55-1) 202 mg of white solid, yield 73.5%. 1 H NMR (400MHz,DMSO-d 6 )δ12.91(s,1H),7.78(d,J＝1.5Hz,1H),7.68–7.59(m,2H),7.46–7.40(m,2H), 7.22–7.16(m,2H),4.41(t,J=7.4Hz,2H),3.05(t,J=7.4Hz,2H),2.76(s,3H).
步骤②：(4-(2-(5-氰基-2-(3，5-二甲基异恶唑-4-甲酰氨基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(55-2)Step ②: (4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl Base) phenyl) diethyl phosphonate (55-2)
Figure PCTCN2023071429-appb-000249
Figure PCTCN2023071429-appb-000249
氩气氛围下，将150毫克55-1、142毫克碳酸铯、35毫克四三苯基膦钯和86微升亚磷酸二乙酯和2毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-(5-氰基-2-(3，5-二甲基异恶唑-4-甲酰氨基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(55-2)白色固体72毫克，收率42.9％。1H NMR(400MHz,CDCl 3)δ12.40(s,1H),7.71(dd,J＝13.1,7.7Hz,2H),7.56(d,J＝1.4Hz,1H),7.43(dd,J＝8.3,1.4Hz,1H),7.30–7.22(m,2H),6.98(d,J＝8.3Hz,1H),4.42(t,J＝7.2Hz,2H),4.15–4.01(m,4H),3.21(t,J＝7.2Hz,2H),2.81(s,3H),2.60(s,3H),1.31(t,J＝7.1Hz,6H). Under an argon atmosphere, 150 mg of 55-1, 142 mg of cesium carbonate, 35 mg of tetrakistriphenylphosphine palladium, 86 μl of diethyl phosphite and 2 ml of tetrahydrofuran were mixed, and stirred at reflux overnight at 100°C. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4 -Formylamino)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid diethyl ester (55-2) 72 mg of white solid, yield 42.9%. 1H NMR (400MHz, CDCl 3 ) δ12.40(s, 1H), 7.71(dd, J=13.1, 7.7Hz, 2H), 7.56(d, J=1.4Hz, 1H), 7.43(dd, J=8.3 ,1.4Hz,1H),7.30–7.22(m,2H),6.98(d,J＝8.3Hz,1H),4.42(t,J＝7.2Hz,2H),4.15–4.01(m,4H),3.21 (t,J=7.2Hz,2H),2.81(s,3H),2.60(s,3H),1.31(t,J=7.1Hz,6H).
步骤③：(4-(2-(5-氰基-2-(3，5-二甲基异恶唑-4-甲酰氨基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-55)Step ③: (4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl Base) phenyl) phosphonic acid (Ⅰ-55)
Figure PCTCN2023071429-appb-000250
Figure PCTCN2023071429-appb-000250
将70毫克55-2溶于2毫升二氯甲烷，冰浴，加入71微升三甲基碘硅烷，滴加完毕移去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(5-氰基-2-(3，5-二甲基异恶唑-4-甲酰氨基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-55)白色固体26毫克，收率41.3％。 1H NMR(400MHz,DMSO-d 6)δ12.94(s,1H),7.59(dd,J＝97.6,73.1Hz,7H),4.43(s,2H),3.11(s,2H),2.77(s,3H),2.50(s,3H). Dissolve 70 mg of 55-2 in 2 ml of dichloromethane, put in an ice bath, add 71 µl of iodotrimethylsilane, remove the ice bath after the dropwise addition, and stir overnight at room temperature; Reflux overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4 -Formylamino)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-55) white solid 26 mg, yield 41.3%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.94(s, 1H), 7.59(dd, J=97.6, 73.1Hz, 7H), 4.43(s, 2H), 3.11(s, 2H), 2.77( s,3H),2.50(s,3H).
实施例56(4-(2-(5-氰基-2-(噻吩-2-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-56)Example 56 (4-(2-(5-cyano-2-(thiophene-2-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (Ⅰ -56)
Figure PCTCN2023071429-appb-000251
Figure PCTCN2023071429-appb-000251
步骤①：N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)噻吩-2-甲酰胺(56-1)Step ①: N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)thiophene-2-carboxamide (56-1)
Figure PCTCN2023071429-appb-000252
Figure PCTCN2023071429-appb-000252
将200毫克53-3、92毫克2-噻吩甲酸、136毫克EDCI、28毫克HOBT、164毫克三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)噻吩-2-甲酰胺(56-1)白色固体226毫克，收率85.3％。 1H NMR(300MHz,DMSO-d 6)δ12.81(s,1H),7.76(d,J＝5.7Hz,3H),7.66(s,2H),7.44(d,J＝7.9Hz,2H),7.25(d,J＝8.0Hz,2H),7.18(t,J＝4.4Hz,1H),4.43(t,J＝7.3Hz,2H),3.10(t,J＝7.3Hz,2H). A mixture of 200 mg of 53-3, 92 mg of 2-thiophenecarboxylic acid, 136 mg of EDCI, 28 mg of HOBT, 164 mg of triethylamine and 2 mL of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazole -2-yl)thiophene-2-carboxamide (56-1) 226 mg of white solid, yield 85.3%. 1 H NMR (300MHz, DMSO-d 6 )δ12.81(s, 1H), 7.76(d, J=5.7Hz, 3H), 7.66(s, 2H), 7.44(d, J=7.9Hz, 2H) , 7.25(d, J=8.0Hz, 2H), 7.18(t, J=4.4Hz, 1H), 4.43(t, J=7.3Hz, 2H), 3.10(t, J=7.3Hz, 2H).
步骤②：(4-(2-(5-氰基-2-(噻吩-2-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(56-2)Step ②: Diethyl (4-(2-(5-cyano-2-(thiophene-2-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid Esters (56-2)
Figure PCTCN2023071429-appb-000253
Figure PCTCN2023071429-appb-000253
氩气氛围下，将200毫克56-1、180毫克碳酸铯、48毫克四三苯基膦钯和180微升亚磷酸二乙酯和2毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-(5-氰基-2-(噻吩-2-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(56-2)白色固体120毫克，收率53.3％。1H NMR(300MHz,CDCl 3)δ12.25(s,1H),7.91(dd,J＝3.7,1.3Hz,1H),7.78–7.73(m,1H),7.73–7.68(m,1H),7.62–7.52(m,2H),7.47(dd,J＝8.3,1.5Hz,1H),7.40–7.29(m,2H),7.16(dd,J＝5.0,3.7Hz,1H),7.07(d,J＝8.3Hz,1H),4.46(t,J＝7.2Hz,2H),4.14–3.96(m,4H),3.26(t,J＝7.2Hz,2H),1.32(d,J＝7.1Hz,6H). Under an argon atmosphere, 200 mg of 56-1, 180 mg of cesium carbonate, 48 mg of tetrakistriphenylphosphine palladium, 180 microliters of diethyl phosphite and 2 milliliters of tetrahydrofuran were mixed, and stirred at reflux overnight at 100°C. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-cyano-2-(thiophene-2-carboxamido)-1H-benzene And[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid diethyl ester (56-2) 120 mg white solid, yield 53.3%. 1H NMR (300MHz, CDCl 3 )δ12.25(s,1H),7.91(dd,J=3.7,1.3Hz,1H),7.78–7.73(m,1H),7.73–7.68(m,1H),7.62 –7.52(m,2H),7.47(dd,J＝8.3,1.5Hz,1H),7.40–7.29(m,2H),7.16(dd,J＝5.0,3.7Hz,1H),7.07(d,J ＝8.3Hz, 1H), 4.46(t, J＝7.2Hz, 2H), 4.14–3.96(m, 4H), 3.26(t, J＝7.2Hz, 2H), 1.32(d, J＝7.1Hz, 6H ).
步骤③：(4-(2-(5-氰基-2-(噻吩-2-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-56)Step ③: (4-(2-(5-cyano-2-(thiophene-2-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (Ⅰ -56)
Figure PCTCN2023071429-appb-000254
Figure PCTCN2023071429-appb-000254
将60毫克56-2溶于2毫升二氯甲烷，冰浴，加入62微升三甲基碘硅烷，滴加完毕移去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(5-氰基-2-(噻吩-2-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(Ⅰ-56)白色固体18毫克，收率29.1％。 1H NMR(300MHz,DMSO-d 6)δ12.84(s,1H),7.80(d,J＝5.7Hz,3H),7.67(s,2H),7.59(dd,J＝12.9,7.8Hz,2H),7.44(dd,J＝8.1,3.3Hz,2H),7.19(t,J＝4.3Hz,1H),4.45(t,J＝7.2Hz,2H),3.16(d,J＝15.3Hz,2H). Dissolve 60 mg of 56-2 in 2 ml of dichloromethane, put in an ice bath, add 62 µl of iodotrimethylsilane, remove the ice bath after the dropwise addition, and stir overnight at room temperature; Reflux overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(5-cyano-2-(thiophene-2-carboxamido)-1H-benzene And[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid diethyl ester (I-56) white solid 18 mg, yield 29.1%. 1 H NMR (300MHz, DMSO-d 6 )δ12.84(s, 1H), 7.80(d, J=5.7Hz, 3H), 7.67(s, 2H), 7.59(dd, J=12.9, 7.8Hz, 2H), 7.44(dd, J=8.1, 3.3Hz, 2H), 7.19(t, J=4.3Hz, 1H), 4.45(t, J=7.2Hz, 2H), 3.16(d, J=15.3Hz, 2H).
实施例57(4-(2-(5-氰基-2-(3-甲基丁酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-57)Example 57 (4-(2-(5-cyano-2-(3-methylbutanylamino)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I -57)
Figure PCTCN2023071429-appb-000255
Figure PCTCN2023071429-appb-000255
步骤①：N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-3-甲基丁酰胺(57-1)Step ①: N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-3-methylbutanamide (57-1)
Figure PCTCN2023071429-appb-000256
Figure PCTCN2023071429-appb-000256
将200毫克53-3、72毫克异戊酸、136毫克EDCI、28毫克HOBT、164毫克三乙胺和2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-3-甲基丁酰胺(57-1)白色固体196毫克，收率78.4％。 1H NMR(300MHz,DMSO-d 6)δ10.64(s,1H),8.07(s,1H),7.73(d,J＝8.3Hz,1H),7.60(d,J＝8.3Hz,1H),7.42(d,J＝7.9Hz,2H),7.08(d,J＝8.1Hz,2H),4.35(d,J＝7.4Hz,2H),3.00(t,J＝7.4Hz,2H),2.32(d,J＝7.1Hz,2H),2.10(p,J＝6.8Hz,1H),0.97(d,J＝6.7Hz,6H). A mixture of 200 mg of 53-3, 72 mg of isovaleric acid, 136 mg of EDCI, 28 mg of HOBT, 164 mg of triethylamine, and 2 mL of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromophenethyl)-5-cyano-1H-benzo[d]imidazole -2-yl)-3-methylbutyramide (57-1) 196 mg of white solid, yield 78.4%. 1 H NMR (300MHz,DMSO-d 6 )δ10.64(s,1H),8.07(s,1H),7.73(d,J=8.3Hz,1H),7.60(d,J=8.3Hz,1H) ,7.42(d,J=7.9Hz,2H),7.08(d,J=8.1Hz,2H),4.35(d,J=7.4Hz,2H),3.00(t,J=7.4Hz,2H),2.32 (d, J=7.1Hz, 2H), 2.10(p, J=6.8Hz, 1H), 0.97(d, J=6.7Hz, 6H).
步骤②：(4-(2-(5-氰基-2-(3-甲基丁酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(57-2)Step ②: (4-(2-(5-cyano-2-(3-methylbutanylamino)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid diethyl Esters (57-2)
Figure PCTCN2023071429-appb-000257
Figure PCTCN2023071429-appb-000257
氩气氛围下，将177毫克57-1、167毫克碳酸铯、47毫克四三苯基膦钯和96微升亚磷酸二乙酯和2毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-(5-氰基-2-(3-甲基丁酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(57-2)白色固体102毫克，收率50.7％。 1H NMR(300MHz,CDCl 3)δ7.76–7.62(m,3H),7.45(dd,J＝8.3,1.4Hz,1H),7.28–7.22(m,2H),7.08(d,J＝8.4Hz,1H),4.45(t,J＝7.2Hz,2H),4.22–3.98(m,4H),3.20(t,J＝7.2Hz,2H),2.42(d,J＝7.1Hz,2H),2.24(dq,J＝13.5,6.7Hz,1H),1.33(t,J＝7.1Hz,6H),1.03(d,J＝6.6Hz,6H). Under an argon atmosphere, 177 mg of 57-1, 167 mg of cesium carbonate, 47 mg of tetrakistriphenylphosphine palladium, 96 microliters of diethyl phosphite and 2 milliliters of tetrahydrofuran were mixed, and stirred overnight at reflux at 100°C. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(5-cyano-2-(3-methylbutanylamino)-1H-benzene And[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid diethyl ester (57-2) white solid 102 mg, yield 50.7%. 1 H NMR (300MHz, CDCl 3 ) δ7.76–7.62 (m, 3H), 7.45 (dd, J=8.3, 1.4Hz, 1H), 7.28–7.22 (m, 2H), 7.08 (d, J=8.4 Hz,1H),4.45(t,J=7.2Hz,2H),4.22–3.98(m,4H),3.20(t,J=7.2Hz,2H),2.42(d,J=7.1Hz,2H), 2.24(dq,J=13.5,6.7Hz,1H),1.33(t,J=7.1Hz,6H),1.03(d,J=6.6Hz,6H).
步骤③：(4-(2-(5-氰基-2-(3-甲基丁酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-57)Step ③: (4-(2-(5-cyano-2-(3-methylbutanylamino)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (Ⅰ -57)
Figure PCTCN2023071429-appb-000258
Figure PCTCN2023071429-appb-000258
将60毫克57-2溶于2毫升二氯甲烷，冰浴，加入62微升三甲基碘硅烷，滴加完毕移 去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(5-氰基-2-(3-甲基丁酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-57)白色固体19毫克，收率35.8％。1H NMR(400MHz,DMSO-d 6)δ10.71(s,1H),8.07(s,1H),7.85–7.68(m,1H),7.67–7.45(m,4H),7.39–7.24(m,3H),4.37(t,J＝7.6Hz,2H),3.07(t,J＝7.6Hz,2H),2.35(d,J＝7.2Hz,2H),2.18–2.09(m,1H),0.98(d,J＝6.6Hz,6H). Dissolve 60 mg of 57-2 in 2 ml of dichloromethane, put in an ice bath, add 62 µl of iodotrimethylsilane, remove the ice bath after the dropwise addition, and stir overnight at room temperature; Reflux overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(5-cyano-2-(3-methylbutanylamino)-1H-benzene And[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-57) white solid 19 mg, yield 35.8%. 1H NMR (400MHz,DMSO-d 6 )δ10.71(s,1H),8.07(s,1H),7.85–7.68(m,1H),7.67–7.45(m,4H),7.39–7.24(m, 3H), 4.37(t, J=7.6Hz, 2H), 3.07(t, J=7.6Hz, 2H), 2.35(d, J=7.2Hz, 2H), 2.18–2.09(m, 1H), 0.98( d,J=6.6Hz,6H).
实施例58(4-(2-(2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-58)Example 58 (4-(2-(2-amino-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-58)
Figure PCTCN2023071429-appb-000259
Figure PCTCN2023071429-appb-000259
步骤①：(4-(2-((4-氰基-2-硝基苯基)氨基)乙基)苯基)膦酸二乙酯(58-1)Step ①: (4-(2-((4-cyano-2-nitrophenyl)amino)ethyl)phenyl)phosphonic acid diethyl ester (58-1)
Figure PCTCN2023071429-appb-000260
Figure PCTCN2023071429-appb-000260
氩气氛围下，将500毫克53-1、706毫克碳酸铯、167毫克四三苯基膦钯和372微升亚磷酸二乙酯和5毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-((4-氰基-2-硝基苯基)氨基)乙基)苯基)膦酸二乙酯(58-1)白色固体340毫克，收率58.4％。 1H NMR(300MHz,CDCl 3)δ8.52(d,J＝2.0Hz,1H),8.44(s,1H),7.82(dd,J＝13.1,7.9Hz,2H),7.62(dd,J＝8.9,2.0Hz,1H),7.38(dd,J＝8.0,3.8Hz,2H),6.92(d,J＝9.0Hz,1H),4.24–4.04(m,4H),3.67(td,J＝7.0,5.3Hz,2H),3.12(t,J＝7.0Hz,2H),1.34(t,J＝7.0Hz,6H). Under an argon atmosphere, 500 mg of 53-1, 706 mg of cesium carbonate, 167 mg of tetrakistriphenylphosphine palladium, 372 microliters of diethyl phosphite and 5 milliliters of tetrahydrofuran were mixed, and stirred at reflux overnight at 100°C. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-((4-cyano-2-nitrophenyl)amino)ethyl)phenyl ) diethyl phosphonate (58-1) white solid 340 mg, yield 58.4%. 1 H NMR (300MHz, CDCl 3 ) δ8.52(d, J=2.0Hz, 1H), 8.44(s, 1H), 7.82(dd, J=13.1, 7.9Hz, 2H), 7.62(dd, J= 8.9,2.0Hz,1H),7.38(dd,J=8.0,3.8Hz,2H),6.92(d,J=9.0Hz,1H),4.24–4.04(m,4H),3.67(td,J=7.0 ,5.3Hz,2H),3.12(t,J=7.0Hz,2H),1.34(t,J=7.0Hz,6H).
步骤②：(4-(2-((2-氨基-4-氰基苯基)氨基)乙基)苯基)膦酸二乙酯(58-2)Step ②: Diethyl (4-(2-((2-amino-4-cyanophenyl)amino)ethyl)phenyl)phosphonate (58-2)
Figure PCTCN2023071429-appb-000261
Figure PCTCN2023071429-appb-000261
将340毫克58-1、1.13克化连二亚硫酸钠、1毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得(4-(2-((2-氨基-4-氰基苯基)氨基)乙基)苯基)膦酸二乙酯(58-2)白色固体180毫克，收率58.1％。 1H NMR(300MHz,CDCl 3)δ7.84–7.73(m,2H),7.39–7.30(m,2H),7.16(dd,J＝8.2,1.9Hz,1H),6.94(d,J＝1.8Hz,1H),6.62(d,J＝8.3Hz,1H),4.24 –4.01(m,5H),3.48(t,J＝7.1Hz,2H),3.24(s,1H),3.03(t,J＝7.0Hz,2H),1.34(t,J＝7.1Hz,6H). A mixture of 340 mg of 58-1, 1.13 g of sodium dithionite, 1 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain (4-(2-((2-amino-4-cyanophenyl)amino)ethyl ) phenyl) diethyl phosphonate (58-2) white solid 180 mg, yield 58.1%. 1 H NMR (300MHz, CDCl 3 ) δ7.84–7.73 (m, 2H), 7.39–7.30 (m, 2H), 7.16 (dd, J=8.2, 1.9Hz, 1H), 6.94 (d, J=1.8 Hz,1H),6.62(d,J=8.3Hz,1H),4.24 –4.01(m,5H),3.48(t,J=7.1Hz,2H),3.24(s,1H),3.03(t,J ＝7.0Hz, 2H), 1.34(t, J＝7.1Hz, 6H).
步骤③：(4-(2-(2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(58-3)Step ③: Diethyl (4-(2-(2-amino-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonate (58-3)
Figure PCTCN2023071429-appb-000262
Figure PCTCN2023071429-appb-000262
将180毫克58-2和154毫克溴化氢溶于3毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-(2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸二乙酯(58-3)白色固体157毫克，收率81.7％。 1H NMR(300MHz,DMSO-d 6)δ9.00(s,2H),7.80(d,J＝1.4Hz,1H),7.66–7.50(m,4H),7.43(dd,J＝8.0,3.9Hz,2H),4.46(t,J＝7.2Hz,2H),3.94(dqd,J＝14.0,7.4,3.9Hz,4H),3.08(t,J＝7.2Hz,2H),1.20(t,J＝7.1Hz,6H). 180 mg of 58-2 and 154 mg of hydrogen bromide were dissolved in 3 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(2-amino-5-cyano-1H-benzo[d]imidazole-1- Base) ethyl) phenyl) phosphonic acid diethyl ester (58-3) white solid 157 mg, yield 81.7%. 1 H NMR (300MHz, DMSO-d 6 ) δ9.00(s, 2H), 7.80(d, J=1.4Hz, 1H), 7.66–7.50(m, 4H), 7.43(dd, J=8.0, 3.9 Hz,2H),4.46(t,J=7.2Hz,2H),3.94(dqd,J=14.0,7.4,3.9Hz,4H),3.08(t,J=7.2Hz,2H),1.20(t,J =7.1Hz,6H).
步骤④：(4-(2-(2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-58)Step ④: (4-(2-(2-amino-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-58)
Figure PCTCN2023071429-appb-000263
Figure PCTCN2023071429-appb-000263
室温下将50毫克58-3与2毫升浓盐酸的混合物搅拌均匀，90℃回流加热15小时。反应液抽滤，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-(2-(2-氨基-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(1-58)白色固体22毫克，收率51.1％。 1H NMR(300MHz,DMSO-d 6)δ7.62–7.52(m,3H),7.38(dd,J＝8.0,3.4Hz,2H),7.35–7.26(m,2H),7.13(s,2H),4.28(t,J＝7.7Hz,2H),2.96(t,J＝7.7Hz,2H). A mixture of 50 mg of 58-3 and 2 ml of concentrated hydrochloric acid was stirred evenly at room temperature, and heated under reflux at 90°C for 15 hours. The reaction solution was suction filtered, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-(2-(2-amino-5-cyano-1H-benzo[d]imidazol-1-yl ) ethyl) phenyl) phosphonic acid (1-58) white solid 22 mg, yield 51.1%. 1 H NMR (300MHz,DMSO-d 6 )δ7.62–7.52(m,3H),7.38(dd,J＝8.0,3.4Hz,2H),7.35–7.26(m,2H),7.13(s,2H ), 4.28(t, J=7.7Hz, 2H), 2.96(t, J=7.7Hz, 2H).
实施例59(4-(2-(2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5，6-二甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-59)Example 59 (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5,6-dimethoxy-1H-benzo[d ]imidazol-1-yl)ethyl)phenyl)phosphonic acid (Ⅰ-59)
Figure PCTCN2023071429-appb-000264
Figure PCTCN2023071429-appb-000264
步骤①：乙基1-乙基-3-甲基-1H-吡唑-5-羟酰胺(59-1)Step ①: Ethyl 1-ethyl-3-methyl-1H-pyrazole-5-hydroxyamide (59-1)
Figure PCTCN2023071429-appb-000265
Figure PCTCN2023071429-appb-000265
2克3-甲基吡唑-5-甲酸乙酯溶于20毫升N,N-二甲基甲酰胺，冰浴下加入2.7克碳酸钾和1.25毫升碘乙烷，室温搅拌过夜。反应液加水，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝100：1柱层析，得乙基1-乙基-3-甲基-1H-吡唑-5-羟酰胺(59-1)无色透明液体1.1克，收率46.5％。ESI-MS(m/z):183.1[M+H] +. 2 g of ethyl 3-methylpyrazole-5-carboxylate was dissolved in 20 ml of N,N-dimethylformamide, 2.7 g of potassium carbonate and 1.25 ml of ethyl iodide were added under ice cooling, and stirred overnight at room temperature. The reaction solution was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=100:1 to obtain ethyl 1-ethyl-3-methyl-1H-pyrazole 1.1 g of 5-hydroxylamide (59-1) is a colorless transparent liquid, with a yield of 46.5%. ESI-MS(m/z):183.1[M+H] + .
步骤②：1-乙基-3-甲基-1H-吡唑-5-羧酸(59-2)Step ②: 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (59-2)
Figure PCTCN2023071429-appb-000266
Figure PCTCN2023071429-appb-000266
1.1克59-1，263毫克氢氧化锂，2毫升水和4毫升甲醇混合物在室温搅拌2小时。反应液旋干，残余物加水稀释，加入1M HCl，析出白色固体，抽滤得1-乙基-3-甲基-1H-吡唑-5-羧酸(59-2)白色固体506毫克，收率59.8％。ESI-MS(m/z):155.1[M+H] +. A mixture of 1.1 g of 59-1, 263 mg of lithium hydroxide, 2 ml of water and 4 ml of methanol was stirred at room temperature for 2 hours. The reaction solution was spin-dried, the residue was diluted with water, 1M HCl was added, a white solid was precipitated, and 506 mg of a white solid of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (59-2) was obtained by suction filtration. Yield 59.8%. ESI-MS(m/z):155.1[M+H] + .
步骤③：1，2-二甲氧基-4，5-二硝基苯(59-3)Step ③: 1,2-dimethoxy-4,5-dinitrobenzene (59-3)
Figure PCTCN2023071429-appb-000267
Figure PCTCN2023071429-appb-000267
在冰浴条件下，将3毫升邻苯二甲醚缓慢滴加于20毫升浓硝酸中，滴加完毕后，反应升至室温，然后80℃加热0.5小时。反应液倒入冰水中搅拌1小时，过滤干燥得黄色固体1，2-二甲氧基-4，5-二硝基苯(59-3)1.77克，收率33.5％。LCMS(ESI)m/z:229.1[M+H] +. Under the condition of ice bath, 3 ml of phthalic dimethyl ether was slowly added dropwise to 20 ml of concentrated nitric acid. After the dropwise addition, the reaction was raised to room temperature, and then heated at 80° C. for 0.5 hour. The reaction solution was poured into ice water and stirred for 1 hour, filtered and dried to obtain 1.77 g of yellow solid 1,2-dimethoxy-4,5-dinitrobenzene (59-3), with a yield of 33.5%. LCMS(ESI)m/z:229.1[M+H] + .
步骤④：4，5-二甲氧基-2-硝基苯胺(59-4)Step ④: 4,5-dimethoxy-2-nitroaniline (59-4)
Figure PCTCN2023071429-appb-000268
Figure PCTCN2023071429-appb-000268
将1.77克59-3、9.45克化连二亚硫酸钠、3毫升氨水和15毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得4，5-二甲氧基-2-硝基苯胺(59-4)黄色固体840毫克，收率54.5％。LCMS(ESI)m/z:199.1[M+H] +. A mixture of 1.77 g of 59-3, 9.45 g of sodium dithionite, 3 ml of aqueous ammonia and 15 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 840 mg of yellow solid 4,5-dimethoxy-2-nitroaniline (59-4) , yield 54.5%. LCMS(ESI)m/z:199.1[M+H] + .
步骤⑤：N-(4-溴苄基)-4，5-二甲氧基-2-硝基苯胺(59-5)Step ⑤: N-(4-bromobenzyl)-4,5-dimethoxy-2-nitroaniline (59-5)
Figure PCTCN2023071429-appb-000269
Figure PCTCN2023071429-appb-000269
将840毫克59-4，1.58克4-溴溴苄和7毫升水加在封管中，在110℃下搅拌10小时。反应液冷却至室温，用乙酸乙酯稀释，加入361毫克碳酸氢钠，搅拌0.5小时，反应液 浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得N-(4-溴苄基)-4，5-二甲氧基-2-硝基苯胺(59-5)红棕色固体1.2克，收率76.4％。 1H NMR(300MHz,CDCl 3)δ8.88(s,1H),7.65(s,1H),7.59–7.47(m,2H),7.28(d,J＝3.0Hz,2H),6.08(s,1H),4.54(d,J＝5.7Hz,2H),3.88(s,3H),3.80(s,3H). Add 840 mg of 59-4, 1.58 g of 4-bromobenzyl bromide and 7 ml of water into a sealed tube and stir at 110°C for 10 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, added 361 mg of sodium bicarbonate, stirred for 0.5 hours, the reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 4: 1 to obtain N-( 4-bromobenzyl)-4,5-dimethoxy-2-nitroaniline (59-5) 1.2 g of reddish-brown solid, yield 76.4%. 1 H NMR (300MHz, CDCl 3 )δ8.88(s,1H),7.65(s,1H),7.59–7.47(m,2H),7.28(d,J=3.0Hz,2H),6.08(s, 1H), 4.54(d, J=5.7Hz, 2H), 3.88(s, 3H), 3.80(s, 3H).
步骤⑥：N1-(4-溴苄基)-4，5-二甲氧基苯-1，2-二胺(59-6)Step ⑥: N1-(4-bromobenzyl)-4,5-dimethoxybenzene-1,2-diamine (59-6)
Figure PCTCN2023071429-appb-000270
Figure PCTCN2023071429-appb-000270
将1.2克59-5、6.2克化连二亚硫酸钠、3毫升氨水和15毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得N1-(4-溴苄基)-4，5-二甲氧基苯-1，2-二胺(59-6)白色固体500毫克，收率45.5％。LCMS(ESI)m/z:337.1[M+H] +. A mixture of 1.2 g of 59-5, 6.2 g of sodium dithionite, 3 ml of ammonia and 15 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 4:1 to obtain N1-(4-bromobenzyl)-4,5-dimethoxybenzene-1,2 - Diamine (59-6) white solid 500 mg, yield 45.5%. LCMS(ESI)m/z:337.1[M+H] + .
步骤⑦：1-(4-溴苄基)-5，6-二甲氧基-1H-苯并[d]咪唑-2-胺(59-7)Step ⑦: 1-(4-bromobenzyl)-5,6-dimethoxy-1H-benzo[d]imidazol-2-amine (59-7)
Figure PCTCN2023071429-appb-000271
Figure PCTCN2023071429-appb-000271
将500毫克59-6和201毫克溴化氰溶于5毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得1-(4-溴苄基)-5，6-二甲氧基-1H-苯并[d]咪唑-2-胺(59-7)灰白色固体400毫克，收率74.4％。 1H NMR(300MHz,CDCl 3)δ7.45–7.33(m,2H),7.09(d,J＝8.2Hz,2H),6.93(s,1H),6.59(s,1H),6.33(s,2H),5.37–5.25(m,2H),3.84(s,6H). Dissolve 500 mg of 59-6 and 201 mg of cyanogen bromide in 5 ml of methanol and stir overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain 1-(4-bromobenzyl)-5,6-dimethoxy-1H-benzo[d]imidazole -2-Amine (59-7) 400 mg off-white solid, yield 74.4%. 1 H NMR (300MHz, CDCl 3 ) δ7.45–7.33(m, 2H), 7.09(d, J=8.2Hz, 2H), 6.93(s, 1H), 6.59(s, 1H), 6.33(s, 2H),5.37–5.25(m,2H),3.84(s,6H).
步骤⑧：N-(1-(4-溴苄基)-5，6-二甲氧基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(59-8)Step ⑧: N-(1-(4-bromobenzyl)-5,6-dimethoxy-1H-benzo[d]imidazol-2-yl)-1-ethyl-3-methyl-1H -pyrazole-5-carboxamide (59-8)
Figure PCTCN2023071429-appb-000272
Figure PCTCN2023071429-appb-000272
将400毫克59-7、180毫克化合物59-2、272毫克EDCI、56毫克HOBT、328微升三乙胺和5毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴苄基)-5，6-二甲氧基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(59-8)白色固体440毫克，收率80％。 1H NMR(400MHz,CDCl 3)δ12.26(s,1H),7.56–7.45(m,2H),7.27–7.20(m,2H),6.89(s,1H),6.74(s,1H),6.63(s,1H),5.35(s,2H),4.70(q,J＝7.1Hz,2H),3.89(s,3H),3.86(s,3H),2.30(s,3H),1.29–1.24(m,3H). A mixture of 400 mg of 59-7, 180 mg of compound 59-2, 272 mg of EDCI, 56 mg of HOBT, 328 μl of triethylamine and 5 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromobenzyl)-5,6-dimethoxy-1H-benzo[ d] Imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (59-8) 440 mg of white solid, yield 80%. 1 H NMR (400MHz, CDCl 3 )δ12.26(s,1H),7.56–7.45(m,2H),7.27–7.20(m,2H),6.89(s,1H),6.74(s,1H), 6.63(s,1H),5.35(s,2H),4.70(q,J=7.1Hz,2H),3.89(s,3H),3.86(s,3H),2.30(s,3H),1.29–1.24 (m,3H).
