CN116444544A - Benzimidazole compound and medical application thereof - Google Patents

Benzimidazole compound and medical application thereof Download PDF

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Publication number
CN116444544A
CN116444544A CN202210023244.6A CN202210023244A CN116444544A CN 116444544 A CN116444544 A CN 116444544A CN 202210023244 A CN202210023244 A CN 202210023244A CN 116444544 A CN116444544 A CN 116444544A
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substituted
alkyl
halogen
hydrogen
ethyl
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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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China Pharmaceutical University
Shanghai Institute of Materia Medica of CAS
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China Pharmaceutical University
Shanghai Institute of Materia Medica of CAS
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Priority to CN202210023244.6A priority Critical patent/CN116444544A/en
Priority to PCT/CN2023/071429 priority patent/WO2023131333A1/en
Publication of CN116444544A publication Critical patent/CN116444544A/en
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • 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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    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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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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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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 System
    • 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
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
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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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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • 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
    • 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 System
    • 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
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • 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

Abstract

The invention provides a benzimidazole compound and medical application thereof. Specifically, the compound has a structure shown in a formula (I), and also relates to pharmaceutically acceptable salts or prodrugs of the compound, a preparation method and application thereof, and a pharmaceutical composition containing the compound, wherein the compound can be used for preparing medicines for treating diseases related to ENPP1 activity.

Description

Benzimidazole compound and medical application thereof
Technical Field
The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular to benzimidazole compounds and medical application thereof.
Background
In recent years, the advent of immunotherapy has shown the potential to alter cancer treatment approaches. Blocking release of anti-tumor T cell responses by immune checkpoints produces a significant response in untreated tumors. One of the main strategies to expand the effectiveness of immunotherapeutic approaches is to find a way to convert immune "cold" tumors to "hot" tumors, and thus overcome the local immunosuppressive mechanisms, restoring the immune surveillance function of the body. One strategy for local immunostimulation is to activate the STING pathway, a key sensory system that allows the innate immune system to respond to infection and tumor growth, coordinating the immune response.
Several decades ago, the outer nucleotide pyrophosphatase/phosphodiesterase I (ENPP 1) was identified as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activity, critical for purinergic signaling. Recently, ENPP1 has become an important phosphodiesterase, which degrades the ligand cGMP-AMP (cGAMP) of STING. In the cytoplasm, cyclic GMP-AMP synthase (cGAS) binds to dsDNA from pathogen or host damaged cells, catalyzing the conversion of GTP and ATP to cyclic GMP-AMP (cGAMP). Subsequently, 2'3' -cGAMP activates STING, triggering an inflammatory response via the TANK-binding kinase 1 (TBK 1) -interferon regulatory factor (IRF 3) pathway, producing type 1 Interferon (IFN) and other cytokines. The link between the cGAS-STING pathway and ENPP1 has emerged, i.e. hydrolysis of cGAMP by ENPP1 reduces cGAS-STING signaling and thus reduces the antitumor immunity of the body.
It was reported that a longer cGAMP half-life was exhibited in ENPP1 knockout mice, suggesting a T thereof 1/2 Depending to a large extent 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 can be produced by stimulating G-protein coupled A 2A And A 2B Adenosine receptors shut down innate and adaptive immune responses, resulting in reduced production of pro-inflammatory cytokines and increased synthesis of anti-inflammatory cytokines, thus reducing adenosine production and enhancing the anti-tumor immunity of the body after inhibition of ENPP 1.
In view of the foregoing, it is highly desirable to develop efficient and safe ENPP1 inhibitors.
Disclosure of Invention
The invention aims to provide a compound with a novel structure or pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a pharmaceutical composition.
It is another object of the present invention to provide a process for the preparation of said compounds, their pharmaceutically acceptable salts.
The final object of the invention is to provide the use of said compounds, their pharmaceutically acceptable salts, in particular in the manufacture of a medicament for the prevention and/or treatment of diseases associated with ENPP1 dysfunction.
In a first aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from: n or C-R 1 ；
Y is selected from: n or C-R 2 ；
Z is selected from: n or C-R 3 ；
W is selected from: n or C-R 4 ；
R 1 Selected from: hydrogen, halogen, cyano, C 1 ～C 6 Alkyl OR-OR f ；
R 2 Selected from: hydrogen, halogen, cyano, substituted with 0-4R h 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 or-NR f C(O)R g ；
R 3 、R 4 Each independently selected from: hydrogen, halogen, 0-4R h 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 or-NR f C(O)R g ；
Alternatively, R 3 And R is 4 Cyclizing the atoms to which they are attached to form 0 to 4R i Substituted saturated orUnsaturated 4-6 membered carbocycle or heterocycle;
l is selected from: c (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 means that the substituted chain is substituted by 1-4R n Substitution; each R is n Independently selected from: hydrogen, halogen, cyano, 0-4R h 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 ；
R t 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 Selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclyl; wherein the substitution means that the substituted chain is substituted by 1-4R L Substitution;
each R is L 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 'A'; or in- (CH) 2 ) m ’P(＝O)(OR j ’) 2 Two OR's in (2) j ' together with the P atom to which they are attached form 0 to 4R m Substituted saturated or unsaturated 4-6 membered heterocyclic ring;
m, m' and n are each independently 0, 1, 2, 3, 4, 5 or 6;
R f 、R g 、R f ' and R g ' each independently selected from: hydrogen, 0-4R h Substituted C 1 ～C 6 Alkyl, 0-4R h Substituted C 2 ～C 6 Alkynyl, 0-4R h Substituted C 2 ～C 6 Alkenyl, 0 to 4R i Substituted 3-6 membered cycloalkyl or 0-4R i Substituted 3-6 membered heterocycloalkyl;
R j’ 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’ The method comprises the steps of carrying out a first treatment on the surface of the m "are each independently 1, 2, 3, 4, 5 or 6;
R h 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 0 to 4R i Substituted 3-6 membered cycloalkyl or 0-4R i Substituted 3-6 membered heterocycloalkyl;
R i selected from: halogen, hydroxy, 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 selected from: halogen, hydroxy, 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 is k’ Each independently selected from: hydrogen, halogen, C 1 ～C 6 Alkyl or halo C 1 ～C 6 An alkyl group.
In another preferred embodiment, each R n Independently selected from: hydrogen, halogen, C 1 ～C 6 Alkyl or halo C 1 ～C 6 An alkyl group.
In a further preferred embodiment of the present invention,is->Wherein ring B is a saturated or unsaturated 4-to 6-membered carbocyclic or heterocyclic ring (e.g., furyl, thienyl, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, cyclohexyl, etc.), and p is 0, 1, 2, 3, or 4; r is R i And R is t Is defined as above.
In a further preferred embodiment of the present invention,is->p、R 1 、R 2 、R i And R is t Is defined as above.
In a further preferred embodiment of the present invention,is->Wherein R is 1 、R 2 、R 3 、R 4 And R is t Is defined as above.
In another preferred embodiment, R s Selected from: substituted C5-C6 aryl, substituted 5-6 membered heteroaryl, substituted [5+6 ]]Aryl, substituted [5+6 ]]Heteroaryl, substituted 6-7 membered heterocycle or substituted spirocycle; wherein the substitution means that the substituted chain is substituted by 1-4R L Substitution; r is R L Is defined as above.
In another preferred embodiment, 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 spirocycle, more preferablyR u And R is v Is defined as R L 。
In another preferred embodiment, a is selected from: hydrogen, substituted C5-C6 aryl, substituted 5-6 membered heteroaryl, substituted [5+6 ]]Aryl, substituted [5+6 ]]Heteroaryl; preferably, a is selected from the following groups substituted: phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, morpholinyl, piperazinyl, piperidinyl, benzimidazolyl, benzopyrazolyl, indolyl,The substitution means being 1-4R n Substitution; r is R n Is defined as above.
In another preferred embodiment, a is selected from: hydrogen, hydrogen,
R 5 And R is 6 Is defined as R n 。
In another preferred embodiment, R s Selected from: preferably +.> Wherein R is u 、R v And R is w Is defined as R L 。
In another preferred embodiment, the compound has the structure shown in (II):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is hydrogen;
R 2 selected from: hydrogen, halogen, cyano, 0-4R h 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 or-NR f C(O)R g ；
R 3 And R is 4 Each independently selected from: hydrogen, halogen, 0-4R h 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 or-NR f C(O)R g ；
Alternatively, R 3 And R is 4 Cyclizing the atoms to which they are attached to form 0 to 4R i Substituted saturated or unsaturated 4-to 6-membered carbocycle or heterocycle;
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, hydrogen,
R 5 And R is 6 Each independently selected from: hydrogen, halogen, cyano, 0-4R h 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 or-NR f C(O)R g ；
R t 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 Selected from: substituted
R u Selected from: - (CH) 2 ) m’ OP(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’ Or- (CH) 2 ) m’ NH 2 SO 2 NR f’ R g’ ；
R v 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 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' and n are each independently 0, 1, 2, 3, 4, 5 or 6;
R f 、R g 、R f’ and R is g’ Each independently selected from: hydrogen, 0-4R h Substituted C 1 ～C 6 Alkyl, 0-4R h Substituted C 2 ～C 6 Alkynyl, 0-4R h Substituted C 2 ～C 6 Alkenyl, is covered with 0-4R i Substituted 3-6 membered cycloalkyl, 0-4R i Substituted 3-6 membered heterocycloalkyl;
R j’ 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’ The method comprises the steps of carrying out a first treatment on the surface of the m "are each independently 1, 2, 3, 4, 5 or 6;
R h 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 Is covered with 0-4R i Substituted 3-to 6-membered cycloalkyl or substituted with 0-4R i Substituted 3-6 membered heterocycloalkyl;
R i selected from: halogen, hydroxy, 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 is k’ Each independently selected from: hydrogen or C 1 ～C 6 An alkyl group.
In another preferred embodiment, R 1 Is hydrogen;
R 2 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 is 4 Each independently selected from: hydrogen, halogen, 0-4R h Substituted C 1 ～C 6 Alkyl, -OR f or-C (O) R f 、-CO 2 R f ；
Alternatively, R 3 And R is 4 Cyclizing the atoms to which they are attached to form 0 to 4R i Substituted saturated or unsaturated 4-to 6-membered carbocycle or heterocycle;
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, hydrogen,
R 5 And R is 6 Each independently selected from: hydrogen, halogen, cyano, 0-4R h 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 or-NR f C(O)R g ；
R t 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 Selected from:
R u selected from: - (CH) 2 ) m’ OP(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’ ；
R v 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 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' and n are each independently 0, 1, 2, 3, 4, 5 or 6;
R f 、R g 、R f’ and R is g’ Each independently selected from: hydrogen, 0-4R h Substituted C 1 ～C 6 Alkyl, 0-4R h Substituted C 2 ～C 6 Alkynyl, 0-4R h Substituted C 2 ～C 6 Alkenyl, 0 to 4R i Substituted 3-6 membered cycloalkyl, 0-4R i Substituted 3-6 membered heterocycloalkyl;
R j’ 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’ The method comprises the steps of carrying out a first treatment on the surface of the m "are each independently 1, 2, 3, 4, 5 or 6;
R h 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 0 to 4R i Substituted 3-6 membered cycloalkyl, 0-4R i Substituted 3-6 membered heterocycloalkyl;
R i selected from: c (C) 1 ～C 6 Alkyl, halogen substituted C 1 ～C 6 An alkyl group;
R a 、R b 、R j 、R k and R is k’ Each independently selected from: hydrogen or C 1 ～C 6 An alkyl group.
In another preferred embodiment, R 1 Is hydrogen.
In another preferred embodiment, each R L 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 is j’ Is defined as above, preferably each R L 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 。
In another preferred embodiment, L is selected from: -NH-or-NHC (O) -.
In a further preferred embodiment of the present invention, Selected from: NH (NH) 2 、/>
In another preferred embodiment, R 1 Is hydrogen or C 1 ～C 6 An alkyl group.