步骤⑨：4-((2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5，6-二甲氧基-1H-苯 并[d]咪唑-1-基)甲基)苯基)膦酸二乙酯(59-9)Step ⑨: 4-((2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5,6-dimethoxy-1H-benzo[d]imidazole- 1-yl)methyl)phenyl)phosphonic acid diethyl ester (59-9)
Figure PCTCN2023071429-appb-000273
Figure PCTCN2023071429-appb-000273
氩气氛围下，将200毫克59-8、196毫克碳酸铯、48毫克四三苯基膦钯和110微升亚磷酸二乙酯和4毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得4-((2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5，6-二甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸二乙酯(59-9)白色固体120毫克，收率53.68％。1H NMR(400MHz,CDCl 3)δ12.32(s,1H),7.91–7.76(m,2H),7.43(dd,J＝8.1,3.7Hz,2H),6.90(s,1H),6.73(s,1H),6.62(s,1H),5.44(s,2H),4.68(q,J＝7.1Hz,2H),4.19–4.02(m,4H),3.85(d,J＝12.2Hz,6H),2.29(s,3H),1.31(t,J＝7.1Hz,9H). Under an argon atmosphere, 200 mg of 59-8, 196 mg of cesium carbonate, 48 mg of tetrakistriphenylphosphine palladium, 110 microliters of diethyl phosphite and 4 milliliters of tetrahydrofuran were mixed, and stirred at reflux overnight at 100°C. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain 4-((2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide )-5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid diethyl ester (59-9) white solid 120 mg, yield 53.68%. 1H NMR (400MHz, CDCl 3 ) δ12.32(s, 1H), 7.91–7.76(m, 2H), 7.43(dd, J=8.1, 3.7Hz, 2H), 6.90(s, 1H), 6.73(s ,1H),6.62(s,1H),5.44(s,2H),4.68(q,J=7.1Hz,2H),4.19–4.02(m,4H),3.85(d,J=12.2Hz,6H) ,2.29(s,3H),1.31(t,J=7.1Hz,9H).
步骤⑩：(4-(2-(2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5，6-二甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-59)Step ⑩: (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5,6-dimethoxy-1H-benzo[d ]imidazol-1-yl)ethyl)phenyl)phosphonic acid (Ⅰ-59)
Figure PCTCN2023071429-appb-000274
Figure PCTCN2023071429-appb-000274
将50毫克59-9溶于2毫升二氯甲烷，冰浴，加入52微升三甲基溴硅烷，滴加完毕移去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5，6-二甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-59)白色固体21毫克，收率46.6％。1H NMR(400MHz,DMSO-d 6)δ12.67(s,1H),7.64(dd,J＝12.7,7.9Hz,2H),7.42(dd,J＝8.2,3.2Hz,2H),7.19(d,J＝7.2Hz,2H),6.60(s,1H),5.47(s,2H),4.55(q,J＝7.0Hz,2H),3.76(s,6H),2.15(s,3H),1.28(t,J＝7.1Hz,3H). Dissolve 50 mg of 59-9 in 2 ml of dichloromethane, put in an ice bath, add 52 µl of trimethylbromosilane, remove the ice bath after the dropwise addition, and stir overnight at room temperature; Reflux overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5- Formamido)-5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-59) white solid 21 mg, yield 46.6%. 1H NMR (400MHz, DMSO-d 6 )δ12.67(s, 1H), 7.64(dd, J=12.7, 7.9Hz, 2H), 7.42(dd, J=8.2, 3.2Hz, 2H), 7.19(d ,J=7.2Hz,2H),6.60(s,1H),5.47(s,2H),4.55(q,J=7.0Hz,2H),3.76(s,6H),2.15(s,3H),1.28 (t,J=7.1Hz,3H).
实施例60(4-(2-(2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-60)Example 60 (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-6,7-dihydro-1H-[1,4]di Oxine[2',3':4,5]benzo[1,2-d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-60)
Figure PCTCN2023071429-appb-000275
Figure PCTCN2023071429-appb-000275
步骤①：6，7-二硝基-2，3-二氢-1，4-苯并二恶英(60-1)Step ①: 6,7-dinitro-2,3-dihydro-1,4-benzodioxin (60-1)
Figure PCTCN2023071429-appb-000276
Figure PCTCN2023071429-appb-000276
在冰浴条件下，将500毫克1,4-苯并二恶烷缓慢滴加于5毫升浓硝酸中，滴加完毕后，反应升至室温，然后80℃加热0.5小时。反应液倒入冰水中搅拌1小时，过滤干燥得黄色固体6，7-二硝基-2，3-二氢-1，4-苯并二恶英(60-1)700毫克，收率84.3％。1H NMR(300MHz,CDCl 3)δ7.46(s,2H),4.43(s,4H). Under the condition of ice bath, 500 mg of 1,4-benzodioxane was slowly added dropwise to 5 ml of concentrated nitric acid. After the dropwise addition, the reaction was raised to room temperature, and then heated at 80° C. for 0.5 hour. The reaction solution was poured into ice water and stirred for 1 hour, filtered and dried to obtain 700 mg of yellow solid 6,7-dinitro-2,3-dihydro-1,4-benzodioxin (60-1), yield 84.3 %. 1H NMR (300MHz, CDCl 3 )δ7.46(s, 2H), 4.43(s, 4H).
步骤②：7-硝基-2，3-二氢苯并[B][1，4]二恶英-6-胺(60-2)Step ②: 7-nitro-2,3-dihydrobenzo[B][1,4]dioxin-6-amine (60-2)
Figure PCTCN2023071429-appb-000277
Figure PCTCN2023071429-appb-000277
将700毫克60-1、3.6克化连二亚硫酸钠、1毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得7-硝基-2，3-二氢苯并[B][1，4]二恶英-6-胺(60-2)黄色固体300毫克，收率49.4％。 1H NMR(400MHz,DMSO-d 6)δ7.41(s,1H),7.13(s,2H),6.44(s,1H),4.35–4.29(m,2H),4.24–4.17(m,2H). A mixture of 700 mg of 60-1, 3.6 g of sodium dithionite, 1 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 7-nitro-2,3-dihydrobenzo[B][1,4]diox En-6-amine (60-2) yellow solid 300 mg, yield 49.4%. 1 H NMR (400MHz,DMSO-d 6 )δ7.41(s,1H),7.13(s,2H),6.44(s,1H),4.35–4.29(m,2H),4.24–4.17(m,2H ).
步骤③：N-(4-溴苄基)-7-硝基-2，3-二氢苯并[B][1，4]二恶英-6-胺(60-3)Step ③: N-(4-bromobenzyl)-7-nitro-2,3-dihydrobenzo[B][1,4]dioxin-6-amine (60-3)
Figure PCTCN2023071429-appb-000278
Figure PCTCN2023071429-appb-000278
将512毫克60-2，973毫克4-溴溴苄和5毫升水加在封管中，在110℃下搅拌10小时。反应液冷却至室温，用乙酸乙酯稀释，加入361毫克碳酸氢钠，搅拌0.5小时，反应液浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得N-(4-溴苄基)-7-硝基-2，3-二氢苯并[B][1，4]二恶英-6-胺(60-3)红棕色固体720毫克，收率75.8％。 1H NMR(300MHz,CDCl 3)δ8.38(s,1H),7.78(s,1H),7.50(dd,J＝8.4,1.8Hz,3H),7.28(s,1H),6.14(s,1H),4.44(d,J＝5.8Hz,2H),4.31(dt,J＝4.6,2.8Hz,2H),4.22(dt,J＝4.0,2.8Hz,2H). Add 512 mg of 60-2, 973 mg of 4-bromobenzyl bromide and 5 ml of water into a sealed tube and stir at 110°C for 10 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, added 361 mg of sodium bicarbonate, stirred for 0.5 hours, the reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 4: 1 to obtain N-( 4-Bromobenzyl)-7-nitro-2,3-dihydrobenzo[B][1,4]dioxin-6-amine (60-3) 720 mg reddish-brown solid, yield 75.8% . 1 H NMR (300MHz, CDCl 3 )δ8.38(s,1H),7.78(s,1H),7.50(dd,J=8.4,1.8Hz,3H),7.28(s,1H),6.14(s, 1H), 4.44(d, J=5.8Hz, 2H), 4.31(dt, J=4.6, 2.8Hz, 2H), 4.22(dt, J=4.0, 2.8Hz, 2H).
步骤④：N6-(4-溴苄基)-2，3-二氢苯并[B][1，4]二恶英-6，7-二胺(60-4)Step ④: N6-(4-bromobenzyl)-2,3-dihydrobenzo[B][1,4]dioxin-6,7-diamine (60-4)
Figure PCTCN2023071429-appb-000279
Figure PCTCN2023071429-appb-000279
将720毫克60-3、3.6克化连二亚硫酸钠、1毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得N6-(4-溴苄基)-2，3-二氢苯并[B][1，4]二恶英-6，7-二胺(60-4)白色固体320毫克，收率48.4％。LCMS(ESI)m/z:335.1[M+H] +. A mixture of 720 mg of 60-3, 3.6 g of sodium dithionite, 1 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain N6-(4-bromobenzyl)-2,3-dihydrobenzo[B][1 ,4] Dioxin-6,7-diamine (60-4) 320 mg white solid, yield 48.4%. LCMS(ESI)m/z:335.1[M+H] + .
步骤⑤：1-(4-溴苄基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯 并[1，2-d]咪唑-2-胺(60-5)Step ⑤: 1-(4-bromobenzyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1, 2-d] imidazol-2-amine (60-5)
Figure PCTCN2023071429-appb-000280
Figure PCTCN2023071429-appb-000280
将320毫克60-4和120毫克溴化氰溶于3毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得1-(4-溴苄基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-2-胺(60-5)灰白色固体260毫克，收率75.6％。 1H NMR(300MHz,DMSO-d 6)δ7.62–7.45(m,2H),7.13(d,J＝8.3Hz,2H),6.59(d,J＝9.6Hz,2H),6.46(s,2H),5.14(s,2H),4.13(s,4H). 320 mg of 60-4 and 120 mg of cyanogen bromide were dissolved in 3 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain 1-(4-bromobenzyl)-6,7-dihydro-1H-[1,4]dioxa Cyclohexeno[2',3':4,5]benzo[1,2-d]imidazol-2-amine (60-5) 260 mg off-white solid, yield 75.6%. 1 H NMR (300MHz, DMSO-d 6 )δ7.62–7.45(m, 2H), 7.13(d, J=8.3Hz, 2H), 6.59(d, J=9.6Hz, 2H), 6.46(s, 2H), 5.14(s, 2H), 4.13(s, 4H).
步骤⑥：N-(1-(4-溴苄基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(60-6)Step ⑥: N-(1-(4-bromobenzyl)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo [1,2-d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (60-6)
Figure PCTCN2023071429-appb-000281
Figure PCTCN2023071429-appb-000281
将200毫克60-5、90毫克化合物7-2、138毫克EDCI、101毫克HOBT、166微升三乙胺和3毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(1-(4-溴苄基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(60-6)白色固体210毫克，收率76.4％。 1H NMR(300MHz,DMSO-d 6)δ12.55(s,1H),7.57–7.52(m,2H),7.37–7.31(m,2H),7.01(d,J＝6.3Hz,2H),6.63(d,J＝0.6Hz,1H),5.33(s,2H),4.57(q,J＝7.1Hz,2H),4.22(s,4H),2.16(s,3H),1.30(t,J＝7.1Hz,3H). A mixture of 200 mg of 60-5, 90 mg of compound 7-2, 138 mg of EDCI, 101 mg of HOBT, 166 μl of triethylamine and 3 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(1-(4-bromobenzyl)-6,7-dihydro-1H-[1,4] Dioxino[2',3':4,5]benzo[1,2-d]imidazol-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5 -Formamide (60-6) 210 mg of white solid, yield 76.4%. 1 H NMR (300MHz,DMSO-d 6 )δ12.55(s,1H),7.57–7.52(m,2H),7.37–7.31(m,2H),7.01(d,J=6.3Hz,2H), 6.63(d,J=0.6Hz,1H),5.33(s,2H),4.57(q,J=7.1Hz,2H),4.22(s,4H),2.16(s,3H),1.30(t,J =7.1Hz,3H).
步骤⑦：(4-((2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-1-基)甲基)苯基)膦酸二乙酯(60-7)Step ⑦: (4-((2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-6,7-dihydro-1H-[1,4]dioxa Cyclohexeno[2',3':4,5]benzo[1,2-d]imidazol-1-yl)methyl)phenyl)phosphonic acid diethyl ester (60-7)
Figure PCTCN2023071429-appb-000282
Figure PCTCN2023071429-appb-000282
200毫克60-6、197毫克碳酸铯、47毫克四三苯基膦钯和104微升亚磷酸二乙酯和4毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-((2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-1-基)甲基)苯基)膦酸二乙酯(60-7)白色固体97毫克，收率43.5％。 1H NMR(300MHz,CDCl 3)δ12.03(s,1H), 7.88–7.74(m,2H),7.44(dd,J＝8.2,3.7Hz,2H),6.85(s,1H),6.73(s,1H),6.62(s,1H),5.36(s,2H),4.68(q,J＝7.1Hz,2H),4.27(s,4H),4.20–4.02(m,4H),2.29(s,3H),1.44(t,J＝7.1Hz,3H),1.32(t,J＝7.1Hz,6H). 200 mg of 60-6, 197 mg of cesium carbonate, 47 mg of tetrakistriphenylphosphine palladium, 104 microliters of diethyl phosphite and 4 milliliters of tetrahydrofuran were mixed, and stirred overnight at reflux at 100°C. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-((2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide base)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazol-1-yl) Diethyl methyl)phenyl)phosphonate (60-7) 97mg white solid, yield 43.5%. 1 H NMR (300MHz, CDCl 3 ) δ12.03(s, 1H), 7.88–7.74(m, 2H), 7.44(dd, J=8.2, 3.7Hz, 2H), 6.85(s, 1H), 6.73( s,1H),6.62(s,1H),5.36(s,2H),4.68(q,J＝7.1Hz,2H),4.27(s,4H),4.20–4.02(m,4H),2.29(s ,3H),1.44(t,J=7.1Hz,3H),1.32(t,J=7.1Hz,6H).
步骤⑧：(4-(2-(2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-60)Step ⑧: (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-6,7-dihydro-1H-[1,4]di Oxine[2',3':4,5]benzo[1,2-d]imidazol-1-yl)ethyl)phenyl)phosphonic acid (I-60)
Figure PCTCN2023071429-appb-000283
Figure PCTCN2023071429-appb-000283
70毫克60-7溶于2毫升二氯甲烷，冰浴，加入68微升三甲基碘硅烷，滴加完毕移去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-6，7-二氢-1H-[1，4]二氧杂环己烯并[2'，3'：4，5]苯并[1，2-d]咪唑-1-基)乙基)苯基)膦酸(Ⅰ-60)白色固体26毫克，收率41.3％。 1H NMR(300MHz,DMSO-d 6)δ7.76–7.62(m,2H),7.48(dd,J＝8.2,3.8Hz,2H),7.05(s,1H),7.01(s,1H),6.63(s,1H),5.46(s,2H),4.54(q,J＝7.1Hz,2H),4.23(s,4H),2.16(s,3H),1.27(t,J＝7.1Hz,3H). Dissolve 70 mg of 60-7 in 2 ml of dichloromethane, put in an ice bath, add 68 µl of iodotrimethylsilane, remove the ice bath after the dropwise addition, and stir at room temperature overnight; the reaction solution is concentrated to dryness, added methanol, and refluxed at 80°C overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(2-(1-ethyl-3-methyl-1H-pyrazole-5- Formamido)-6,7-dihydro-1H-[1,4]dioxino[2',3':4,5]benzo[1,2-d]imidazole-1- Base) ethyl) phenyl) phosphonic acid (I-60) white solid 26 mg, yield 41.3%. 1 H NMR (300MHz,DMSO-d 6 )δ7.76–7.62(m,2H),7.48(dd,J＝8.2,3.8Hz,2H),7.05(s,1H),7.01(s,1H), 6.63(s,1H),5.46(s,2H),4.54(q,J=7.1Hz,2H),4.23(s,4H),2.16(s,3H),1.27(t,J=7.1Hz,3H ).
实施例61(4-(2-(6-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-5-基)乙基)苯基)膦酸(Ⅰ-61)Example 61 (4-(2-(6-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5H-[1,3]dioxole[ 4',5': 4,5]benzo[1,2-d]imidazol-5-yl)ethyl)phenyl)phosphonic acid (I-61)
Figure PCTCN2023071429-appb-000284
Figure PCTCN2023071429-appb-000284
步骤①：5，6-二硝基苯并[d][1，3]间二氧杂环戊烯(61-1)Step ①: 5,6-Dinitrobenzo[d][1,3]dioxole (61-1)
Figure PCTCN2023071429-appb-000285
Figure PCTCN2023071429-appb-000285
在冰浴条件下，将1克1,3-苯并间二氧杂环戊烯缓慢滴加于5毫升浓硝酸中，滴加完毕后，反应升至室温，然后80℃加热0.5小时。反应液倒入冰水中搅拌1小时，过滤干燥得黄色固体5，6-二硝基苯并[d][1，3]间二氧杂环戊烯(61-1)854毫克，收率49.3％。 1H NMR(300MHz,CDCl 3)δ7.33(s,2H),6.29(s,2H). Under the condition of ice bath, 1 g of 1,3-benzodioxole was slowly added dropwise to 5 ml of concentrated nitric acid. After the dropwise addition, the reaction was raised to room temperature, and then heated at 80° C. for 0.5 hour. The reaction solution was poured into ice water and stirred for 1 hour, filtered and dried to obtain 854 mg of yellow solid 5,6-dinitrobenzo[d][1,3]dioxole (61-1), yield 49.3 %. 1 H NMR (300MHz, CDCl 3 )δ7.33(s,2H),6.29(s,2H).
步骤②：6-硝基苯并[d][1，3]间二氧杂环戊烯-5-胺(61-2)Step ②: 6-Nitrobenzo[d][1,3]dioxol-5-amine (61-2)
Figure PCTCN2023071429-appb-000286
Figure PCTCN2023071429-appb-000286
将620毫克61-1、3.2克化连二亚硫酸钠、2毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得6-硝基苯并[d][1，3]间二氧杂环戊烯-5-胺(61-2)黄色固体300毫克，收率56.4％。LCMS(ESI)m/z:183.1[M+H] +. A mixture of 620 mg of 61-1, 3.2 g of sodium dithionite, 2 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 6-nitrobenzo[d][1,3]dioxole-5 - Amine (61-2) 300 mg of yellow solid, yield 56.4%. LCMS(ESI)m/z:183.1[M+H] + .
步骤③：N-(4-溴苄基)-6-硝基苯并[d][1，3]间二氧杂环戊烯-5-胺(61-3)Step ③: N-(4-bromobenzyl)-6-nitrobenzo[d][1,3]dioxol-5-amine (61-3)
Figure PCTCN2023071429-appb-000287
Figure PCTCN2023071429-appb-000287
将366毫克61-2，696毫克4-溴溴苄和5毫升水加在封管中，在110℃下搅拌10小时。反应液冷却至室温，用乙酸乙酯稀释，加入154毫克碳酸氢钠，搅拌0.5小时，反应液浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得N-(4-溴苄基)-6-硝基苯并[d][1，3]间二氧杂环戊烯-5-胺(61-3)红棕色固体380毫克，收率53.9％。 1H NMR(400MHz,DMSO-d 6)δ9.26(t,J＝6.2Hz,1H),7.57–7.52(m,2H),7.50(s,1H),7.36–7.30(m,2H),6.50(s,1H),6.07(s,2H),4.62(d,J＝6.2Hz,2H). Add 366 mg of 61-2, 696 mg of 4-bromobenzyl bromide and 5 ml of water into a sealed tube and stir at 110°C for 10 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, added 154 mg of sodium bicarbonate, stirred for 0.5 hours, the reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 4: 1 to obtain N-( 4-Bromobenzyl)-6-nitrobenzo[d][1,3]dioxol-5-amine (61-3) 380 mg of reddish-brown solid, yield 53.9%. 1 H NMR (400MHz, DMSO-d 6 ) δ9.26(t, J=6.2Hz, 1H), 7.57–7.52(m, 2H), 7.50(s, 1H), 7.36–7.30(m, 2H), 6.50(s,1H),6.07(s,2H),4.62(d,J=6.2Hz,2H).
步骤④：N5-(4-溴苄基)苯并[d][1，3]间二氧杂环戊烯-5，6-二胺(61-4)Step ④: N5-(4-bromobenzyl)benzo[d][1,3]dioxole-5,6-diamine (61-4)
Figure PCTCN2023071429-appb-000288
Figure PCTCN2023071429-appb-000288
将547毫克61-3、2.5克化连二亚硫酸钠、1毫升氨水和10毫升甲醇的混合物室温搅拌1小时。抽滤得滤液，浓缩至干，残余物以石油醚：乙酸乙酯＝4：1柱层析，得N5-(4-溴苄基)苯并[d][1，3]间二氧杂环戊烯-5，6-二胺(61-4)类白色固体280毫克，收率56％。LCMS(ESI)m/z:321.1[M+H] +. A mixture of 547 mg of 61-3, 2.5 g of sodium dithionite, 1 ml of aqueous ammonia and 10 ml of methanol was stirred at room temperature for 1 hour. The filtrate was obtained by suction filtration, concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain N5-(4-bromobenzyl)benzo[d][1,3]dioxa Cyclopentene-5,6-diamine (61-4) 280 mg off-white solid, yield 56%. LCMS(ESI)m/z:321.1[M+H] + .
步骤⑤：5-(4-溴苄基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-6-胺(61-5)Step ⑤: 5-(4-bromobenzyl)-5H-[1,3]dioxole[4',5': 4,5]benzo[1,2-d]imidazole-6 - Amine (61-5)
Figure PCTCN2023071429-appb-000289
Figure PCTCN2023071429-appb-000289
将280毫克61-4和113毫克溴化氰溶于3毫升甲醇，室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得5-(4-溴苄基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-6-胺(61-5)灰白色固体210毫克，收率69.5％。1H NMR(300MHz,DMSO-d 6)δ7.58–7.49(m,2H),7.20–7.08(m,2H),6.81(s,1H),6.75(s,1H),6.39(s,2H),5.85(s,2H),5.18(s,2H).. 280 mg of 61-4 and 113 mg of cyanogen bromide were dissolved in 3 ml of methanol and stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain 5-(4-bromobenzyl)-5H-[1,3]dioxole[4',5': 4,5]benzo[1,2-d]imidazol-6-amine (61-5) 210 mg off-white solid, yield 69.5%. 1H NMR (300MHz,DMSO-d 6 )δ7.58–7.49(m,2H),7.20–7.08(m,2H),6.81(s,1H),6.75(s,1H),6.39(s,2H) ,5.85(s,2H),5.18(s,2H)..
步骤⑥：N-(5-(4-溴苄基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-6-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(61-6)Step ⑥: N-(5-(4-bromobenzyl)-5H-[1,3]dioxole[4',5':4,5]benzo[1,2-d] Imidazol-6-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (61-6)
Figure PCTCN2023071429-appb-000290
Figure PCTCN2023071429-appb-000290
将200毫克61-5、92毫克化合物59-2、141毫克EDCI、105毫克HOBT、172微升三乙胺和3毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得N-(5-(4-溴苄基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-6-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(61-6)白色固体205毫克，收率73.5％。 1H NMR(300MHz,CDCl 3)δ12.19(s,1H),7.53–7.45(m,2H),7.28(s,1H),7.23(d,J＝1.9Hz,1H),6.83(s,1H),6.74(s,1H),6.62(s,1H),5.99(s,2H),5.31(s,2H),4.69(q,J＝7.1Hz,2H),2.30(s,3H),1.46(t,J＝7.1Hz,3H). A mixture of 200 mg 61-5, 92 mg compound 59-2, 141 mg EDCI, 105 mg HOBT, 172 μl triethylamine and 3 ml N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain N-(5-(4-bromobenzyl)-5H-[1,3]dioxole [4',5':4,5]benzo[1,2-d]imidazol-6-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (61-6 ) 205 mg of white solid, yield 73.5%. 1 H NMR (300MHz, CDCl 3 )δ12.19(s,1H),7.53–7.45(m,2H),7.28(s,1H),7.23(d,J＝1.9Hz,1H),6.83(s, 1H),6.74(s,1H),6.62(s,1H),5.99(s,2H),5.31(s,2H),4.69(q,J=7.1Hz,2H),2.30(s,3H), 1.46(t,J=7.1Hz,3H).
步骤⑦：(4-((6-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-5-基)甲基)苯基)膦酸二乙酯(61-7)Step ⑦: (4-((6-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5H-[1,3]dioxole[4' ,5':4,5]benzo[1,2-d]imidazol-5-yl)methyl)phenyl)phosphonic acid diethyl ester (61-7)
Figure PCTCN2023071429-appb-000291
Figure PCTCN2023071429-appb-000291
200毫克61-6、198毫克碳酸铯、47毫克四三苯基膦钯和106微升亚磷酸二乙酯和4毫升四氢呋喃混合，100℃回流搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝200：1柱层析，得(4-((6-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-5-基)甲基)苯基)膦酸二乙酯(61-7)白色固体88毫克，收率39.5％。 1H NMR(400MHz,CDCl 3)δ12.21(s,1H),7.87–7.75(m,2H),7.43(dd,J＝8.1,3.7Hz,2H),6.84(s,1H),6.72(s,1H),6.61(s,1H),5.99(s,2H),5.40(s,2H),4.68(q,J＝7.1Hz,2H),4.22–4.02(m,4H),2.29(s,3H),1.44(t,J＝7.1Hz,3H),1.33(t,J＝7.1Hz,6H). 200 mg of 61-6, 198 mg of cesium carbonate, 47 mg of tetrakistriphenylphosphine palladium, 106 microliters of diethyl phosphite and 4 milliliters of tetrahydrofuran were mixed, and stirred overnight at 100°C under reflux. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=200:1 to obtain (4-((6-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide base)-5H-[1,3]dioxole[4',5':4,5]benzo[1,2-d]imidazol-5-yl)methyl)phenyl)phosphine Acid diethyl ester (61-7) 88 mg white solid, yield 39.5%. 1 H NMR (400MHz, CDCl 3 ) δ12.21(s, 1H), 7.87–7.75(m, 2H), 7.43(dd, J=8.1, 3.7Hz, 2H), 6.84(s, 1H), 6.72( s,1H),6.61(s,1H),5.99(s,2H),5.40(s,2H),4.68(q,J＝7.1Hz,2H),4.22–4.02(m,4H),2.29(s ,3H),1.44(t,J=7.1Hz,3H),1.33(t,J=7.1Hz,6H).
步骤⑧：(4-(2-(6-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-5-基)乙基)苯基)膦酸(Ⅰ-61)Step ⑧: (4-(2-(6-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5H-[1,3]dioxole[ 4',5': 4,5]benzo[1,2-d]imidazol-5-yl)ethyl)phenyl)phosphonic acid (I-61)
Figure PCTCN2023071429-appb-000292
Figure PCTCN2023071429-appb-000292
80毫克61-7溶于2毫升二氯甲烷，冰浴，加入77微升三甲基碘硅烷，滴加完毕移 去冰浴，室温搅拌过夜；反应液浓缩至干，加入甲醇，80℃回流过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1柱层析，得(4-(2-(6-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-5H-[1，3]二氧杂环戊烯并[4'，5'：4，5]苯并[1，2-d]咪唑-5-基)乙基)苯基)膦酸(Ⅰ-61)白色固体18毫克，收率25％。 1H NMR(300MHz,DMSO-d 6)δ7.65(ddd,J＝12.7,8.0,6.2Hz,2H),7.44(td,J＝8.7,8.2,3.3Hz,2H),7.28–7.07(m,2H),6.62(d,J＝3.7Hz,1H),6.02(s,2H),5.45(d,J＝4.7Hz,2H),4.55(qd,J＝7.1,3.1Hz,2H),2.16(d,J＝1.5Hz,3H),1.28(td,J＝7.0,4.8Hz,3H). Dissolve 80 mg of 61-7 in 2 ml of dichloromethane, put in an ice bath, add 77 µl of iodotrimethylsilane, remove the ice bath after the dropwise addition, and stir at room temperature overnight; the reaction solution is concentrated to dryness, added methanol, and refluxed at 80°C overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=10:1 to obtain (4-(2-(6-(1-ethyl-3-methyl-1H-pyrazole-5- Formamido)-5H-[1,3]dioxole[4',5':4,5]benzo[1,2-d]imidazol-5-yl)ethyl)phenyl ) Phosphonic acid (I-61) white solid 18 mg, yield 25%. 1 H NMR (300MHz, DMSO-d 6 ) δ7.65 (ddd, J＝12.7, 8.0, 6.2Hz, 2H), 7.44 (td, J＝8.7, 8.2, 3.3Hz, 2H), 7.28–7.07(m ,2H),6.62(d,J=3.7Hz,1H),6.02(s,2H),5.45(d,J=4.7Hz,2H),4.55(qd,J=7.1,3.1Hz,2H),2.16 (d,J=1.5Hz,3H),1.28(td,J=7.0,4.8Hz,3H).
实施例62Example 62
4-((2-苯甲酰胺-5-氨甲酰-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-62)4-((2-Benzamide-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyl phosphate dihydrogen (I-62)
Figure PCTCN2023071429-appb-000293
Figure PCTCN2023071429-appb-000293
步骤①：4-氯-3-甲氧基-5-硝基苯甲酰胺(62-1)Step ①: 4-chloro-3-methoxy-5-nitrobenzamide (62-1)
Figure PCTCN2023071429-appb-000294
Figure PCTCN2023071429-appb-000294
将10克4-氯-3-甲氧基-5-硝基苯甲酸甲酯和100毫升氨水的混合物在封管中于50℃加热搅拌5小时。将反应液倒入水中搅拌一个小时后过滤，干燥得到淡黄色固体(62-1)7.74g，收率82.5％。LCMS(ESI)m/z[M+H] +:231.3. 1H NMR(400MHz,DMSO-d 6)δ8.34–8.25(m,1H),8.06(d,J＝1.8Hz,1H),7.88(d,J＝1.8Hz,1H),4.03(s,3H). A mixture of 10 g of methyl 4-chloro-3-methoxy-5-nitrobenzoate and 100 ml of ammonia water was heated and stirred at 50° C. for 5 hours in a sealed tube. The reaction solution was poured into water and stirred for one hour, then filtered and dried to obtain 7.74 g of light yellow solid (62-1), with a yield of 82.5%. LCMS (ESI) m/z [M+H] + :231.3. 1 H NMR (400MHz, DMSO-d 6 ) δ8.34–8.25 (m, 1H), 8.06 (d, J=1.8Hz, 1H), 7.88(d,J=1.8Hz,1H),4.03(s,3H).
步骤②：4-((4-羟基苄基)氨基)-3-甲氧基-5-硝基苯甲酰胺(62-2)Step ②: 4-((4-hydroxybenzyl)amino)-3-methoxy-5-nitrobenzamide (62-2)
Figure PCTCN2023071429-appb-000295
Figure PCTCN2023071429-appb-000295
氩气氛下将5克62-1、4克4-(氨基甲基)苯酚、18毫升N,N-二异丙基乙胺和30毫升N,N-二甲基甲酰胺的混合物于80℃加热搅拌过夜。反应液倒入水中搅拌一个小时后过滤，干燥得到红色固体(62-2)4.47克，收率65.7％。LCMS(ESI)m/z[M+H] +:318.4. 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝1.9Hz,1H),7.52(d,J＝2.0Hz,1H),7.08–7.01(m,2H),6.69–6.64(m,2H),4.58(d,J＝6.1Hz,2H),3.87(s,3H). Under an argon atmosphere, a mixture of 5 g of 62-1, 4 g of 4-(aminomethyl)phenol, 18 ml of N,N-diisopropylethylamine and 30 ml of N,N-dimethylformamide was placed at 80°C Heat and stir overnight. The reaction solution was poured into water and stirred for one hour, then filtered and dried to obtain 4.47 g of a red solid (62-2), with a yield of 65.7%. LCMS (ESI) m/z [M+H] + : 318.4. 1 H NMR (400MHz, DMSO-d 6 ) δ8.14 (d, J = 1.9Hz, 1H), 7.52 (d, J = 2.0Hz, 1H),7.08–7.01(m,2H),6.69–6.64(m,2H),4.58(d,J＝6.1Hz,2H),3.87(s,3H).
步骤③：4-((4-((叔丁基二苯基硅基)氧基)苄基)氨基)-3-甲氧基-5-硝基 苯甲酰胺(62-3)Step ③: 4-((4-((tert-butyldiphenylsilyl)oxy)benzyl)amino)-3-methoxy-5-nitrobenzamide (62-3)
Figure PCTCN2023071429-appb-000296
Figure PCTCN2023071429-appb-000296
将3.5克62-2、4.6克叔丁基二苯基氯硅烷、1.5克咪唑和40毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液倒入水中搅拌一个小时后过滤，滤饼干燥后用石油醚打浆一个小时，过滤得到红色固体(62-3)5.4克，收率90.75％。LCMS(ESI)m/z[M+H] +:578.2. A mixture of 3.5 g of 62-2, 4.6 g of tert-butyldiphenylchlorosilane, 1.5 g of imidazole and 40 ml of N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was poured into water and stirred for one hour and then filtered. After the filter cake was dried, it was beaten with petroleum ether for one hour. After filtration, 5.4 g of red solid (62-3) was obtained, with a yield of 90.75%. LCMS(ESI)m/z[M+H] + :578.2.
步骤④：3-氨基-4-((4-((叔丁基二苯基硅基)氧基)苄基)氨基)-5-甲氧基苯甲酰胺(62-4)Step ④: 3-amino-4-((4-((tert-butyldiphenylsilyl)oxy)benzyl)amino)-5-methoxybenzamide (62-4)
Figure PCTCN2023071429-appb-000297
Figure PCTCN2023071429-appb-000297
将6.8克62-3溶于60毫升甲醇中，加入13克连二亚硫酸钠，10毫升氨水，于50℃加热搅拌4小时。反应液抽滤，滤液浓缩至干，残余物以二氯甲烷：甲醇＝99:1柱层析，得黄色油状物(62-4)4.12克，收率62.5％。LCMS(ESI)m/z[M+H] +:526.3. Dissolve 6.8 g of 62-3 in 60 ml of methanol, add 13 g of sodium dithionite and 10 ml of ammonia water, and heat and stir at 50°C for 4 hours. The reaction solution was suction-filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=99:1 to obtain 4.12 g of a yellow oil (62-4), with a yield of 62.5%. LCMS(ESI)m/z[M+H] + :526.3.
步骤⑤：2-氨基-1-(4-((叔丁基二苯基硅基)氧基)苄基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(62-5)Step ⑤: 2-amino-1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide ( 62-5)
Figure PCTCN2023071429-appb-000298
Figure PCTCN2023071429-appb-000298
氩气氛下将3.6克62-4溶于40毫升无水甲醇中，超声溶解后加入4克的溴化氰，室温搅拌2小时，析出白色固体。向反应液中加入乙酸乙酯，继续搅拌1小时，将反应液过滤，滤饼干燥得白色固体(62-5)3克，收率79.6％。LCMS(ESI)m/z[M+H] +:551.3. 1H NMR(400MHz,DMSO-d 6)δ8.67(s,2H),7.63(d,J＝1.5Hz,2H),7.50–7.37(m,10H),7.03(d,J＝8.5Hz,2H),6.71(d,J＝8.6Hz,2H),5.35(s,2H),3.78(s,3H),1.02(s,9H). Under an argon atmosphere, 3.6 g of 62-4 was dissolved in 40 ml of anhydrous methanol. After ultrasonic dissolution, 4 g of cyanogen bromide was added, stirred at room temperature for 2 hours, and a white solid was precipitated. Ethyl acetate was added to the reaction solution, and the stirring was continued for 1 hour. The reaction solution was filtered, and the filter cake was dried to obtain 3 g of white solid (62-5), with a yield of 79.6%. LCMS (ESI) m/z [M+H] + :551.3. 1 H NMR (400MHz, DMSO-d 6 ) δ8.67 (s, 2H), 7.63 (d, J = 1.5Hz, 2H), 7.50– 7.37(m,10H),7.03(d,J=8.5Hz,2H),6.71(d,J=8.6Hz,2H),5.35(s,2H),3.78(s,3H),1.02(s,9H ).
步骤⑥：2-苯甲酰胺-1-(4-((叔丁基二苯基硅基)氧基)苄基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(62-6)Step ⑥: 2-benzamide-1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-7-methoxy-1H-benzo[d]imidazole-5-methanol Amide (62-6)
Figure PCTCN2023071429-appb-000299
Figure PCTCN2023071429-appb-000299
氩气氛下将200毫克62-5、135毫克苯甲酸、418毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、480微升N,N-二异丙基乙胺和4毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应完成后将反应液倒入水中，析出白色固体，搅拌30分钟，过滤干燥得白色固体(62-6)220mg，收率92.8％。LCMS(ESI)m/z[M+H] +:655.3. Under argon atmosphere, 200 mg of 62-5, 135 mg of benzoic acid, 418 mg of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphoric acid A mixture of urea (HATU), 480 μl N,N-diisopropylethylamine and 4 ml anhydrous N,N-dimethylformamide was stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into water, and a white solid was precipitated, stirred for 30 minutes, filtered and dried to obtain 220 mg of a white solid (62-6), with a yield of 92.8%. LCMS(ESI)m/z[M+H] + :655.3.
步骤⑦：2-苯甲酰胺-1-(4-羟基苄基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(62-7)Step ⑦: 2-benzamide-1-(4-hydroxybenzyl)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide (62-7)
Figure PCTCN2023071429-appb-000300
Figure PCTCN2023071429-appb-000300
氩气氛下将220毫克62-6溶于4毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将400微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得灰白色固体(62-7)130毫克，收率93.5％。LCMS(ESI)m/z[M+H] +:417.1. Under an argon atmosphere, dissolve 220 mg of 62-6 in 4 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 400 μl of tetrabutylammonium fluoride three times, slowly drop into the reaction solution, and stir at room temperature 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 130 mg of off-white solid (62-7) was obtained, with a yield of 93.5%. LCMS(ESI)m/z[M+H] + :417.1.
步骤⑧：4-((2-苯甲酰胺-5-氨甲酰-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基二乙基磷酸酯(62-8)Step ⑧: 4-((2-benzamide-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyldiethylphosphate (62 -8)
Figure PCTCN2023071429-appb-000301
Figure PCTCN2023071429-appb-000301
氩气氛下将130毫克62-7溶于3毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入110微升氰基磷酸二乙酯，随后缓慢加入135微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝97:3柱层析，得淡黄色固体(62-8)110毫克，收率63.9％。LCMS(ESI)m/z[M+H] +:553.6. 1H NMR(400MHz,DMSO-d 6)δ12.99(s,1H),8.27–8.22(m,2H),7.99(s,1H),7.68(d,J＝1.3Hz,1H),7.53–7.41(m,5H),7.37(d,J＝1.4Hz,2H),7.18–7.12(m,2H),5.62(s,2H),4.11(dt,J＝8.4,7.0Hz,4H),3.93(s,3H),1.21(td,J＝7.1,1.0Hz,6H). Under an argon atmosphere, 130 mg of 62-7 was dissolved in 3 ml of ultra-dry dimethyl sulfoxide, and after stirring for 10 minutes in an ice bath, 110 μl of diethyl cyanophosphate was added, followed by 135 μl of tris Ethylamine, stirred in an ice bath for 30 minutes, then stirred overnight at room temperature. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was subjected to column chromatography with dichloromethane:methanol=97:3 to obtain 110 mg of light yellow solid (62-8) with a yield of 63.9%. LCMS(ESI)m/z[M+H] + :553.6. 1 H NMR(400MHz,DMSO-d 6 )δ12.99(s,1H),8.27–8.22(m,2H),7.99(s,1H ),7.68(d,J=1.3Hz,1H),7.53–7.41(m,5H),7.37(d,J=1.4Hz,2H),7.18–7.12(m,2H),5.62(s,2H) ,4.11(dt,J=8.4,7.0Hz,4H),3.93(s,3H),1.21(td,J=7.1,1.0Hz,6H).
步骤⑨：4-((2-苯甲酰胺-5-氨甲酰-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-62)Step ⑨: 4-((2-benzamide-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)methyl)phenyl phosphate dihydrogen (I-62 )
Figure PCTCN2023071429-appb-000302
Figure PCTCN2023071429-appb-000302
氩气氛下，将40毫克62-8溶于2毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入200微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入 冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-62)17毫克，收率47.2％。LCMS(ESI)m/z[M-H] ﹣:495.1. 1H NMR(400MHz,DMSO-d 6)δ12.98(s,1H),8.27(d,J＝7.3Hz,2H),8.00(s,1H),7.70(s,1H),7.50(q,J＝8.7,7.4Hz,3H),7.44–7.34(m,4H),7.11(d,J＝8.2Hz,2H),5.61(s,2H),3.97(s,3H). Under an argon atmosphere, 40 mg of 62-8 was dissolved in 2 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, then 200 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 17 mg of white solid (I-62), with a yield of 47.2%. LCMS (ESI) m/z [MH] - : 495.1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.98 (s, 1H), 8.27 (d, J = 7.3Hz, 2H), 8.00 (s, 1H),7.70(s,1H),7.50(q,J=8.7,7.4Hz,3H),7.44–7.34(m,4H),7.11(d,J=8.2Hz,2H),5.61(s,2H ),3.97(s,3H).
实施例63 4-((5-氨甲酰-7-甲氧基-2-(5-甲基吡嗪-2-甲酰胺基)-1H苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-63)Example 63 4-((5-carbamoyl-7-methoxy-2-(5-methylpyrazine-2-carboxamido)-1H benzo[d]imidazol-1-yl)methyl ) Phenyl dihydrogen phosphate (I-63)
Figure PCTCN2023071429-appb-000303
Figure PCTCN2023071429-appb-000303
步骤①：1-(4-((叔丁基二苯基硅基)氧基)苄基)-7-甲氧基-2-(5-甲基吡嗪-2-甲酰胺基)-1H-苯并[d]咪唑-5-甲酰胺(63-1)Step ①: 1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-7-methoxy-2-(5-methylpyrazine-2-carboxamido)-1H -Benzo[d]imidazole-5-carboxamide (63-1)
Figure PCTCN2023071429-appb-000304
Figure PCTCN2023071429-appb-000304
氩气氛下，将300毫克62-5、152毫克5-甲基吡嗪-2-羧酸、418毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、480微升N,N-二异丙基乙胺和5毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应完成后将反应液倒入水中，析出白色固体，搅拌30分钟，过滤干燥得白色固体(63-1)340mg，收率92.4％。LCMS(ESI)m/z[M+H] +:671.3. Under argon atmosphere, 300 mg of 62-5, 152 mg of 5-methylpyrazine-2-carboxylic acid, 418 mg of N,N,N',N'-tetramethyl-O-(7-azabenzo A mixture of triazol-1-yl)urea hexafluorophosphate (HATU), 480 μl N,N-diisopropylethylamine and 5 ml anhydrous N,N-dimethylformamide was stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into water, and a white solid was precipitated, stirred for 30 minutes, filtered and dried to obtain 340 mg of a white solid (63-1), with a yield of 92.4%. LCMS(ESI)m/z[M+H] + :671.3.
步骤②：1-(4-羟基苄基)-7-甲氧基-2-(5-甲基吡嗪-2-甲酰胺基)-1H-苯并[d]咪唑-5-甲酰胺(63-2)Step ②: 1-(4-hydroxybenzyl)-7-methoxy-2-(5-methylpyrazine-2-carboxamido)-1H-benzo[d]imidazole-5-carboxamide ( 63-2)
Figure PCTCN2023071429-appb-000305
Figure PCTCN2023071429-appb-000305
氩气氛下，将340毫克63-1溶于4毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将600微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得白色固体(63-2)219毫克，收率100％。LCMS(ESI)m/z[M+H] +:433.1. Under an argon atmosphere, dissolve 340 mg of 63-1 in 4 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 600 μl of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, room temperature Stir for 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 219 mg of white solid (63-2) was obtained, with a yield of 100%. LCMS(ESI)m/z[M+H] + :433.1.
步骤③：4-((5-氨甲酰-7-甲氧基-2-(5-甲基吡嗪-2-甲酰胺基)-1H苯并[d]咪唑-1-基)甲基)苯基二乙基磷酸酯(63-3)Step ③: 4-((5-carbamoyl-7-methoxy-2-(5-methylpyrazine-2-carboxamido)-1H benzo[d]imidazol-1-yl)methyl ) phenyl diethyl phosphate (63-3)
Figure PCTCN2023071429-appb-000306
Figure PCTCN2023071429-appb-000306
氩气氛下，将215毫克63-2溶于4毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入116微升氰基磷酸二乙酯，随后缓慢加入142微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝97:3柱层析，得淡黄色固体(63-3)110毫克，收率39.1％。LCMS(ESI)m/z[M+H] +:569.4. 1H NMR(400MHz,DMSO-d 6)δ13.06(s,1H),9.34(s,1H),8.65(s,1H),8.00(s,1H),7.71(s,1H),7.45(d,J＝8.3Hz,2H),7.38(d,J＝9.7Hz,2H),7.15(d,J＝8.3Hz,2H),5.62(s,2H),4.10(p,J＝7.3Hz,4H),3.94(s,3H),2.57(s,3H),1.21(td,J＝7.0,1.0Hz,6H). Under an argon atmosphere, dissolve 215 mg of 63-2 in 4 ml of ultra-dry dimethyl sulfoxide, stir in an ice bath for 10 minutes, add 116 μl of diethyl cyanophosphate, and then slowly add 142 μl Triethylamine, stirred in an ice bath for 30 minutes, then placed at room temperature and stirred overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was subjected to column chromatography with dichloromethane:methanol=97:3 to obtain 110 mg of light yellow solid (63-3) with a yield of 39.1%. LCMS (ESI) m/z [M+H] + :569.4. 1 H NMR (400MHz, DMSO-d 6 ) δ13.06 (s, 1H), 9.34 (s, 1H), 8.65 (s, 1H), 8.00(s,1H),7.71(s,1H),7.45(d,J=8.3Hz,2H),7.38(d,J=9.7Hz,2H),7.15(d,J=8.3Hz,2H), 5.62(s,2H),4.10(p,J=7.3Hz,4H),3.94(s,3H),2.57(s,3H),1.21(td,J=7.0,1.0Hz,6H).
步骤④：4-((5-氨甲酰-7-甲氧基-2-(5-甲基吡嗪-2-甲酰胺基)-1H苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-63)Step ④: 4-((5-carbamoyl-7-methoxy-2-(5-methylpyrazine-2-carboxamido)-1H benzo[d]imidazol-1-yl)methyl ) Phenyl dihydrogen phosphate (I-63)
Figure PCTCN2023071429-appb-000307
Figure PCTCN2023071429-appb-000307
氩气氛下，将45毫克63-3溶于3毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入200微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-63)30毫克，收率75.1％。LCMS(ESI)m/z[M+H] +:513.2. 1H NMR(400MHz,DMSO-d 6)δ13.05(s,1H),9.33(s,1H),8.72–8.64(m,1H),8.00(s,1H),7.73(s,1H),7.38(s,2H),7.35(s,2H),7.07(d,J＝8.0Hz,2H),5.58(s,2H),3.95(s,3H),2.58(s,3H). Under an argon atmosphere, 45 mg of 63-3 was dissolved in 3 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, then 200 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 30 mg of white solid (I-63), with a yield of 75.1%. LCMS (ESI) m/z [M+H] + :513.2. 1 H NMR (400MHz, DMSO-d 6 ) δ13.05 (s, 1H), 9.33 (s, 1H), 8.72–8.64 (m, 1H ),8.00(s,1H),7.73(s,1H),7.38(s,2H),7.35(s,2H),7.07(d,J＝8.0Hz,2H),5.58(s,2H),3.95 (s,3H),2.58(s,3H).
实施例64 4-((5-氨甲酰-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-64)Example 64 4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d ]imidazol-1-yl)methyl)phenyl phosphate dihydrogen (I-64)
Figure PCTCN2023071429-appb-000308
Figure PCTCN2023071429-appb-000308
步骤①：1-(4-((叔丁基二苯基硅基)氧基)苄基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-酰胺(64-1)Step ①: 1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)- 7-Methoxy-1H-benzo[d]imidazole-5-amide (64-1)
Figure PCTCN2023071429-appb-000309
Figure PCTCN2023071429-appb-000309
氩气氛下，将300毫克62-5、170毫克1-乙基-3-甲基-1H-吡唑-5-羧酸、418毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、480微升N,N-二异丙 基乙胺和5毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应完成后将反应液倒入水中，析出固体，搅拌30分钟，过滤干燥得灰白色固体(64-1)320mg，收率85.5％。LCMS(ESI)m/z[M+H] +:687.3. Under argon atmosphere, 300 mg of 62-5, 170 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 418 mg of N,N,N',N'-tetramethyl-O -(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (HATU), 480 μl N,N-diisopropylethylamine and 5 ml anhydrous N,N-dimethylformamide The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into water, and a solid was precipitated, stirred for 30 minutes, filtered and dried to obtain 320 mg of an off-white solid (64-1), with a yield of 85.5%. LCMS(ESI)m/z[M+H] + :687.3.
步骤②：2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-1-(4-羟基苄基)-7-甲氧基-1H-苯并[d]咪唑-5-酰胺(64-2)Step ②: 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-(4-hydroxybenzyl)-7-methoxy-1H-benzo[d] Imidazol-5-amide (64-2)
Figure PCTCN2023071429-appb-000310
Figure PCTCN2023071429-appb-000310
氩气氛下，将320毫克64-1溶于4毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将400微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得灰色固体(64-2)208毫克，收率100％。LCMS(ESI)m/z[M+H] +:449.2. Under an argon atmosphere, dissolve 320 mg of 64-1 in 4 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 400 μl of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, room temperature Stir for 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 208 mg of gray solid (64-2) was obtained, with a yield of 100%. LCMS(ESI)m/z[M+H] + :449.2.
步骤③：4-((5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基二乙基磷酸酯(64-3)Step ③: 4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d] Imidazol-1-yl)methyl)phenyl diethylphosphate (64-3)
Figure PCTCN2023071429-appb-000311
Figure PCTCN2023071429-appb-000311
氩气氛下将208毫克64-2溶于4毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入147微升氰基磷酸二乙酯，随后缓慢加入180微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝96:4柱层析，得淡黄色固体(64-3)210毫克，收率77.5％。LCMS(ESI)m/z[M+H] +:585.0.1H NMR(400MHz,DMSO-d 6)δ12.93(s,1H),7.98(s,1H),7.67(d,J＝1.3Hz,1H),7.40–7.34(m,4H),7.15(dd,J＝8.7,1.2Hz,2H),6.65(s,1H),5.54(s,2H),4.57(q,J＝7.1Hz,2H),4.15–4.06(m,4H),3.91(s,3H),2.16(s,3H),1.30(t,J＝7.1Hz,3H),1.22(td,J＝7.1,1.0Hz,6H). Under an argon atmosphere, 208 mg of 64-2 was dissolved in 4 ml of ultra-dry dimethyl sulfoxide, and after stirring for 10 minutes in an ice bath, 147 μl of diethyl cyanophosphate was added, followed by the slow addition of 180 μl of tris Ethylamine, stirred in an ice bath for 30 minutes, then stirred overnight at room temperature. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was subjected to column chromatography with dichloromethane:methanol=96:4 to obtain 210 mg of light yellow solid (64-3) with a yield of 77.5%. LCMS(ESI) m/z[M+H] + :585.0.1H NMR(400MHz,DMSO-d 6 )δ12.93(s,1H),7.98(s,1H),7.67(d,J＝1.3Hz ,1H),7.40–7.34(m,4H),7.15(dd,J＝8.7,1.2Hz,2H),6.65(s,1H),5.54(s,2H),4.57(q,J＝7.1Hz, 2H), 4.15–4.06(m, 4H), 3.91(s, 3H), 2.16(s, 3H), 1.30(t, J＝7.1Hz, 3H), 1.22(td, J＝7.1, 1.0Hz, 6H ).
步骤④：4-((5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-64)Step ④: 4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzo[d] Imidazol-1-yl)methyl)phenyl phosphate dihydrogen (I-64)
Figure PCTCN2023071429-appb-000312
Figure PCTCN2023071429-appb-000312
氩气氛下，将60毫克64-3溶于3毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入250微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入 冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-64)32毫克，收率59.3％。 1H NMR(400MHz,DMSO-d 6)δ12.92(s,1H),7.98(s,1H),7.67(s,1H),7.39–7.35(m,2H),7.33(d,J＝8.2Hz,2H),7.10(d,J＝8.1Hz,2H),6.67(s,1H),5.52(s,2H),4.57(q,J＝7.1Hz,2H),3.93(s,3H),2.17(s,3H),1.31(t,J＝7.1Hz,3H). Under an argon atmosphere, 60 mg of 64-3 was dissolved in 3 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, and then 250 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 32 mg of white solid (I-64), with a yield of 59.3%. 1 H NMR (400MHz,DMSO-d 6 )δ12.92(s,1H),7.98(s,1H),7.67(s,1H),7.39–7.35(m,2H),7.33(d,J=8.2 Hz,2H),7.10(d,J=8.1Hz,2H),6.67(s,1H),5.52(s,2H),4.57(q,J=7.1Hz,2H),3.93(s,3H), 2.17(s,3H),1.31(t,J=7.1Hz,3H).
实施例65 4-((5-氨基甲酰基-7-甲氧基-2-(1-甲基-1H-咪唑-5-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-65)Example 65 4-((5-carbamoyl-7-methoxy-2-(1-methyl-1H-imidazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl ) methyl) phenyl dihydrogen phosphate (I-65)
Figure PCTCN2023071429-appb-000313
Figure PCTCN2023071429-appb-000313
步骤①：1-(4-((叔丁基二苯基硅基)氧基)苄基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺)-7-甲氧基-1H-苯并[d]咪唑-5-酰胺(65-1)Step ①: 1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)- 7-Methoxy-1H-benzo[d]imidazole-5-amide (65-1)
Figure PCTCN2023071429-appb-000314
Figure PCTCN2023071429-appb-000314
氩气氛下，将300毫克62-5、139毫克1-甲基-1H-咪唑-5-羧酸、418毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、480微升N,N-二异丙基乙胺和5毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应完成后将反应液倒入水中，析出固体，搅拌30分钟，过滤干燥得灰白色固体(65-1)303mg，收率84.4％。LCMS(ESI)m/z[M+H] +:650.3. Under argon atmosphere, 300 mg of 62-5, 139 mg of 1-methyl-1H-imidazole-5-carboxylic acid, 418 mg of N,N,N',N'-tetramethyl-O-(7-aza A mixture of benzotriazol-1-yl)urea hexafluorophosphate (HATU), 480 μl N,N-diisopropylethylamine and 5 ml anhydrous N,N-dimethylformamide was stirred overnight at room temperature. After the reaction was completed, the reaction solution was poured into water, and a solid was precipitated, stirred for 30 minutes, filtered and dried to obtain 303 mg of an off-white solid (65-1), with a yield of 84.4%. LCMS(ESI)m/z[M+H] + :650.3.
步骤②：1-(4-羟基苄基)-7-甲氧基-2-(1-甲基-1H-咪唑-5-甲酰胺)-1H-苯并[d]咪唑-5甲酰胺(65-2)Step ②: 1-(4-hydroxybenzyl)-7-methoxy-2-(1-methyl-1H-imidazole-5-carboxamide)-1H-benzo[d]imidazole-5 carboxamide ( 65-2)
Figure PCTCN2023071429-appb-000315
Figure PCTCN2023071429-appb-000315
氩气氛下，将300毫克65-1溶于4毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将400微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得灰色固体(65-2)130毫克，收率68.1％。LCMS(ESI)m/z[M+H] +:421.2. Under an argon atmosphere, dissolve 300 mg of 65-1 in 4 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 400 μl of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, room temperature Stir for 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 130 mg of gray solid (65-2) was obtained, with a yield of 68.1%. LCMS(ESI)m/z[M+H] + :421.2.
步骤③：4-((5-氨基甲酰基-7-甲氧基-2-(1-甲基-1H-咪唑-5-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)苯基二乙基磷酸酯(65-3)Step ③: 4-((5-carbamoyl-7-methoxy-2-(1-methyl-1H-imidazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl ) methyl) phenyl diethyl phosphate (65-3)
Figure PCTCN2023071429-appb-000316
Figure PCTCN2023071429-appb-000316
氩气氛下，将130毫克65-2溶于2毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入80微升氰基磷酸二乙酯，随后缓慢加入100微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝96:4柱层析，得淡黄色固体(65-3)39毫克，收率22.7％。LCMS(ESI)m/z[M+H] +:557.1. 1H NMR(400MHz,CD 3OD)δ7.78(s,1H),7.68(s,2H),7.37(s,3H),7.11(d,J＝8.1Hz,2H),5.67(s,2H),4.17(p,J＝7.4Hz,4H),3.95(s,3H),3.78(s,3H),1.31–1.27(m,6H). Under an argon atmosphere, dissolve 130 mg of 65-2 in 2 ml of ultra-dry dimethyl sulfoxide, stir in an ice bath for 10 minutes, add 80 μl of diethyl cyanophosphate, and then slowly add 100 μl of Triethylamine, stirred in an ice bath for 30 minutes, then placed at room temperature and stirred overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was subjected to column chromatography with dichloromethane:methanol=96:4 to obtain 39 mg of light yellow solid (65-3) with a yield of 22.7%. LCMS (ESI) m/z [M+H] + :557.1. 1 H NMR (400MHz, CD 3 OD) δ7.78 (s, 1H), 7.68 (s, 2H), 7.37 (s, 3H), 7.11 (d,J=8.1Hz,2H),5.67(s,2H),4.17(p,J=7.4Hz,4H),3.95(s,3H),3.78(s,3H),1.31–1.27(m, 6H).
步骤④：4-((5-氨基甲酰基-7-甲氧基-2-(1-甲基-1H-咪唑-5-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(I-65)Step ④: 4-((5-carbamoyl-7-methoxy-2-(1-methyl-1H-imidazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl ) methyl) phenyl dihydrogen phosphate (I-65)
Figure PCTCN2023071429-appb-000317
Figure PCTCN2023071429-appb-000317
氩气氛下，将38毫克65-3溶于2毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入300微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-65)24毫克，收率70.59％。LCMS(ESI)m/z[M+H] +:501.2. 1H NMR(400MHz,DMSO-d 6)δ7.98(s,1H),7.94(s,1H),7.73(s,1H),7.32(d,J＝9.3Hz,3H),7.04(d,J＝8.1Hz,2H),5.48(s,2H),3.91(s,3H),3.75(s,3H). Under an argon atmosphere, 38 mg of 65-3 was dissolved in 2 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, then 300 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 24 mg of white solid (I-65), with a yield of 70.59%. LCMS (ESI) m/z [M+H] + :501.2. 1 H NMR (400MHz, DMSO-d 6 ) δ7.98 (s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.32(d, J=9.3Hz, 3H), 7.04(d, J=8.1Hz, 2H), 5.48(s, 2H), 3.91(s, 3H), 3.75(s, 3H).
实施例66 4-(2-(2-(1-(1H-吡唑-1-基)乙酰氨基)-5-氨基甲酰基-7-甲氧基-1H-苯并[d]咪唑-1-)乙基)苯基磷酸二氢(I-66)Example 66 4-(2-(2-(1-(1H-pyrazol-1-yl)acetylamino)-5-carbamoyl-7-methoxy-1H-benzo[d]imidazole-1 -) Ethyl) phenyl dihydrogen phosphate (I-66)
Figure PCTCN2023071429-appb-000318
Figure PCTCN2023071429-appb-000318
步骤①：2-(2-(1H-吡唑-1-基)乙酰氨基)-1-(4-((叔丁基二苯基甲硅基)氧基)苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(66-1)Step ①: 2-(2-(1H-pyrazol-1-yl)acetylamino)-1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-7-methyl Oxy-1H-benzo[d]imidazole-5-carboxamide (66-1)
Figure PCTCN2023071429-appb-000319
Figure PCTCN2023071429-appb-000319
氩气氛下，将500毫克16-5溶于8毫升无水N,N-二甲基甲酰胺中，加入136毫克2-(1H-吡唑-1-基)乙酸、680毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)和800微升N,N-二异丙基乙胺，室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝97:3柱层析，得白色固体(66-1)166毫克，收率27.9％。LCMS(ESI)m/z[M+H] +:673.3. Under an argon atmosphere, 500 mg of 16-5 was dissolved in 8 ml of anhydrous N,N-dimethylformamide, 136 mg of 2-(1H-pyrazol-1-yl)acetic acid, 680 mg of N,N, N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (HATU) and 800 μl N,N-diisopropylethylamine, stirred at room temperature overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was subjected to column chromatography with dichloromethane:methanol=97:3 to obtain 166 mg of white solid (66-1) with a yield of 27.9%. LCMS(ESI)m/z[M+H] + :673.3.
步骤②：2-(2-(1H-吡唑-1-基)乙酰氨基)-1-(4-羟基苯乙基)-7-甲氧基-1H-苯并[d]咪唑-5-甲酰胺(66-2)Step ②: 2-(2-(1H-pyrazol-1-yl)acetamido)-1-(4-hydroxyphenethyl)-7-methoxy-1H-benzo[d]imidazole-5- Formamide (66-2)
Figure PCTCN2023071429-appb-000320
Figure PCTCN2023071429-appb-000320
氩气氛下，将160毫克66-1溶于4毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将400微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得灰白色固体(66-2)103毫克，收率100％。LCMS(ESI)m/z[M+H] +:435.1. Under an argon atmosphere, dissolve 160 mg of 66-1 in 4 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 400 μl of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, room temperature Stir for 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 103 mg of off-white solid (66-2) was obtained, with a yield of 100%. LCMS(ESI)m/z[M+H] + :435.1.
步骤③：4-(2-(2-(1-(1H-吡唑-1-基)乙酰氨基)-5-氨基甲酰基-7-甲氧基-1H-苯并[d]咪唑-1-乙基)乙基)苯基二乙基磷酸酯(66-3)Step ③: 4-(2-(2-(1-(1H-pyrazol-1-yl)acetylamino)-5-carbamoyl-7-methoxy-1H-benzo[d]imidazole-1 -Ethyl) ethyl) phenyl diethyl phosphate (66-3)
Figure PCTCN2023071429-appb-000321
Figure PCTCN2023071429-appb-000321
氩气氛下，将40毫克66-2溶于2毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入21微升氰基磷酸二乙酯，随后缓慢加入32微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝96:4柱层析，得淡黄色固体(66-3)15毫克，收率29％。LCMS(ESI)m/z[M+H] +:571.2. 1H NMR(400MHz,DMSO-d 6)δ12.67(s,1H),7.99(s,1H),7.78(s,1H),7.59(s,1H),7.44(s,1H),7.34(s,2H),7.14(q,J＝8.3Hz,4H),6.28(s,1H),4.93(s,2H),4.35(t,J＝7.5Hz,2H),4.12(p,J＝7.2Hz,4H),3.96 (s,3H),2.89(d,J＝9.5Hz,2H),1.25(t,J＝7.1Hz,6H). Under an argon atmosphere, dissolve 40 mg of 66-2 in 2 ml of ultra-dry dimethyl sulfoxide, stir in an ice bath for 10 minutes, add 21 μl of diethyl cyanophosphate, and then slowly add 32 μl Triethylamine, stirred in an ice bath for 30 minutes, then placed at room temperature and stirred overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was subjected to column chromatography with dichloromethane:methanol=96:4 to obtain 15 mg of light yellow solid (66-3) with a yield of 29%. LCMS (ESI) m/z [M+H] + :571.2. 1 H NMR (400MHz, DMSO-d 6 ) δ12.67 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.59(s,1H),7.44(s,1H),7.34(s,2H),7.14(q,J=8.3Hz,4H),6.28(s,1H),4.93(s,2H),4.35(t ,J=7.5Hz,2H),4.12(p,J=7.2Hz,4H),3.96(s,3H),2.89(d,J=9.5Hz,2H),1.25(t,J=7.1Hz,6H ).
步骤④：4-(2-(2-(1-(1H-吡唑-1-基)乙酰氨基)-5-氨基甲酰基-7-甲氧基-1H-苯并[d]咪唑-1-)乙基)苯基磷酸二氢(I-66)Step ④: 4-(2-(2-(1-(1H-pyrazol-1-yl)acetylamino)-5-carbamoyl-7-methoxy-1H-benzo[d]imidazole-1 -) Ethyl) phenyl dihydrogen phosphate (I-66)
Figure PCTCN2023071429-appb-000322
Figure PCTCN2023071429-appb-000322
氩气氛下，将26毫克66-3溶于2毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入300微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-66)8毫克，收率34.8％。LCMS(ESI)m/z[M+H] +:515.1. 1H NMR(400MHz,DMSO-d 6)δ12.52(s,1H),7.99(s,1H),7.75(s,1H),7.62(s,1H),7.37(s,1H),7.32(s,2H),7.14(q,J＝8.3Hz,4H),6.31(s,1H),4.78(s,2H),4.43(t,J＝7.5Hz,2H),3.94(s,3H),2.82(d,J＝9.5Hz,2H). Under an argon atmosphere, 26 mg of 66-3 was dissolved in 2 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, then 300 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 8 mg of white solid (I-66), with a yield of 34.8%. LCMS (ESI) m/z[M+H] + :515.1. 1 H NMR (400MHz,DMSO-d 6 )δ12.52(s,1H),7.99(s,1H),7.75(s,1H), 7.62(s,1H),7.37(s,1H),7.32(s,2H),7.14(q,J=8.3Hz,4H),6.31(s,1H),4.78(s,2H),4.43(t ,J=7.5Hz,2H),3.94(s,3H),2.82(d,J=9.5Hz,2H).