In another preferred embodiment, R 2 Selected from: hydrogen, halogen, cyano, -CO 2 R f 、-C(O)NR f R g The method comprises the steps of carrying out a first treatment on the surface of the More preferably, R 2 Selected from: hydrogen, halogen, cyano, -CO 2 C 1 ～C 6 Alkyl, -C (O) NH 2 。
In another preferred embodiment, R 3 And R is 4 Each independently selected from: hydrogen, halogen, C 1 ～C 6 Alkyl, -OR f 、-NR f R g The method comprises the steps of carrying out a first treatment on the surface of the More preferably, R 3 Selected from hydrogen, halogen or C 1 ～C 6 An alkyl group; r is R 4 Selected from: hydrogen, halogen, C 1 ～C 6 Alkyl, -OC 1 ～C 6 An alkyl group.
In another preferred embodiment, the prodrug of the compound has a structure represented by formula III
In the method, in the process of the invention,
e is selected from: o or NH;
R x and R is y Each independently selected from: - (CH) 2 ) m” -CO 2 R k’ 、-(CH 2 ) m” -OCOR k’ 、C 1 ～C 6 Alkyl or halo C 1 ～C 6 An alkyl group; or-ER x and-ER y Together with the P atoms to which they are attached form 0 to 4R m Substituted saturated or unsaturated 4-6 membered heterocyclic ring;
m”、X、Y、Z、W、R m 、R k’ the definitions of L and A are as described above.
In another preferred embodiment, -ER x and-ER y Together with the P atoms to which they are attached form 0 to 4R m Substitution ofR m Selected from: halogen, hydroxy, 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 (e.g. chlorobenzene), C 1 ～C 6 Alkyl-substituted phenyl, halogen-substituted 5-6 membered heteroaryl, C 1 ～C 6 Alkyl substituted 5-6 membered heteroaryl.
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 groups corresponding to specific compounds in the examples.
In another preferred embodiment, the compound is selected from the following compounds:
in a second aspect of the invention there is provided a pharmaceutical composition comprising 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 vehicle.
In a third aspect, the present invention provides the use of a compound according to the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the second aspect, in the manufacture of an immunoadjuvant or ENPP1 inhibiting medicament.
In a fourth aspect, the present invention provides the use of a compound according to the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, or a second pharmaceutical composition, for the manufacture of a medicament for the treatment of a disease associated with ENPP1 activity, said disease associated with ENPP1 activity being one or more of a disease associated with inflammatory, autoimmune, infectious, cancer, precancerous syndrome.
In a fifth aspect of the invention there is provided a method of treating a disorder associated with ENPP1 activity, the method comprising administering to a subject a therapeutically effective amount of a compound according to the first aspect, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to the second aspect.
In another preferred embodiment, the compounds of the present invention may be formulated into powders, tablets, granules, capsules, solutions, emulsions, suspensions, and the like.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor designs and develops a compound with a novel structure through extensive and intensive research, and experimental results show that the compound has a good inhibition effect on ENPP1 and can be used for preparing medicines for treating ENPP1 or diseases related to ENPP1 activity. The present invention has been completed on the basis of this finding.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2 O-is equivalent to-OCH 2 -。
The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having the indicated number of carbon atoms (i.e., C1-C6 refers to containing 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, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like. In this application, alkyl is also intended to include substituted alkyl groups, i.e., one or more positions in the alkyl group are substituted, especially 1-4 substituents, and may be substituted at any position.
The term "alkenyl" means a straight or branched hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms (or C2-C8) in length. For example, in the present invention, "C2-C6 alkenyl" contains alkenyl groups of 2, 3, 4, 5 or 6 carbon atoms, and "C3-C6 alkenyl". Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl includes substituted alkenyl.
The term "alkynyl" denotes a straight or branched hydrocarbon radical containing one or more triple bonds and typically ranging in length from 2 to 20 carbon atoms (or C2-C8). In the present invention, "C2-C6 alkynyl" refers to straight or branched chain alkynyl groups having 2, 3, 4, 5 or 6 carbon atoms, including but not limited to ethynyl, propynyl or the like. In the present invention, alkynyl also includes substituted alkynyl groups, and substituents may be halo, hydroxy, cyano, nitro, and the like.
The term "alkylamino" refers to an alkyl group attached to the remainder of the molecule through an amino group, in the present invention, "C 1 ～C 6 Alkylamino "has formula C 1 ～C 6 alkyl-NH-.
The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, e.g., -CH 2 CH 2 CH 2 CH 2 -. Alkyl (or alkylene) groups typically have 1 to 24 carbon atoms, with those groups having 3 or fewer carbon atoms (e.g., C) 1 ～C 3 An alkylene group). Similarly, "alkenylene" or "alkynylene" refer to an unsaturated form of "alkylene" having a double or triple bond, respectively. Examples of "alkenylene" or "alkynylene" include, but are not limited to: ethenylene, propenylene, etc.
In the present invention, "C1-C6 alkoxy (C1-C6 alkyl-O-)" means a straight or branched or cyclic alkoxy group having 1 to 6 carbon atoms (e.g., C3-C6 cycloalkoxy group), representative examples include (but are not limited to): methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably C1-C3 alkoxy.
The term "cycloalkyl" is intended to include saturated monocyclic or bicyclic (e.g., fused bicyclic or spirobicyclic) or polycyclic cyclic alkyl groups. In the present invention, the term "3-to 6-membered cycloalkyl group" means a cyclic alkyl group having 3, 4, 5 and 6 carbon atoms. Representative cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. It is understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (e.g., 1-methylcyclopropyl and 2-methylcyclopropyl), are included in the definition of "cycloalkyl".
The term "heterocycloalkyl" refers to cycloalkyl groups 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 may be monocyclic, bicyclic or polycyclic ring systems. In the present invention, "3-6 membered heterocycloalkyl" means a group in which 1 or 2 ring C atoms in a C3-6 cycloalkyl group are substituted with heteroatoms selected from N, O and S, and examples of heterocycloalkyl include, but are not limited to: pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidone, hydantoin, dioxolane, phthalimide, piperidine, 1, 4-dioxane, morpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. Heterocycloalkyl groups can be attached to the remainder of the molecule via a ring carbon or heteroatom.
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, for example bridged or spiro. The heterocyclic group is preferably a 3-10 membered heterocyclic group, more preferably a 5-8 membered heterocyclic group, still more preferably a 4-6 membered heterocyclic group, still more preferably a 5-6 membered heterocyclic group. Examples of heterocyclyl groups include, but are not limited to: oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like. The heterocyclic group may be fused to an aryl, heteroaryl, heterocyclic or cycloalkyl ring (e.g., to form a [5+5], [6+5] or [6+6] fused ring system, etc.), wherein the ring attached to the parent structure is a heterocyclic group.
In the present invention, the term "aryl" refers to an aromatic ring group containing no heteroatoms in the ring, which may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Such as phenyl (i.e., C6 aryl or six-membered aryl), naphthyl (i.e., C10 aryl or [6+6] aryl), and the like, wherein six-membered aryl is also intended to include six-membered aryl and 5-6 membered cycloalkyl and six-membered aryl and 5-6 membered heterocyclyl. The term "[5+6] aryl" refers to a fused 6, 5 bicyclic ring system. Aryl is preferably C6-C12 aryl, more preferably C6-C10 aryl. Examples of aryl groups include phenyl, naphthyl. Aryl groups may be optionally substituted or unsubstituted.
The term "heteroaryl" refers to a cyclic aromatic group having 1 to 3 atoms which are heteroatoms selected from the group N, S and O, which may be monocyclic or in the form of condensed rings. 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, (1, 2, 4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. The term "[5+6] heteroaryl" refers to fused 6, 5 bicyclic ring systems such as benzothienyl, benzofuranyl, benzimidazolyl, benzotriazole, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, and the like.
"carbocycle or heterocycle" alone or as part of another group in the present invention refers to a monocyclic or bicyclic saturated, partially saturated or aromatic carbocycle (e.g., cycloalkyl, cycloalkenyl, phenyl, etc., as described above), or a monocyclic or bicyclic saturated, partially saturated or aromatic heterocycle (e.g., heteroalkyl, heterocyclyl, heteroaryl, etc., as described above), wherein 4-6 membered carbocycle or heterocycle refers to a carbocycle or heterocycle containing 4-6 ring atoms, preferably a 5-6 membered carbocycle or heterocycle. Examples of carbocycles or heterocycles include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1, 2, 3) -triazolyl, and (1, 2, 4) -triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.
In the present invention, "amino" means having the structure-N (R) (R '), R and R' may 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' may be the same or different in the dialkylamine fragment.
In the present invention, each of the above-mentioned alkyl groups, alkoxy groups, cycloalkyl groups, heteroaryl groups, heterocycloalkyl groups, alkenyl groups, alkynyl groups, heterocyclic groups, carbocyclyl groups and the like may be substituted or unsubstituted.
Unless otherwise indicated, it is assumed that any heteroatom in an underfilling state has sufficient hydrogen atoms to complement its valence.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a single halogen substituent or a multiple halogen substituent, the latter such as trifluoromethyl or containing Cl) 3 Alkyl group of (c), cyano group, nitro group, oxo group (e.g., =o), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, alkynyl group, heterocycle, aromatic ring, OR group a 、SR a 、S(＝O)R e 、S(＝O) 2 R e 、P(＝O) 2 R e 、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 is a Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, carbocycle or heterocycle, R b 、R c And R is d Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, carbocycle or heterocycle, or R b And R is c Together with the N atom, may form a heterocyclic ring; r is R e Can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring. Typical substituents described above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, carbocycle or heterocycle, may be optionally substituted. Such as (but not limited to): halogen, hydroxy, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, C1-C6 ureido, and the like.
The term "halo" or "halogen" includes fluoro, chloro, bromo and iodo.
The term "hydroxy" refers to-OH.
In the present invention-C (O) NR a R b -C (O) OR, -C (O) R, -NRC (O) R, -C (O) -represents a carbonyl group (-c=o-) formed by linking two atoms of carbon and oxygen through a double bond.
Active ingredient
As used herein, the term "compound of the invention" or "active ingredient of the invention" is used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer 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 included within the scope of the invention.
The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
Conventional techniques for preparing/separating 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 gabiz and Martin g.schmid (eds.), chiral Separations, methods and Protocols, methods in Molecular Biology, vol.243,2004; m.stalcup, chiral Separations, annu.rev.animal.chem.3:341-63, 2010; fumigs et al (EDs.), VOGEL' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.TH ED, longman Scientific and Technical Ltd., essex,1991,809-816; heller, acc.chem.Res.1990,23,128.
Pharmaceutically acceptable salts
The term "pharmaceutically acceptable salt" refers to salts (including zwitterionic and like internal salts) that have efficacy similar to the parent compound and are biologically or otherwise acceptable (e.g., are neither toxic nor harmful to the subject). Accordingly, embodiments of the present invention provide pharmaceutically acceptable salts of the compounds of the present invention. The term "salt" as used herein means any of the following acid salts formed from inorganic and/or organic acids, as well as basic salts formed from inorganic and/or organic bases. Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of an acid or base (e.g., an equivalent amount of an acid or base) in a medium (e.g., such medium may allow precipitation of the salt therein; or with water as a medium followed by lyophilization).
Exemplary acid salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methylsulfonate ("mesylate"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and the like. Suitable acid salts may be prepared by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid (e.g., hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid). Furthermore, acids suitable for forming pharmaceutically acceptable salts are also selected from the following references: (1) stahl et al, camill G (eds.) Handbook of Pharmaceutical salts properties, selection and use (2002); (2) zurich, wiley-VCH.S. bergel al, journal of Pharmaceutical Sciences (1977) 66 (1), 1-19; (3) gould, international J.of pharmaceuticals (1986) 33,201-217; (4) anderson el al, the Practice of Medicinal Chemistry (1996), academic Press, new York; (5) the Orange Book (Food & Drug Administration, washing, D.C. on The same web site).