实施例67 4-(2-(5-氨基甲酰基-2-(1,3-二甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-67)Example 67 4-(2-(5-carbamoyl-2-(1,3-dimethyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d ]imidazol-1-yl)ethyl)phenyl phosphate dihydrogen (Ⅰ-67)
Figure PCTCN2023071429-appb-000323
Figure PCTCN2023071429-appb-000323
操作过程和反应条件同实施例66相同,不同的是步骤①中原料为1,3-二甲基-1H-吡唑-5-羧酸，白色固体，收率47.2％。 1H NMR(400MHz,DMSO-d 6)δ8.02(s,1H),7.66(d,J＝1.3Hz,1H),7.42–7.35(m,2H),7.20(d,J＝8.3Hz,2H),7.13–7.07(m,2H),6.67(s,1H),4.52(t,J＝7.9Hz,2H),4.15(s,3H),4.00(s,3H),3.01(t,J＝7.9Hz,2H),2.19(s,3H). The operation process and reaction conditions are the same as in Example 66, except that the raw material in step ① is 1,3-dimethyl-1H-pyrazole-5-carboxylic acid, a white solid, and the yield is 47.2%. 1 H NMR (400MHz, DMSO-d 6 )δ8.02(s, 1H), 7.66(d, J=1.3Hz, 1H), 7.42–7.35(m, 2H), 7.20(d, J=8.3Hz, 2H),7.13–7.07(m,2H),6.67(s,1H),4.52(t,J＝7.9Hz,2H),4.15(s,3H),4.00(s,3H),3.01(t,J =7.9Hz,2H),2.19(s,3H).
实施例68 4-(2-(2-苯甲酰胺-5-氨基甲酰基-7-甲氧基-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-68)Example 68 4-(2-(2-benzamide-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)ethyl)phenyl phosphate dihydrogen (Ⅰ -68)
Figure PCTCN2023071429-appb-000324
Figure PCTCN2023071429-appb-000324
操作过程和反应条件同实施例66相同,不同的是步骤①中原料为苯甲酸，白色固 体，收率20.3％。1H NMR(400MHz,DMSO-d 6)δ12.88(s,1H),8.25(s,2H),8.00(s,1H),7.68(s,1H),7.51(d,J＝7.7Hz,3H),7.36(d,J＝15.1Hz,2H),7.23(d,J＝8.0Hz,2H),7.10(d,J＝8.1Hz,2H),4.59(s,2H),4.00(s,3H),3.05(dd,J＝9.2,6.4Hz,2H). The operation process and reaction conditions are the same as in Example 66, except that the raw material in step ① is benzoic acid, a white solid, and the yield is 20.3%. 1H NMR (400MHz, DMSO-d 6 )δ12.88(s,1H),8.25(s,2H),8.00(s,1H),7.68(s,1H),7.51(d,J＝7.7Hz,3H ),7.36(d,J=15.1Hz,2H),7.23(d,J=8.0Hz,2H),7.10(d,J=8.1Hz,2H),4.59(s,2H),4.00(s,3H ),3.05(dd,J=9.2,6.4Hz,2H).
实施例69 4-(2-(5-氨基甲酰基-7-甲氧基-2-(6-甲基烟酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-69)Example 69 4-(2-(5-carbamoyl-7-methoxy-2-(6-methylnicotinyl)-1H-benzo[d]imidazol-1-yl)ethyl)benzene dihydrogen phosphate (Ⅰ-69)
Figure PCTCN2023071429-appb-000325
Figure PCTCN2023071429-appb-000325
操作过程和反应条件同实施例66相同,不同的是步骤①中原料为6-甲基烟酸，白色固体，收率50％。 1H NMR(400MHz,DMSO-d 6)δ12.91(s,1H),9.16(d,J＝2.1Hz,1H),8.43(d,J＝8.5Hz,1H),8.03(s,1H),7.68(s,1H),7.45(d,J＝8.1Hz,1H),7.39(d,J＝6.1Hz,2H),7.22(d,J＝8.4Hz,2H),7.09(d,J＝7.8Hz,2H),4.60(t,J＝7.6Hz,2H),4.02(s,3H),3.05(t,J＝7.7Hz,2H),2.58(s,3H). The operation process and reaction conditions are the same as in Example 66, except that the raw material in step ① is 6-methylnicotinic acid, a white solid, and the yield is 50%. 1 H NMR (400MHz,DMSO-d 6 )δ12.91(s,1H),9.16(d,J=2.1Hz,1H),8.43(d,J=8.5Hz,1H),8.03(s,1H) ,7.68(s,1H),7.45(d,J=8.1Hz,1H),7.39(d,J=6.1Hz,2H),7.22(d,J=8.4Hz,2H),7.09(d,J= 7.8Hz, 2H), 4.60(t, J=7.6Hz, 2H), 4.02(s, 3H), 3.05(t, J=7.7Hz, 2H), 2.58(s, 3H).
实施例70 4-((2-(2-(1H-吡唑-1-基)乙酰胺基)-5-氰基-1H-苯并[d]咪唑-1-甲基)甲基)苯基磷酸二氢(Ⅰ-70)Example 70 4-((2-(2-(1H-pyrazol-1-yl)acetamido)-5-cyano-1H-benzo[d]imidazole-1-methyl)methyl)benzene dihydrogen phosphate (Ⅰ-70)
Figure PCTCN2023071429-appb-000326
Figure PCTCN2023071429-appb-000326
步骤①：4-(4-羟基苄基)氨基)-3-硝基苯甲腈(70-1)Step ①: 4-(4-hydroxybenzyl)amino)-3-nitrobenzonitrile (70-1)
Figure PCTCN2023071429-appb-000327
Figure PCTCN2023071429-appb-000327
氩气氛下，将6.2克4-氯-3-硝基苯甲腈、5克4-(氨甲基)苯酚、29毫升N,N-二异丙基乙胺和100毫升N,N-二甲基甲酰胺的混合物于100℃加热搅拌1小时。反应液倒入水中搅拌一个小时后过滤，干燥得到黄色固体(70-1)8.7克，收率95.6％。LCMS(ESI)m/z[M-H] ﹣:268.0. Under argon atmosphere, 6.2 g of 4-chloro-3-nitrobenzonitrile, 5 g of 4-(aminomethyl)phenol, 29 ml of N,N-diisopropylethylamine and 100 ml of N,N-di The mixture of methylformamide was stirred with heating at 100°C for 1 hour. The reaction solution was poured into water and stirred for one hour, then filtered and dried to obtain 8.7 g of yellow solid (70-1), with a yield of 95.6%. LCMS(ESI)m/z[MH] ﹣ :268.0.
步骤②：4-((4-((叔丁基二苯基甲硅烷基)氧基)苄基)氨基)-3-硝基苯甲腈(70-2)Step ②: 4-((4-((tert-butyldiphenylsilyl)oxy)benzyl)amino)-3-nitrobenzonitrile (70-2)
Figure PCTCN2023071429-appb-000328
Figure PCTCN2023071429-appb-000328
将280毫克70-1、429毫克叔丁基二苯基氯硅烷、142毫克咪唑和8毫升超干二氯甲烷的混合物室温搅拌2小时。反应液用水和饱和食盐水洗两遍，有机相用无水硫酸钠干燥，旋干后用甲醇打浆过夜，过滤得到黄色固体(70-2)515毫克，收率97.75％。LCMS(ESI)m/z[M+H] +:508.2. A mixture of 280 mg of 70-1, 429 mg of tert-butyldiphenylchlorosilane, 142 mg of imidazole and 8 ml of ultra-dry dichloromethane was stirred at room temperature for 2 hours. The reaction solution was washed twice with water and saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried and beaten with methanol overnight, and filtered to obtain 515 mg of yellow solid (70-2), with a yield of 97.75%. LCMS(ESI)m/z[M+H] + :508.2.
步骤③：3-氨基-4-((4-((叔丁基二苯基甲硅烷基)氧基)苄基)氨基)苯甲腈(70-3)Step ③: 3-amino-4-((4-((tert-butyldiphenylsilyl)oxy)benzyl)amino)benzonitrile (70-3)
Figure PCTCN2023071429-appb-000329
Figure PCTCN2023071429-appb-000329
将8克70-2溶于110毫升甲醇中，加入14克连二亚硫酸钠，10毫升氨水，于50℃加热搅拌4小时。反应液抽滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝80:20柱层析，得淡黄色固体(70-3)3.33克，收率44.4％。LCMS(ESI)m/z[M+H] +:478.2. Dissolve 8 g of 70-2 in 110 ml of methanol, add 14 g of sodium dithionite and 10 ml of ammonia water, and heat and stir at 50°C for 4 hours. The reaction solution was suction-filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 80:20 to obtain 3.33 g of light yellow solid (70-3) with a yield of 44.4%. LCMS(ESI)m/z[M+H] + :478.2.
步骤④：2-氨基-1-(4-((叔丁基二苯基甲硅烷基)氧基)苄基)-1H-苯并[d]咪唑-5-腈(70-4)Step ④: 2-amino-1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile (70-4)
Figure PCTCN2023071429-appb-000330
Figure PCTCN2023071429-appb-000330
氩气氛下，将3.3克70-3溶于40毫升无水甲醇中，超声后加入8克的溴化氰，室温搅拌2小时。向反应液中加入水，继续搅拌1小时，将反应液过滤，滤饼干燥得白色固体(70-4)3.4克，收率97.6％。LCMS(ESI)m/z[M+H] +:503.3. Under an argon atmosphere, 3.3 g of 70-3 was dissolved in 40 ml of anhydrous methanol, 8 g of cyanogen bromide was added after sonication, and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the stirring was continued for 1 hour. The reaction solution was filtered, and the filter cake was dried to obtain 3.4 g of white solid (70-4), with a yield of 97.6%. LCMS(ESI)m/z[M+H] + :503.3.
步骤⑤：2-氨基-1-(4-((叔丁基二苯基甲硅烷基)氧基)苄基)-1H-苯并[d]咪唑-5-腈(70-5)Step ⑤: 2-amino-1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile (70-5)
Figure PCTCN2023071429-appb-000331
Figure PCTCN2023071429-appb-000331
氩气氛下，将650毫克70-4、228毫克2-(1H-吡唑-1-基)乙酸、1克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、1.14毫升N,N-二异丙基乙胺和10 毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水洗涤，有机相浓缩至干。残余物以二氯甲烷：甲醇＝97:3柱层析，得白色固体(70-5)584毫克，收率73.9％。LCMS(ESI)m/z[M+H] +:611.4. Under argon atmosphere, 650 mg of 70-4, 228 mg of 2-(1H-pyrazol-1-yl)acetic acid, 1 g of N,N,N',N'-tetramethyl-O-(7-aza A mixture of benzotriazol-1-yl)urea hexafluorophosphate (HATU), 1.14 mL of N,N-diisopropylethylamine and 10 mL of anhydrous N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was extracted with water and ethyl acetate, the organic phase was washed with water and saturated brine, and the organic phase was concentrated to dryness. The residue was subjected to column chromatography with dichloromethane:methanol=97:3 to obtain 584 mg of white solid (70-5) with a yield of 73.9%. LCMS(ESI)m/z[M+H] + :611.4.
步骤⑥：N-(5-氰基-1-(4-羟基苄基)-1H-苯并[d]咪唑-2-基)-2-(1H-吡唑-1-基)乙酰胺(70-6)Step ⑥: N-(5-cyano-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2-yl)-2-(1H-pyrazol-1-yl)acetamide ( 70-6)
Figure PCTCN2023071429-appb-000332
Figure PCTCN2023071429-appb-000332
氩气氛下，将560毫克70-5溶于7毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将800微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得灰色固体(70-6)310毫克，收率90.7％。LCMS(ESI)m/z[M+H] +:373.1. Under an argon atmosphere, dissolve 560 mg of 70-5 in 7 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 800 μl of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, room temperature Stir for 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 310 mg of gray solid (70-6) was obtained, with a yield of 90.7%. LCMS(ESI)m/z[M+H] + :373.1.
步骤⑦：N-(5-氰基-1-(4-羟基苄基)-1H-苯并[d]咪唑-2-基)-2-(1H-吡唑-1-基)乙酰胺(70-7)Step ⑦: N-(5-cyano-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2-yl)-2-(1H-pyrazol-1-yl)acetamide ( 70-7)
Figure PCTCN2023071429-appb-000333
Figure PCTCN2023071429-appb-000333
氩气氛下，将100毫克70-6溶于3毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入62微升氰基磷酸二乙酯，随后缓慢加入74微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝97:3制备薄层，得淡黄色固体(70-7)58毫克，收率42.6％。LCMS(ESI)m/z[M+H] +:509.3. 1H NMR(400MHz,DMSO-d 6)δ7.78(s,1H),7.65(s,2H),7.46(s,1H),7.35(s,3H),7.14(d,J＝8.4Hz,2H),6.28(s,1H),5.28(s,2H),5.02(d,J＝17.2Hz,2H),4.13(q,J＝7.4Hz,4H),1.24(t,J＝7.0Hz,6H). Under an argon atmosphere, dissolve 100 mg of 70-6 in 3 ml of ultra-dry dimethyl sulfoxide, stir in an ice bath for 10 minutes, add 62 μl of diethyl cyanophosphate, and then slowly add 74 μl Triethylamine, stirred in an ice bath for 30 minutes, then placed at room temperature and stirred overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was prepared into a thin layer with dichloromethane:methanol=97:3 to obtain 58 mg of light yellow solid (70-7) with a yield of 42.6%. LCMS (ESI) m/z [M+H] + :509.3. 1 H NMR (400MHz, DMSO-d 6 ) δ7.78 (s, 1H), 7.65 (s, 2H), 7.46 (s, 1H), 7.35(s,3H),7.14(d,J=8.4Hz,2H),6.28(s,1H),5.28(s,2H),5.02(d,J=17.2Hz,2H),4.13(q,J ＝7.4Hz, 4H), 1.24(t, J＝7.0Hz, 6H).
步骤⑧：4-((2-(2-(1H-吡唑-1-基)乙酰胺基)-5-氰基-1H-苯并[d]咪唑-1-甲基)甲基)苯基磷酸二氢(Ⅰ-70)Step ⑧: 4-((2-(2-(1H-pyrazol-1-yl)acetamido)-5-cyano-1H-benzo[d]imidazole-1-methyl)methyl)benzene dihydrogen phosphate (Ⅰ-70)
Figure PCTCN2023071429-appb-000334
Figure PCTCN2023071429-appb-000334
氩气氛下，将38毫克70-7溶于3毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加 入200微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-70)20毫克，收率58.8％。LCMS(ESI)m/z[M-H] ﹣:451.1. 1H NMR(400MHz,DMSO-d 6)δ7.79(d,J＝2.3Hz,2H),7.66(s,2H),7.46(d,J＝1.7Hz,1H),7.32(d,J＝8.2Hz,2H),7.09(d,J＝8.2Hz,2H),6.28(t,J＝2.1Hz,1H),5.27(s,2H),5.06(s,2H). Under an argon atmosphere, 38 mg of 70-7 was dissolved in 3 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, and then 200 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 20 mg of white solid (I-70), with a yield of 58.8%. LCMS (ESI) m/z [MH] - : 451.1. 1 H NMR (400MHz, DMSO-d 6 ) δ7.79 (d, J = 2.3Hz, 2H), 7.66 (s, 2H), 7.46 (d, J＝1.7Hz, 1H), 7.32(d, J＝8.2Hz, 2H), 7.09(d, J＝8.2Hz, 2H), 6.28(t, J＝2.1Hz, 1H), 5.27(s, 2H) ,5.06(s,2H).
实施例71 4-((5-氰基-2-(3,5-二甲基异恶唑-4-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(Ⅰ-71)Example 71 4-((5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)methyl)benzene dihydrogen phosphate (Ⅰ-71)
Figure PCTCN2023071429-appb-000335
Figure PCTCN2023071429-appb-000335
步骤①：N-(1-(4-((叔丁基二苯基甲硅烷基)氧基)苄基)-5-氰基-1H-苯并[d]咪唑-2-基)-3,5-二甲基异恶唑-4-甲酰胺(71-1)Step ①: N-(1-(4-((tert-butyldiphenylsilyl)oxy)benzyl)-5-cyano-1H-benzo[d]imidazol-2-yl)-3 ,5-Dimethylisoxazole-4-carboxamide (71-1)
Figure PCTCN2023071429-appb-000336
Figure PCTCN2023071429-appb-000336
氩气氛下，将300毫克70-4、169毫克3,5-二甲基异恶唑-4-羧酸、456毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、522微升N,N-二异丙基乙胺和5毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。将反应液倒入水中搅拌1小时，逐渐析出固体，过滤，滤饼干燥得白色固体(71-1)360毫克，收率96.5％。LCMS(ESI)m/z[M+H] +:626.4. Under an argon atmosphere, 300 mg of 70-4, 169 mg of 3,5-dimethylisoxazole-4-carboxylic acid, 456 mg of N,N,N',N'-tetramethyl-O-(7- A mixture of azabenzotriazol-1-yl)urea hexafluorophosphate (HATU), 522 μl N,N-diisopropylethylamine and 5 ml anhydrous N,N-dimethylformamide was stirred at room temperature overnight. The reaction solution was poured into water and stirred for 1 hour, the solid gradually precipitated out, filtered, and the filter cake was dried to obtain 360 mg of white solid (71-1), with a yield of 96.5%. LCMS(ESI)m/z[M+H] + :626.4.
步骤②：N-(5-氰基-1-(4-羟基苄基)-1H-苯并[d]咪唑-2-基)-3,5-二甲基异恶唑-4-甲酰胺(71-2)Step ②: N-(5-cyano-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2-yl)-3,5-dimethylisoxazole-4-carboxamide (71-2)
Figure PCTCN2023071429-appb-000337
Figure PCTCN2023071429-appb-000337
氩气氛下，将300毫克71-1溶于4毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将800微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。将反应液倒入水中，产物逐渐析出。过滤干燥得灰色固体(71-2)120毫克，收率64.5％。LCMS(ESI)m/z[M+H] +:388.2. Under an argon atmosphere, dissolve 300 mg of 71-1 in 4 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 800 microliters of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, at room temperature Stir for 1 hour. The reaction solution was poured into water, and the product gradually precipitated out. After filtration and drying, 120 mg of gray solid (71-2) was obtained, with a yield of 64.5%. LCMS(ESI)m/z[M+H] + :388.2.
步骤③：4-((5-氰基-2-(3,5-二甲基异恶唑-4-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二乙酯(71-3)Step ③: 4-((5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)methyl)benzene diethyl phosphate (71-3)
Figure PCTCN2023071429-appb-000338
Figure PCTCN2023071429-appb-000338
氩气氛下，将120毫克71-2溶于3毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入150微升氰基磷酸二乙酯，随后缓慢加入200微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝97:3制备薄层，得粉红色固体(71-3)66毫克，收率40.7％。LCMS(ESI)m/z[M+H] +:524.2.1H NMR(400MHz,CD 3OD)δ7.79(s,1H),7.56(dd,J＝8.4,1.5Hz,1H),7.44(d,J＝8.3Hz,1H),7.38(d,J＝8.3Hz,2H),7.19(d,J＝8.2Hz,2H),5.49(s,2H),4.19(p,J＝7.3Hz,4H),2.70(s,3H),2.47(s,3H),1.30(td,J＝7.1,1.1Hz,6H). Under an argon atmosphere, dissolve 120 mg of 71-2 in 3 ml of ultra-dry dimethyl sulfoxide, stir in an ice bath for 10 minutes, add 150 μl of diethyl cyanophosphate, and then slowly add 200 μl Triethylamine, stirred in an ice bath for 30 minutes, then placed at room temperature and stirred overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was prepared into a thin layer with dichloromethane:methanol=97:3 to obtain 66 mg of pink solid (71-3) with a yield of 40.7%. LCMS (ESI) m/z [M+H] + : 524.2.1H NMR (400MHz, CD 3 OD) δ7.79 (s, 1H), 7.56 (dd, J = 8.4, 1.5Hz, 1H), 7.44 ( d,J=8.3Hz,1H),7.38(d,J=8.3Hz,2H),7.19(d,J=8.2Hz,2H),5.49(s,2H),4.19(p,J=7.3Hz, 4H),2.70(s,3H),2.47(s,3H),1.30(td,J=7.1,1.1Hz,6H).
步骤④：4-((5-氰基-2-(3,5-二甲基异恶唑-4-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(Ⅰ-71)Step ④: 4-((5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)methyl)benzene dihydrogen phosphate (Ⅰ-71)
Figure PCTCN2023071429-appb-000339
Figure PCTCN2023071429-appb-000339
氩气氛下，将55毫克71-3溶于3毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入217微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-71)10毫克，收率20.4％。 1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),7.80(s,1H),7.63(s,1H),7.57(s,1H),7.25(s,2H),7.10(d,J＝8.2Hz,2H),5.38(s,2H),2.71(s,3H),2.46(s,3H). Under an argon atmosphere, 55 mg of 71-3 was dissolved in 3 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, and then 217 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 10 mg of white solid (I-71), with a yield of 20.4%. 1 H NMR (400MHz,DMSO-d 6 )δ13.01(s,1H),7.80(s,1H),7.63(s,1H),7.57(s,1H),7.25(s,2H),7.10( d, J=8.2Hz, 2H), 5.38(s, 2H), 2.71(s, 3H), 2.46(s, 3H).
实施例72 4-((2-苯甲酰胺-5-氰基-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(Ⅰ-72)Example 72 4-((2-benzamide-5-cyano-1H-benzo[d]imidazol-1-yl)methyl)phenyl phosphate dihydrogen (I-72)
Figure PCTCN2023071429-appb-000340
Figure PCTCN2023071429-appb-000340
操作过程和反应条件同实施例71相同,不同的是步骤①中原料为苯甲酸，白色固体，收率47.5％。LCMS(ESI)m/z[M+H] +:505.1. 1H NMR(400MHz,DMSO-d 6)δ13.06(s,1H),8.27(d,J＝7.3Hz,2H),7.83(s,1H),7.66(s,2H),7.54(d,J＝7.6Hz,1H),7.50(d,J＝7.2Hz,2H),7.45(d,J＝10.3Hz,2H),7.11(d,J＝8.2Hz,2H),5.50(s,2H). The operation process and reaction conditions are the same as in Example 71, except that the raw material in step ① is benzoic acid, a white solid, and the yield is 47.5%. LCMS (ESI) m/z [M+H] + : 505.1. 1 H NMR (400MHz, DMSO-d 6 ) δ13.06 (s, 1H), 8.27 (d, J = 7.3Hz, 2H), 7.83 ( s,1H),7.66(s,2H),7.54(d,J=7.6Hz,1H),7.50(d,J=7.2Hz,2H),7.45(d,J=10.3Hz,2H),7.11( d,J=8.2Hz,2H),5.50(s,2H).
实施例73 4-((5-氰基-2-(6-甲基烟酰胺)-1H-苯并[d]咪唑-1-基)甲基)苯基磷酸二氢(Ⅰ-73)Example 73 4-((5-cyano-2-(6-methylnicotinamide)-1H-benzo[d]imidazol-1-yl)methyl)phenyl dihydrogen phosphate (I-73)
Figure PCTCN2023071429-appb-000341
Figure PCTCN2023071429-appb-000341
操作过程和反应条件同实施例71相同,不同的是步骤①中原料为6-甲基烟酸，白色固体，收率88％。LCMS(ESI)m/z[M+H] +:464.1. 1H NMR(400MHz,DMSO-d 6)δ13.07(s,1H),9.23(s,1H),8.43(d,J＝8.1Hz,1H),7.85(s,1H),7.70(d,J＝1.6Hz,2H),7.45(d,J＝8.2Hz,2H),7.40(d,J＝8.1Hz,1H),7.11(d,J＝8.2Hz,2H),5.51(s,2H),2.55(s,3H). The operation process and reaction conditions are the same as in Example 71, except that the raw material in step ① is 6-methylnicotinic acid, a white solid, and the yield is 88%. LCMS (ESI) m/z [M+H] + : 464.1. 1 H NMR (400MHz, DMSO-d 6 ) δ13.07 (s, 1H), 9.23 (s, 1H), 8.43 (d, J = 8.1 Hz,1H),7.85(s,1H),7.70(d,J=1.6Hz,2H),7.45(d,J=8.2Hz,2H),7.40(d,J=8.1Hz,1H),7.11( d, J=8.2Hz, 2H), 5.51(s, 2H), 2.55(s, 3H).
实施例74 4-(2-(5-氰基-2-(3,5-二甲基异恶唑-4-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-74)Example 74 4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl ) Phenyl dihydrogen phosphate (Ⅰ-74)
Figure PCTCN2023071429-appb-000342
Figure PCTCN2023071429-appb-000342
步骤①：4-((4-羟基苯乙基)氨基)-3-硝基苯甲腈(74-1)Step ①: 4-((4-hydroxyphenethyl)amino)-3-nitrobenzonitrile (74-1)
Figure PCTCN2023071429-appb-000343
Figure PCTCN2023071429-appb-000343
氩气氛下，将5克4-氯-3-硝基苯甲腈、4.5克4-(2-氨基乙基)苯酚、25毫升N,N-二异丙基乙胺和70毫升N,N-二甲基甲酰胺的混合物于100℃加热搅拌1小时。反应液倒入水中搅拌一个小时后过滤，干燥得到黄色固体(74-1)7.7克，收率100％。LCMS(ESI)m/z[M-H] ﹣:282.1. Under argon atmosphere, 5 g of 4-chloro-3-nitrobenzonitrile, 4.5 g of 4-(2-aminoethyl)phenol, 25 ml of N,N-diisopropylethylamine and 70 ml of N,N -The mixture of dimethylformamide was heated and stirred at 100°C for 1 hour. The reaction solution was poured into water and stirred for one hour, then filtered and dried to obtain 7.7 g of yellow solid (74-1), with a yield of 100%. LCMS(ESI)m/z[MH] ﹣ :282.1.
步骤②：4-((4-((叔丁基二苯基甲硅烷基)氧基)苯乙基)氨基)-3-硝基苯甲腈(74-2)Step ②: 4-((4-((tert-butyldiphenylsilyl)oxy)phenethyl)amino)-3-nitrobenzonitrile (74-2)
Figure PCTCN2023071429-appb-000344
Figure PCTCN2023071429-appb-000344
将50毫克74-1、100微升叔丁基二苯基氯硅烷、30毫克咪唑和2毫升超干二氯甲烷的混合物室温搅拌2小时。反应液用水和饱和食盐水洗两遍，有机相用无水硫酸钠干 燥，旋干后用甲醇打浆过夜，过滤得到黄色固体(74-2)90毫克，收率97.82％。LCMS(ESI)m/z[M+H] +:522.2. A mixture of 50 mg of 74-1, 100 μl of tert-butyldiphenylchlorosilane, 30 mg of imidazole, and 2 ml of ultra-dry dichloromethane was stirred at room temperature for 2 hours. The reaction solution was washed twice with water and saturated brine, and the organic phase was dried with anhydrous sodium sulfate, spin-dried and beaten with methanol overnight, and filtered to obtain 90 mg of yellow solid (74-2), with a yield of 97.82%. LCMS(ESI)m/z[M+H] + :522.2.
步骤③：3-氨基-4-((4-((叔丁基二苯基甲硅烷基)氧基)苯乙基)氨基)苯甲腈(74-3)Step ③: 3-amino-4-((4-((tert-butyldiphenylsilyl)oxy)phenethyl)amino)benzonitrile (74-3)
Figure PCTCN2023071429-appb-000345
Figure PCTCN2023071429-appb-000345
将12克74-2溶于120毫升甲醇中，加入20克连二亚硫酸钠，15毫升氨水，于50℃加热搅拌4小时。反应液抽滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝80:20柱层析，得白色固体(74-3)4.91克，收率43.45％。LCMS(ESI)m/z[M+H] +:492.2. Dissolve 12 grams of 74-2 in 120 milliliters of methanol, add 20 grams of sodium dithionite and 15 milliliters of ammonia water, and heat and stir at 50°C for 4 hours. The reaction solution was suction-filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 80:20 to obtain 4.91 g of white solid (74-3) with a yield of 43.45%. LCMS(ESI)m/z[M+H] + :492.2.
步骤④：2-氨基-1-(4-((叔丁基二苯基硅烷基)氧基)苯乙基)-1H-苯并[d]咪唑-5-腈(74-4)Step ④: 2-amino-1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-1H-benzo[d]imidazole-5-carbonitrile (74-4)
Figure PCTCN2023071429-appb-000346
Figure PCTCN2023071429-appb-000346
氩气氛下，将4.6克74-3溶于60毫升无水甲醇中，超声后加入11克的溴化氰，室温搅拌2小时。向反应液中加入水，继续搅拌1小时，将反应液过滤，滤饼干燥得白色固体(74-4)4.3克，收率89％。LCMS(ESI)m/z[M+H] +:517.4. Under an argon atmosphere, 4.6 g of 74-3 was dissolved in 60 ml of anhydrous methanol, 11 g of cyanogen bromide was added after sonication, and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the stirring was continued for 1 hour. The reaction solution was filtered, and the filter cake was dried to obtain 4.3 g of white solid (74-4), with a yield of 89%. LCMS(ESI)m/z[M+H] + :517.4.
步骤⑤：N-(1-(4-((叔丁基二苯基甲硅烷基)氧基)苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-3,5-二甲基异恶唑-4-甲酰胺(74-5)Step ⑤: N-(1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)- 3,5-Dimethylisoxazole-4-carboxamide (74-5)
Figure PCTCN2023071429-appb-000347
Figure PCTCN2023071429-appb-000347
氩气氛下，将600毫克74-4、327毫克3,5-二甲基异恶唑-4-羧酸、1克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、1毫升N,N-二异丙基乙胺和10毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液倒入水中，析出固体，过滤得灰白色固体(74-5)542毫克，收率72.9％。LCMS(ESI)m/z[M+H] +:640.4. Under argon atmosphere, 600 mg of 74-4, 327 mg of 3,5-dimethylisoxazole-4-carboxylic acid, 1 g of N,N,N',N'-tetramethyl-O-(7- A mixture of azabenzotriazol-1-yl)urea hexafluorophosphate (HATU), 1 mL of N,N-diisopropylethylamine, and 10 mL of anhydrous N,N-dimethylformamide was stirred overnight at room temperature . The reaction solution was poured into water, a solid was precipitated, and 542 mg of an off-white solid (74-5) was obtained by filtration, with a yield of 72.9%. LCMS(ESI)m/z[M+H] + :640.4.
步骤⑥：N-(5-氰基-1-(4-羟基苯乙基)-1H-苯并[d]咪唑-2-基)-3,5-二甲基异恶唑-4-甲酰胺(74-6)Step ⑥: N-(5-cyano-1-(4-hydroxyphenethyl)-1H-benzo[d]imidazol-2-yl)-3,5-dimethylisoxazole-4-methanol Amide (74-6)
Figure PCTCN2023071429-appb-000348
Figure PCTCN2023071429-appb-000348
氩气氛下，将30毫克74-5溶于1毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将64微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。向反应液中加水，产物逐渐析出。过滤干燥得白色固体(74-6)18毫克，收率95.7％。LCMS(ESI)m/z[M+H] +:402.1. Under an argon atmosphere, dissolve 30 mg of 74-5 in 1 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 64 μl of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, at room temperature Stir for 1 hour. Water was added to the reaction solution, and the product gradually precipitated out. After filtration and drying, 18 mg of white solid (74-6) was obtained, with a yield of 95.7%. LCMS(ESI)m/z[M+H] + :402.1.
步骤⑦：4-(2-(5-氰基-2-(3,5-二甲基异恶唑-4-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二乙酯(74-7)Step ⑦: 4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl ) diethyl phenyl phosphate (74-7)
Figure PCTCN2023071429-appb-000349
Figure PCTCN2023071429-appb-000349
氩气氛下，将18毫克74-6溶于1毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入10微升氰基磷酸二乙酯，随后缓慢加入13微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝70:1制备薄层，得淡黄色固体(74-7)20毫克，收率83.3％。1H NMR(400MHz,CD 3OD)δ7.70(s,1H),7.47(d,J＝8.3Hz,1H),7.23(d,J＝8.3Hz,1H),7.13(d,J＝8.2Hz,2H),7.02(d,J＝8.1Hz,2H),4.45(t,J＝6.9Hz,2H),4.20–4.12(m,4H),3.15(t,J＝6.8Hz,2H),2.77(s,3H),2.54(s,3H),1.31(t,J＝7.0Hz,6H). Under an argon atmosphere, dissolve 18 mg of 74-6 in 1 ml of ultra-dry dimethyl sulfoxide, stir in an ice bath for 10 minutes, add 10 μl of diethyl cyanophosphate, and then slowly add 13 μl Triethylamine, stirred in an ice bath for 30 minutes, then placed at room temperature and stirred overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was prepared into a thin layer with dichloromethane:methanol=70:1 to obtain 20 mg of light yellow solid (74-7), with a yield of 83.3%. 1H NMR (400MHz, CD 3 OD) δ7.70(s, 1H), 7.47(d, J=8.3Hz, 1H), 7.23(d, J=8.3Hz, 1H), 7.13(d, J=8.2Hz ,2H),7.02(d,J=8.1Hz,2H),4.45(t,J=6.9Hz,2H),4.20–4.12(m,4H),3.15(t,J=6.8Hz,2H),2.77 (s,3H),2.54(s,3H),1.31(t,J=7.0Hz,6H).
步骤⑧：4-(2-(5-氰基-2-(3,5-二甲基异恶唑-4-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-74)Step ⑧: 4-(2-(5-cyano-2-(3,5-dimethylisoxazole-4-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl ) Phenyl dihydrogen phosphate (Ⅰ-74)
Figure PCTCN2023071429-appb-000350
Figure PCTCN2023071429-appb-000350
氩气氛下，将20毫克74-7溶于2毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入200微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-74)8毫克，收率44.7％。LCMS(ESI)m/z[M-H] ﹣:480.2. 1H NMR(400MHz,DMSO-d 6)δ12.94(s,1H),7.79(d,J＝1.6Hz,1H),7.64(dd,J＝8.3,1.6Hz,1H),7.59(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,2H),7.10–7.01(m,2H),4.40(t,J＝7.6Hz,2H),3.02(t,J＝7.6Hz,2H),2.78(s,3H),2.51(s,3H). Under an argon atmosphere, 20 mg of 74-7 was dissolved in 2 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, then 200 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 8 mg of white solid (I-74), with a yield of 44.7%. LCMS (ESI) m/z [MH] - : 480.2.1 H NMR (400MHz, DMSO-d 6 ) δ12.94 (s, 1H), 7.79 (d, J = 1.6Hz, 1H), 7.64 (dd, J=8.3,1.6Hz,1H),7.59(d,J=8.4Hz,1H),7.24(d,J=8.4Hz,2H),7.10–7.01(m,2H),4.40(t,J=7.6 Hz,2H),3.02(t,J=7.6Hz,2H),2.78(s,3H),2.51(s,3H).
实施例75 4-(2-(2-苯甲酰胺-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-75)Example 75 4-(2-(2-benzamide-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl phosphate dihydrogen (I-75)
Figure PCTCN2023071429-appb-000351
Figure PCTCN2023071429-appb-000351
步骤①：N-(1-(4-((叔丁基二苯基甲硅烷基)氧基)苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)苯甲酰胺(75-1)Step ①: N-(1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)benzene Formamide (75-1)
Figure PCTCN2023071429-appb-000352
Figure PCTCN2023071429-appb-000352
氩气氛下，将100毫克74-4、50毫克苯甲酸、148毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、168微升N,N-二异丙基乙胺和3毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液倒入水中，析出固体，过滤得白色固体(75-1)100毫克，收率83.3％。LCMS(ESI)m/z[M+H] +:621.3. Under argon atmosphere, 100 mg of 74-4, 50 mg of benzoic acid, 148 mg of N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluoro A mixture of urea phosphate (HATU), 168 μl N,N-diisopropylethylamine and 3 ml anhydrous N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was poured into water, a solid was precipitated, and 100 mg of white solid (75-1) was obtained by filtration, with a yield of 83.3%. LCMS(ESI)m/z[M+H] + :621.3.
步骤②：N-(5-氰基-1-(4-羟基苯乙基)-1H-苯并[d]咪唑-2-基)苯甲酰胺(75-2)Step ②: N-(5-cyano-1-(4-hydroxyphenethyl)-1H-benzo[d]imidazol-2-yl)benzamide (75-2)
Figure PCTCN2023071429-appb-000353
Figure PCTCN2023071429-appb-000353
氩气氛下，将50毫克75-1溶于2毫升的无水四氢呋喃中，在冰浴下搅拌10分钟后将120微升四丁基氟化铵稀释三倍后缓慢滴入反应液中，室温搅拌1小时。向反应液中加水，产物逐渐析出。过滤干燥得白色固体(75-2)30毫克，收率97.4％。LCMS(ESI)m/z[M+H] +:383.1. Under an argon atmosphere, dissolve 50 mg of 75-1 in 2 ml of anhydrous tetrahydrofuran, stir in an ice bath for 10 minutes, then dilute 120 μl of tetrabutylammonium fluoride three times and slowly drop into the reaction solution, room temperature Stir for 1 hour. Water was added to the reaction solution, and the product gradually precipitated out. After filtration and drying, 30 mg of white solid (75-2) was obtained, with a yield of 97.4%. LCMS(ESI)m/z[M+H] + :383.1.
步骤③：4-(2-(2-苯甲酰胺-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二乙酯(75-3)Step ③: Diethyl 4-(2-(2-benzamide-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenylphosphate (75-3)
Figure PCTCN2023071429-appb-000354
Figure PCTCN2023071429-appb-000354
氩气氛下，将30毫克75-2溶于2毫升的超干二甲基亚砜中，于冰浴下搅拌10分钟后，加入24微升氰基磷酸二乙酯，随后缓慢加入30微升三乙胺，冰浴搅拌30分钟后，放于室温搅拌过夜。反应液用水和乙酸乙酯萃取，有机相用水和饱和食盐水充分洗涤后，浓缩至干。残余物以二氯甲烷：甲醇＝70:1制备薄层，得淡黄色固体(75-3)32毫克，收率78％。 1H NMR(400MHz,DMSO-d 6)δ12.94(s,1H),8.25(d,J＝7.4Hz,2H),7.78(s,1H),7.62(d,J＝8.5Hz,1H),7.53(dd,J＝13.6,7.6Hz,4H),7.27(d,J＝8.1Hz,2H),7.05(d,J＝8.1Hz,2H),4.51(t,J＝7.1Hz,2H),4.11–4.03(m,4H),3.14(t,J＝7.2Hz,2H),1.21(td,J＝7.0,6.6,1.6Hz,6H). Under an argon atmosphere, dissolve 30 mg of 75-2 in 2 ml of ultra-dry dimethyl sulfoxide, stir in an ice bath for 10 minutes, add 24 μl of diethyl cyanophosphate, and then slowly add 30 μl Triethylamine, stirred in an ice bath for 30 minutes, then placed at room temperature and stirred overnight. The reaction solution was extracted with water and ethyl acetate, and the organic phase was fully washed with water and saturated brine, and then concentrated to dryness. The residue was prepared into a thin layer with dichloromethane:methanol=70:1 to obtain 32 mg of light yellow solid (75-3) with a yield of 78%. 1 H NMR (400MHz,DMSO-d 6 )δ12.94(s,1H),8.25(d,J=7.4Hz,2H),7.78(s,1H),7.62(d,J=8.5Hz,1H) ,7.53(dd,J=13.6,7.6Hz,4H),7.27(d,J=8.1Hz,2H),7.05(d,J=8.1Hz,2H),4.51(t,J=7.1Hz,2H) ,4.11–4.03(m,4H),3.14(t,J=7.2Hz,2H),1.21(td,J=7.0,6.6,1.6Hz,6H).
步骤④：4-(2-(2-苯甲酰胺-5-氰基-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-75)Step ④: 4-(2-(2-benzamide-5-cyano-1H-benzo[d]imidazol-1-yl)ethyl)phenyl phosphate dihydrogen (Ⅰ-75)
Figure PCTCN2023071429-appb-000355
Figure PCTCN2023071429-appb-000355
氩气氛下，将30毫克75-3溶于2毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入200微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-75)5毫克，收率19.2％。LCMS(ESI)m/z[M-H] ﹣:461.1. 1H NMR(400MHz,DMSO-d 6)δ8.25(d,J＝7.3Hz,2H),7.82(s,1H),7.66–7.57(m,2H),7.57–7.47(m,3H),7.26(d,J＝8.1Hz,2H),7.05(d,J＝8.1Hz,2H),4.48(t,J＝7.3Hz,2H),3.11(d,J＝7.5Hz,2H). Under an argon atmosphere, 30 mg of 75-3 was dissolved in 2 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, and then 200 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 5 mg of white solid (I-75), with a yield of 19.2%. LCMS (ESI) m/z [MH] - : 461.1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.25 (d, J = 7.3Hz, 2H), 7.82 (s, 1H), 7.66–7.57 ( m,2H),7.57–7.47(m,3H),7.26(d,J=8.1Hz,2H),7.05(d,J=8.1Hz,2H),4.48(t,J=7.3Hz,2H), 3.11(d,J=7.5Hz,2H).
实施例76 4-(2-(5-氰基-2-(6-甲基烟酰胺)-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-76)Example 76 4-(2-(5-cyano-2-(6-methylnicotinamide)-1H-benzo[d]imidazol-1-yl)ethyl)phenyl dihydrogen phosphate (Ⅰ-76 )
Figure PCTCN2023071429-appb-000356
Figure PCTCN2023071429-appb-000356
操作过程和反应条件同实施例75相同,不同的是步骤①中原料为6-甲基烟酸，白色固体，收率87.2％。LCMS(ESI)m/z[M+H] +:478.2. 1H NMR(400MHz,DMSO-d 6)δ12.97(s,1H),9.18(s,1H),8.40(d,J＝7.9Hz,1H),7.82(s,1H),7.70–7.60(m,2H),7.43(d,J＝8.1Hz,1H),7.25(d,J＝8.1Hz,2H),7.04(d,J＝8.0Hz,2H),4.49(t,J＝7.1Hz,2H),3.08(t,J＝7.3Hz,2H),2.57(s,3H). The operation process and reaction conditions are the same as in Example 75, except that the raw material in step ① is 6-methylnicotinic acid, a white solid, and the yield is 87.2%. LCMS (ESI) m/z [M+H] + : 478.2. 1 H NMR (400MHz, DMSO-d 6 ) δ12.97 (s, 1H), 9.18 (s, 1H), 8.40 (d, J = 7.9 Hz,1H),7.82(s,1H),7.70–7.60(m,2H),7.43(d,J=8.1Hz,1H),7.25(d,J=8.1Hz,2H),7.04(d,J =8.0Hz, 2H), 4.49(t, J=7.1Hz, 2H), 3.08(t, J=7.3Hz, 2H), 2.57(s, 3H).
实施例77 4-(2-(5-氰基-2-(5-甲基吡嗪-2-甲酰胺基)-1H-苯并[d]咪唑-1-基)乙基)苯基磷酸二氢(Ⅰ-77)Example 77 4-(2-(5-cyano-2-(5-methylpyrazine-2-carboxamido)-1H-benzo[d]imidazol-1-yl)ethyl)phenylphosphoric acid Dihydro(Ⅰ-77)
Figure PCTCN2023071429-appb-000357
Figure PCTCN2023071429-appb-000357
操作过程和反应条件同实施例75相同,不同的是步骤①中原料为5-甲基吡嗪-2-羧酸，白色固体，收率87.2％。 1H NMR(400MHz,DMSO-d 6)δ13.03(s,1H),9.36(s,1H),8.71(s,1H),7.87(s,1H),7.64(s,2H),7.23(s,2H),7.02(d,J＝8.0Hz,2H),4.48(s,2H),3.07(s,2H),2.61(s,3H). The operation process and reaction conditions are the same as in Example 75, except that the raw material in step ① is 5-methylpyrazine-2-carboxylic acid, a white solid, and the yield is 87.2%. 1 H NMR (400MHz,DMSO-d 6 )δ13.03(s,1H),9.36(s,1H),8.71(s,1H),7.87(s,1H),7.64(s,2H),7.23( s,2H),7.02(d,J=8.0Hz,2H),4.48(s,2H),3.07(s,2H),2.61(s,3H).
实施例78(4-((5-氰基-2-((2-甲基吡啶-4-基)氨基甲酰基)-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸(Ⅰ-78)Example 78 (4-((5-cyano-2-((2-methylpyridin-4-yl)carbamoyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl ) Phosphonic acid (Ⅰ-78)
Figure PCTCN2023071429-appb-000358
Figure PCTCN2023071429-appb-000358
步骤①：4-(4-溴苄基)氨基)-3-硝基苯甲腈(78-1)Step ①: 4-(4-bromobenzyl)amino)-3-nitrobenzonitrile (78-1)
Figure PCTCN2023071429-appb-000359
Figure PCTCN2023071429-appb-000359
氩气氛下，将5克4-氯-3-硝基苯甲腈、4.5毫升(4-溴苯基)甲胺、23毫升N,N-二异丙基乙胺和50毫升N,N-二甲基甲酰胺的混合物于100℃加热搅拌1小时。反应液倒入水中搅拌一个小时后过滤，干燥得到黄色固体(78-1)9.1克，收率100％。LCMS(ESI)m/z[M+H] +:332.1. 1H NMR(400MHz,DMSO-d 6)δ9.18(t,J＝6.3Hz,1H),8.53(d,J＝2.1Hz,1H),7.75(dd,J＝9.0,2.1Hz,1H),7.57–7.50(m,2H),7.36–7.31(m,2H),6.97(d,J＝9.1Hz,1H),4.68(d,J＝6.3Hz,2H). Under argon atmosphere, 5 g of 4-chloro-3-nitrobenzonitrile, 4.5 ml of (4-bromophenyl) methylamine, 23 ml of N,N-diisopropylethylamine and 50 ml of N,N- The mixture of dimethylformamide was stirred with heating at 100°C for 1 hour. The reaction solution was poured into water and stirred for one hour, then filtered and dried to obtain 9.1 g of yellow solid (78-1), with a yield of 100%. LCMS (ESI) m/z[M+H] + :332.1. 1 H NMR (400MHz, DMSO-d 6 ) δ9.18(t, J=6.3Hz, 1H), 8.53(d, J=2.1Hz, 1H), 7.75(dd, J＝9.0, 2.1Hz, 1H), 7.57–7.50(m, 2H), 7.36–7.31(m, 2H), 6.97(d, J＝9.1Hz, 1H), 4.68(d ,J＝6.3Hz,2H).
步骤②：3-氨基-4-((4-溴苄基)氨基)苯甲腈(78-2)Step ②: 3-amino-4-((4-bromobenzyl)amino)benzonitrile (78-2)
Figure PCTCN2023071429-appb-000360
Figure PCTCN2023071429-appb-000360
将5克78-1溶于无水甲醇中，加入锌粉，冰浴下搅拌10分钟后，缓慢滴加5毫升冰醋酸，滴毕室温搅拌1小时。向反应液中加入100毫升二氯甲烷，硅藻土过滤，滤液旋干，得到淡黄色固体(78-2)5.1克。LCMS(ESI)m/z[M+H] +:302.1. Dissolve 5 grams of 78-1 in anhydrous methanol, add zinc powder, stir in ice bath for 10 minutes, slowly add 5 milliliters of glacial acetic acid dropwise, and stir for 1 hour at room temperature after dropping. 100 ml of dichloromethane was added to the reaction liquid, filtered through celite, and the filtrate was spin-dried to obtain 5.1 g of light yellow solid (78-2). LCMS(ESI)m/z[M+H] + :302.1.
步骤③：1-(4-溴苄基)-5-氰基-1H-苯并[d]咪唑-2-羧酸(78-3)Step ③: 1-(4-bromobenzyl)-5-cyano-1H-benzo[d]imidazole-2-carboxylic acid (78-3)
Figure PCTCN2023071429-appb-000361
Figure PCTCN2023071429-appb-000361
氩气氛下，将5.1克78-2、6.5毫升乙醛酸乙酯的甲苯溶液、3克醋酸锌和30毫升无水甲醇的混合物于65℃加热搅拌3小时。反应液过滤，滤饼以二氯甲烷：甲醇＝10:1打浆，得白色固体(78-3)2.3克，收率38.3％。LCMS(ESI)m/z[M-H] ﹣:354.0、356.0. Under an argon atmosphere, a mixture of 5.1 g of 78-2, 6.5 ml of ethyl glyoxylate in toluene, 3 g of zinc acetate and 30 ml of anhydrous methanol was heated and stirred at 65°C for 3 hours. The reaction solution was filtered, and the filter cake was slurried with dichloromethane:methanol=10:1 to obtain 2.3 g of white solid (78-3), with a yield of 38.3%. LCMS(ESI)m/z[MH] ﹣ :354.0, 356.0.
步骤④：1-(4-溴苄基)-5-氰基-1H-苯并[d]咪唑-2-羧酸(78-4)Step ④: 1-(4-bromobenzyl)-5-cyano-1H-benzo[d]imidazole-2-carboxylic acid (78-4)
Figure PCTCN2023071429-appb-000362
Figure PCTCN2023071429-appb-000362
氩气氛下，将300毫克78-3、179毫克2-甲基吡啶-4-胺、630毫克N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(HATU)、1毫升N,N-二异丙基乙胺和5毫升无水N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝98:2柱层析，得白色固体(78-4)69毫克，收率18.4％。LCMS(ESI)m/z[M+H] +:446.1、448.1. 1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.46(s,1H),8.37(d,J＝5.6Hz,1H),7.94(d,J＝8.6Hz,1H),7.82(dd,J＝11.9,2.1Hz,2H),7.66(d,J＝5.7Hz,1H),7.52(d,J＝8.4Hz,2H),7.21(d,J＝8.3Hz,2H),5.98(s,2H),2.45(s,3H). Under argon atmosphere, 300 mg of 78-3, 179 mg of 2-methylpyridin-4-amine, 630 mg of N,N,N',N'-tetramethyl-O-(7-azabenzotriazole -1-yl)urea hexafluorophosphate (HATU), 1 mL of N,N-diisopropylethylamine and 5 mL of anhydrous N,N-dimethylformamide was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=98:2 to obtain 69 mg of white solid (78-4) with a yield of 18.4%. LCMS (ESI) m/z [M+H] + : 446.1, 448.1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.44 (s, 1H), 8.46 (s, 1H), 8.37 (d, J =5.6Hz,1H),7.94(d,J=8.6Hz,1H),7.82(dd,J=11.9,2.1Hz,2H),7.66(d,J=5.7Hz,1H),7.52(d,J =8.4Hz, 2H), 7.21(d, J=8.3Hz, 2H), 5.98(s, 2H), 2.45(s, 3H).
步骤⑤：(4-((5-氰基-2-((2-甲基吡啶-4-基)氨基甲酰基)-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸二乙酯(78-5)Step ⑤: (4-((5-cyano-2-((2-methylpyridin-4-yl)carbamoyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl ) diethyl phosphonate (78-5)
Figure PCTCN2023071429-appb-000363
Figure PCTCN2023071429-appb-000363
氩气氛下将55毫克78-4、25毫克四(三苯基膦)钯、100微升三乙胺、30微升亚磷酸二乙酯和2毫升超干四氢呋喃的混合物于100℃加热搅拌过夜。反应液过滤，滤液浓缩至干。残余物用水和乙酸乙酯萃取，有机相浓缩至干。残余物以二氯甲烷：甲醇＝50:1制备薄层，得淡黄色固体(78-5)40毫克，收率70.8％。LCMS(ESI)m/z[M+H] +:504.2. 1H NMR(400MHz,CDCl 3)δ8.31(d,J＝5.8Hz,1H),8.28(s,1H),7.75(dd,J＝8.4,6.6Hz,2H),7.73–7.69(m,3H),7.68–7.64(m,1H),7.40(dd,J＝8.2,3.8Hz,2H),6.12(s, 2H),4.11–4.01(m,4H),2.50(s,3H),1.27(t,J＝7.1Hz,6H). Under an argon atmosphere, heat and stir a mixture of 55 mg of 78-4, 25 mg of tetrakis(triphenylphosphine) palladium, 100 μl of triethylamine, 30 μl of diethyl phosphite and 2 ml of ultra-dry tetrahydrofuran at 100°C overnight . The reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness. The residue was prepared into a thin layer with dichloromethane:methanol=50:1 to obtain 40 mg of light yellow solid (78-5) with a yield of 70.8%. LCMS (ESI) m/z [M+H] + :504.2. 1 H NMR (400MHz, CDCl 3 ) δ8.31 (d, J=5.8Hz, 1H), 8.28 (s, 1H), 7.75 (dd, J=8.4,6.6Hz,2H),7.73–7.69(m,3H),7.68–7.64(m,1H),7.40(dd,J=8.2,3.8Hz,2H),6.12(s,2H),4.11 –4.01(m,4H),2.50(s,3H),1.27(t,J=7.1Hz,6H).
步骤⑥：(4-((5-氰基-2-((2-甲基吡啶-4-基)氨基甲酰基)-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸(I-78)Step ⑥: (4-((5-cyano-2-((2-methylpyridin-4-yl)carbamoyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl ) Phosphonic acid (I-78)
Figure PCTCN2023071429-appb-000364
Figure PCTCN2023071429-appb-000364
氩气氛下，将20毫克78-5溶于2毫升无水二氯甲烷中，冰浴下搅拌5分钟后缓慢加入200微升三甲基溴硅烷，室温搅拌过夜。向反应液中加入4毫升甲醇，将反应液倒入冰水中继续搅拌2个小时。反应液过滤，得白色固体(I-78)5.6毫克，收率31.6％。LCMS(ESI)m/z[M-H] ﹣:446.1. 1H NMR(400MHz,DMSO-d 6)δ11.79(s,1H),8.48(d,J＝5.6Hz,2H),8.02(s,1H),7.93(d,J＝8.6Hz,1H),7.85(td,J＝10.1,8.6,3.8Hz,2H),7.61(dd,J＝12.7,7.8Hz,2H),7.27(dd,J＝8.2,3.2Hz,2H),6.06(s,2H),2.53(s,3H). Under an argon atmosphere, 20 mg of 78-5 was dissolved in 2 ml of anhydrous dichloromethane, stirred in an ice bath for 5 minutes, and then 200 μl of bromotrimethylsilane was slowly added, and stirred overnight at room temperature. 4 ml of methanol was added to the reaction solution, and the reaction solution was poured into ice water and stirred for 2 hours. The reaction solution was filtered to obtain 5.6 mg of white solid (I-78), with a yield of 31.6%. LCMS (ESI) m/z [MH] - : 446.1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.79 (s, 1H), 8.48 (d, J = 5.6Hz, 2H), 8.02 (s, 1H), 7.93(d, J=8.6Hz, 1H), 7.85(td, J=10.1, 8.6, 3.8Hz, 2H), 7.61(dd, J=12.7, 7.8Hz, 2H), 7.27(dd, J =8.2,3.2Hz,2H),6.06(s,2H),2.53(s,3H).
实施例79(4-((5-氰基-2-(吡嗪-2-基氨基甲酰基)-1H-苯并[d]咪唑-1-基)甲基)苯基)膦酸(I-79)Example 79 (4-((5-cyano-2-(pyrazin-2-ylcarbamoyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)phosphonic acid (I -79)
Figure PCTCN2023071429-appb-000365
Figure PCTCN2023071429-appb-000365
操作过程和反应条件同实施例78相同,不同的是步骤④中原料为吡嗪-2-胺，白色固体，收率28.2％。LCMS(ESI)m/z[M+H] +:435.1. 1H NMR(400MHz,DMSO-d 6)δ11.16(s,1H),9.30(d,J＝1.5Hz,1H),8.53(t,J＝2.0Hz,1H),8.50(dd,J＝5.8,2.0Hz,2H),7.92(d,J＝8.6Hz,1H),7.82(dd,J＝8.6,1.5Hz,1H),7.61(dd,J＝12.7,7.9Hz,2H),7.31(dd,J＝8.2,3.2Hz,2H),6.08(s,2H). The operation process and reaction conditions are the same as in Example 78, except that the raw material in step ④ is pyrazin-2-amine, a white solid, and the yield is 28.2%. LCMS (ESI) m/z [M+H] + : 435.1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.16 (s, 1H), 9.30 (d, J = 1.5Hz, 1H), 8.53 ( t,J=2.0Hz,1H),8.50(dd,J=5.8,2.0Hz,2H),7.92(d,J=8.6Hz,1H),7.82(dd,J=8.6,1.5Hz,1H), 7.61(dd,J=12.7,7.9Hz,2H),7.31(dd,J=8.2,3.2Hz,2H),6.08(s,2H).
实施例80(4-(2-(5-氰基-2-((2-甲基吡啶-4-基)氨基甲酰基)-1H-苯并[d]咪唑-1-基)乙基)苯基)膦酸(I-80)Example 80 (4-(2-(5-cyano-2-((2-methylpyridin-4-yl)carbamoyl)-1H-benzo[d]imidazol-1-yl)ethyl) Phenyl)phosphonic acid (I-80)
Figure PCTCN2023071429-appb-000366
Figure PCTCN2023071429-appb-000366
操作过程和反应条件同实施例78相同,不同的是步骤①中原料为2-(4-溴苯基)乙-1-胺，白色固体，收率35.2％。LCMS(ESI)m/z[M+H]+:462.1. 1H NMR(400MHz,DMSO-d 6)δ11.58(s,1H),8.47(d,J＝5.9Hz,1H),8.40(d,J＝8.5Hz,1H),8.00–7.90(m,2H),7.87–7.71(m,2H),7.58-7.52(m,2H),7.34-7.30(m,2H),5.00–4.91(m,2H),3.20(d,J＝7.8Hz,2H),2.54(s,3H). The operation process and reaction conditions are the same as in Example 78, except that the raw material in step ① is 2-(4-bromophenyl)ethan-1-amine, a white solid, and the yield is 35.2%. LCMS (ESI) m/z [M+H]+: 462.1. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.58 (s, 1H), 8.47 (d, J=5.9Hz, 1H), 8.40 ( d,J＝8.5Hz,1H),8.00–7.90(m,2H),7.87–7.71(m,2H),7.58-7.52(m,2H),7.34-7.30(m,2H),5.00–4.91( m, 2H), 3.20(d, J=7.8Hz, 2H), 2.54(s, 3H).
实施例81(6-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)吡啶-3-基)膦酸(I-81)Example 81 (6-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl )Methyl)pyridin-3-yl)phosphonic acid (I-81)
Figure PCTCN2023071429-appb-000367
Figure PCTCN2023071429-appb-000367
步骤①：(5-溴吡啶-2-基)甲基叔丁基氨基甲酸酯(81-1)Step ①: (5-bromopyridin-2-yl)methyl tert-butyl carbamate (81-1)
Figure PCTCN2023071429-appb-000368
Figure PCTCN2023071429-appb-000368
氩气氛下，将3.5克5-溴哌啶腈，18.8毫升二碳酸二叔丁酯，1.55克六水合氯化镍和甲醇混合物室温搅拌3分钟，分批加入7.25克硼氢化钠，室温搅拌4小时。反应液浓缩至干，残余物加水，乙酸乙酯萃取，有机相浓缩至干；残余物以石油醚：乙酸乙酯＝85:15柱层析，得(5-溴吡啶-2-基)甲基叔丁基氨基甲酸酯(81-1)白色固体2.67克，收率49％。 1H NMR(400MHz,CDCl 3)δ8.51(d,J＝2.5Hz,1H),7.66(dd,J＝8.3,2.5Hz,1H),7.36–7.19(m,1H),4.44(d,J＝5.7Hz,2H),1.48(s,9H). Under argon atmosphere, stir 3.5 grams of 5-bromopiperidine nitrile, 18.8 milliliters of di-tert-butyl dicarbonate, 1.55 grams of nickel chloride hexahydrate and methanol mixture at room temperature for 3 minutes, add 7.25 grams of sodium borohydride in batches, and stir at room temperature for 4 minutes. Hour. The reaction solution was concentrated to dryness, the residue was added with water, extracted with ethyl acetate, and the organic phase was concentrated to dryness; the residue was subjected to column chromatography with petroleum ether:ethyl acetate=85:15 to obtain (5-bromopyridin-2-yl)methanol 2.67 g of tert-butyl carbamate (81-1) was a white solid, with a yield of 49%. 1 H NMR (400MHz, CDCl 3 ) δ8.51(d, J=2.5Hz, 1H), 7.66(dd, J=8.3, 2.5Hz, 1H), 7.36–7.19(m, 1H), 4.44(d, J＝5.7Hz, 2H), 1.48(s, 9H).
步骤②：5-溴吡啶-2-甲胺(81-2)Step ②: 5-Bromopyridine-2-methylamine (81-2)
Figure PCTCN2023071429-appb-000369
Figure PCTCN2023071429-appb-000369
将2.67克81-1，6毫升三氟乙酸，40毫升二氯甲烷混合物室温搅拌6小时。反应液浓缩至干，加入60毫升乙醚，室温搅拌30分钟，过滤得5-溴吡啶-2-甲胺(81-2)白色固体1.42克，收率82％。 1H NMR(400MHz,DMSO-d 6)δ8.72(d,J＝2.5Hz,1H),8.49–8.19(m,3H),8.06(dd,J＝8.4,2.5Hz,1H),7.56(d,J＝8.4Hz,1H),4.24(s,2H). A mixture of 2.67 g of 81-1, 6 ml of trifluoroacetic acid, and 40 ml of dichloromethane was stirred at room temperature for 6 hours. The reaction solution was concentrated to dryness, 60 ml of diethyl ether was added, stirred at room temperature for 30 minutes, and 1.42 g of white solid 5-bromopyridine-2-methylamine (81-2) was obtained by filtration, with a yield of 82%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.72 (d, J=2.5Hz, 1H), 8.49–8.19 (m, 3H), 8.06 (dd, J=8.4, 2.5Hz, 1H), 7.56( d,J=8.4Hz,1H),4.24(s,2H).
步骤③：4-(5-溴吡啶-2-基甲基)氨基)-3-硝基苯甲腈(81-3)Step ③: 4-(5-bromopyridin-2-ylmethyl)amino)-3-nitrobenzonitrile (81-3)
Figure PCTCN2023071429-appb-000370
Figure PCTCN2023071429-appb-000370
将1.4克4-氯-3-硝基苯甲腈，1.42克81-2，1.34毫升N,N-二异丙基乙胺和20毫升N,N-二甲基甲酰胺混合物100℃搅拌2小时。反应液倒入300毫升水中，过滤得4-(5-溴吡啶-2-基甲基)氨基)-3-硝基苯甲腈(81-3)黄色固体2.23克，收率87％。ESI-MS(m/z):333.1[M+H] +. 1.4 g of 4-chloro-3-nitrobenzonitrile, 1.42 g of 81-2, 1.34 ml of N,N-diisopropylethylamine and 20 ml of N,N-dimethylformamide were stirred at 100°C for 2 Hour. The reaction solution was poured into 300 ml of water, and filtered to obtain 2.23 g of 4-(5-bromopyridin-2-ylmethyl)amino)-3-nitrobenzonitrile (81-3) as a yellow solid, with a yield of 87%. ESI-MS(m/z):333.1[M+H] + .
步骤④：3-氨基-4-(5-溴吡啶-2-甲基)氨基苯甲腈(81-4)Step ④: 3-Amino-4-(5-bromopyridin-2-methyl)aminobenzonitrile (81-4)
Figure PCTCN2023071429-appb-000371
Figure PCTCN2023071429-appb-000371
氩气氛下，将2.23克81-3，5.84克连二亚硫酸钠，2毫升氨水和30毫升甲醇混合物室温搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝4:1柱层析，得3-氨基-4-(5-溴吡啶-2-甲基)氨基苯甲腈(81-4)粉色固体381毫克，收率19％。ESI-MS(m/z)[M+H] +:303.1. Under an argon atmosphere, a mixture of 2.23 g of 81-3, 5.84 g of sodium dithionite, 2 ml of aqueous ammonia and 30 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether:ethyl acetate=4:1 to obtain 3-amino-4-(5-bromopyridine-2-methyl)aminobenzonitrile (81 -4) 381 mg of pink solid, yield 19%. ESI-MS(m/z)[M+H] + :303.1.
步骤⑤：2-氨基-1-(5-溴吡啶-2-基)甲基)-1H-苯并咪唑-5-甲腈(81-5)Step ⑤: 2-Amino-1-(5-bromopyridin-2-yl)methyl)-1H-benzimidazole-5-carbonitrile (81-5)
Figure PCTCN2023071429-appb-000372
Figure PCTCN2023071429-appb-000372
氩气氛下，将381毫克81-4，666毫克溴化氰和5毫升甲醇混合物室温搅拌4小时。反应液过滤得2-氨基-1-(5-溴吡啶-2-基)甲基)-1H-苯并咪唑-5-甲腈(81-5)粉色固体410毫克，收率99％。ESI-MS(m/z)[M+H] +:328.1. Under an argon atmosphere, a mixture of 381 mg of 81-4, 666 mg of cyanogen bromide and 5 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was filtered to obtain 410 mg of 2-amino-1-(5-bromopyridin-2-yl)methyl)-1H-benzimidazole-5-carbonitrile (81-5) as a pink solid, with a yield of 99%. ESI-MS(m/z)[M+H] + :328.1.