Exemplary basic salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), salts containing organic bases (e.g., organic amines) (e.g., dicyclohexylamine), t-butylamine, choline, and salts with amino acids (e.g., arginine, lysine), and the like. Basic nitrogen-containing groups can form quaternary ammonium salts with, for example, lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. The compounds bearing acidic groups can be mixed with suitable pharmaceutically acceptable salts to prepare alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed from suitable organic ligands (e.g., quaternary ammonium salts). In addition, pharmaceutically acceptable esters can be used to improve the solubility or hydrolytic properties of the compounds in the presence of carboxyl or hydroxyl groups.
All such acid and base salts are pharmaceutically acceptable salts within the scope of the invention and, for the purposes of this invention, are considered equivalent to the corresponding parent compounds of the invention.
In addition, when the compounds of the present invention contain both basic groups (such as, but not limited to, primary, secondary, tertiary aliphatic or cyclic amines, aromatic or heteroaryl amines, pyridines or imidazoles) and acidic groups (such as, but not limited to, tetrazoles or carboxylic acids), the zwitterionic species that can be formed ("inner salts") are also encompassed within the term "salts" of the present patent. Certain compounds of the invention may exist in zwitterionic form, having both anionic and cationic centers in the same compound, and having a net neutral charge, such zwitterionic also being encompassed by the invention.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent ENPP1 enzyme inhibitory activity, the compound of the present invention or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) ENPP1 enzyme-related diseases such as inflammatory diseases (acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, airway inflammation and interstitial cystitis caused by house dust mites), autoimmune diseases, infectious diseases (e.g., hepatitis b virus, human papilloma virus, nasopharyngeal carcinoma-related EB virus, herpes simplex virus), cancers (e.g., cancers such as colon cancer, breast cancer, lung cancer, melanoma, liver cancer, stomach cancer, cervical cancer, ovarian cancer, fibrosarcoma and squamous cell carcinoma, brain cancer, etc.), pre-cancerous syndromes.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention within a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
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 the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include 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 as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-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 nonaqueous carriers, diluents, solvents or excipients 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 (e.g., STING agonists).
When administered in combination, the pharmaceutical composition also includes a pharmaceutical composition in combination with one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., STING agonists). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately or sequentially with the compounds of the present invention for preventing and/or treating diseases associated with the activity or expression level of STING kinase.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
Process for the preparation of compounds
The following schemes describe methods for preparing compounds of formula I. In some cases, the order of the steps of the reaction scheme may be altered to promote the reaction or to avoid unwanted side reaction products. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains.
Protecting groups may 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. The protecting group may also be a polymeric resin.
Typically, in the preparation scheme, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ℃ to 150 ℃, preferably 10 ℃ to 100 ℃). The reaction time is usually 0.1 hours to 60 hours, preferably 0.5 to 48 hours.
Preferably, the compound of formula I has a structure represented by formula vi, which can be prepared by the following method:
wherein n, a, b=r above u 、R 1 、R 2 、R 3 、R 4 、R u 、R v And R is w Is defined as above;
s 1) reacting a compound i with a compound i' in the presence of a base (e.g. potassium carbonate, triethylamine) in an organic solvent (e.g. n-butanol) to give a compound ii;
s 2) in an organic solvent, carrying out reduction reaction on the compound ii and a reducing agent (such as sodium dithionite) to obtain a compound iii;
s 3) reacting the compound iii with cyanide (such as cyanogen bromide) in an organic solvent to obtain a compound iv;
s 4) in an organic solvent, compound iv is reacted with a carboxylic acid in the presence of condensing agents such as EDCI and HOBTReacting to obtain a compound v;
s 5) in an organic solvent, treating the compound v by n-butyllithium and triisopropyl borate, or treating by trimethyl bromosilane, or treating by phosphorus oxychloride to obtain the compound vi.
The invention has the main advantages that:
1. the compound disclosed by the invention is novel in structure and has an excellent ENPP1 enzyme inhibition effect;
2. The compound of the invention can be used as an ENPP1 inhibitor, effectively reduce the degradation of cGAMP and promote the secretion of I-type interferon;
3. the compound provides a new choice for clinically screening and/or preparing medicines for diseases related to the ENPP1 activity.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Examples
The invention will be further specifically illustrated by the following detailed experimental procedures in examples. These exemplary compounds are depicted in neutral form in the examples below. In some cases, the compounds are isolated as salts according to the method and/or intrinsic molecular properties used for final purification. These examples are merely illustrative of the invention and are not intended to limit the scope of the patent in any way. Unless defined or otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Example 1 (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)
Step (1): 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (1-1)
2 g of 3-methylpyrazole-5-carboxylic acid ethyl ester were dissolved in 20 ml of N, N-dimethylformamide, and 2.7 g of potassium carbonate and 1.25 ml of iodoethyl were added in an ice bathThe alkane was stirred overnight at room temperature. The reaction mixture was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate = 100:1 column chromatography purification gave 1.1 g of ethyl 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (1-1) as a colorless transparent liquid, with a yield of 46.5%. ESI-MS (m/z): 183.1[ M+H ]] + .
Step (2): 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1-2)
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 mixture was dried by spinning, the residue was diluted with water, 1M HCl was added to precipitate a white solid, and the white solid 506 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (1-2) was obtained by suction filtration, with a yield of 59.8%. ESI-MS (m/z): 155.1[ M+H ]] + .
Step (3): 4- ((4-bromophenylethyl) amino) -3-nitrobenzonitrile (1-3)
1 g of 4-chloro-3-nitrobenzonitrile, 2.2 g of 4-bromophenylethylamine, 1.5 g of potassium carbonate and 554 ml of triethylamine are dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, and the solid was suction-filtered to obtain 1.1 g of 4- ((4-bromophenyl ethyl) amino) -3-nitrobenzonitrile (1-3) as a yellow solid, with a yield of 58%. ESI-MS (m/z): 346.0[ M+H ] ] + .
Step (4): 3-amino-4- ((4-bromophenyl ethyl) amino) benzonitrile (1-4)
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. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4:1 column chromatography purification1 g of 3-amino-4- ((4-bromophenyl ethyl) amino) benzonitrile (1-4) is obtained as a white solid with a yield of 60%. ESI-MS (m/z): 316.1[ M+H ]] + .
Step (5): 2-amino-1- (4-bromophenyl ethyl) -1H-benzo [ d ] imidazole-5-carbonitrile (1-5)
100 mg of 1-4 and 40 mg of cyanogen bromide were dissolved in 2 ml of methanol and stirred at room temperature overnight. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 2-amino-1- (4-bromophenyl ethyl) -1H-benzo [ d ]]Imidazole-5-carbonitrile (1-5) was 95 mg as a white solid in 88% yield. ESI-MS (m/z): 341.1[ M+H ]] + .
Step (6): n- (1- (4-bromophenyl ethyl) -5-cyano-1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (1-6)
A mixture of 100 mg 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 was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain N- (1- (4-bromophenyl ethyl) -5-cyano-1H-benzo [ d) ]Imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (1-6) as a white solid 102 mg in 72.9% yield. 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).
Step (7): (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)
100 mg of the compounds 1-6 are dissolved in 2 ml of tetrahydrofuran under the protection of nitrogen, after stirring for 20 minutes at-78 ℃, 409 mg of n-butyllithium are added, after stirring for 1 hour at-78 ℃, 157 mg of triisopropyl borate are added, after stirring for 1 hour at room temperature, and quenching is performed by adding 3M HCl. Extracting with dichloromethane, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=200: purifying by column chromatography 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) was found to be a pale yellow solid, 25 mg, in 26.9% yield. ESI-MS (m/z): 443.10[ M+H ]] + .
Example 2 (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)
Step (1): 4- ((4-bromobenzyl) amino) -3-nitrobenzonitrile (2-1)
1 g of 4-chloro-3-nitrobenzonitrile, 2 g of 4-bromobenzylamine, 1.5 g of potassium carbonate and 1 mg of triethylamine are dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, and the solid was suction-filtered to obtain 1.5 g of a yellow solid of 4- ((4-bromobenzyl) amino) -3-nitrobenzonitrile (2-1) 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).
Step (2): 3-amino-4- ((4-bromobenzyl) amino) benzonitrile (2-2)
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. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4:1 column chromatography gave 1.1 g of 3-amino-4- ((4-bromobenzyl) amino) benzonitrile (2-2) as a white solid in 67.1% yield. ESI-MS (m/z): 302.0[ M+H ]] + .
Step (3): 2-amino-1- (4-bromobenzyl) -1H-benzo [ d ] imidazole-5-carbonitrile (2-3)
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 was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: 1 column chromatography to obtain 2-amino-1- (4-bromobenzyl) -1H-benzo [ d ]]Imidazole-5-carbonitrile (2-3) was 1.1 g as a white solid in 84.6% yield. ESI-MS (m/z): 327.1[ M+H ]] + .
Step (4): n- (1- (4-bromobenzyl) -5-cyano-1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (2-4)
A mixture of 750 mg 2-3, 424 mg of Compound 1-2, 710 mg EDCI, 105 mg HOBT, 611. Mu.l triethylamine and 4 ml N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: 1 column chromatography to obtain N- (1- (4-bromobenzyl) -5-cyano-1H-benzo [ d ] ]Imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (2-4) as a white solid 610 mg in 57.4% yield. 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).
Step (5): (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)
200 mg of compound 2-4 are dissolved in 2 ml of tetrahydrofuran under the protection of nitrogen, after stirring for 20 minutes at-78 ℃, 1 ml of n-butyllithium is added, after stirring for 1 hour at-78 ℃, 398 mg of triisopropyl borate is added, after stirring for 1 hour at room temperature, quenching is performed by adding 3M HCl. Extracting with dichloromethane, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=200: purifying by column chromatography 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) was 42 mg as a pale yellow solid in 22.7% yield. 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).
Example 3 (4- (2- (5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) ethyl) phenyl) boronic acid (I-3)
Step (1): 4-hydroxy-3-methoxy-5-nitrobenzonitrile (3-1)
2 g of 3-methoxy-4-hydroxybenzonitrile was dissolved in 20 ml of acetic acid, 714. Mu.l of nitric acid was slowly added under ice bath, the ice bath was removed after the addition, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate = 4:1 column chromatography purification gave 1.5 g of 4-hydroxy-3-methoxy-5-nitrobenzonitrile (3-1) as a yellow solid with a yield of 56.7%. ESI-MS (m/z): 193.0[ M-H ] ] - .
Step (2): 4-chloro-3-methoxy-5-nitrobenzonitrile (3-2)
1 g of 3-1 is dissolved in 10 ml of N, N-dimethylformamide, 1.1 ml of oxalyl chloride is slowly added in an ice bath, the ice bath is removed after the dropwise addition, and the mixture is stirred at 80 ℃ for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate = 4:1 column chromatography purification gave 4-chloro-3-methoxy-5-nitrobenzonitrile (3-2) as a pale yellow solid (0.71 g) in 64.8% yield. 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).
Step (3): 4- ((4-bromophenylethyl) amino) -3-methoxy-5-nitrobenzonitrile (3-3)
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1 g of 3-2, 1.9 g of 4-bromophenylethylamine, 1.3 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, and the solid was suction-filtered to obtain 1.2 g of a yellow solid of 4- ((4-bromophenyl ethyl) amino) -3-methoxy-5-nitrobenzonitrile (3-3) with a yield of 67.8%. ESI-MS (m/z): 376.1[ M+H ]] + .
Step (4): 3-amino-4- ((4-bromophenyl ethyl) amino) -5-methoxybenzonitrile (3-4)
A mixture of 1 g of 3-3, 3.2 g of sodium dithionite, 2 ml of ammonia water and 10 ml of methanol was stirred at room temperature for 1 hour. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4: column chromatography 1 afforded 3-amino-4- ((4-bromophenyl ethyl) amino) -5-methoxybenzonitrile (3-4) as a white solid 740 mg in 80.4% yield. 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).
Step (5): 2-amino-1- (4-bromophenyl ethyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carbonitrile (3-5)
220 mg of 3-4 and 74 mg of cyanogen bromide are dissolved in 2 ml of methanol and stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 2-amino-1- (4-bromophenyl ethyl) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carbonitrile (3-5) was 206 mg as a white solid in 87.3% yield. ESI-MS (m/z): 371.1[ M+H ]] + .