步骤⑥：5-溴吡啶-2-甲基-5-氰基苯并-2-基-1-乙基-3-甲基吡唑-5-甲酰胺(81-6)Step ⑥: 5-bromopyridine-2-methyl-5-cyanobenzo-2-yl-1-ethyl-3-methylpyrazole-5-carboxamide (81-6)
Figure PCTCN2023071429-appb-000373
Figure PCTCN2023071429-appb-000373
将410毫克81-5，572毫克2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，440微升N，N-二异丙基乙胺，32毫克1-乙基-3-甲基吡唑-5-羧酸和5毫升N,N-二甲基甲酰胺混合物室温搅拌4小时。反应液加入水中，过滤得5-溴吡啶-2-甲基-5-氰基苯并-2-基-1-乙基-3-甲基吡唑-5-甲酰胺(81-6)灰色固体310毫克，收率53％。 1H NMR(400MHz,DMSO-d 6)δ13.01(s,1H),8.59(d,J＝2.4Hz,1H),8.07(dd,J＝8.4,2.4Hz,1H),7.96(s,1H), 7.84(d,J＝1.5Hz,1H),7.68(dd,J＝8.3,1.6Hz,1H),7.60(d,J＝8.4Hz,1H),7.46(d,J＝8.4Hz,1H),6.60(s,1H),5.57(s,2H),4.52(d,J＝7.1Hz,2H),2.15(s,3H),1.26(t,J＝7.1Hz,3H). 410 mg 81-5, 572 mg 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 440 μl N,N-di A mixture of isopropylethylamine, 32 mg of 1-ethyl-3-methylpyrazole-5-carboxylic acid and 5 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was added to water, filtered to obtain 5-bromopyridine-2-methyl-5-cyanobenzo-2-yl-1-ethyl-3-methylpyrazole-5-carboxamide (81-6) gray Solid 310 mg, yield 53%. 1 H NMR (400MHz, DMSO-d 6 )δ13.01(s, 1H), 8.59(d, J=2.4Hz, 1H), 8.07(dd, J=8.4, 2.4Hz, 1H), 7.96(s, 1H), 7.84(d, J＝1.5Hz, 1H), 7.68(dd, J＝8.3, 1.6Hz, 1H), 7.60(d, J＝8.4Hz, 1H), 7.46(d, J＝8.4Hz, 1H),6.60(s,1H),5.57(s,2H),4.52(d,J=7.1Hz,2H),2.15(s,3H),1.26(t,J=7.1Hz,3H).
步骤⑦：6-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-甲基)吡啶-3-基膦酸酯(81-7)Step ⑦: 6-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-methyl)pyridin-3-ylphosphonic acid Esters (81-7)
Figure PCTCN2023071429-appb-000374
Figure PCTCN2023071429-appb-000374
氩气氛下，将300毫克81-6，74.88毫克四三苯基磷钯，250微升亚磷酸二乙酯，270微升三乙胺和5毫升无水四氢呋喃混合物90℃封管搅拌6小时。反应液浓缩，残余物以石油醚：乙酸乙酯＝1:1柱层析得6-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-甲基)吡啶-3-基膦酸酯(81-7)灰色固体180毫克，收率53％。 1H NMR(400MHz,DMSO-d 6)δ13.03(s,1H),8.74–8.67(m,1H),8.10(dd,J＝12.7,8.2Hz,1H),7.85(s,1H),7.69(d,J＝7.9Hz,1H),7.63(d,J＝8.4Hz,1H),7.57(d,J＝8.1Hz,1H),6.54(s,1H),5.67(s,2H),4.49(q,J＝7.1Hz,2H),4.01(pd,J＝7.1,2.8Hz,4H),2.13(s,3H),1.25–1.21(m,3H),1.22–1.14(m,6H). Under an argon atmosphere, a mixture of 300 mg of 81-6, 74.88 mg of tetrakistriphenylphosphopalladium, 250 μl of diethyl phosphite, 270 μl of triethylamine and 5 ml of anhydrous tetrahydrofuran was stirred at 90° C. for 6 hours. The reaction solution was concentrated, and the residue was purified by petroleum ether: ethyl acetate = 1:1 column chromatography to obtain 6-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamide) -1H-Benzo-1-methyl)pyridin-3-ylphosphonate (81-7) gray solid 180 mg, yield 53%. 1 H NMR (400MHz,DMSO-d 6 )δ13.03(s,1H),8.74–8.67(m,1H),8.10(dd,J=12.7,8.2Hz,1H),7.85(s,1H), 7.69(d, J=7.9Hz, 1H), 7.63(d, J=8.4Hz, 1H), 7.57(d, J=8.1Hz, 1H), 6.54(s, 1H), 5.67(s, 2H), 4.49(q, J＝7.1Hz, 2H), 4.01(pd, J＝7.1, 2.8Hz, 4H), 2.13(s, 3H), 1.25–1.21(m, 3H), 1.22–1.14(m, 6H) .
步骤⑧：6-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-甲基吡啶-3-基膦酸(I-81)Step ⑧: 6-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-methylpyridin-3-ylphosphonic acid ( I-81)
Figure PCTCN2023071429-appb-000375
Figure PCTCN2023071429-appb-000375
氩气氛下将10毫克81-7，3.84毫克碘代三甲基硅烷和500微升二氯甲烷混合物室温搅拌4小时，反应液加入150微升甲醇淬灭后倒入5毫升水中抽滤得(6-((5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1H-苯并[d]咪唑-1-基)甲基)吡啶-3-基)膦酸(I-81)白色固体5毫克，收率56％。 1H NMR(400MHz,DMSO-d 6)δ13.03(s,1H),8.63(d,J＝6.5Hz,1H),8.10-7.91(m,1H),7.85(s,1H),7.67(d,J＝8.3Hz,1H),7.58(d,J＝8.3Hz,1H),7.46(d,J＝7.9Hz,1H),6.60(s,1H),5.62(s,2H),4.51(d,J＝7.4Hz,2H),2.14(s,3H),1.25(t,J＝7.0Hz,3H). Under an argon atmosphere, a mixture of 10 mg of 81-7, 3.84 mg of iodotrimethylsilane and 500 microliters of dichloromethane was stirred at room temperature for 4 hours, and the reaction solution was quenched by adding 150 microliters of methanol and poured into 5 milliliters of water to obtain ( 6-((5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)methyl) Pyridin-3-yl)phosphonic acid (I-81) white solid 5 mg, yield 56%. 1 H NMR (400MHz, DMSO-d 6 ) δ13.03(s, 1H), 8.63(d, J=6.5Hz, 1H), 8.10-7.91(m, 1H), 7.85(s, 1H), 7.67( d,J=8.3Hz,1H),7.58(d,J=8.3Hz,1H),7.46(d,J=7.9Hz,1H),6.60(s,1H),5.62(s,2H),4.51( d,J=7.4Hz,2H),2.14(s,3H),1.25(t,J=7.0Hz,3H).
实施例82 2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-基)乙基磷酸二氢酯(I-82)Example 82 2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-yl)ethyl dihydrogen phosphate (I -82)
Figure PCTCN2023071429-appb-000376
Figure PCTCN2023071429-appb-000376
步骤①：4-(2-羟乙基氨基)-3-硝基苯甲腈(82-1)Step ①: 4-(2-hydroxyethylamino)-3-nitrobenzonitrile (82-1)
Figure PCTCN2023071429-appb-000377
Figure PCTCN2023071429-appb-000377
将5克4-氯-3-硝基苯甲腈，3.3毫升乙醇胺，14.5毫升N,N-二异丙基乙胺和60毫升N,N-二甲基甲酰胺混合物100℃搅拌2小时。反应液倒入500毫升水中，过滤得4-(2-羟乙基氨基)-3-硝基苯甲腈(82-1)黄色固体4.6克，收率81％。ESI-MS(m/z)[M+H] +:208.1. A mixture of 5 g of 4-chloro-3-nitrobenzonitrile, 3.3 ml of ethanolamine, 14.5 ml of N,N-diisopropylethylamine and 60 ml of N,N-dimethylformamide was stirred at 100° C. for 2 hours. The reaction solution was poured into 500 ml of water, and filtered to obtain 4.6 g of 4-(2-hydroxyethylamino)-3-nitrobenzonitrile (82-1) as a yellow solid, with a yield of 81%. ESI-MS(m/z)[M+H] + :208.1.
步骤②：3-氨基-4-(2-羟乙基氨基)苯甲腈(82-2)Step ②: 3-amino-4-(2-hydroxyethylamino)benzonitrile (82-2)
Figure PCTCN2023071429-appb-000378
Figure PCTCN2023071429-appb-000378
氩气氛下将4.6克82-1，19.34克连二亚硫酸钠，4毫升氨水和50毫升甲醇混合物室温搅拌4小时。反应液过滤，滤液浓缩至干，残余物以二氯甲烷：甲醇＝98:2柱层析，得3-氨基-4-(2-羟乙基氨基)苯甲腈(82-2)粉色固体1.6克，收率41％。ESI-MS(m/z)[M+H] +:178.1. A mixture of 4.6 g of 82-1, 19.34 g of sodium dithionite, 4 ml of ammonia and 50 ml of methanol was stirred at room temperature for 4 hours under an argon atmosphere. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=98:2 to obtain 3-amino-4-(2-hydroxyethylamino)benzonitrile (82-2) as a pink solid 1.6 g, yield 41%. ESI-MS(m/z)[M+H] + :178.1.
步骤③：2-氨基-1-羟乙基-1H-苯并咪唑-5-甲腈(82-3)Step ③: 2-amino-1-hydroxyethyl-1H-benzimidazole-5-carbonitrile (82-3)
Figure PCTCN2023071429-appb-000379
Figure PCTCN2023071429-appb-000379
氩气氛下，将1.6克82-2，4.78克溴化氰和15毫升甲醇混合物室温搅拌4小时。反应液过滤得2-氨基-1-羟乙基-1H-苯并咪唑-5-甲腈(82-3)粉色固体1.8克，收率98％。 1H NMR(400MHz,DMSO-d 6)δ8.97(s,2H),7.83(s,1H),7.72(s,2H),4.27(s,2H),3.71(s,2H). Under an argon atmosphere, a mixture of 1.6 g of 82-2, 4.78 g of cyanogen bromide and 15 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was filtered to obtain 1.8 g of 2-amino-1-hydroxyethyl-1H-benzimidazole-5-carbonitrile (82-3) as a pink solid, with a yield of 98%. 1 H NMR (400MHz,DMSO-d 6 )δ8.97(s,2H),7.83(s,1H),7.72(s,2H),4.27(s,2H),3.71(s,2H).
步骤④：5-氰基-1-羟乙基-1H-苯并-2-咪唑-1-乙基-3-甲基吡唑-5-甲酰胺(82-4)Step ④: 5-cyano-1-hydroxyethyl-1H-benzo-2-imidazole-1-ethyl-3-methylpyrazole-5-carboxamide (82-4)
Figure PCTCN2023071429-appb-000380
Figure PCTCN2023071429-appb-000380
将500毫克82-3，2.8克2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，1.3 毫升N，N-二异丙基乙胺，765毫克1-乙基-3-甲基吡唑-5-羧酸和8毫升N,N-二甲基甲酰胺混合物室温搅拌4小时。反应液加入水中，过滤得5-氰基-1-羟乙基-1H-苯并-2-咪唑-1-乙基-3-甲基吡唑-5-甲酰胺(82-4)灰色固体760毫克，收率91％。 1H NMR(400MHz,DMSO-d 6)δ12.94(s,1H),7.81(s,1H),7.69(d,J＝1.6Hz,2H),6.68(s,1H),4.92(d,J＝6.0Hz,1H),4.60(q,J＝7.0Hz,2H),4.27(t,J＝5.3Hz,2H),3.79(d,J＝5.5Hz,2H),2.18(s,3H),1.35(t,J＝7.1Hz,3H). 500 mg of 82-3, 2.8 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1.3 ml of N,N-diiso A mixture of propylethylamine, 765 mg of 1-ethyl-3-methylpyrazole-5-carboxylic acid and 8 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was added to water and filtered to obtain 5-cyano-1-hydroxyethyl-1H-benzo-2-imidazole-1-ethyl-3-methylpyrazole-5-carboxamide (82-4) as a gray solid 760 mg, yield 91%. 1 H NMR (400MHz, DMSO-d 6 )δ12.94(s,1H),7.81(s,1H),7.69(d,J=1.6Hz,2H),6.68(s,1H),4.92(d, J＝6.0Hz, 1H), 4.60(q, J＝7.0Hz, 2H), 4.27(t, J＝5.3Hz, 2H), 3.79(d, J＝5.5Hz, 2H), 2.18(s, 3H) ,1.35(t,J=7.1Hz,3H).
步骤⑤：2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并噻唑-1-基)乙基磷酸二乙酯(82-5)Step ⑤: 2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzothiazol-1-yl) ethyl diethyl phosphate ( 82-5)
Figure PCTCN2023071429-appb-000381
Figure PCTCN2023071429-appb-000381
氩气氛下，将50毫克82-4，30微升氰基磷酸二乙酯，36微升三乙胺，300微升二氯甲烷和200微升二甲亚砜混合物室温搅拌4小时。反应液浓缩至干，残余物加水后以乙酸乙酯萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝20:1柱层析得2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并噻唑-1-基)乙基磷酸二乙酯(82-5)白色固体23毫克，收率34％。 1H NMR(400MHz,DMSO-d 6)δ12.98(s,1H),7.82(s,1H),7.74(d,J＝1.1Hz,2H),6.72(s,1H),4.60(q,J＝7.0Hz,2H),4.51(d,J＝5.1Hz,2H),4.44–4.28(m,2H),3.87–3.64(m,4H),2.18(s,3H),1.35(t,J＝7.1Hz,3H),1.03(td,J＝7.1,0.9Hz,6H). Under an argon atmosphere, a mixture of 50 mg of 82-4, 30 µl of diethylcyanophosphate, 36 µl of triethylamine, 300 µl of dichloromethane and 200 µl of dimethylsulfoxide was stirred at room temperature for 4 hours. The reaction solution was concentrated to dryness, the residue was extracted with ethyl acetate after adding water, and the organic phase was concentrated to dryness; -Ethyl-3-methylpyrazole-5-carboxamido)-1H-benzothiazol-1-yl)ethyl phosphate diethyl ester (82-5) white solid 23 mg, yield 34%. 1 H NMR (400MHz, DMSO-d 6 )δ12.98(s,1H),7.82(s,1H),7.74(d,J=1.1Hz,2H),6.72(s,1H),4.60(q, J＝7.0Hz, 2H), 4.51(d, J＝5.1Hz, 2H), 4.44–4.28(m, 2H), 3.87–3.64(m, 4H), 2.18(s, 3H), 1.35(t,J =7.1Hz,3H),1.03(td,J=7.1,0.9Hz,6H).
步骤⑥：2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-基)乙基磷酸二氢酯(I-82)Step ⑥: 2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-yl) ethyl dihydrogen phosphate (I -82)
Figure PCTCN2023071429-appb-000382
Figure PCTCN2023071429-appb-000382
氩气氛下，将20毫克82-5，47.8毫克碘代三甲基硅烷和400微升二氯甲烷混合物室温搅拌4小时，反应液加入50微升甲醇淬灭后倒入3毫升水中抽滤得棕色固体2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-基)乙基磷酸二氢酯(I-82)5mg，收率28％。 1H NMR(400MHz,DMSO-d 6)δ13.00(s,1H),7.82(s,2H),7.73(d,J＝8.5Hz,1H),6.68(s,1H),4.60(t,J＝7.0Hz,4H),3.65(t,J＝6.7Hz,2H),2.19(s,3H),1.40–1.32(m,3H). Under an argon atmosphere, a mixture of 20 mg of 82-5, 47.8 mg of iodotrimethylsilane and 400 μl of dichloromethane was stirred at room temperature for 4 hours, and the reaction solution was quenched by adding 50 μl of methanol and poured into 3 ml of water for suction filtration to obtain Brown solid 2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-yl)ethyl dihydrogen phosphate (I- 82) 5 mg, yield 28%. 1 H NMR (400MHz, DMSO-d 6 )δ13.00(s,1H),7.82(s,2H),7.73(d,J=8.5Hz,1H),6.68(s,1H),4.60(t, J＝7.0Hz, 4H), 3.65(t, J＝6.7Hz, 2H), 2.19(s, 3H), 1.40–1.32(m, 3H).
实施例83(2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-基)乙基) 苯基二氢磷酸酯(I-83)Example 83 (2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-yl)ethyl)phenyldihydro Phosphate (I-83)
Figure PCTCN2023071429-appb-000383
Figure PCTCN2023071429-appb-000383
步骤①：2-(4-(叔丁基二苯基硅氧基)苯基)乙烷-1-胺(83-1)Step ①: 2-(4-(tert-butyldiphenylsilyloxy)phenyl)ethane-1-amine (83-1)
Figure PCTCN2023071429-appb-000384
Figure PCTCN2023071429-appb-000384
将7克2-(4-(叔丁基二苯基硅氧基)苯基)乙烷-1-胺，7毫升三氟乙酸和70毫升二氯甲烷混合物室温搅拌6小时。反应液浓缩至干，加入80毫升乙醚，室温搅拌30分钟，过滤得2-(4-(叔丁基二苯基硅氧基)苯基)乙烷-1-胺(83-1)白色固体5.5克，收率99％。ESI-MS(m/z)[M+H] +:376.3. A mixture of 7 g of 2-(4-(tert-butyldiphenylsilyloxy)phenyl)ethan-1-amine, 7 ml of trifluoroacetic acid and 70 ml of dichloromethane was stirred at room temperature for 6 hours. The reaction solution was concentrated to dryness, 80 ml of ether was added, stirred at room temperature for 30 minutes, and filtered to obtain 2-(4-(tert-butyldiphenylsilyloxy)phenyl)ethan-1-amine (83-1) as a white solid 5.5 grams, yield 99%. ESI-MS(m/z)[M+H] + :376.3.
步骤②：4-((4-(叔丁基二苯基硅氧基)苯乙基氨基)-3-硝基苯甲腈(83-2)Step ②: 4-((4-(tert-butyldiphenylsilyloxy)phenethylamino)-3-nitrobenzonitrile (83-2)
Figure PCTCN2023071429-appb-000385
Figure PCTCN2023071429-appb-000385
将2克4-氯-3-硝基苯甲腈，4.95克83-1，4毫升N,N-二异丙基乙胺和70毫升N,N-二甲基甲酰胺混合物100℃搅拌2小时。反应液倒入500毫升水中，过滤得4-((4-(叔丁基二苯基硅氧基)苯乙基氨基)-3-硝基苯甲腈(83-2)黄色固体5.2克，收率91％。ESI-MS(m/z)[M+H] +:522.3. A mixture of 2 g of 4-chloro-3-nitrobenzonitrile, 4.95 g of 83-1, 4 ml of N,N-diisopropylethylamine and 70 ml of N,N-dimethylformamide was stirred at 100°C for 2 Hour. The reaction solution was poured into 500 ml of water, filtered to obtain 5.2 g of 4-((4-(tert-butyldiphenylsilyloxy)phenethylamino)-3-nitrobenzonitrile (83-2) yellow solid, Yield 91%.ESI-MS (m/z) [M+H] + :522.3.
步骤③：3-氨基-4-(4-(叔丁基二苯基硅氧基)苯乙基氨基)苯甲腈(83-3)Step ③: 3-amino-4-(4-(tert-butyldiphenylsilyloxy)phenethylamino)benzonitrile (83-3)
Figure PCTCN2023071429-appb-000386
Figure PCTCN2023071429-appb-000386
氩气氛下将5克83-2，8.35克连二亚硫酸钠，5毫升氨水和100毫升甲醇混合物室温搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1:1柱层析，得3-氨基-4-(4-(叔丁基二苯基硅氧基)苯乙基氨基)苯甲腈(83-3)粉色固体2.5克，收率53％。ESI-MS(m/z)[M+H] +:492.3. A mixture of 5 g of 83-2, 8.35 g of sodium dithionite, 5 ml of ammonia and 100 ml of methanol was stirred at room temperature for 4 hours under an argon atmosphere. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 3-amino-4-(4-(tert-butyldiphenylsilyloxy)phenethyl Amino)benzonitrile (83-3) pink solid 2.5 g, yield 53%. ESI-MS(m/z)[M+H] + :492.3.
步骤④：3-氨基-4-(4-(叔丁基二苯基硅氧基)苯乙基氨基)苯甲腈(83-4)Step ④: 3-amino-4-(4-(tert-butyldiphenylsilyloxy)phenethylamino)benzonitrile (83-4)
Figure PCTCN2023071429-appb-000387
Figure PCTCN2023071429-appb-000387
氩气氛下，将2.5克83-3，2.69克溴化氰和25毫升甲醇混合物室温搅拌2小时。反应液过滤得3-氨基-4-(4-(叔丁基二苯基硅氧基)苯乙基氨基)苯甲腈(83-4)白色固体2.3克，收率88％。ESI-MS(m/z)[M+H] +:517.3. Under an argon atmosphere, a mixture of 2.5 g of 83-3, 2.69 g of cyanogen bromide and 25 ml of methanol was stirred at room temperature for 2 hours. The reaction solution was filtered to obtain 2.3 g of 3-amino-4-(4-(tert-butyldiphenylsilyloxy)phenethylamino)benzonitrile (83-4) as a white solid, with a yield of 88%. ESI-MS(m/z)[M+H] + :517.3.
步骤⑤：N-(1-(4-((叔丁基二苯基甲硅基)氧基)苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(83-5)Step ⑤: N-(1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-5-cyano-1H-benzo[d]imidazol-2-yl)- 1-Ethyl-3-methyl-1H-pyrazole-5-carboxamide (83-5)
Figure PCTCN2023071429-appb-000388
Figure PCTCN2023071429-appb-000388
将1.6克83-4，2.36克2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，1.63毫升N，N-二异丙基乙胺，955毫克1-乙基-3-甲基吡唑-5-羧酸和20毫升N,N-二甲基甲酰胺混合物室温搅拌4小时。反应液加入水中，过滤得N-(1-(4-((叔丁基二苯基甲硅基)氧基)苯乙基)-5-氰基-1H-苯并[d]咪唑-2-基)-1-乙基-3-甲基-1H-吡唑-5-甲酰胺(83-5)灰色固体1.58克，收率78％。ESI-MS(m/z)[M+H] +:653.3. 1.6 g of 83-4, 2.36 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1.63 ml of N,N-diiso A mixture of propylethylamine, 955 mg of 1-ethyl-3-methylpyrazole-5-carboxylic acid and 20 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was added to water, filtered to obtain N-(1-(4-((tert-butyldiphenylsilyl)oxy)phenethyl)-5-cyano-1H-benzo[d]imidazole-2 -yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (83-5) gray solid 1.58 g, yield 78%. ESI-MS(m/z)[M+H] + :653.3.
步骤⑥：5-氰基-1-(4-羟基苯乙基)-1H-苯并-2-咪唑-1-乙基-3-甲基吡唑-5-甲酰胺(83-6)Step ⑥: 5-cyano-1-(4-hydroxyphenethyl)-1H-benzo-2-imidazole-1-ethyl-3-methylpyrazole-5-carboxamide (83-6)
Figure PCTCN2023071429-appb-000389
Figure PCTCN2023071429-appb-000389
氩气氛下将500毫克83-5溶于6毫升四氢呋喃，将1克四丁基氟化铵于0摄氏度下加入反应液室温搅拌2小时。反应液浓缩至干，残余物加水后以乙酸乙酯萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝30:1柱层析，得5-氰基-1-(4-羟基苯乙基)-1H-苯并-2-咪唑-1-乙基-3-甲基吡唑-5-甲酰胺(83-6)白色固体280毫克，收率88％。ESI-MS(m/z)[M+H] +:415.2. Under an argon atmosphere, 500 mg of 83-5 was dissolved in 6 ml of tetrahydrofuran, and 1 g of tetrabutylammonium fluoride was added to the reaction solution at 0°C and stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, the residue was extracted with ethyl acetate after adding water, and the organic phase was concentrated to dryness; the residue was subjected to column chromatography with dichloromethane:methanol=30:1 to obtain 5-cyano-1-(4-hydroxy Phenylethyl)-1H-benzo-2-imidazole-1-ethyl-3-methylpyrazole-5-carboxamide (83-6) 280 mg white solid, yield 88%. ESI-MS(m/z)[M+H] + :415.2.
步骤⑦：4-(2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并咪唑-1-基)乙基)苯基磷酸二乙酯(83-7)Step ⑦: 4-(2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzimidazol-1-yl)ethyl)benzene diethyl phosphate (83-7)
Figure PCTCN2023071429-appb-000390
Figure PCTCN2023071429-appb-000390
氩气氛下，将100毫克83-6，47.28毫克氰基磷酸二乙酯，67微升三乙胺，1毫升二氯甲烷和200微升二甲亚砜混合物室温搅拌1.5小时。反应液浓缩至干，残余物加水后以乙酸乙酯萃取，有机相浓缩至干；残余物以二氯甲烷：甲醇＝20:1柱层析得4-(2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并咪唑-1-基)乙基)苯基磷酸二乙酯(83-7)淡黄色固体50毫克，收率38％。 1H NMR(600MHz,CD 3OD)δ7.72(d,J＝1.5Hz,1H),7.48(dd,J＝8.4,1.5Hz,1H),7.27(d,J＝8.4Hz,1H),7.17–7.06(m,2H),7.05–6.95(m,2H),6.72(s,1H),4.66(q,J＝7.1Hz,2H),4.48(t,J＝6.8Hz,2H),4.19–4.07(m,4H),2.26(s,3H),1.40(t,J＝7.2Hz,3H),1.29(m,6H). Under an argon atmosphere, a mixture of 100 mg of 83-6, 47.28 mg of diethylcyanophosphate, 67 µl of triethylamine, 1 ml of methylene chloride and 200 µl of dimethylsulfoxide was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to dryness, the residue was extracted with ethyl acetate after adding water, and the organic phase was concentrated to dryness; -(1-Ethyl-3-methylpyrazole-5-carboxamido)-1H-benzimidazol-1-yl)ethyl)phenyl phosphate diethyl ester (83-7) pale yellow solid 50 mg , yield 38%. 1 H NMR (600MHz, CD 3 OD) δ 7.72 (d, J = 1.5Hz, 1H), 7.48 (dd, J = 8.4, 1.5Hz, 1H), 7.27 (d, J = 8.4Hz, 1H), 7.17–7.06(m,2H),7.05–6.95(m,2H),6.72(s,1H),4.66(q,J=7.1Hz,2H),4.48(t,J=6.8Hz,2H),4.19 –4.07(m,4H),2.26(s,3H),1.40(t,J=7.2Hz,3H),1.29(m,6H).
步骤⑧：4-(2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-基)乙基)苯基二氢磷酸酯(I-83)Step ⑧: 4-(2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-yl)ethyl)phenyl Dihydrogen Phosphate (I-83)
Figure PCTCN2023071429-appb-000391
Figure PCTCN2023071429-appb-000391
氩气氛下，将50毫克83-7，90.74毫克碘代三甲基硅烷和1毫升二氯甲烷混合物室温搅拌0.5小时，反应液加入150微升甲醇淬灭后倒入10毫升水中抽滤得黑色固体4-(2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并-1-基)乙基)苯基二氢磷酸酯(I-83)23mg，收率51％。 1H NMR(400MHz,CD 3OD)δ7.77(s,1H),7.54(d,J＝8.4Hz,1H),7.31(d,J＝8.3Hz,1H),7.11(s,4H),6.78(s,1H),4.72(q,J＝7.1Hz,2H),4.48(t,J＝7.0Hz,2H),3.14(t,J＝6.8Hz,2H),2.30(s,3H),1.45(t,J＝7.1Hz,3H). Under argon atmosphere, stir 50 mg of 83-7, 90.74 mg of iodotrimethylsilane and 1 ml of dichloromethane at room temperature for 0.5 hours, add 150 μl of methanol to quench the reaction solution and pour it into 10 ml of water to obtain a black Solid 4-(2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzo-1-yl)ethyl)phenyldihydro Phosphate (I-83) 23 mg, yield 51%. 1 H NMR (400MHz, CD 3 OD) δ7.77(s, 1H), 7.54(d, J=8.4Hz, 1H), 7.31(d, J=8.3Hz, 1H), 7.11(s, 4H), 6.78(s,1H),4.72(q,J=7.1Hz,2H),4.48(t,J=7.0Hz,2H),3.14(t,J=6.8Hz,2H),2.30(s,3H), 1.45(t,J=7.1Hz,3H).
实施例84 4-(2-(5-氰基-2-1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并噻唑-1-基乙氧基)甲基)苯基膦酸(I-84)Example 84 4-(2-(5-cyano-2-1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzothiazol-1-ylethoxy)methyl ) Phenylphosphonic acid (I-84)
Figure PCTCN2023071429-appb-000392
Figure PCTCN2023071429-appb-000392
步骤①：(2-(4-溴苄基)氧基)乙基氨基甲酸叔丁酯(84-1)Step ①: tert-butyl (2-(4-bromobenzyl)oxy)ethylcarbamate (84-1)
Figure PCTCN2023071429-appb-000393
Figure PCTCN2023071429-appb-000393
将1克1-溴-4-溴甲基苯，1毫升(2-羟乙基)氨基甲酸叔丁酯和0.368克钠氢和20毫升N，N-二甲基甲酰胺混合物室温搅拌3小时。反应液加水以乙酸乙酯萃取，有机相浓缩至干得1.23克(2-(4-溴苄基)氧基)乙基氨基甲酸叔丁酯(84-1)无色液体，收率58％。ESI-MS(m/z)[M+H] +:330.1. A mixture of 1 g of 1-bromo-4-bromomethylbenzene, 1 ml of (2-hydroxyethyl) tert-butyl carbamate and 0.368 g of sodium hydrogen and 20 ml of N, N-dimethylformamide was stirred at room temperature for 3 hours . The reaction solution was extracted with water and ethyl acetate, and the organic phase was concentrated to dryness to obtain 1.23 g of (2-(4-bromobenzyl)oxy)ethylcarbamate tert-butyl ester (84-1) as a colorless liquid, yield 58% . ESI-MS(m/z)[M+H] + :330.1.
步骤②：2-(4-溴苄氧基)乙胺(84-2)Step ②: 2-(4-Bromobenzyloxy)ethylamine (84-2)
Figure PCTCN2023071429-appb-000394
Figure PCTCN2023071429-appb-000394
将1.23克84-1，3毫升三氟乙酸和20毫升二氯甲烷混合物室温搅拌6小时。反应液浓缩至干，加入50毫升乙醚，室温搅拌30分钟，过滤得2-(4-溴苄氧基)乙胺(84-2)白色固体820毫克，收率96％。 1H NMR(400MHz,DMSO-d 6)δ7.90(s,3H),7.57(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),4.52(s,2H),3.61(t,J＝5.2Hz,2H),3.04(t,J＝5.2Hz,2H). A mixture of 1.23 g of 84-1, 3 ml of trifluoroacetic acid and 20 ml of dichloromethane was stirred at room temperature for 6 hours. The reaction solution was concentrated to dryness, 50 ml of diethyl ether was added, stirred at room temperature for 30 minutes, and 820 mg of white solid 2-(4-bromobenzyloxy)ethylamine (84-2) was obtained by filtration, with a yield of 96%. 1 H NMR (400MHz, DMSO-d 6 )δ7.90(s, 3H), 7.57(d, J=8.4Hz, 2H), 7.36(d, J=8.4Hz, 2H), 4.52(s, 2H) ,3.61(t,J=5.2Hz,2H),3.04(t,J=5.2Hz,2H).
步骤③：4-(2-(4-溴苄氧基)乙基氨基)-3-硝基苯甲腈(84-3)Step ③: 4-(2-(4-bromobenzyloxy)ethylamino)-3-nitrobenzonitrile (84-3)
Figure PCTCN2023071429-appb-000395
Figure PCTCN2023071429-appb-000395
将692毫克4-氯-3-硝基苯甲腈，820毫克84-2，1.31毫升N,N-二异丙基乙胺和20毫升N,N-二甲基甲酰胺混合物100℃搅拌2小时。反应液倒入250毫升水中，过滤得4-((4-(叔丁基二苯基硅氧基)苯乙基氨基)-3-硝基苯甲腈(84-3)黄色固体630毫克，收率45％。 1H NMR(400MHz,DMSO-d 6)δ8.65(s,1H),8.53(d,J＝2.1Hz,1H),7.83(ddd,J＝9.0,2.1,0.7Hz,1H),7.62–7.42(m,2H),7.26(dd,J＝13.0,8.7Hz,3H),4.52(s,2H),3.79–3.60(m,4H). 692 mg of 4-chloro-3-nitrobenzonitrile, 820 mg of 84-2, 1.31 ml of N,N-diisopropylethylamine and 20 ml of N,N-dimethylformamide were stirred at 100°C for 2 Hour. The reaction solution was poured into 250 ml of water, filtered to obtain 630 mg of 4-((4-(tert-butyldiphenylsilyloxy)phenethylamino)-3-nitrobenzonitrile (84-3) yellow solid, Yield 45% .1 H NMR (400MHz, DMSO-d 6 )δ8.65(s,1H),8.53(d,J=2.1Hz,1H),7.83(ddd,J=9.0,2.1,0.7Hz, 1H),7.62–7.42(m,2H),7.26(dd,J＝13.0,8.7Hz,3H),4.52(s,2H),3.79–3.60(m,4H).