Step (6): n- (1- (4-bromophenyl ethyl) -5-cyano-7-methoxy-1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (3-6)
A mixture of 1.18 g 3-5, 588 mg of Compound 1-2, 1.48 g EDCI, 147 mg HOBT, 846. Mu.l triethylamine and 10 ml N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain N- (1- (4-bromophenyl ethyl) -5-cyano-7-methoxy-1H-benzo [ d ]]Imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (3-6) as a white solid 920 mg in 57% yield. 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).
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)
100 mg of compound 3-6 was dissolved in 2 ml of tetrahydrofuran under nitrogen, stirred at-78℃for 20 minutes, then 473. Mu.l of n-butyllithium was added, stirred at-78℃for 1 hour, then 788. Mu.l of triisopropyl borate was added, stirred at room temperature for 1 hour, and then quenched with 3M HCl. Extracting with dichloromethane, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=200: purifying by column chromatography 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) was found to be a pale yellow solid, 20 mg, in 21.5% yield. 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).
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)
Step (1): 4- ((4-bromobenzyl) amino) -3-methoxy-5-nitrobenzonitrile (4-1)
1 g of 3-2, 1.75 g of 4-bromobenzylamine, 1.3 g of potassium carbonate and 1 ml of triethylamine are dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution is added with water, solid is separated out, and the 4- ((4-bromobenzyl) amino) -3-methoxy-5-nitrobenzonitrile (4-1) yellow solid is obtained by suction filtration, 1.5 g, and the yield is 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).
Step (2): 3-amino-4- ((4-bromobenzyl) amino) -5-methoxybenzonitrile (4-2)
A mixture of 1.6 g of 4-1, 5.3 g of sodium dithionite, 2 ml of ammonia water and 15 ml of methanol was stirred at room temperature for 1 hour. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4:1 column chromatography purification gave 3-amino-4- ((4-bromobenzyl) amino) -5-methoxybenzonitrile (4-2) as a white solid 1 g in 68% yield. 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).
Step (3): 2-amino-1- (4-bromobenzyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carbonitrile (4-3)
940 mg of 4-2 and 360 mg of cyanogen bromide were dissolved in 5 ml of methanol and stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 2-amino-1- (4-bromobenzyl) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carbonitrile (4-3) was 900 mg as a white solid in 89% yield. ESI-MS (m/z): 357.1[ M+H ]] + .
Step (4): n- (1- (4-bromobenzyl) -5-cyano-7-methoxy-1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (4-4)
A mixture of 936 mg of 4-3, 485 mg of Compound 1-2, 1.22 mg of EDCI, 121 mg of HOBT, 698. Mu.l 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 taken up in methylene chloride: methanol=200: purifying by 1 column chromatography 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 as a white solid in 55.7% yield. 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).
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)
100 mg of Compound 4-4 are dissolved in 2 ml of tetrahydrofuran under nitrogen, after stirring for 20 minutes at-78℃486. Mu.l of n-butyllithium are added, after stirring for 1 hour at-78℃187. Mu.l of triisopropyl borate are added, after stirring for 1 hour at room temperature, and quenched by addition of 3M HCl. Extracting with dichloromethane, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=200: purifying by column chromatography 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) was found to be a pale yellow solid, 16 mg, in 17.2% yield. 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).
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)
Step (1): 4-hydroxy-3-methoxy-5-nitrobenzoic acid ethyl ester (5-1)
5 g of ethyl vanillic acid are dissolved in 42 ml of acetic acid, 4.2 ml of nitric acid are slowly added in an ice bath, the ice bath is removed after the addition, and the mixture is stirred at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate = 4: purification by 1 column chromatography gave 3.2 g of ethyl 4-hydroxy-3-methoxy-5-nitrobenzoate (5-1) as a brown solid in 52.1% yield. ESI-MS (m/z): 264.1[ M+Na ] ] + .
Step (2): 4-chloro-3-methoxy-5-nitrobenzoic acid ethyl ester (5-2)
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5 g of 5-1 are dissolved in 45 ml of N, N-dimethylformamide, 5.3 ml of oxalyl chloride are slowly added in an ice bath, the ice bath is removed after the dropwise addition, and the mixture is stirred at 80 ℃ for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate, the organic phase was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate = 4: purification by 1 column chromatography gave ethyl 4-chloro-3-methoxy-5-nitrobenzoate (5-2) as an off-white solid 3.5 g in 65% yield. ESI-MS (m/z): 282.0[ M+Na] + .
Step (3): 4- ((4-bromobenzyl) amino) -3-methoxy-5-nitrobenzoic acid ethyl ester (5-3)
1 g of 5-2, 1.43 g of 4-bromophenylethylamine, 1 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, and the solid was suction-filtered to give ethyl 4- ((4-bromobenzyl) amino) -3-methoxy-5-nitrobenzoate (5-3) as a yellow solid (1.2 g) in 76% yield. ESI-MS (m/z): 409.1[ M+H ]] + .
Step (4): 3-amino-4- ((4-bromobenzyl) amino) -5-methoxybenzoic acid methyl ester (5-4)
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. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4:1 column chromatography purification gave methyl 3-amino-4- ((4-bromobenzyl) amino) -5-methoxybenzoate (5-4) as a white solid 130 mg in 70.1% yield. 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).
Step (5): 2-amino-1- (4-bromobenzyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxylic acid ethyl ester (5-5)
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 was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 2-amino-1- (4-bromobenzyl) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carboxylic acid ethyl ester (5-5) 470 mg as white solid in 86.5% yield. ESI-MS (m/z): 404.1[ M+H ]] + .
Step (6): 1- (4-bromobenzyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxylic acid ethyl ester (5-6)
A mixture of 530 mg of 5-5, 222 mg of Compound 1-2, 611 mg of EDCI, 61 mg of HOBT, 350. Mu.l of triethylamine and 5 ml of N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 1- (4-bromobenzyl) -2- (1-ethyl-3-methyl)1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carboxylic acid ethyl ester (5-6) 370 mg as white solid in 52% yield. 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).
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)
100 mg of compound 5-6 were dissolved in 2 ml of tetrahydrofuran under nitrogen, stirred at-78℃for 20 minutes, then 473. Mu.l of n-butyllithium were added, stirred at-78℃for 1 hour, then 788. Mu.l of triisopropyl borate were added, stirred at room temperature for 1 hour, and then quenched with 3M HCl. Extracting with dichloromethane, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=200: purifying by column chromatography to obtain (4- ((5- (ethoxycarbonyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-formamide) -7-methoxy-1H-benzo [ d)]Imidazol-1-yl) methyl) phenyl) boronic acid (i-5) was found to be a pale yellow solid, 23 mg, 24.6% yield. 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).
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)
Step (1): 4-chloro-3-methoxy-5-nitrobenzamide (6-1)
5 g of methyl 4-chloro-3-methoxy-5-nitrobenzoate and 70 ml of ammonia were placed in a sealed tube and stirred at 50℃for 5 hours. The reaction solution was stirred in water for 1 hour, and then dried by filtration to obtain 3.77 g of a yellow solid (6-1) in a yield of 80.4%. LCMS (ESI) M/z [ M+H] + :231.5.
Step (2): 4- ((4-bromophenylethyl) amino) -3-methoxy-5-nitrobenzamide (6-2)
1 g of 6-1, 2.6 g of 4-bromophenylethylamine, 1.3 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, and the solid was suction-filtered to obtain 1.3 g of 4- ((4-bromophenyl ethyl) amino) -3-methoxy-5-nitrobenzamide (6-2) as a yellow solid, with a yield of 60.1%. LCMS (ESI) M/z [ M+Na] + :418.0.
Step (3): 3-amino-4- ((4-bromophenyl ethyl) amino) -5-methoxybenzamide (6-3)
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. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4: purification by 1 column chromatography gave 3-amino-4- ((4-bromophenyl ethyl) amino) -5-methoxybenzamide (6-3) as a white solid 850 mg in 65.5% yield. LCMS (ESI) m/z 364.1[ M+H ]] + .
Step (4): 2-amino-1- (4-bromophenyl ethyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (6-4)
850 mg of 6-3 and 247 mg of cyanogen bromide were dissolved in 2 ml of methanol and stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 2-amino-1- (4-bromophenyl ethyl) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carboxamide (6-4) 560 mg as white solid in 95.8% yield. LCMS (ESI) M/z [ M+Na ] + :389.1.
Step (5): 1- (4-bromophenyl ethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (6-5)
A mixture of 300 mg 6-4, 220 mg of Compound 1-2, 370 mg of EDCI, 37 mg of HOBT, 210. Mu.l of triethylamine and 2 ml of N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 1- (4-bromophenyl ethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-formamide) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carboxamide (6-5) 240 mg as a white solid in 58.8% yield. 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).
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)
100 mg of compound I-6 were dissolved in 2 ml of tetrahydrofuran under nitrogen, stirred at-78℃for 20 minutes, then 473. Mu.l of n-butyllithium were added, stirred at-78℃for 1 hour, then 788. Mu.l of triisopropyl borate were added, stirred at room temperature for 1 hour, and then quenched with 3M HCl. By dichloro methylExtracting with alkane, concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=200: purifying by column chromatography 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) was found to be a pale yellow solid 15 mg, with a yield of 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).
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)
Step (1): 4- ((4-bromophenylethyl) amino) -3-methoxy-5-nitrobenzoic acid ethyl ester (7-1)
1 g of 5-2, 1.5 g of 4-bromophenylethylamine, 1.0 g of potassium carbonate and 1 ml of triethylamine were dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, and the solid was suction-filtered to obtain 1.15 g of ethyl 4- ((4-bromophenyl ethyl) amino) -3-methoxy-5-nitrobenzoate (7-1) as a yellow solid, with a yield of 70.5%. LCMS (ESI) m/z 423.1[ M+H ]] + .
Step (2): 3-amino-4- ((4-bromophenyl ethyl) amino) -5-methoxybenzoic acid ethyl ester (7-2)
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. Suction filtering to obtain filtrate, concentrating to dry, and removing residue with stoneOil ether: ethyl acetate = 4: purification by column chromatography gave ethyl 3-amino-4- ((4-bromophenyl ethyl) amino) -5-methoxybenzoate (7-2) as a white solid 950 mg in 63.9% yield. LCMS (ESI) m/z 339.1[ M+H ]] + .
Step (3): 2-amino-1- (4-bromophenyl ethyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxylic acid ethyl ester (7-3)
860 mg of 7-2 and 278 mg of cyanogen bromide were dissolved in 8 ml of methanol and stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 2-amino-1- (4-bromophenyl ethyl) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carboxylic acid ethyl ester (7-3) 800 mg as white solid in 87.5% yield. LCMS (ESI) m/z 418.1[ M+H ]] + .
Step (4): 1- (4-bromophenyl ethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxylic acid ethyl ester (7-4)
A mixture of 1 g 3-5, 481 mg of Compound 1-2, 1.2 g EDCI, 120 mg HOBT, 536. Mu.l triethylamine and 10 ml N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain 1- (4-bromophenyl ethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-formamide) -7-methoxy-1H-benzo [ d ]]Imidazole-5-carboxylic acid ethyl ester (7-4) 870 mg as white solid in 61.8% yield. 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).
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)
100 mg of Compound 7-4 were dissolved in 2 ml of tetrahydrofuran under nitrogen, stirred at-78℃for 20 minutes, 433. Mu.l of n-butyllithium were added, stirred at-78℃for 1 hour, 166. Mu.l of triisopropylborate were added, stirred at room temperature for 1 hour, and quenched by addition of 3M HCl. Extracting with dichloromethane, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=200: purifying by column chromatography to obtain (4- (2- (5- (ethoxycarbonyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-formamide) -7-methoxy-1H-benzo [ d) ]Imidazol-1-yl) ethyl) phenyl) boronic acid (i-7) as a pale yellow solid 17 mg in 18.1% yield. 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).
Example 8 (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)
Step (1): diethyl (4- (2- (5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) ethyl) phenyl) phosphonate (8-1)
200 mg of 1-6, 204 mg of cesium carbonate, 48 mg of palladium tetraphenylphosphine, 115. Mu.l of diethyl phosphite and 2 ml of tetrahydrofuran are mixed and stirred at 100℃under reflux overnight. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by column chromatography to obtain diethyl (4- (2-(5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ]]Imidazol-1-yl) ethyl) phenyl) phosphonate (8-1) as a white solid 120 mg in 53.6% yield. ESI-MS (m/z): 535.3[ M+H ]] + .
Step (2): (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)
50 mg of 8-1 was dissolved in 2 ml of methylene chloride, and then 62. Mu.l of trimethylbromosilane was added thereto, and the ice bath was removed after the completion of the dropwise addition, and stirred overnight at room temperature; the reaction was concentrated to dryness, methanol was added and refluxed overnight at 80 ℃. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=10: purifying by column chromatography 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) as a white solid 21 mg in 29.3% yield. 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).
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)
The procedure and reaction conditions were the same as in example 8, except that in step (1) the starting material was 2-4 as a white solid in a yield of 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).
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)
The procedure and reaction conditions were the same as in example 8, except that in step (1), the starting material was 3-6 as a white solid in 43.2% yield. 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).
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)
The procedure and reaction conditions were the same as in example 8, except that in step (1), the starting material was I-8 as a white solid in 36.1% yield. 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).
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)
The procedure and reaction conditions were the same as in example 8, except that in step (1) the starting material was 5-6 as a white solid in 29.3% yield. 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).
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)
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The procedure and reaction conditions were the same as in example 8, except that in step (1) the starting material was 6-5 as a white solid in 28.5% yield. ESI-MS (m/z): 527.3[ M+H ]] + .
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)
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)
A mixture of 200 mg of 7-4, 176 mg of cesium carbonate, 42 mg of tetrakis (triphenylphosphine) palladium, 100. Mu.l of diethyl phosphite and 5 ml of anhydrous tetrahydrofuran was heated and stirred at 110℃for 36 hours under a nitrogen atmosphere. Concentrating the reaction solution to dryness, adding water into the residue, extracting with ethyl acetate, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=20:1 column chromatography to give off-white solid 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) 95 mg, yield 43%. ESI-MS (m/z): 612.4[ M+H ]] + .
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)
A mixture of 95 mg of compound 14-1, 103. Mu.l of trimethylbromosilane and 2 ml of anhydrous dichloromethane was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was stirred at 80℃for 16 hours. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=60: 6 preparation of a thin layer to give 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 in 43% yield. ESI-MS (m/z): 555.3[ M+H ]] + .
Example 15 (4- (2- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) ethyl) phenyl) phosphonic acid (I-15)
Step (1): 3-nitro-4- ((4-bromophenyl ethyl) amino) benzamide (15-1)
A mixture of 700 mg of 4-chloro-3-nitrobenzamide, 1.4 g of 4-bromophenylethylamine, 965 mg of potassium carbonate, 1 ml of triethylamine and 3 ml of n-butanol was stirred at 100℃overnight. Water was added to precipitate a solid, and the residue was taken up in petroleum ether: ethyl acetate=5:1 column chromatography purification gave 920 mg of 3-nitro-4- ((4-bromophenyl ethyl) amino) benzamide (15-1) as a yellow solid in 72% yield. ESI-MS (m/z): 364.1[ M+H ] ] + .
Step (2): 3-amino-4- ((4-bromophenyl ethyl) amino) benzamide (15-2)
920 mg of 3-nitro-4- ((4-bromophenylethyl) amino) benzamide, 3.08 g of sodium dithionite, 2 ml of ammonia water and 10 ml of methanol were mixedThe mixture was stirred at 45℃for 0.5 hour with heating. The reaction was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate = 2:1 column chromatography purification gave 3-amino-4- ((4-bromophenyl ethyl) amino) benzamide (15-2) as a yellow-like solid in 500 mg, 59% yield. ESI-MS (m/z): 334.1[ M+H ]] + .
Step (3): 2-amino-1- (4-bromophenyl ethyl) -1H-benzo [ d ] imidazole-5-carboxamide (15-3)
500 mg of 3-amino-4- ((4-bromophenylethyl) amino) benzamide, 191 mg of cyanogen bromide and 5 ml of methanol were stirred at room temperature overnight. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=20: purifying by 1 column chromatography to obtain white solid 2-amino-1- (4-bromophenyl ethyl) -1H-benzo [ d ]]Imidazole-5-carboxamide (15-3) 450 mg, 84% yield. LCMS (ESI) m/z 359.1[ M+H ]] + .
Step (4): 1- (4-bromophenyl ethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazole-5-carboxamide (15-4)
A mixture of 322 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 539 mg of EDCI, 81 mg of HOBT, 482. Mu.l of triethylamine and 5 ml of N, N-dimethylformamide was stirred under an ice bath for 0.5H. 624 mg of 2-amino-1- (4-bromophenyl ethyl) -1H-benzo [ d ] ]Imidazole-5-carboxamide was added to the mixture and stirred overnight at room temperature. Water was added and the solid precipitated and the residue was taken up in dichloromethane: methanol=20:1 column chromatography to give 1- (4-bromophenyl ethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d]Imidazole-5-carboxamide (15-4) 720 mg as a white solid in 84% yield. 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).
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)
200 mg of 1- (4-bromophenyl-ethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] are reacted under nitrogen]A mixture of imidazole-5-carboxamide, 197 mg cesium carbonate, 47 mg tetrakis (triphenylphosphine) palladium, 112 μl diethyl phosphite and 5 ml anhydrous tetrahydrofuran was heated and stirred at 110deg.C for 36 hours. Concentrating the reaction solution to dryness, adding water into the residue, extracting with ethyl acetate, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=20:1 column chromatography to give diethyl (4- (2- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d) as an off-white solid]Imidazol-1-yl) ethyl) phenyl) phosphonate (15-5) 85 mg in 38% yield. LCMS (ESI) m/z 553.4[ M+H ] ] + .
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)
85 mg of diethyl (4- (2- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] are reacted under nitrogen]Imidazol-1-yl) ethyl) phenyl) phosphonate, 142 μl of trimethylbromosilane, and 2 ml of anhydrous dichloromethane were stirred overnight at room temperature. The reaction mixture was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was stirred at 80℃for 16 hours. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=60: 6 preparing a thin layer to give 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 milliGram, 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).
Example 16 dihydro 4- (2- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) ethyl) phenyl phosphate (I-16)
Step (1): (4- ((tert-Butyldiphenylsilyl) oxy) phenethyl) carbamic acid tert-butyl ester (16-1)
1 g of t-butyl (4-hydroxyphenylethyl) carbamate was dissolved in 10 ml of anhydrous methylene chloride, 670 mg of imidazole was added, and after stirring in an ice bath for ten minutes, 2.31 g of t-butyldiphenylchlorosilane diluted one-time was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with methylene chloride, and the organic phase was washed with saturated brine and concentrated to dryness to give 2 g of a pale yellow oil (16-1) in 100% yield. LCMS (ESI) M/z [ M+Na ] + :498.8.
Step (2): 2- (4- ((tert-Butyldiphenylsilyl) oxy) phenyl) ethan-1-amine (16-2)
2 g of 16-1 are dissolved in 25 ml of dichloromethane, 10 ml of trifluoroacetic acid are added and stirred at room temperature for 1 hour. The reaction solution was concentrated, then a small amount of methylene chloride and a large amount of n-hexane were added, and concentrated to dryness. Small amount of dichloromethane and large amount of petroleum ether are added, the dichloromethane is removed by rotary evaporation, and the product is separated out. Filtration and drying gave 1.03 g of white solid (16-2) in 50.2% yield. LCMS (ESI) M/z [ M+H] + :376.2.
Step (3): 4- ((4- ((tert-Butyldiphenylsilyl) oxy) phenethyl) amino) -3-methoxy-5-nitrobenzamide (16-3)
840 mg of 6-1 are dissolved in 15 ml of anhydrous N, N-dimethylformamide under argon, 2 ml of N, N-diisopropylethylamine are added, and after stirring at room temperature for 20 minutes 430 mg of 16-2 are added and heated at 110℃overnight. After the reaction was completed, water was added to the reaction mixture to precipitate an orange solid, which was then filtered and dried to obtain 860 mg of an orange solid (16-3) in 88.8% yield. LCMS (ESI) M/z [ M+Na] + :592.6.
Step (4): 3-amino-4- ((4- ((tert-butyldiphenylsilyl) oxy) phenethyl) amino) -5-methoxybenzamide (16-4)
113 mg of 16-3 are dissolved in 10 ml of methanol, 173 mg of sodium dithionite and 1.5 ml of aqueous ammonia are added, and the mixture is heated and stirred at 55℃for 3 hours. The reaction solution was filtered off with suction, the filtrate was concentrated to dryness and the residue was taken up in methylene chloride: methanol=99:1 column chromatography gave a yellow oil (16-4) 60 mg, 56% yield. LCMS (ESI) M/z [ M+H ] + :540.7.
Step (5): 2-amino-1- (4- ((tert-butyldiphenylsilyl) oxy) phenethyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (16-5)
Under argon atmosphere, 850 mg of 16-4 was dissolved in 15 ml of anhydrous methanol, and 800 mg of cyanogen bromide was added after ultrasonic dissolution, followed by stirring at room temperature for 2 hours. A white solid precipitated. Adding ethyl acetate into the reaction solution, stirring for 1 hr, filtering the reaction solution, concentrating and drying to obtain white solid (16-5) 518 mlGram, yield 58.5%. LCMS (ESI) M/z [ M+H] + :565.4.
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)
5.64 g of 16-5 are dissolved in 80 ml of anhydrous N, N-dimethylformamide under argon, 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) hexafluoro-urea phosphate (HATU) and 8.3 ml of N, N-diisopropylethylamine are added and stirred at room temperature overnight. After the completion of the reaction, the reaction solution was poured into water, and a white solid was precipitated, stirred for 30 minutes, and dried by filtration to give 5.7 g of a white solid (16-6) in a yield of 81.4%. LCMS (ESI) M/z [ M+H] + :701.8.
Step (7): 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1- (4-hydroxyphenylethyl) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (16-7)
5.7 g of 16-6 was dissolved in 100 ml of anhydrous tetrahydrofuran under argon atmosphere, and after stirring for 10 minutes in an ice bath, 15 ml of tetrabutylammonium fluoride was diluted three times and then slowly dropped into the reaction solution, and stirring was carried out at room temperature for 1 hour. The reaction solution was poured into water, and the product was gradually precipitated. Filtration and drying gave 3.76 g of an off-white solid (16-7) in 100% yield. 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).
Step (8): 4- (2- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) ethyl) phenylphosphoric acid dihydro (I-16)
100 mg of 16-7 was dissolved in 1 ml of anhydrous pyridine under the protection of nitrogen, the mixture was cooled to-15℃and stirred for 10 minutes, 100. Mu.l of phosphorus oxychloride was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 30 minutes and poured into an aqueous sodium hydrogencarbonate solution. Extracted with dichloromethane and the organic phase concentrated to dryness, the residue was extracted with dichloromethane: methanol=10: purifying by 1 column chromatography to obtain 4- (2- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d)]Imidazol-1-yl) ethyl) phenylphosphoric acid dihydro (I-16) as a pale yellow solid 12 mg, yield 10.23%. LCMS (ESI) M/z [ M+K] + :581.2.
Example 17- ((2-amino-5-cyano-1H-benzo [ d ] imidazol-1-yl) methyl) benzenesulfonamide (I-17)
Step (1): 4- (((4-cyano-2-nitrophenyl) amino) methyl) benzenesulfonamide (17-1)
500 mg of 4-chloro-3-nitrobenzonitrile, 1 g of sulfamuron, 758 mg of potassium carbonate and 1 ml of triethylamine are dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, which was suction-filtered to give 4- (((4-cyano-2-nitrophenyl) amino) methyl) benzenesulfonamide (17-1) as a yellow solid (400 mg) in 43.9% yield. LCMS (ESI) M/z [ M-H] - :331.0.