步骤④：3-氨基-4-(2-((4-溴苄氧基)乙基)氨基)苯甲腈(84-4)Step ④: 3-amino-4-(2-((4-bromobenzyloxy)ethyl)amino)benzonitrile (84-4)
Figure PCTCN2023071429-appb-000396
Figure PCTCN2023071429-appb-000396
氩气氛下，将630毫克84-3，2.91克连二亚硫酸钠，0.6毫升氨水和15毫升甲醇混合物室温搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1:1柱层析，得3-氨基-4-(4-(叔丁基二苯基硅氧基)苯乙基氨基)苯甲腈(84-4)粉色固体132毫克，收率23％。ESI-MS(m/z)[M+H] +:346.1. Under an argon atmosphere, a mixture of 630 mg of 84-3, 2.91 g of sodium dithionite, 0.6 ml of ammonia and 15 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 3-amino-4-(4-(tert-butyldiphenylsilyloxy)phenethyl Amino)benzonitrile (84-4) pink solid 132 mg, yield 23%. ESI-MS(m/z)[M+H] + :346.1.
步骤⑤：2-氨基-1-(2-((4-溴苄基)氧基)乙基)-1H-苯并咪唑-5-甲腈(84-5)Step ⑤: 2-amino-1-(2-((4-bromobenzyl)oxy)ethyl)-1H-benzimidazole-5-carbonitrile (84-5)
Figure PCTCN2023071429-appb-000397
Figure PCTCN2023071429-appb-000397
氩气氛下，将132毫克84-4，202毫克溴化氰和2毫升甲醇混合物室温搅拌2小时。反应液过滤得2-氨基-1-(2-((4-溴苄基)氧基)乙基)-1H-苯并咪唑-5-甲腈(84-5)白色固体140毫克，收率99％。 1H NMR(400MHz,DMSO-d 6)δ8.95(s,2H),7.83(d,J＝1.4Hz,1H),7.77–7.65(m,2H),7.51–7.32(m,2H),7.08(d,J＝8.2Hz,2H),4.43(d,J＝4.5Hz,4H),3.74(t,J＝5.0Hz,2H). Under an argon atmosphere, a mixture of 132 mg of 84-4, 202 mg of cyanogen bromide and 2 ml of methanol was stirred at room temperature for 2 hours. The reaction solution was filtered to obtain 140 mg of 2-amino-1-(2-((4-bromobenzyl)oxy)ethyl)-1H-benzimidazole-5-carbonitrile (84-5) as a white solid, yield 99%. 1 H NMR (400MHz,DMSO-d 6 )δ8.95(s,2H),7.83(d,J＝1.4Hz,1H),7.77–7.65(m,2H),7.51–7.32(m,2H), 7.08(d, J=8.2Hz, 2H), 4.43(d, J=4.5Hz, 4H), 3.74(t, J=5.0Hz, 2H).
步骤⑥：N-(1-(2-((4-溴苄氧基)乙基)-5-氰基-1H-苯并咪唑-2-基)-1-乙基-3-甲基吡唑-5-甲腈(84-6)Step ⑥: N-(1-(2-((4-bromobenzyloxy)ethyl)-5-cyano-1H-benzimidazol-2-yl)-1-ethyl-3-methylpyridine Azole-5-carbonitrile (84-6)
Figure PCTCN2023071429-appb-000398
Figure PCTCN2023071429-appb-000398
将140毫克84-5，172.1毫克2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，131.38毫升N，N-二异丙基乙胺，69.69毫克1-乙基-3-甲基吡唑-5-羧酸和5毫升N,N-二甲基甲酰胺混合物室温搅拌4小时。反应液加入水中，过滤得N-(1-(2-((4-溴苄氧基)乙基)-5-氰基-1H-苯并咪唑-2-基)-1-乙基-3-甲基吡唑-5-甲酰胺(84-6)灰色固体108.2毫克，收率57％。 1H NMR(400MHz,DMSO-d 6)δ12.88(s,1H),7.82(s,1H),7.76–7.64(m,2H),7.39(d,J＝8.0Hz,2H),7.06(d,J＝8.1Hz,2H),6.66(s,1H),4.58(q,J＝7.1Hz,2H),4.45(d,J＝7.1Hz,4H),3.83(t,J＝5.2Hz,2H),2.18(s,3H),1.34(t,J＝7.1Hz,3H). 140 mg 84-5, 172.1 mg 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 131.38 ml N,N-diiso A mixture of propylethylamine, 69.69 mg of 1-ethyl-3-methylpyrazole-5-carboxylic acid and 5 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was added to water, filtered to obtain N-(1-(2-((4-bromobenzyloxy)ethyl)-5-cyano-1H-benzimidazol-2-yl)-1-ethyl-3 -Methylpyrazole-5-carboxamide (84-6) gray solid 108.2 mg, yield 57%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.88(s, 1H), 7.82(s, 1H ),7.76–7.64(m,2H),7.39(d,J=8.0Hz,2H),7.06(d,J=8.1Hz,2H),6.66(s,1H),4.58(q,J=7.1Hz ,2H),4.45(d,J=7.1Hz,4H),3.83(t,J=5.2Hz,2H),2.18(s,3H),1.34(t,J=7.1Hz,3H).
步骤⑦：(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1H-苯并咪唑-1-基)乙氧基)甲基)苯基)膦酸二乙酯(84-7)Step ⑦: (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzimidazol-1-yl) Ethoxy)methyl)phenyl)phosphonic acid diethyl ester (84-7)
Figure PCTCN2023071429-appb-000399
Figure PCTCN2023071429-appb-000399
氩气氛下，将100毫克84-6，23毫克四三苯基磷钯，40微升亚磷酸二乙酯，55微升三乙胺和2毫升无水四氢呋喃混合物90℃封管搅拌6小时。反应液浓缩，残余物以石油醚：乙酸乙酯＝1:1柱层析得(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺 基)-1H-苯并咪唑-1-基)乙氧基)甲基)苯基)膦酸二乙酯(84-7)灰色固体55毫克，收率49％。 1H NMR(400MHz,DMSO-d 6)δ12.96(s,1H),7.82(s,1H),7.72(q,J＝8.4Hz,2H),7.55(dd,J＝12.9,7.7Hz,2H),7.26(dd,J＝8.0,3.9Hz,2H),6.68(s,1H),4.58(d,J＝10.7Hz,4H),4.49(t,J＝5.2Hz,2H),3.97(p,J＝7.0Hz,4H),3.87(t,J＝5.2Hz,2H),2.17(s,3H),1.33(t,J＝7.1Hz,3H),1.20(t,J＝7.1Hz,6H). Under an argon atmosphere, a mixture of 100 mg of 84-6, 23 mg of tetrakistriphenylphosphopalladium, 40 μl of diethyl phosphite, 55 μl of triethylamine and 2 ml of anhydrous tetrahydrofuran was sealed and stirred at 90°C for 6 hours. The reaction solution was concentrated, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole Diethyl-5-formamido)-1H-benzimidazol-1-yl)ethoxy)methyl)phenyl)phosphonate (84-7) 55 mg gray solid, yield 49%. 1 H NMR (400MHz, DMSO-d 6 )δ12.96(s,1H),7.82(s,1H),7.72(q,J=8.4Hz,2H),7.55(dd,J=12.9,7.7Hz, 2H), 7.26(dd, J=8.0, 3.9Hz, 2H), 6.68(s, 1H), 4.58(d, J=10.7Hz, 4H), 4.49(t, J=5.2Hz, 2H), 3.97( p, J=7.0Hz, 4H), 3.87(t, J=5.2Hz, 2H), 2.17(s, 3H), 1.33(t, J=7.1Hz, 3H), 1.20(t, J=7.1Hz, 6H).
步骤⑧：(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1H-苯并咪唑-1-基)乙氧基)甲基)苯基)膦酸(I-84)Step ⑧: (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzimidazol-1-yl) Ethoxy)methyl)phenyl)phosphonic acid (I-84)
Figure PCTCN2023071429-appb-000400
Figure PCTCN2023071429-appb-000400
氩气氛下，将10毫克84-7，35.46毫克碘代三甲基硅烷和500微升二氯甲烷混合物室温搅拌0.5小时，反应液加入50微升甲醇淬灭后倒入3毫升水中抽滤得(4-(2-(5-氰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-1H-苯并咪唑-1-基)乙氧基)甲基)苯基)膦酸(I-84)黑色固体1.3mg，收率14％。 1H NMR(400MHz,DMSO-d 6)δ12.96(s,1H),7.82(s,1H),7.74(q,J＝8.6Hz,2H),7.55(m,2H),7.20(d,J＝7.6Hz,2H),6.70(s,1H),4.55(m,6H),3.86(s,2H),2.18(s,3H),1.35(t,J＝7.2Hz,3H). Under an argon atmosphere, a mixture of 10 mg of 84-7, 35.46 mg of iodotrimethylsilane and 500 μl of dichloromethane was stirred at room temperature for 0.5 hours, and the reaction solution was quenched by adding 50 μl of methanol and poured into 3 ml of water for suction filtration to obtain (4-(2-(5-cyano-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzimidazol-1-yl)ethoxy )methyl)phenyl)phosphonic acid (I-84) black solid 1.3 mg, yield 14%. 1 H NMR (400MHz, DMSO-d 6 )δ12.96(s,1H),7.82(s,1H),7.74(q,J=8.6Hz,2H),7.55(m,2H),7.20(d, J＝7.6Hz, 2H), 6.70(s, 1H), 4.55(m, 6H), 3.86(s, 2H), 2.18(s, 3H), 1.35(t, J＝7.2Hz, 3H).
实施例85 4-(2-(5-氰基-2-(1-乙基-3-甲基吡唑-5-甲酰胺基)-1H-苯并噻唑-1-基)乙氧基)甲基)苯基膦酸(I-85)Example 85 4-(2-(5-cyano-2-(1-ethyl-3-methylpyrazole-5-carboxamido)-1H-benzothiazol-1-yl)ethoxy) Methyl)phenylphosphonic acid (I-85)
Figure PCTCN2023071429-appb-000401
Figure PCTCN2023071429-appb-000401
步骤①：4-氯-3-甲氧基-5-硝基苯甲酰胺(85-1)Step ①: 4-chloro-3-methoxy-5-nitrobenzamide (85-1)
Figure PCTCN2023071429-appb-000402
Figure PCTCN2023071429-appb-000402
将4克4-氯-3-甲氧基-5-硝基苯甲酸甲酯溶于50毫升氨水，50摄氏度搅拌6小时，反应液加入200毫升水中，抽滤得4-氯-3-甲氧基-5-硝基苯甲酰胺(85-1)黄色固体3.26克，收率87％。 1H NMR(400MHz,DMSO-d 6)δ8.28(s,1H),8.03(d,J＝1.8Hz,1H),7.86(d,J＝1.9Hz,1H),7.77(s,1H),4.00(s,3H). Dissolve 4 grams of 4-chloro-3-methoxy-5-nitrobenzoic acid methyl ester in 50 ml of ammonia water, stir at 50 degrees Celsius for 6 hours, add the reaction solution to 200 ml of water, and suction filter to obtain 4-chloro-3-methyl Oxy-5-nitrobenzamide (85-1) 3.26 g of yellow solid, yield 87%. 1 H NMR (400MHz, DMSO-d 6 )δ8.28(s, 1H), 8.03(d, J=1.8Hz, 1H), 7.86(d, J=1.9Hz, 1H), 7.77(s, 1H) ,4.00(s,3H).
步骤②：1-溴-4-(2-溴乙氧基)苯(85-2)Step ②: 1-bromo-4-(2-bromoethoxy)benzene (85-2)
Figure PCTCN2023071429-appb-000403
Figure PCTCN2023071429-appb-000403
将3克85-1，5.04克三苯基磷，2.14克四溴化碳和25毫升四氢呋喃的混合物室温搅拌30分钟。反应液浓缩，残余物以100％石油醚柱层析得1-溴-4-(2-溴乙氧基)苯(85-2)白色固体3.56克，收率92％。 1H NMR(400MHz,DMSO-d 6)δ7.68–7.29(m,2H),7.13–6.77(m,2H),4.41–4.15(m,2H),3.78(dd,J＝6.1,4.7Hz,2H). A mixture of 3 g of 85-1, 5.04 g of triphenylphosphine, 2.14 g of carbon tetrabromide and 25 ml of tetrahydrofuran was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was subjected to 100% petroleum ether column chromatography to obtain 3.56 g of 1-bromo-4-(2-bromoethoxy)benzene (85-2) as a white solid, with a yield of 92%. 1 H NMR (400MHz,DMSO-d 6 )δ7.68–7.29(m,2H),7.13–6.77(m,2H),4.41–4.15(m,2H),3.78(dd,J＝6.1,4.7Hz ,2H).
步骤③：2-(2-(4-溴苯氧基)乙基)异吲哚啉-1，3-二酮(85-3)Step ③: 2-(2-(4-bromophenoxy)ethyl)isoindoline-1,3-dione (85-3)
Figure PCTCN2023071429-appb-000404
Figure PCTCN2023071429-appb-000404
将3.56克85-2，4.71克邻苯二甲酰亚胺钾和30毫升N,N-二甲基甲酰胺混合物与室温搅拌6小时。反应液加300毫升水，析出固体，抽滤得2-(2-(4-溴苯氧基)乙基)异吲哚啉-1，3-二酮(85-3)白色固体4.38克，收率99％。 1H NMR(400MHz,DMSO-d 6)δ7.98–7.63(m,4H),7.49–7.27(m,2H),6.89–6.77(m,2H),4.19(t,J＝5.7Hz,2H),3.93(t,J＝5.7Hz,2H). A mixture of 3.56 g of 85-2, 4.71 g of potassium phthalimide and 30 ml of N,N-dimethylformamide was stirred at room temperature for 6 hours. 300 ml of water was added to the reaction solution to precipitate a solid, which was suction filtered to obtain 4.38 g of 2-(2-(4-bromophenoxy)ethyl)isoindoline-1,3-dione (85-3) as a white solid. Yield 99%. 1 H NMR (400MHz, DMSO-d 6 )δ7.98–7.63(m,4H),7.49–7.27(m,2H),6.89–6.77(m,2H),4.19(t,J＝5.7Hz,2H ),3.93(t,J=5.7Hz,2H).
步骤④：2-(4-溴苯氧基)乙烷-1-胺(85-4)Step ④: 2-(4-Bromophenoxy)ethane-1-amine (85-4)
Figure PCTCN2023071429-appb-000405
Figure PCTCN2023071429-appb-000405
将4.3克85-3，1.4毫升水合肼，100毫升乙醇混合物80摄氏度搅拌3小时。反应液抽滤，滤液浓缩至干，得2-(4-溴苯氧基)乙烷-1-胺(85-4)白色固体1.4克，收率52％。ESI-MS(m/z)[M+H] +:216.1. A mixture of 4.3 g of 85-3, 1.4 ml of hydrazine hydrate and 100 ml of ethanol was stirred at 80°C for 3 hours. The reaction solution was filtered with suction, and the filtrate was concentrated to dryness to obtain 1.4 g of 2-(4-bromophenoxy)ethan-1-amine (85-4) as a white solid, with a yield of 52%. ESI-MS(m/z)[M+H] + :216.1.
步骤⑤：4-(2-(4-溴苯氧基)乙基)氨基)-3-甲氧基-5-硝基苯甲酰胺(85-5)Step ⑤: 4-(2-(4-bromophenoxy)ethyl)amino)-3-methoxy-5-nitrobenzamide (85-5)
Figure PCTCN2023071429-appb-000406
Figure PCTCN2023071429-appb-000406
将1.4克85-4，1.5克5-1，3毫升N,N-二异丙基乙胺和20毫升N,N-二甲基甲酰胺混合物于100摄氏度搅拌1小时。反应液加入300毫升水中，抽滤得4-(2-(4-溴苯氧基)乙基)氨基)-3-甲氧基-5-硝基苯甲酰胺(85-5)白色固体1.36克，收率51％。ESI-MS(m/z)[M+H] +:410.1. A mixture of 1.4 g of 85-4, 1.5 g of 5-1, 3 ml of N,N-diisopropylethylamine and 20 ml of N,N-dimethylformamide was stirred at 100°C for 1 hour. The reaction solution was added to 300 ml of water, and suction filtered to obtain 4-(2-(4-bromophenoxy)ethyl)amino)-3-methoxy-5-nitrobenzamide (85-5) as a white solid 1.36 grams, yield 51%. ESI-MS(m/z)[M+H] + :410.1.
步骤⑥：3-氨基-4-(2-(4-溴苯氧基)乙基)氨基)-5-甲氧基苯甲酰胺(85-6)Step ⑥: 3-amino-4-(2-(4-bromophenoxy)ethyl)amino)-5-methoxybenzamide (85-6)
Figure PCTCN2023071429-appb-000407
Figure PCTCN2023071429-appb-000407
氩气氛下，将1.36克85-5，2.88克连二亚硫酸钠，1毫升氨水和15毫升甲醇混合物室温搅拌4小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1:1柱层析，得3-氨基-4-(2-(4-溴苯氧基)乙基)氨基)-5-甲氧基苯甲酰胺(85-6)粉色固体280毫克，收率22％。 1H NMR(400MHz,DMSO-d 6)δ7.63(s,1H),7.45(d,J＝8.9Hz,2H),6.99(s,1H),6.95–6.85(m,3H),6.78(d,J＝1.9Hz,1H),4.77(s,2H),4.12(s,1H),3.99(t,J＝5.3Hz,2H),3.70(s,3H),3.29(s,2H). Under an argon atmosphere, a mixture of 1.36 g of 85-5, 2.88 g of sodium dithionite, 1 ml of ammonia and 15 ml of methanol was stirred at room temperature for 4 hours. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 1:1 to obtain 3-amino-4-(2-(4-bromophenoxy)ethyl)amino)- 5-methoxybenzamide (85-6) 280 mg of pink solid, yield 22%. 1 H NMR (400MHz, DMSO-d 6 ) δ7.63(s, 1H), 7.45(d, J=8.9Hz, 2H), 6.99(s, 1H), 6.95–6.85(m, 3H), 6.78( d, J=1.9Hz, 1H), 4.77(s, 2H), 4.12(s, 1H), 3.99(t, J=5.3Hz, 2H), 3.70(s, 3H), 3.29(s, 2H).
步骤⑦：2-氨基-1-(2-(4-溴苯氧基)乙基)-7-甲氧基-1H-苯并咪唑-5-甲酰胺(85-7)Step ⑦: 2-amino-1-(2-(4-bromophenoxy)ethyl)-7-methoxy-1H-benzimidazole-5-carboxamide (85-7)
Figure PCTCN2023071429-appb-000408
Figure PCTCN2023071429-appb-000408
氩气氛下，将280毫克85-6，390毫克溴化氰和2毫升甲醇混合物室温搅拌2小时。反应液过滤得2-氨基-1-(2-(4-溴苯氧基)乙基)-7-甲氧基-1H-苯并咪唑-5-甲酰胺(85-7)白色固体295毫克，收率98％。 1H NMR(400MHz,DMSO-d 6)δ8.70(s,2H),8.09(s,1H),7.50(d,J＝1.3Hz,1H),7.47–7.40(m,4H),7.00–6.37(m,2H),4.65(d,J＝5.7Hz,2H),4.32(t,J＝5.2Hz,2H),3.91(s,3H). Under an argon atmosphere, a mixture of 280 mg of 85-6, 390 mg of cyanogen bromide and 2 ml of methanol was stirred at room temperature for 2 hours. The reaction solution was filtered to obtain 295 mg of white solid 2-amino-1-(2-(4-bromophenoxy)ethyl)-7-methoxy-1H-benzimidazole-5-carboxamide (85-7) , yield 98%. 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,2H),8.09(s,1H),7.50(d,J=1.3Hz,1H),7.47–7.40(m,4H),7.00– 6.37(m, 2H), 4.65(d, J=5.7Hz, 2H), 4.32(t, J=5.2Hz, 2H), 3.91(s, 3H).
步骤⑧：1-(2-(4-溴苯氧基)乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并咪唑-5-甲酰胺(85-8)Step ⑧: 1-(2-(4-bromophenoxy)ethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy -1H-benzimidazole-5-carboxamide (85-8)
Figure PCTCN2023071429-appb-000409
Figure PCTCN2023071429-appb-000409
将150毫克85-7，185毫克2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，163微升N，N-二异丙基乙胺，74.15毫克1-乙基-3-甲基吡唑-5-羧酸和3毫升N,N-二甲基甲酰胺混合物室温搅拌4小时。反应液加入水中，过滤得1-(2-(4-溴苯氧基)乙基)-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并咪唑-5-甲酰胺(85-8)灰色固体100毫克，收率50％。 1H NMR(400MHz,DMSO-d 6)δ12.87(s,1H),8.01(s,1H),7.67(s,1H),7.51–7.27(m,4H),6.90(d,J＝8.6Hz,2H),6.45(s,1H),4.70(d,J＝6.1Hz,2H),4.58(q,J＝7.1Hz,2H),4.41(t,J＝5.8Hz,2H),3.92(s,3H),2.17(s,3H),1.33(t,J＝7.1Hz,3H). 150 mg 85-7, 185 mg 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 163 μl N,N-di A mixture of isopropylethylamine, 74.15 mg of 1-ethyl-3-methylpyrazole-5-carboxylic acid and 3 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was added to water, filtered to obtain 1-(2-(4-bromophenoxy)ethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7 -Methoxy-1H-benzimidazole-5-carboxamide (85-8) gray solid 100 mg, yield 50%. 1 H NMR (400MHz,DMSO-d 6 )δ12.87(s,1H),8.01(s,1H),7.67(s,1H),7.51–7.27(m,4H),6.90(d,J=8.6 Hz, 2H), 6.45(s, 1H), 4.70(d, J=6.1Hz, 2H), 4.58(q, J=7.1Hz, 2H), 4.41(t, J=5.8Hz, 2H), 3.92( s,3H),2.17(s,3H),1.33(t,J=7.1Hz,3H).
步骤⑨：(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲 氧基-1H-苯并咪唑-1-基乙氧基)苯基)膦酸二乙酯(85-9)Step ⑨: (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzene Imidazol-1-ylethoxy)phenyl)phosphonic acid diethyl ester (85-9)
Figure PCTCN2023071429-appb-000410
Figure PCTCN2023071429-appb-000410
氩气氛下，将50毫克85-8，16毫克四三苯基磷钯，18微升亚磷酸二乙酯，26微升三乙胺和2毫升无水四氢呋喃混合物90℃封管搅拌6小时。反应液浓缩，残余物以石油醚：乙酸乙酯＝2:1柱层析得((4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并咪唑-1-基乙氧基)苯基)膦酸二乙酯(85-9)白色固体36毫克，收率65％。 1H NMR(400MHz,DMSO-d 6)δ12.89(s,1H),8.04(s,1H),7.68(s,1H),7.60(t,J＝10.6Hz,2H),7.41(s,2H),7.08(s,2H),6.59(s,1H),4.75(s,2H),4.60(d,J＝7.2Hz,2H),4.49(s,2H),3.99–3.86(m,7H),2.18(s,3H),1.35(t,J＝7.2Hz,3H),1.20(t,J＝7.1Hz,6H). Under an argon atmosphere, a mixture of 50 mg of 85-8, 16 mg of tetrakistriphenylphosphopalladium, 18 μl of diethyl phosphite, 26 μl of triethylamine and 2 ml of anhydrous tetrahydrofuran was sealed and stirred at 90°C for 6 hours. The reaction solution was concentrated, and the residue was purified by column chromatography with petroleum ether: ethyl acetate = 2:1 ((4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H- Pyrazole-5-carboxamido)-7-methoxy-1H-benzimidazol-1-ylethoxy)phenyl)phosphonic acid diethyl ester (85-9) white solid 36 mg, yield 65 % .1 H NMR (400MHz, DMSO-d 6 ) δ12.89(s, 1H), 8.04(s, 1H), 7.68(s, 1H), 7.60(t, J=10.6Hz, 2H), 7.41( s,2H),7.08(s,2H),6.59(s,1H),4.75(s,2H),4.60(d,J＝7.2Hz,2H),4.49(s,2H),3.99–3.86(m ,7H),2.18(s,3H),1.35(t,J=7.2Hz,3H),1.20(t,J=7.1Hz,6H).
步骤⑩：(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并咪唑-1-基乙氧基)苯基)膦酸二乙酯(I-85)Step ⑩: (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzene Imidazol-1-ylethoxy)phenyl)phosphonic acid diethyl ester (I-85)
Figure PCTCN2023071429-appb-000411
Figure PCTCN2023071429-appb-000411
氩气氛下，将10毫克85-9，16.7毫克碘代三甲基硅烷和500微升二氯甲烷混合物室温搅拌1小时，反应液加入30微升甲醇淬灭后倒入3毫升水中抽滤得(4-(2-(5-氨基甲酰基-2-(1-乙基-3-甲基-1H-吡唑-5-甲酰胺基)-7-甲氧基-1H-苯并咪唑-1-基乙氧基)苯基)膦酸二乙酯(I-85)黑色固体3.8mg，收率42％。 1H NMR(400MHz,DMSO-d 6)δ12.89(s,1H),8.04(s,1H),7.68(s,1H),7.60(t,J＝10.6Hz,2H),7.41(s,2H),7.08(s,2H),6.59(s,1H),4.75(s,2H),4.60(d,J＝7.2Hz,2H),4.49(s,2H),3.90(s,3H),2.18(s,3H),1.35(t,J＝7.2Hz,3H). Under an argon atmosphere, a mixture of 10 mg of 85-9, 16.7 mg of iodotrimethylsilane and 500 μl of dichloromethane was stirred at room temperature for 1 hour, and the reaction solution was quenched by adding 30 μl of methanol and poured into 3 ml of water for suction filtration to obtain (4-(2-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzimidazole- 1-ylethoxy)phenyl)phosphonic acid diethyl ester (I-85) black solid 3.8 mg, yield 42%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.89 (s, 1H), 8.04(s,1H),7.68(s,1H),7.60(t,J=10.6Hz,2H),7.41(s,2H),7.08(s,2H),6.59(s,1H),4.75(s ,2H),4.60(d,J=7.2Hz,2H),4.49(s,2H),3.90(s,3H),2.18(s,3H),1.35(t,J=7.2Hz,3H).
实施例86化合物对ENPP1酶的抑制活性测试The inhibitory activity test of embodiment 86 compound to ENPP1 enzyme
1、实验方法1. Experimental method
将384孔板置于冰上，将5μl Reaction buffer(20mM Tris(pH 7.4),250nM NaCl,500μM CaCl 2,1μM ZnCl 2)和1μl化合物溶液(用PBS溶液稀释)，2μl ENPP1蛋白溶液(150nM，用PBS溶液配制)混合均匀，各设3个复孔，并设置阴性和阳性化合物对照。封膜，振荡混匀，500g离心1分钟，置于室温或者37℃的培养箱中孵育1小时；1小时后，每孔中加入2μl 2’3’-cGAMP溶液(5μM,LAL water稀释)，封膜，振荡混匀，500g离心1分钟，置于室温或者37℃的培养箱中孵育1小时；孵育完成后， 将384孔板置于95℃水浴中加热10分钟，终止酶活反应。检测产物AMP荧光反应：按照AMP-Glo TM Assay试剂盒说明，每孔加入10μl Reagent I，轻度混匀，离心使液体保持在底部，置于室温或者37℃的培养箱中1小时；1小时后加入20μl AMP Detection Solution(
Figure PCTCN2023071429-appb-000412
One Solution:Reagent II＝1ml:10μl；冰上配制，现配现用)，振荡混匀，轻度离心，使液体始终保持在底部，置于室温或者37℃培养箱中避光孵育1小时；1小时后使用酶标仪测定荧光值(luminescence)。其中化合物的筛选浓度为10μM和1μM。 Put the 384-well plate on ice, put 5μl Reaction buffer (20mM Tris (pH 7.4), 250nM NaCl, 500μM CaCl 2 , 1μM ZnCl 2 ) and 1μl compound solution (diluted with PBS solution), 2μl ENPP1 protein solution (150nM, Prepared with PBS solution) and mixed evenly, each set up 3 duplicate wells, and set negative and positive compound controls. Seal the membrane, shake and mix well, centrifuge at 500g for 1 minute, and incubate at room temperature or in an incubator at 37°C for 1 hour; after 1 hour, add 2 μl of 2'3'-cGAMP solution (5 μM, diluted in LAL water) to each well, Seal the film, shake and mix well, centrifuge at 500g for 1 minute, and incubate at room temperature or in an incubator at 37°C for 1 hour; after incubation, heat the 384-well plate in a 95°C water bath for 10 minutes to terminate the enzymatic reaction. Detection of product AMP fluorescence reaction: According to the instructions of the AMP-Glo TM Assay kit, add 10 μl Reagent I to each well, mix gently, centrifuge to keep the liquid at the bottom, and place it in an incubator at room temperature or 37°C for 1 hour; 1 hour Then add 20μl AMP Detection Solution (
Figure PCTCN2023071429-appb-000412
One Solution: Reagent II＝1ml:10μl; prepared on ice, ready to use), vortexed to mix, gently centrifuged to keep the liquid at the bottom, and incubated at room temperature or in a 37°C incubator in the dark for 1 hour; After 1 hour, the fluorescence value (luminescence) was measured using a microplate reader. The screening concentrations of the compounds are 10 μM and 1 μM.
结果分析：抑制率(％)＝100×(AMP average negative control-AMP sample)/AMP average  negative control。 Result analysis: Inhibition rate (%)=100×(AMP average negative control -AMP sample )/AMP average negative control .
2、实验结果2. Experimental results
测试结果表明化合物Ⅰ-8、Ⅰ-9、Ⅰ-10、Ⅰ-11、Ⅰ-12、Ⅰ-13、Ⅰ-15、Ⅰ-16等8个化合物在10μM浓度对ENPP1抑制率为86-93％，明显优于阳性药ENPP1-IN-1(WO2019046778 A1实施例55)(表1)；且化合物Ⅰ-9、Ⅰ-11、Ⅰ-12、Ⅰ-13、Ⅰ-16对ENPP1活性抑制IC 50值为86-647nM，表明其对ENPP1的抑制率明显高于阳性药ENPP1-IN-1(表2)。 The test results showed that 8 compounds, including compounds I-8, I-9, I-10, I-11, I-12, I-13, I-15, and I-16, had an inhibitory rate of 86-93% to ENPP1 at a concentration of 10 μM. %, significantly better than the positive drug ENPP1-IN-1 (WO2019046778 A1 Example 55) (Table 1); and compound Ⅰ-9, Ⅰ-11, Ⅰ-12, Ⅰ-13, Ⅰ-16 inhibited IC of ENPP1 activity The 50 value was 86-647nM, indicating that its inhibitory rate to ENPP1 was significantly higher than that of the positive drug ENPP1-IN-1 (Table 2).