Step (2): 4- (((2-amino-4-cyanophenyl) amino) methyl) benzenesulfonamide (17-2)
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. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4: purification by 1 column chromatography gave 4- (((2-amino-4-cyanophenyl) amino) methyl) benzenesulfonamide (17-2) as a white solid 630 mg in 69.2% yield. LCMS (ESI) M/z [ M+H] + :303.1.
Step (3): 4- ((2-amino-5-cyano-1H-benzo [ d ] imidazol-1-yl) methyl) benzenesulfonamide (I-17)
100 mg of 17-2 and 42 mg of cyanogen bromide were dissolved in 2 ml of methanol and stirred at room temperature overnight. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by column chromatography to obtain 4- ((2-amino-5-cyano-1H-benzo [ d) ]Imidazol-1-yl) methyl benzenesulfonamide (i-17) as a white solid 75 mg in 69.3% yield. 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＝8.4,1.5Hz,1H),7.57(d,J＝8.4Hz,1H),7.47(d,J＝8.3Hz,2H),7.40(s,2H),5.58(s,2H).
Example 18 Ethyl 2-amino-1- (4-sulfamoyl-benzyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-18)
The procedure and reaction conditions were the same as in example 17, except that ethyl 4-chloro-3-nitrobenzoate was used as the starting material in step (1) in the form of a white solid with a yield of 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).
Example 19 2-amino-7-methoxy-1- (4-sulfamoyl-benzyl) -1H-benzo [ d ] imidazole-5-carboxamide (I-19)
The procedure and reaction conditions were the same as in example 17, except that in step (1), the starting material was 6-1 as a white solid in 53.6% yield. 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).
Example 20 Ethyl 2-amino-7-methoxy-1- (4-sulfamoyl-benzyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-20)
The procedure and reaction conditions were the same as in example 17, except that in step (1), the starting material was 5-2 as a white solid in 58.4% yield. 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).
Example 21N- (5-cyano-1- (4-sulfamoyl-benzyl) -1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (I-21)
A mixture of 100 mg I-17, 56 mg of Compound 1-2, 142 mg EDCI, 14 mg HOBT, 81. Mu.l triethylamine and 2 ml N, N-dimethylformamide was stirred overnight at room temperature. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by 1 column chromatography to obtain N- (5-cyano-1- (4-sulfamoyl benzyl) -1H-benzo [ d ] ]Imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (i-21) as a white solid 74 mg in 52.3% yield. 1 H NMR(300MHz,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).
Example 22 Ethyl 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1- (4-sulfamoyl-benzyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-22)
The procedure and reaction conditions were the same as in example 21, except that in the step (II) the starting material was I-18 as a white solid in 60.3% yield. 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＝8.5,2.0Hz,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).
Example 23 Ethyl 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1- (4-sulfamoylbenzyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-23)
The procedure and reaction conditions were the same as in example 21, except that in the step (II) the starting material was I-20 as a white solid in 60.3% yield. 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).
Example 24 4- (2- (2-amino-5-cyano-1H-benzo [ d ] imidazol-1-yl) ethyl) benzenesulfonamide (I-24)
The procedure and reaction conditions were the same as in example 17, except that in the step (ii) the starting material was 4- (2-aminoethyl) benzenesulfonamide as a white solid in a yield of 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).
Example 25 Ethyl 2-amino-1- (4-sulfamoylphenethyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-25)
The procedure and reaction conditions were the same as in example 17, except that in step (1) the starting materials were I-18 and 4- (2-aminoethyl) benzenesulfonamide as white solids in 58.4% yield. 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).
Example 26 2-amino-7-methoxy-1- (4-sulfamoylphenethyl) -1H-benzo [ d ] imidazole-5-carboxamide (I-26)
The procedure and reaction conditions were the same as in example 17, except that in step (1), 6-1 and 4- (2-aminoethyl) benzenesulfonamide were used as starting materials, and a white solid was obtained in a yield of 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).
Example 27 Ethyl 2-amino-7-methoxy-1- (4-sulfamoylphenethyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-27)
The procedure and reaction conditions were the same as in example 17, except that in step (1), the starting materials were 5-2 and 4- (2-)Aminoethyl) benzenesulfonamide, a white solid, yield 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).
Example 28N- (5-cyano-1- (4-sulfamoylphenethyl) -1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (I-28)
The procedure and reaction conditions were the same as in example 21, except that in the step (I-24) as a white solid was used, and the yield was 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).
Example 29 Ethyl 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1- (4-sulfamoylphenethyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-29)
The procedure and reaction conditions were the same as in example 21, except that in the step (A) the starting material was I-25 as a white solid, and the yield was 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＝7.4Hz,2H),4.31(dt,J＝16.1,6.9Hz,2H),2.21(s,3H),1.35(q,J＝6.9Hz,6H).
Example 30 Ethyl 2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1- (4-sulfamoylphenethyl) -1H-benzo [ d ] imidazole-5-carboxylate (I-30)
The procedure and reaction conditions were the same as in example 21, except that in the step (A) the starting material was I-27 as a white solid in 57.6% yield. 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).
Example 31- ((2-amino-5-cyano-7-methoxy-1H-benzo [ d ] imidazol-1-yl) methyl) benzenesulfonamide (I-31)
Step (1): 4- (((4-cyano-2-methoxy-6-nitrophenyl) amino) methyl) benzenesulfonamide (31-1)
1 g of 3-2, 1.75 g of sulfamuron, 1.3 g of potassium carbonate and 1 ml of triethylamine are dissolved in 4 ml of n-butanol and stirred at 100℃for 2 hours. The reaction solution was added with water to precipitate a solid, which was suction-filtered to give 4- (((4-cyano-2-methoxy-6-nitrophenyl) amino) methyl) benzenesulfonamide (31-1) as a yellow solid, 0.9 g, 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).
Step (2): 4- (((2-amino-4-cyano-6-methoxyphenyl) amino) methyl) benzenesulfonamide (31-2)
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 brought to room temperatureStirring is carried out for 1 hour. Suction filtration to obtain filtrate, concentration to dryness, residue with petroleum ether: ethyl acetate = 4: purification by 1 column chromatography gave 4- (((2-amino-4-cyano-6-methoxyphenyl) amino) methyl) benzenesulfonamide (31-2) as a white solid 580 mg in 66.2% yield. ESI-MS (m/z): 333.0[ M+H ]] + .
Step (3): 4- ((2-amino-5-cyano-7-methoxy-1H-benzo [ d ] imidazol-1-yl) methyl) benzenesulfonamide (I-31)
500 mg of 31-2 and 191 mg of cyanogen bromide were dissolved in 5 ml of methanol and stirred at room temperature overnight. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=200: purifying by column chromatography to obtain 4- ((2-amino-5-cyano-7-methoxy-1H-benzo [ d)]Imidazol-1-yl) methyl) benzenesulfonamide (i-31) was a white solid, 420 mg, yield 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).
Example 32 4- (2- (2-amino-5-cyano-7-methoxy-1H-benzo [ d ] imidazol-1-yl) ethyl) benzenesulfonamide (I-32)
The procedure and reaction conditions were the same as in example 31, except that in step (1), 4- (2-aminoethyl) benzenesulfonamide was used as the starting material, which was a white solid in 71.4% yield. 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).
Example 33 2-amino-1- (4-sulfamoyl-benzyl) -1H-benzo [ d ] imidazole-5-carboxamide (I-33)
The procedure and reaction conditions were the same as in example 31, except that in step (1), 4-chloro-3-nitrobenzamide was used as the starting material, and a white solid was used in a yield of 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).
Example 34 2-amino-1- (4-sulfamoylphenethyl) -1H-benzo [ d ] imidazole-5-carboxamide (I-34)
The procedure and reaction conditions were the same as in example 31, except that in step (1), 4-chloro-3-nitrobenzamide and 4- (2-aminoethyl) benzenesulfonamide were used as starting materials, and a white solid was obtained in a yield of 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).
Example 35 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)
Step (1): (E) -4-bromo-2, 6-difluorobenzaldehyde oxime (35-1)
2 g of 4-bromo-2, 6-difluorobenzaldehyde are dissolved in 30 ml of ethanol at room temperature, 880 mg of hydroxylamine hydrochloride and 1.04 g of potassium acetate are added and reacted at 22℃for 30 minutes. After the reaction is completed, adding ice water under an ice bath, stirring for one hour, carrying out suction filtration, and using ethanol as a filter cake: water = 1:1 cold filtration and washing, residue with petroleum ether: ethyl acetate = 10: purifying by 1 column chromatography to obtain white solid (E) -4-bromo-2, 6-difluorobenzeneFormaldoxime (35-1) 1.4 g, 66% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.96(s,1H),8.10(s,1H),7.65–7.52(m,2H).
Step (2): (4-bromo-2, 6-fluorophenyl) methylamine (35-2)
1.4 g of (E) -4-bromo-2, 6-difluorobenzaldehyde oxime was dissolved in 10 ml of acetic acid, and 2.9 g of zinc powder was added at 65℃and stirred with heating for two hours. Concentrating the reaction solution to dryness, adding water into the residue, and extracting with ethyl acetate; the aqueous phase was treated with sodium bicarbonate solids and the pH was adjusted to 8-9. Suction filtration, extraction of the filtrate with ethyl acetate and concentration of the organic phase to dryness gave 680 mg of (4-bromo-2, 6-fluorophenyl) methylamine as a yellow oil in a yield of 56%. ESI-MS (m/z): 222.0[ M+H ]] + .
Step (3): 4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) -3-p-nitrophenyl cyano (35-3)
A mixture of 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-butanol was stirred at 100℃overnight. Water was added to precipitate a solid, and the residue was taken up in petroleum ether: ethyl acetate=2:1 column chromatography purification gave 1.1 g of 4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) -3-p-nitrophenyl cyano (35-3) as a yellow solid in 55% yield.
Step (4): 3-amino-4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) benzonitrile (35-4)
A mixture of 1.1 g of 4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) -3-p-nitrocyano, 3.9 g of sodium dithionite and 10 ml of methanol was stirred with heating at 45℃for 0.5 h. Concentrating the reaction solution to dryness, and removing residuesThe remainder is petroleum ether: ethyl acetate = 1:1 column chromatography purification gave 560 mg of 3-amino-4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) benzonitrile (35-4) as a pale yellow solid in 56% yield. ESI-MS (m/z): 338.0[ M+H ]] + .
Step (5): 2-amino-1- (4-bromo-2, 6-difluorobenzyl bromide) -1H-benzo [ d ] imidazole-5-carbonitrile (35-5)
560 mg of 3-amino-4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) benzonitrile, 211 mg of cyanogen bromide and 5 ml of methanol are stirred at room temperature overnight. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=20: purifying by 1 column chromatography to obtain off-white solid 2-amino-1- (4-bromo-2, 6-difluorobenzyl bromide) -1H-benzo [ d ]]Imidazole-5-carbonitrile (35-5) was 490 mg in 81% yield. 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).
Step (6): 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)
A mixture of 221 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 371 mg of EDCI, 56 mg of HOBT, 332. Mu.l of triethylamine and 4 ml of N, N-dimethylformamide was stirred under an ice bath for 0.5H. 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 and the solid precipitated and the residue was taken up in dichloromethane: methanol=20:1 column chromatography to give N- (1- (4-bromo-2, 6-difluorobenzyl bromide) -5-cyano-1H-benzo [ d ] as a white solid]Imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (35-6) 450 mg, 67% yield. 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).
Step (7): 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)
200 mg of N- (1- (4-bromo-2, 6-difluorobenzyl bromide) -5-cyano-1H-benzo [ d ] are reacted under nitrogen]A mixture of imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide, 196 mg cesium carbonate, 47 mg tetrakis (triphenylphosphine) palladium, 111. Mu.l diethyl phosphite and 5 ml anhydrous tetrahydrofuran was heated and stirred at 110℃for 36 hours. Concentrating the reaction solution to dryness, adding water into the residue, extracting with ethyl acetate, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=20:1 column chromatography to afford diethyl (4- ((5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d) as an off-white solid]Imidazol-1-yl) methyl) -3, 5-fluorophenyl phosphonate (I-35) 54 mg in 24% yield. 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).
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)
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)
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54 mg of diethyl (4- ((5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d) are reacted under nitrogen]A mixture of imidazol-1-yl) methyl) -3, 5-fluorophenyl phosphonate, 101 μl of trimethylbromosilane and 2 ml of anhydrous dichloromethane was stirred overnight at room temperature. The reaction mixture was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was stirred at 80℃for 16 hours. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=60: 6 preparing a thin layer to give 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 in 50% yield. 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).
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)
Step (1): 4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) -3-nitrobenzoic acid ethyl ester (37-1)
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 at 100℃overnight. Water was added to precipitate a solid, and the residue was taken up in petroleum ether: ethyl acetate=5:1 column chromatography purification gave ethyl 4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) -3-nitrobenzoate (37-1) as a yellow solid (1.03 g, 57% yield). LCMS (ESI) m/z 295.2[ M+H ]] + .
Step (2): 3-amino-4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) benzoic acid ethyl ester (37-2)
A mixture of 1.03 g of ethyl 4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) -3-nitrobenzoate, 3.1 g of sodium dithionite and 10 ml of methanol was stirred with heating at 45℃for 0.5 h. The reaction was concentrated to dryness and the residue was taken up in petroleum ether:
ethyl acetate = 3:1 column chromatography purification gave ethyl 3-amino-4- ((4-bromo-2, 6-difluorobenzyl bromide) amino) benzoate (37-2) as a pale yellow solid (520 mg) in 54% yield. 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).
Step (3): 2-amino-1- (4-bromo-2, 6-difluorobenzyl bromide) -1H-benzo [ d ] imidazole-5-carboxylic acid ethyl ester (37-3)
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 at room temperature overnight. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=20: purifying by 1 column chromatography 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).
Step (4): 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)
208 mg of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid were taken up in an ice bathA mixture of g EDCI, 52 mg HOBT, 311. Mu.l triethylamine and 4 ml N, N-dimethylformamide was stirred for 0.5 h. 460 mg of 2-amino-1- (4-bromo-2, 6-difluorobenzyl bromide) -1H-benzo [ d ]]Imidazole-5-carboxylic acid ethyl ester was added to the mixture and stirred overnight at room temperature. Water was added and the solid precipitated and the residue was taken up in dichloromethane: methanol=20:1 column chromatography to give 1- (4-bromo-2, 6-difluorobenzyl bromide) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] as a white solid]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).
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)
200 mg of 1- (4-bromo-2, 6-difluorobenzyl bromide) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] are reacted under nitrogen]A mixture of imidazole-5-carboxylic acid ethyl ester, 179 mg cesium carbonate, 43 mg tetrakis (triphenylphosphine) palladium, 101. Mu.l diethyl phosphite and 5 ml anhydrous tetrahydrofuran was heated and stirred at 110℃for 36 hours. Concentrating the reaction solution to dryness, adding water into the residue, extracting with ethyl acetate, and concentrating the organic phase to dryness; the residue was taken up in methylene chloride: methanol=20:1 column chromatography to give off-white solid 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) 96 mg, 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).
Example 38 (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)
Step (1): (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)
54 mg of 1- (4- (diethoxyphosphoryl) -2, 6-difluorobenzyl bromide) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] are reacted under nitrogen]A mixture of imidazole-5-carboxylic acid ethyl ester, 97. Mu.l of trimethylbromosilane and 2 ml of anhydrous dichloromethane was stirred overnight at room temperature. The reaction mixture was concentrated to dryness, 2 ml of methanol was added to the residue, and the mixture was stirred at 80℃for 16 hours. The reaction was concentrated to dryness and the residue was taken up in dichloromethane: methanol=10: 1 preparing a thin layer to give 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 in 55% yield. 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).
Example 39 (4- (2- (5-cyano-2- ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carbamoyl) -1H-benzo [ d ] imidazol-1-yl) ethyl) phenyl) phosphonic acid (I-39)
Step (1): 5-cyano-1H-benzo [ d ] imidazole-2-carboxylic acid (39-1)
1 g of 3, 4-diaminobenzonitrile was dispersed in 10 ml of anhydrous dichloromethane under argon atmosphere, 1.25 ml of methyl 2, 2-trichloroacetate was added, 1.5 ml of trifluoroacetic acid was added under ice bath, and stirring was carried out for 1 hour. The reaction solution was filtered, 15 ml of 1.5M sodium hydroxide was added to the filtrate, and methylene chloride was removed by concentration. 15 ml of methanol was added to the residue and stirred for 4 hours. 1M hydrochloric acid was slowly added dropwise to the reaction solution to gradually precipitate a solid, which was dried to obtain 800 mg of a pale yellow solid (39-1) in a yield of 57.1%. LCMS (ESI) M/z [ M+H] + :188.1.
Step (2): 1-ethyl-3-methyl-1H-pyrazol-5-amine (39-2)
2 g of (Z) -3-amino-2-enenitrile are dissolved in 40 ml of absolute ethanol under argon, 4.8 g of ethylhydrazine oxalate and 8.5 ml of triethylamine are added, and the mixture is heated and stirred at 80℃for 4 hours. The reaction solution is filtered, and the filtrate is concentrated to dryness to obtain light yellow liquid. The residue was taken up in methylene chloride: methanol=50:1 column chromatography purification gave 2.7 g of a pale yellow solid (39-2) in 88.5% yield. 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).
Step (3): 5-cyano-N- (1-ethyl-3-methyl-1H-pyrazol-5-yl) -1H-benzo [ d ] imidazole-2-carboxamide (39-3)
400 mg of 39-1 are dissolved in 15 ml of N, N-dimethylformamide under argon, 450 mg of 39-2, 1.2 g of N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluoro-phosphate urea (HATU) and 2 ml of N, N-diisopropylethylamine are added and stirred at room temperature overnight. Diluting the reaction solution with water, extracting with dichloromethane, and mixing the organic phase with water 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 taken up in petroleum ether: ethyl acetate=3:2 column chromatography purification gave 330 mg of a pale yellow solid (39-3) in 48.5% yield. LCMS (ESI) M/z [ M+H] + :295.2.
Step (4): 1- (4-bromophenyl-ethyl) -5-cyano-N- (1-ethyl-3-methyl-1H-pyrazol-5-yl) -1H-benzo [ d ] imidazole-2-carboxamide (39-4)
180 mg of 39-3 was dissolved in 10 ml of dimethyl sulfoxide, 50 mg of potassium hydroxide and 250 mg of p-bromophenyl ethyl bromide were added thereto, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with water and saturated brine, followed by removal of dimethyl sulfoxide. The organic phase was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate=7:3 column chromatography purification gave 150 mg of a pale yellow solid (39-4) in 51.5% yield. 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).
Step (5): (4- (2- (5-cyano-2- ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carbamoyl) -1H benzo [ d ] imidazol-1-yl) ethyl) phenyl) phosphonic acid diethyl ester (39-5)
50 mg of 39-4 was dissolved in 6 ml of anhydrous tetrahydrofuran under argon atmosphere, and 15 mg of tetrakis (triphenylphosphine) palladium, 85. Mu.l of triethylamine and 34. Mu.l of diethyl phosphite were added thereto and stirred at 100℃for 12 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was extracted with ethyl acetate after adding water and the organic phase was concentrated to dryness. The residue was taken up in methylene chloride: methanol=50:1 to prepare a thin layer, a white solid (39-5) 30 mg, 53.6% yield. LCMS (ESI) M/z [ M+H] + :535,2.
Step (6): (4- (2- (5-cyano-2- ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carbamoyl) -1H benzo [ d ] imidazol-1-yl) ethyl) phenyl) phosphonic acid (I-39)
30 mg of 39-5 was dissolved in 5 ml of anhydrous dichloromethane under argon atmosphere, and after stirring for 10 minutes in ice bath, 70. Mu.l of trimethyliodosilane was slowly added, followed by stirring at room temperature overnight. To the reaction solution, 3 ml of methanol and 3 ml of water were added, and after stirring until a solid was precipitated, stirring was continued for 3 hours. The reaction solution was filtered to give 10 mg of an off-white solid (I-39) in 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).
Example 40 (4- ((5-cyano-2- ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carbamoyl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) phosphonic acid (I-40)
Step (1): 1- (4-bromophenyl) -5-cyano-N- (1-ethyl-3-methyl-1H-pyrazol-5-yl) -1H-benzo [ d ] imidazole-2-carboxamide (40-1)
200 mg of 39-3 was dissolved in 10 ml of dimethyl sulfoxide, 60 mg of potassium hydroxide and 250 mg of p-bromobenzyl bromide were added thereto, and the mixture was stirred at room temperature for 16 hours. Adding ethyl acetate, water and saturated salt into the reaction solutionThe water was thoroughly washed to remove dimethyl sulfoxide. The organic phase was concentrated to dryness and the residue was taken up in petroleum ether: ethyl acetate=7: purification by 3 column chromatography gave 80 mg of a pale yellow solid (40-1) in 25.5% yield. 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).
Step (2): (4- ((5-cyano-2- ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carbamoyl) -1H benzo [ d ] imidazol-1-yl) methyl) phenyl) phosphonic acid diethyl ester (40-2)
40 mg of 40-1 was dissolved in 5 ml of anhydrous tetrahydrofuran under argon atmosphere, and 15 mg of tetrakis (triphenylphosphine) palladium, 85. Mu.l of triethylamine and 50. Mu.l of diethyl phosphite were added thereto, followed by stirring at 100℃for 12 hours. The reaction solution was filtered, and the filtrate was concentrated. The residue was extracted with ethyl acetate after adding water and the organic phase was concentrated to dryness. The residue was taken up in methylene chloride: methanol=50:1 to give a thin layer of light yellow oil (40-2) 20 mg, 44.4% yield. LCMS (ESI) M/z [ M+H] + :521.2.
Step (3): (4- ((5-cyano-2- ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carbamoyl) -1H benzo [ d ] imidazol-1-yl) methyl) phenyl) phosphonic acid (I-40)
20 mg of 40-2 was dissolved in 4 ml of anhydrous methylene chloride under argon atmosphere, stirred in an ice bath for 10 minutes, and 60. Mu.l of trimethyliodosilane was slowly added dropwise, followed by stirring at room temperature overnight. To the reaction solution, 3 ml of methanol and 3 ml of water were added, and after stirring until a solid was precipitated, stirring was continued for 3 hours. The reaction solution was filtered to give 7 mg of an off-white solid (I-40) in 39.3% yield. LCMS (ESI) M/z [ M-H] + :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).
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)
4 g of 16-7 are dissolved in a mixture of 40 ml of dry dichloromethane and 40 ml of dry dimethyl sulfoxide under argon, after stirring for 10 minutes in an ice bath, 1.7 g of diethyl cyanophosphate are added, followed by slow addition of 2.4 ml of triethylamine, after stirring for 30 minutes in an ice bath, and stirring is carried out at room temperature overnight. The reaction mixture was extracted with water and dichloromethane, and the organic phase was washed thoroughly with water and concentrated to dryness. Beating sequentially with diethyl ether and ethyl acetate, drying to obtain 3.9 g of tan 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).
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)
Step (1): 4-acetamido-2-hydroxy-5-nitrobenzoic acid methyl ester (42-1)
30 g of methyl acetamido-o-methoxybenzoate was dissolved in 300 ml of trifluoroacetic acid, 16.6 g of potassium nitrate was added under ice bath and stirred at room temperature for 4 hours. The reaction solution was filtered, and the cake was washed with water to neutrality and dried to give 27 g of orange solid (42-1) in 74% yield. LCMS (ESI) M/z [ M+H] + :255.0.
Step (2): 4-acetamido-5-nitro-2- (prop-2-yn-1-yloxy) benzoic acid methyl ester (42-2)
A mixture of 27 g 42-1, 19.98 g potassium carbonate, 13.5 ml 3-bromopropyne and 200 ml N, N-dimethylformamide was stirred for 2 hours at 80℃under argon. The reaction mixture was stirred with water for 1 hour, and then dried by filtration to give 28 g of a yellow solid (42-2) in 98% yield. LCMS (ESI) M/z [ M+H ] + :293.0.