ENPP1-IN-1的结构：
Figure PCTCN2023071429-appb-000413
The structure of ENPP1-IN-1:
Figure PCTCN2023071429-appb-000413
表1.化合物对ENPP1抑制活性(10μM)Table 1. Compounds' inhibitory activity against ENPP1 (10 μM)
Figure PCTCN2023071429-appb-000414
Figure PCTCN2023071429-appb-000414
Figure PCTCN2023071429-appb-000415
Figure PCTCN2023071429-appb-000415
表2.化合物对ENPP1活性抑制IC 50 Table 2. IC 50 of Compounds Inhibiting ENPP1 Activity
Figure PCTCN2023071429-appb-000416
Figure PCTCN2023071429-appb-000416
实施例87化合物对人源THP1-Dual细胞中I型干扰素通路(ISG)的激活Example 87 Compounds Activate Type I Interferon Pathway (ISG) in Human THP1-Dual Cells
1、实验方法1. Experimental method
200μl(96孔板，透明平底)每孔，包含2μl 2’3’-cGAMP溶液或者化合物溶液或者溶剂(阴性对照)，10万人源THP1-Dual细胞。2’3’-cGAMP的终浓度为10μM(溶剂为LAL water)，化合物的终浓度为10μM、1μM两个浓度(溶剂为DMSO)，每个浓度设3个重复孔。阳性对照化合物为ENPP1-IN-1，阴性对照为DMSO。体系中DMSO终浓度为1％。设置溶剂组、化合物组、2’3’-cGAMP组、2’3’-cGAMP+化合物组、空白组，调整细胞浓度至5.05×10 5/ml，每孔加入198μl的细胞悬液，空白组加200μl培养液。每孔加2μl溶剂或者2’3’-cGAMP溶液或者化合物溶液，细胞培养箱孵育24小时进行检测。检测显色反应：24小时后，每孔取20μl的细胞上清培养液至新的96孔板中(黑色、底透明)，每孔加入50μl显色液Quanti-Lucia，立即上机测定荧光值,重复实验2次。 200 μl (96-well plate, transparent flat bottom) per well, containing 2 μl 2'3'-cGAMP solution or compound solution or solvent (negative control), 100,000 THP1-Dual cells. The final concentration of 2'3'-cGAMP was 10 μM (the solvent was LAL water), the final concentration of the compound was 10 μM and 1 μM (the solvent was DMSO), and three replicate wells were set for each concentration. The positive control compound is ENPP1-IN-1, and the negative control is DMSO. The final concentration of DMSO in the system was 1%. Set solvent group, compound group, 2'3'-cGAMP group, 2'3'-cGAMP+compound group, blank group, adjust the cell concentration to 5.05×10 5 /ml, add 198 μl of cell suspension to each well, add 200 μl culture solution. Add 2 μl of solvent or 2'3'-cGAMP solution or compound solution to each well, and incubate for 24 hours in a cell incubator for detection. Detection of color reaction: After 24 hours, take 20 μl of cell supernatant culture solution from each well to a new 96-well plate (black, transparent bottom), add 50 μl of chromogenic solution Quanti-Lucia to each well, and immediately measure the fluorescence value on the machine , repeat the experiment 2 times.
结果分析：ISG Fold change(Normalize to Control)：Lum sample/Lum Control；Fold change(Normalized to cGAMP):Lum compound+cGAMP/Lum cGAMP Result analysis: ISG Fold change (Normalize to Control): Lum sample /Lum Control ; Fold change (Normalized to cGAMP): Lum compound+cGAMP /Lum cGAMP
2、实验结果2. Experimental results
实验结果表明，单一化合物对细胞中的STING没有直接激活效果，在加入外源2’3’-cGAMP后，细胞中STING通路被激活。Ⅰ-9、Ⅰ-11、Ⅰ-12、Ⅰ-59、I-67在10μM浓度下对2’3’-cGAMP的激活具有一定程度的增强效果；化合物Ⅰ-9、Ⅰ-16、I-59、I-67在1μM浓度下对2’3’-cGAMP激活的增强效果具有优于阳性药ENPP1-IN-1。The experimental results show that a single compound has no direct activation effect on STING in cells, and the STING pathway in cells is activated after adding exogenous 2'3'-cGAMP. Ⅰ-9, Ⅰ-11, Ⅰ-12, Ⅰ-59, and I-67 have a certain degree of enhancement effect on the activation of 2'3'-cGAMP at a concentration of 10 μM; compounds Ⅰ-9, Ⅰ-16, I- 59. The enhancing effect of I-67 on the activation of 2'3'-cGAMP at the concentration of 1 μM is superior to that of the positive drug ENPP1-IN-1.
表3.化合物对ISG的激活(10μM)Table 3. Activation of ISG by compounds (10 μM)
Figure PCTCN2023071429-appb-000417
Figure PCTCN2023071429-appb-000417
Figure PCTCN2023071429-appb-000418
Figure PCTCN2023071429-appb-000418
表4.化合物对ISG的激活(1μM)Table 4. Activation of ISG by compounds (1 μM)
Figure PCTCN2023071429-appb-000419
Figure PCTCN2023071429-appb-000419
Figure PCTCN2023071429-appb-000420
Figure PCTCN2023071429-appb-000420
实施例88药物组合物的制备The preparation of embodiment 88 pharmaceutical composition
药片pill
Figure PCTCN2023071429-appb-000421
Figure PCTCN2023071429-appb-000421
将上述物质混合均匀，通过常规工艺制备1000片药片。可以使用适当的水性或非水性包衣以提高适口程度、改善外观和稳定性或延缓吸收。The above-mentioned substances were mixed uniformly, and 1000 tablets were prepared by conventional techniques. Appropriate aqueous or non-aqueous coatings may be used to enhance palatability, improve appearance and stability or delay absorption.
胶囊capsule
化合物I-16  90克Compound I-16 90g
淀粉        135克Starch 135 grams
微晶纤维素  85克Microcrystalline Cellulose 85g
按常规方法，将上述物质混合均匀，装入普通明胶胶囊，制备1000颗胶囊。According to the conventional method, the above-mentioned substances were mixed evenly, and packed into ordinary gelatin capsules to prepare 1000 capsules.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (15)

  1. 式(I)化合物、或其药学上可接受的盐或前药：Formula (I) compound, or its pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2023071429-appb-100001
    Figure PCTCN2023071429-appb-100001
    其中，in,
    X选自：N或C-R 1； X is selected from: N or CR 1 ;
    Y选自：N或C-R 2； Y is selected from: N or CR 2 ;
    Z选自：N或C-R 3； Z is selected from: N or CR 3 ;
    W选自：N或C-R 4； W is selected from: N or CR4 ;
    R 1选自：氢、卤素、氰基、C 1～C 6烷基或-OR f； R 1 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl or -OR f ;
    R 2选自：氢、卤素、氰基、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
    R 3、R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
    或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
    或者，R 2和R 3与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 2 and R 3 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
    L选自：C 1～C 6亚烷基、-NH-、-NR aC(O)(CH 2) n-、-C(O)NR b(CH 2) n-； L is selected from: C 1 ~ C 6 alkylene, -NH-, -NR a C(O)(CH 2 ) n -, -C(O)NR b (CH 2 ) n -;
    A选自：氢、取代或未取代的C5～C12芳基、取代或未取代的5-12元杂芳基、C 1～C 6烷基、取代或未取代的C3-C12环烷基、取代或未取代的4-12元杂环基、C 1～C 6亚烷基(取代或未取代的5-12元杂芳基)；其中，所述取代是指被1-4个R n取代；各R n独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g、-NR fC(O)R g； A is selected from: hydrogen, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, C1 - C6 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, Substituted or unsubstituted 4-12 membered heterocyclic group, C 1 ~C 6 alkylene group (substituted or unsubstituted 5-12 membered heteroaryl group); wherein, the substitution refers to 1-4 R n Substitution; each R n is independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g , -NR f C(O)R g ;
    R t选自：-(CH 2) nR L’、-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n R L' , -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N -(CH 2 ) m R s ;
    R s选自：取代的C5～C12芳基、取代的5-12元杂芳基、取代的5-12元杂环基；其中，所述取代是指被1-4个R L取代； R s is selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclic; wherein, the substitution refers to being substituted by 1-4 RL ;
    各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’、-(CH 2) m’NH 2SO 2NR f’R g’；或者在-(CH 2) m’P(＝O)(OR j’) 2和-(CH 2) m’OP(＝O)(OR j’) 2中两个OR j’与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； Each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen-substituted C 1 -C 6 alkyl, -OR f' , -NR f' R g' , -C( O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -(CH 2 ) m' OP(=O)( OR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m ' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' , -(CH 2 ) m' NH 2 SO 2 NR f' R g' ; or in -(CH 2 ) m' P(=O)(OR j' ) 2 and -(CH 2 ) m' OP In (=O)(OR j' ) 2, two OR j' and their connected P atoms together form 0-4 saturated or unsaturated 4-6 membered heterocyclic rings substituted by R m ;
    R L’独立地选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’、-(CH 2) m’NH 2SO 2NR f’R g’；或者在-(CH 2) m’P(＝O)(OR j’) 2和-(CH 2) m’OP(＝O)(OR j’) 2中两个OR j’与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； R L' is independently selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' , -(CH 2 ) m' NH 2 SO 2 NR f' R g' ; or in -(CH 2 ) m In ' P(=O)(OR j' ) 2 and -(CH 2 ) m' OP(=O)(OR j' ) 2, two OR j' and their connected P atoms together form 0 to 4 R m -substituted saturated or unsaturated 4-6 membered heterocyclic rings;
    m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
    R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i or 3-6 membered heterocycloalkane substituted by 0-4 R i base;
    R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
    R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , 3-6 membered cycloalkyl group substituted by 0-4 R i or 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
    R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基； R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl or cyano;
    R m选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基、苯基、5-6元杂芳基、卤素取代的苯基、C 1～C 6烷基取代的苯基、卤素取代的5-6元杂芳基、C 1～C 6烷基取代的5-6元杂芳基； R m is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl, C 1 ~C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ~C 6 alkyl substituted 5 -6 membered heteroaryl;
    R a、R b、R j、R k和R k’各自独立地选自：氢、卤素、C 1～C 6烷基或卤代C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  2. 如权利要求1所述的式(I)化合物、或其药学上可接受的盐或前药：Formula (I) compound or its pharmaceutically acceptable salt or prodrug as claimed in claim 1:
    Figure PCTCN2023071429-appb-100002
    Figure PCTCN2023071429-appb-100002
    其中，in,
    X选自：N或C-R 1； X is selected from: N or CR 1 ;
    Y选自：N或C-R 2； Y is selected from: N or CR 2 ;
    Z选自：N或C-R 3； Z is selected from: N or CR 3 ;
    W选自：N或C-R 4； W is selected from: N or CR4 ;
    R 1选自：氢、卤素、氰基、C 1～C 6烷基或-OR f； R 1 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl or -OR f ;
    R 2选自：氢、卤素、氰基、被0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 Rf , -C(O) NRfRg , or -NRfC (O) Rg ;
    R 3、R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
    或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
    L选自：C 1～C 6亚烷基、-NH-、-NR aC(O)(CH 2) n-、-C(O)NR b(CH 2) n-； L is selected from: C 1 ~ C 6 alkylene, -NH-, -NR a C(O)(CH 2 ) n -, -C(O)NR b (CH 2 ) n -;
    A选自：氢、取代的C5～C12芳基、取代的5-12元杂芳基；其中，所述取代是指被1-4个R n取代；各R n独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g、-NR fC(O)R g； A is selected from: hydrogen, substituted C5-C12 aryl, substituted 5-12 membered heteroaryl; wherein, the substitution refers to being substituted by 1-4 R n ; each R n is independently selected from: hydrogen, Halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O) NR f R g , -NR f C(O)R g ;
    R t选自：-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
    R s选自：取代的C5～C12芳基、取代的5-12元杂芳基、取代的5-12元杂环基；其中，所述取代是指被1-4个R L取代； R s is selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclic; wherein, the substitution refers to being substituted by 1-4 RL ;
    各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’、-(CH 2) m’NH 2SO 2NR f’R g’；或者在-(CH 2) m’P(＝O)(OR j’) 2和-(CH 2) m’OP(＝O)(OR j’) 2中两个OR j’与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； Each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen-substituted C 1 -C 6 alkyl, -OR f' , -NR f' R g' , -C( O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -(CH 2 ) m' OP(=O)( OR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m ' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' , -(CH 2 ) m' NH 2 SO 2 NR f' R g' ; or in -(CH 2 ) m' P(=O)(OR j' ) 2 and -(CH 2 ) m' OP In (=O)(OR j' ) 2, two OR j' and their connected P atoms together form 0-4 saturated or unsaturated 4-6 membered heterocyclic rings substituted by R m ;
    m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
    R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i or 3-6 membered heterocycloalkane substituted by 0-4 R i base;
    R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
    R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、0～4个R i取代的3～6元环烷基或0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , 3-6 membered cycloalkyl group substituted by 0-4 R i or 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
    R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基； R i is selected from: halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen substituted C 1 -C 6 alkyl or cyano;
    R m选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基或氰基、苯基、5-6元杂芳基、卤素取代的苯基、C 1～C 6烷基取代的苯基、卤素取代的5-6元杂芳基、C 1～C 6烷基取代的5-6元杂芳基； R m is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl or cyano, Phenyl, 5-6 membered heteroaryl, halogen substituted phenyl, C 1 ~C 6 alkyl substituted phenyl, halogen substituted 5-6 membered heteroaryl, C 1 ~C 6 alkyl substituted 5 -6 membered heteroaryl;
    R a、R b、R j、R k和R k’各自独立地选自：氢、卤素、C 1～C 6烷基或卤代C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen, halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  3. 如权利要求1-2中任一项所述的化合物、或其药学上可接受的盐或前药，其特征在于，A选自：氢、取代的C5～C6芳基、取代的5～6元杂芳基、取代的[5+6]芳基、取代的[5+6]杂芳基；优选地，A选自取代的下组基团：苯基、吡咯基、咪唑基、吡唑基、呋喃基、噻吩基、噻唑基、恶唑基、吡啶基、吡嗪基、哒嗪基、吗啉基、哌嗪基、哌啶基、苯并咪唑基、苯并吡唑基、吲哚基、
    Figure PCTCN2023071429-appb-100003
    所述取代是指被1-4个R n取代；R n的定义权利要求1所述。     The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from: hydrogen, substituted C5-C6 aryl, substituted 5-6 Elementary heteroaryl, substituted [5+6] aryl, substituted [5+6] heteroaryl; preferably, A is selected from the group of substituted groups: phenyl, pyrrolyl, imidazolyl, pyrazole Base, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, morpholinyl, piperazinyl, piperidinyl, benzimidazolyl, benzopyrazolyl, ind Indolyl,
    Figure PCTCN2023071429-appb-100003
    The substitution refers to being substituted by 1-4 R n ; the definition of R n is described in claim 1.
  4. 如权利要求1-3中任一项所述的化合物、或其药学上可接受的盐或前药，其特征在于，A选自：氢、
    Figure PCTCN2023071429-appb-100004
    Figure PCTCN2023071429-appb-100005
    R 5和R 6的定义同权利要求1中R n。     The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or prodrug thereof, wherein A is selected from: hydrogen,
    Figure PCTCN2023071429-appb-100004
    Figure PCTCN2023071429-appb-100005
    The definitions of R 5 and R 6 are the same as R n in claim 1.
  5. 如权利要求1-4中任一项所述的化合物、或其药学上可接受的盐或前药，其特征在于，所述化合物具有(II)所示的结构：The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure shown in (II):
    Figure PCTCN2023071429-appb-100006
    Figure PCTCN2023071429-appb-100006
    其中，in,
    R 1为氢； R 1 is hydrogen;
    R 2选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O) NRfRg or -NRfC (O) Rg ;
    R 3和R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , - CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
    或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
    L选自：-NH-、-NR aC(O)(CH 2) n-或-C(O)NR b(CH 2) n-； L is selected from: -NH-, -NR a C (O) (CH 2 ) n - or -C (O) NR b (CH 2 ) n -;
    A选自：氢、
    Figure PCTCN2023071429-appb-100007
    Figure PCTCN2023071429-appb-100008
    A is selected from: hydrogen,
    Figure PCTCN2023071429-appb-100007
    Figure PCTCN2023071429-appb-100008
    R 5和R 6各自独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
    R t选自：-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
    R s选自：
    Figure PCTCN2023071429-appb-100009
    Figure PCTCN2023071429-appb-100010
    Rs are selected from:
    Figure PCTCN2023071429-appb-100009
    Figure PCTCN2023071429-appb-100010
    R u选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’或-(CH 2) m’NH 2SO 2NR f’R g’； R u is selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' or -(CH 2 ) m' NH 2 SO 2 NR f' R g' ;
    R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R v is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
    R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R w is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
    m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
    R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、被0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycle substituted by 0-4 R i alkyl;
    R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
    R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、被0～4个R i取代的3～6元环烷基或被0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i or a 3-6 membered heterocycloalkyl group substituted by 0-4 R i ;
    R i选自：卤素、羟基、氨基、C 1～C 6烷基、C 1～C 6烷氧基、C 1～C 6烷氨基、卤素取代的C 1～C 6烷基、氰基； R i is selected from: halogen, hydroxyl, amino, C 1 ~C 6 alkyl, C 1 ~C 6 alkoxy, C 1 ~C 6 alkylamino, halogen substituted C 1 ~C 6 alkyl, cyano;
    R a、R b、R j、R k和R k’各自独立地选自：氢或C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  6. 如权利要求1-5中任一项所述的化合物、或其药学上可接受的盐或前药，其特征在于，R 1为氢； The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt or prodrug thereof, wherein R is hydrogen;
    R 2选自：氢、氰基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 2 is selected from: hydrogen, cyano, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O ) R g ;
    R 3和R 4各自独立地选自：氢、卤素、0～4个R h取代的C 1～C 6烷基、-OR f或-C(O)R f、-CO 2R f； R 3 and R 4 are each independently selected from: hydrogen, halogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f or -C(O)R f , -CO 2 R f ;
    或者，R 3和R 4与它们连接的原子环化形成0～4个R i取代的饱和或不饱和的4～6元碳环或杂环； Alternatively, R 3 and R 4 are cyclized with the atoms they are connected to form a saturated or unsaturated 4-6 membered carbocyclic or heterocyclic ring substituted by 0 to 4 R i ;
    L选自：-NH-、-NR aC(O)(CH 2) n-或-C(O)NR b(CH 2) n-； L is selected from: -NH-, -NR a C (O) (CH 2 ) n - or -C (O) NR b (CH 2 ) n -;
    A选自：氢、
    Figure PCTCN2023071429-appb-100011
    A is selected from: hydrogen,
    Figure PCTCN2023071429-appb-100011
    R 5和R 6各自独立地选自：氢、卤素、氰基、0～4个R h取代的C 1～C 6烷基、-OR f、-NR fR g、-C(O)R f、-CO 2R f、-C(O)NR fR g或-NR fC(O)R g； R 5 and R 6 are each independently selected from: hydrogen, halogen, cyano, C 1 to C 6 alkyl substituted by 0 to 4 Rh, -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g or -NR f C(O)R g ;
    R t选自：-(CH 2) n-R s、-(CH 2) n-O-(CH 2) mR s或-(CH 2) n-N-(CH 2) mR s； R t is selected from: -(CH 2 ) n -R s , -(CH 2 ) n -O-(CH 2 ) m R s or -(CH 2 ) n -N-(CH 2 ) m R s ;
    R s选自：
    Figure PCTCN2023071429-appb-100012
    Rs are selected from:
    Figure PCTCN2023071429-appb-100012
    R u选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’； R u is selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' ;
    R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R v is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
    R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R w is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
    m、m’和n分别独立地为0、1、2、3、4、5或6；m, m' and n are independently 0, 1, 2, 3, 4, 5 or 6;
    R f、R g、R f’和R g’各自独立地选自：氢、0～4个R h取代的C 1～C 6烷基、0～4个R h取代的C 2～C 6炔基、0～4个R h取代的C 2～C 6烯基、0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R f , R g , R f' and R g' are each independently selected from: hydrogen, C 1 to C 6 alkyl substituted by 0 to 4 Rh , C 2 to C 6 substituted by 0 to 4 Rh Alkynyl, C 2 -C 6 alkenyl substituted by 0-4 R h , 3-6 membered cycloalkyl substituted by 0-4 R i , 3-6 membered heterocycloalkane substituted by 0-4 R i base;
    R j’各自独立地选自：氢、卤素、C 1～C 6烷基、卤代C 1～C 6烷基、-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’；m”分别独立地为1、2、3、4、5或6； R j' are each independently selected from: hydrogen, halogen, C 1 ~C 6 alkyl, halogenated C 1 ~C 6 alkyl, -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' ; m" are independently 1, 2, 3, 4, 5 or 6;
    R h选自：卤素、-OR j、-NR jR k、-C(O)R j、-CO 2R k、-C(O)NR jR k、-NR jC(O)R k、0～4个R i取代的3～6元环烷基、0～4个R i取代的3～6元杂环烷基； R h is selected from: halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R k , -C(O)NR j R k , -NR j C(O)R k , a 3-6 membered cycloalkyl group substituted by 0-4 R i , a 3-6-membered heterocycloalkyl group substituted by 0-4 R i ;
    R i选自：C 1～C 6烷基、卤素取代的C 1～C 6烷基； R i is selected from: C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl;
    R a、R b、R j、R k和R k’各自独立地选自：氢或C 1～C 6烷基。 R a , R b , R j , R k and R k' are each independently selected from: hydrogen or C 1 -C 6 alkyl.
  7. 如权利要求1所述的化合物、或其药学上可接受的盐或前药，其特征在于，各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’P(OR j’) 2、-(CH 2) m’B(OR j’) 2或-(CH 2) m’SO 2NR f’R g’；m’、R f’、R g’和R j’的定义如权利要求1所述，优选地各R L独立地选自：-B(OH) 2、P(＝O)(OH) 2、P(＝O)(OCH 2CH 3) 2、P(＝O)(OCH 2CF 3) 2、P(＝O)(OCH 2COOCH 3) 2、P(＝O)(OCH 2COOCH 2CH 3) 2、P(＝O)(OCH 2COOCH 2CH 2CH 3) 2、P(＝O)(OCH 2COOC(CH 3) 3) 2、P(＝O)(OCH 2OCOCH 3) 2、P(＝O)(OCH 2OCOCH 2CH 3) 2、P(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、P(＝O)(OCH 2OCOC(CH 3) 3) 2、P(＝O)(NHCH 2COOCH 3) 2、P(＝O)(NHCH 2COOCH 2CH 3) 2、P(＝O)(NHCH 2COOCH 2CH 2CH 3) 2、SO 2NH 2。 The compound according to claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen substitution C 1 ~ C 6 alkyl, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' P(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 or -(CH 2 ) m' SO 2 NR f' R g' ; m', R f' , R g' and R j' are as defined in claim 1, Preferably each R L is independently selected from: -B(OH) 2 , P(=O)(OH) 2 , P(=O)(OCH 2 CH 3 ) 2 , P(=O)(OCH 2 CF 3 ) 2 , P(=O)(OCH 2 COOCH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , P( =O)(OCH 2 COOC(CH 3 ) 3 ) 2 , P(=O)(OCH 2 OCOCH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOC(CH 3 ) 3 ) 2 , P(=O)(NHCH 2 COOCH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 , SO 2 NH 2 .
  8. 如权利要求1所述的化合物、或其药学上可接受的盐或前药，其特征在于，各R L独立地选自：氢、C 1～C 6烷基、卤素、氰基、卤素取代的C 1～C 6烷基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’、-NR f’C(O)R g’、-OP(＝O)(OR j’) 2、-P(＝O)(OR j’) 2、-P(＝O)(NHR j’) 2、-P(OR j’) 2、-B(OR j’) 2或-SO 2NR f’R g’；优选地，各R L独立地选自：H、卤素(如F)、-B(OH) 2、P(＝O)(OH) 2、P(＝O)(OCH 2CH 3) 2、P(＝O)(OCH 2CF 3) 2、P(＝O)(OCH 2COOCH 3) 2、P(＝O)(OCH 2COOCH 2CH 3) 2、P(＝O)(OCH 2COOCH 2CH 2CH 3) 2、 P(＝O)(OCH 2COOC(CH 3) 3) 2、P(＝O)(OCH 2OCOCH 3) 2、P(＝O)(OCH 2OCOCH 2CH 3) 2、P(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、P(＝O)(OCH 2OCOC(CH 3) 3) 2、P(＝O)(NHCH 2COOCH 3) 2、P(＝O)(NHCH 2COOCH 2CH 3) 2、P(＝O)(NHCH 2COOCH 2CH 2CH 3) 2、SO 2NH 2、OP(＝O)(OH) 2、OP(＝O)(OCH 2CH 3) 2、OP(＝O)(OCH 2CF 3) 2、OP(＝O)(OCH 2COOCH 3) 2、OP(＝O)(OCH 2COOCH 2CH 3) 2、OP(＝O)(OCH 2COOCH 2CH 2CH 3) 2、OP(＝O)(OCH 2COOC(CH 3) 3) 2、OP(＝O)(OCH 2OCOCH 3) 2、OP(＝O)(OCH 2OCOCH 2CH 3) 2、OP(＝O)(OCH 2OCOCH 2CH 2CH 3) 2、OP(＝O)(OCH 2OCOC(CH 3) 3) 2、OP(＝O)(NHCH 2COOCH 3) 2、OP(＝O)(NHCH 2COOCH 2CH 3) 2、OP(＝O)(NHCH 2COOCH 2CH 2CH 3) 2。 The compound according to claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein each R L is independently selected from: hydrogen, C 1 -C 6 alkyl, halogen, cyano, halogen substitution C 1 ~ C 6 alkyl, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' , -NR f' C(O)R g' , -OP(=O)(OR j' ) 2 , -P(=O)(OR j' ) 2 , -P(=O)(NHR j' ) 2 , -P(OR j' ) 2 , -B(OR j' ) 2 or -SO 2 NR f' R g' ; preferably, each R L is independently selected from: H, halogen (such as F), -B (OH) 2 , P(=O)(OH) 2 , P(=O)(OCH 2 CH 3 ) 2 , P(=O)(OCH 2 CF 3 ) 2 , P(=O)(OCH 2 COOCH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 3 ) 2 , P(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , P(=O)(OCH 2 COOC(CH 3 ) 3 ) 2 , P(=O)(OCH 2 OCOCH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 3 ) 2 , P(=O)(OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , P( =O)(OCH 2 OCOC(CH 3 ) 3 ) 2 , P(=O)(NHCH 2 COOCH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , P(=O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 , SO 2 NH 2 , OP(=O)(OH) 2 , OP(=O)(OCH 2 CH 3 ) 2 , OP(=O)(OCH 2 CF 3 ) 2 , OP(=O)(OCH 2 COOCH 3 ) 2 , OP(=O)(OCH 2 COOCH 2 CH 3 ) 2 , OP(=O)(OCH 2 COOCH 2 CH 2 CH 3 ) 2 , OP(=O )(OCH 2 COOC(CH 3 ) 3 ) 2 , OP(=O)(OCH 2 OCOCH 3 ) 2 , OP(=O)(OCH 2 OCOCH 2 CH 3 ) 2 , OP(=O)(OCH 2 OCOCH 2 CH 2 CH 3 ) 2 , OP(=O)(OCH 2 OCOC(CH 3 ) 3 ) 2 , OP(=O)(NHCH 2 COOCH 3 ) 2 , OP(=O)(NHCH 2 COOCH 2 CH 3 ) 2 , OP(=O)(NHCH 2 COOCH 2 CH 2 CH 3 ) 2 .
  9. 如权利要求1所述的化合物、或其药学上可接受的盐或前药，其特征在于，所述化合物具有式IV所示的结构The compound according to claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure shown in formula IV
    Figure PCTCN2023071429-appb-100013
    Figure PCTCN2023071429-appb-100013
    y和q各自独立地为0、1、2、3；y and q are each independently 0, 1, 2, 3;
    M选自：键、O或CH 2； M is selected from: bond, O or CH2 ;
    R u选自：-(CH 2) m’OP(＝O)(OR j’) 2、-(CH 2) m’P(＝O)(NHR j’) 2、-(CH 2) m’P(＝O)(OR j’) 2、-(CH 2) m’B(OR j’) 2、-(CH 2) m’SO 2NR f’R g’、-(CH 2) m’NHSO 2R f’或-(CH 2) m’NH 2SO 2NR f’R g’； R u is selected from: -(CH 2 ) m' OP(=O)(OR j' ) 2 , -(CH 2 ) m' P(=O)(NHR j' ) 2 , -(CH 2 ) m' P(=O)(OR j' ) 2 , -(CH 2 ) m' B(OR j' ) 2 , -(CH 2 ) m' SO 2 NR f' R g' , -(CH 2 ) m' NHSO 2 R f' or -(CH 2 ) m' NH 2 SO 2 NR f' R g' ;
    R v选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R v is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
    R w选自：氢、C 1～C 6烷基、卤素取代的C 1～C 6烷基、卤素、氰基、-OR f’、-NR f’R g’、-C(O)R f’、-CO 2R f’、-C(O)NR f’R g’或-NR f’C(O)R g’； R w is selected from: hydrogen, C 1 ~C 6 alkyl, halogen substituted C 1 ~C 6 alkyl, halogen, cyano, -OR f' , -NR f' R g' , -C(O)R f' , -CO 2 R f' , -C(O)NR f' R g' or -NR f' C(O)R g' ;
    m’、R 1、R 2、R 3、R 4、R f’、R g’、R j’、L和A的定义如权利要求1所述。 m', R 1 , R 2 , R 3 , R 4 , R f' , R g' , R j' , L and A are as defined in claim 1.
  10. 如权利要求9所述的化合物、或其药学上可接受的盐或前药，其特征在于，所述化合物具有式V所示的结构The compound according to claim 9, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure shown in formula V
    Figure PCTCN2023071429-appb-100014
    Figure PCTCN2023071429-appb-100014
    q、R u、R v、R w、R 1、R 2、R 3、R 4、L和A的定义如权利要求9所述。 q, R u , R v , R w , R 1 , R 2 , R 3 , R 4 , L and A are as defined in claim 9.
  11. 如权利要求1所述的化合物的前药，其特征在于，其具有式III或III’所示的结构The prodrug of the compound as claimed in claim 1, is characterized in that, it has the structure shown in formula III or III'
    Figure PCTCN2023071429-appb-100015
    Figure PCTCN2023071429-appb-100015
    式中，In the formula,
    E选自：O或NH；E is selected from: O or NH;
    R x和R y各自独立地选自：-(CH 2) m”-CO 2R k’、-(CH 2) m”-OCOR k’、C 1～C 6烷基或卤代C 1～C 6烷基；或者-ER x和-ER y与它们连接的P原子共同形成0～4个R m取代的饱和或不饱和的4～6元杂环； R x and R y are each independently selected from: -(CH 2 ) m" -CO 2 R k' , -(CH 2 ) m" -OCOR k' , C 1 ～C 6 alkyl or halogenated C 1 ～ C 6 alkyl; or -ER x and -ER y together with the P atom they are connected to form a saturated or unsaturated 4-6 membered heterocyclic ring substituted by 0 to 4 R m ;
    m”、X、Y、Z、W、R m、R k’、L和A的定义如权利要求1所述。 The definitions of m", X, Y, Z, W, R m , R k' , L and A are as described in claim 1.
  12. 如权利要求1-11中任一项所述的化合物、或其药学上可接受的盐或前药，其特征在于，其特征在于，所述化合物选自以下化合物：The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound is selected from the following compounds:
    Figure PCTCN2023071429-appb-100016
    Figure PCTCN2023071429-appb-100016
    Figure PCTCN2023071429-appb-100017
    Figure PCTCN2023071429-appb-100017
    Figure PCTCN2023071429-appb-100018
    Figure PCTCN2023071429-appb-100018
    Figure PCTCN2023071429-appb-100019
    Figure PCTCN2023071429-appb-100019
    Figure PCTCN2023071429-appb-100020
    Figure PCTCN2023071429-appb-100020
    Figure PCTCN2023071429-appb-100021
    Figure PCTCN2023071429-appb-100021
  13. 一种药物组合物，其含有治疗有效量的一种或多种如权利要求1-12中任一项所述的化合物、或其药学上可接受的盐或前药，和药学上可接受的载体、辅料或赋形剂。A pharmaceutical composition, which contains one or more compounds as described in any one of claims 1-12, or its pharmaceutically acceptable salt or prodrug, and pharmaceutically acceptable carrier, adjuvant or excipient.
  14. 如权利要求1-12中任一项所述的化合物、或其药学上可接受的盐或前药或权利要求13所述的药物组合物在制备免疫佐剂或抑制ENPP1药物中的用途。Use of the compound as described in any one of claims 1-12, or a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition described in claim 13 in the preparation of an immune adjuvant or a drug that inhibits ENPP1.
  15. 如权利要求1-13中任一项所述的化合物、或其药学上可接受的盐或前药或权利要求13所述的药物组合物在制备治疗与ENPP1活性相关的疾病的药物中的用途，所述与ENPP1活性相关的疾病是与炎性、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。Use of the compound as described in any one of claims 1-13, or its pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in claim 13 in the preparation of a drug for the treatment of diseases associated with ENPP1 activity , the disease associated with ENPP1 activity is one or more of the diseases associated with inflammation, autoimmune disease, infectious disease, cancer, and precancerous syndrome.
PCT/CN2023/071429 2022-01-10 2023-01-09 Benzimidazole compound and medical use thereof WO2023131333A1 (en)

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WO2021061803A1 (en) * 2019-09-23 2021-04-01 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Phosphodiesterase inhibitors and use

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1612733A (en) * 2001-11-09 2005-05-04 贝林格尔·英格海姆药物公司 Benzimidazoles useful as protein kinase inhibitors
US20070066606A1 (en) * 2003-09-12 2007-03-22 Wolfgang Stahle Benzylbenzimidazolyl derivatives
WO2008153701A1 (en) * 2007-05-24 2008-12-18 Schering Corporation Compounds for inhibiting ksp kinesin activity
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