Step (3): 4-acetamido-2-methyl-5-nitrobenzofuran-7-carboxylic acid methyl ester (42-3)
A mixture of 28 g of 42-2 and 150 ml of N-methylpyrrolidone was stirred for 2 hours at 210℃under argon. The reaction solution was stirred with water for 1 hour, and then filtered and dried to obtain 14 g of a brown yellow solid (42-3) with a yield of 50%. LCMS (ESI) M/z [ M+H] + :293.0.
Step (4): 4-amino-2-methyl-5-nitrobenzofuran-7-carboxylic acid methyl ester (42-4)
A mixture of 14 g 42-3, 33 g potassium carbonate and 180 ml methanol was stirred overnight at room temperature. The reaction mixture was stirred with water for 30 minutes, and then dried by filtration to give 7.6 g of an orange solid (42-4) in 63% yield. LCMS (ESI) M/z [ M+H] + :251.0.
Step (5): 4-chloro-2-methyl-5-nitrobenzofuran-7-carboxylic acid methyl ester (42-5)
A mixture of 7.6 g 42-4, 5.34 g cuprous chloride, 6.5 ml t-butyl nitrite and 70 ml acetonitrile was stirred under argon 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, and the organic phase was dried over anhydrous sodium sulfate, and 6.7 g of a yellow-like solid (42-5) was obtained by filtration, concentration and drying in 82% yield. LCMS (ESI) M/z [ M+H] + :270.0.
Step (6): 4-chloro-2-methyl-5-nitro-1-benzofuran-7-carboxamide (42-6)
A mixture of 6.7 g of 42-5 and 80 ml of ammonia was stirred at 50℃overnight. The reaction solution was filtered and dried to give 5.3 g of a earthy yellow solid (42-6) in 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).
Step (7): 4- ((4-bromophenyl) amino) -2-methyl-5-nitrobenzofuran-7-carboxamide (42-7)
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 stirred with heating at 100℃for 1 hour. The reaction mixture was stirred with water for 1 hour, and then dried by filtration to give 1.4 g of a yellow solid (42-7) in 89% yield. LCMS (ESI) M/z [ M+H] + :404.0.
Step (8): 5-amino-4- ((4-bromophenyl) amino) -2-methylbenzofuran-7-carboxamide (42-8)
A mixed solution of 1.4 g 42-7, 5 g sodium dithionite, 6 ml ammonia water and 25 ml methanol was stirred at room temperature for 3 hours. The reaction solution was filtered off with suction, the filtrate was concentrated, and the residue was taken up in ethyl acetate: petroleum ether=1:1 column chromatography purification gave 600 mg of a pale yellow solid (42-8) in 47% yield. LCMS (ESI) M/z [ M+H] + :374.0.
Step (9): 2-amino-1- (4-bromophenyl) -7-methyl-1H-benzofuran [4,5-d ] imidazole-5-carboxamide (42-9)
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. Adding petroleum ether into the reaction solution: 200 ml of ethyl acetate=1:1 solution was stirred for 1 hour, and dried by filtration to give 517 mg of a white solid (42-9) in 81% yield. LCMS (ESI) M/z [ M+H ] + :399.0.
Step (c): 1- (4-bromophenyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methyl-1H-benzofuran [4,5-d ] imidazole-5-carboxamide (42-10)
A mixture of 517 mg 42-9, 301 mg 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 743 mg 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 570. Mu.l N, N-diisopropylethylamine and 6 ml N, N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was stirred with water, filtered and dried to give 395 mg of a brown solid (42-10) in 57% yield. LCMS (ESI) M/z [ M+H] + :535.0.
Step (a)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)
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A mixture of 395 mg of 42-10 mg of tetraphenylphosphine palladium, 86 mg of diethyl phosphite, 204 mg of triethylamine and 5 ml of anhydrous tetrahydrofuran was stirred at 110℃for 4 hours under argon. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified with petroleum ether: ethyl acetate=1:1 column chromatography purification gave 320 mg of a white solid (42-11) in 73% yield. LCMS (ESI) M/z [ M+H] + :593.0.
Step (a)(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)
50 mg of 42-11 was dissolved in methylene chloride, and 85 mg of iodotrimethylsilane was slowly added dropwise under an argon ice bath condition, and the mixture was stirred at room temperature for 2 hours after the completion of the dropwise addition. Methanol and water were added to the reaction mixture, followed by stirring for 4 hours and filtration to obtain 13 mg of pale yellow solid (I-42) in 29% yield. 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).
EXAMPLE 43 diethyl (4- ((5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) phosphonate (I-43)
Step (1): 4- ((4-bromobenzyl) amino) -3-nitrobenzonitrile (43-1)
10 g of 4-chloro-3-nitronitrile, 12 ml of 4-bromobenzylamine, 48 ml of N, N-diisopropylethylamine and 100 ml of N, N-dimethylformamide are stirred at 100℃for 1 hour. The reaction mixture was stirred with water for one hour, and then dried by filtration to give 15 g of a yellow solid (43-1) in 82% yield. LCMS (ESI) M/z [ M+H] + :332.0.
Step (2): 3-amino-4- ((4-bromobenzyl) amino) benzonitrile (43-2)
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 filtered off with suction, the filtrate was concentrated, and the residue was taken up in ethyl acetate: petroleum ether=1:1 column chromatography purification gave 7 g of a pale yellow solid (43-2) in 51% yield. LCMS (ESI) M/z [ M+H ] + :302.0.
Step (3): 2-amino-1- (4-bromobenzyl) -1H-benzo [ d ] imidazole-5-carbonitrile (43-3)
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. Adding petroleum ether into the reaction solution: 200 ml of ethyl acetate=1:1 solution was stirred for 1 hour, and dried by filtration to give 6.5 g of a white solid (43-3) in 86% yield. LCMS (ESI) M/z [ M+H] + :327.0.
Step (4): n- (1- (4-bromophenyl) -5-cyano-1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (43-4)
A mixture of 6.6 g of 43-3, 3.7 g of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 9.2 g of 2- (7-azabenzotriazol) -N, N, N ', 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 mixture was stirred with water, and then dried by filtration to give 5.3 g of a brown solid (43-4) in 57% yield. LCMS (ESI) M/z [ M+H] + :463.1.
Step (5): diethyl (4- ((5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) phosphonate (I-43)
A mixture of 5.3 g of 43-4, 1.4 g of palladium tetraphenylphosphine, 2.4 ml of diethyl phosphite, 6 ml of triethylamine and 50 ml of anhydrous tetrahydrofuran was stirred at 110℃for 4 hours under argon. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified with petroleum ether: ethyl acetate=1:1 column chromatography purification gave 3.5 g of white solid (I-43) in 56% yield. 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).
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)
Step (1): 4- ((4-bromophenyl) amino) -2-methyl-5-nitrobenzofuran-7-carboxamide (44-1)
A mixed solution of 1.5 g of compound 42-6, 1.76 g of p-bromophenylethylamine, 3.8 g of N, N-diisopropylethylamine and 20 ml of N, N-dimethylformamide was stirred at 100℃for 1 hour. The reaction mixture was stirred with water, and then dried by filtration to give 1.83 g of a yellow solid (44-1) in a yield of 74%. LCMS (ESI) M/z [ M+H] + :418.0.
Step (2): 5-amino-4- ((4-bromophenyl) amino) -2-methylbenzofuran-7-carboxamide (44-2)
A mixture of 1.83 g 44-1, 5 g sodium dithionite, 4 ml ammonia water and 20 ml methanol was stirred at room temperature for 2 hours. The reaction solution was filtered off with suction, the filtrate was concentrated, and the residue was taken up in ethyl acetate: petroleum ether=1:1 column chromatography purification gives 1.03 g of pale yellow solid (44-2) in 61% yield. LCMS (ESI) M/z [ M+H] + :388.0.
Step (3): 2-amino-1- (4-bromophenyl) -7-methyl-1H-benzofuran [4,5-d ] imidazole-5-carboxamide (44-3)
A mixture of 1.03 g 44-2, 2.3 g cyanogen bromide and 10 ml methanol was stirred at room temperature for 4 hours. Adding petroleum ether into the reaction solution: 80 ml of ethyl acetate=1:1 solution was stirred for 1 hour and filtered off with suction to give 0.85 g of a white solid (44-3) in 80% yield. LCMS (ESI) M/z [ M+H ] + :413.0.
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)
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-aza) are reactedA mixture of benzotriazol) -N, 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 mixture was stirred with water, and dried by filtration to give 820 mg of a brown solid (44-4) in a yield of 72%. LCMS (ESI) M/z [ M+H] + :551.0.
Step (5): diethyl (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) phosphonate (44-5)
A mixed solution of 380 mg of 44-4, 73 mg of tetrakis triphenylphosphine palladium, 173 mg of diethyl phosphite, 190 mg of triethylamine and 5 ml of anhydrous tetrahydrofuran was stirred at 110℃for 4 hours under argon. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified with petroleum ether: ethyl acetate=1:1 column chromatography purification gave 320 mg of a white solid (44-5) in 76% yield. LCMS (ESI) M/z [ M+H] + :607.0.
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)
100 mg of 44-5 was dissolved in methylene chloride, 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 in this order, stirred for 2 hours, and filtered to obtain 55 mg of an off-white solid (I-44) in 60% yield. 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).
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)
Step (1): 4-chloro-2-methyl-5-nitrobenzofuran-7-carbonitrile (45-1)
450 mg of 42-6, 645. Mu.l of thionyl chloride and 5 ml of N, N-dimethylformamide were mixed in a tube-sealed and heated to 120℃and stirred for 3 hours. The reaction mixture was stirred with water, filtered and dried to give a tan solid (45-1) 180 mg in 43% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.69(d,J＝1.2Hz,1H),7.13–7.07(m,1H),2.60(s,3H).
Step (2): 4- ((4-bromophenyl) amino) -2-methyl-5-nitrobenzofuran-7-carbonitrile (45-2)
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℃for 30 minutes. The reaction mixture was stirred with water for 1 hour, and then was dried by filtration to give 270 mg of a yellow solid (45-2) in 91% yield. LCMS (ESI) M/z [ M+H] + :386.0.
Step (3): 5-amino-4- ((4-bromophenyl) amino) -2-methylbenzofuran-7-carbonitrile (45-3)
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 filtered off with suction, the filtrate was concentrated, and the residue was taken up in ethyl acetate: petroleum oilPurification by ether=1:1 column chromatography gave 136 mg of a pale yellow solid (45-3) in 55% yield. LCMS (ESI) M/z [ M+H] + :356.0.
Step (4): 2-amino-1- (4-bromophenyl) -7-methyl-1H-benzofuran [4,5-d ] imidazole-5-carbonitrile (45-4)
A mixed solution of 80 mg of 45-3, 100 mg of cyanogen bromide and 800. Mu.l of methanol was stirred at room temperature for 2 hours. Adding petroleum ether into the reaction solution: 80 ml of ethyl acetate=1:1 solution was stirred for 1 hour and filtered off with suction to give 50 mg of a white solid (45-4) in 58% yield. LCMS (ESI) M/z [ M+H] + :381.0.
Step (5): n- (1- (4-bromophenyl) -5-cyano-7-methyl-1H-benzofuran [4,5-d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (45-5)
A mixture of 50 mg 45-4, 41 mg 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 100 mg 2- (7-azabenzotriazol) -N, N, N, N-tetramethylurea hexafluorophosphate, 35 mg N, N-diisopropylethylamine and 500. Mu.l N, N-dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was stirred with water, and then dried by filtration to give 37 mg of a brown solid (45-5) in 55% yield. LCMS (ESI) M/z [ M+H ] + :517.0.
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)
Under argon atmosphere, 37 mg of 45-5 mg, 8.3 mg of tetraphenylphosphine palladium, 20 mg of diethyl phosphite, 14.5 mg of triethylamine and 1 ml of anhydrous tetrahydrofuran are mixed and stirred for 4 hours at 110 DEG C. The reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified with petroleum ether: ethyl acetate=1:1 column chromatography purification gave 27 mg of a white solid (45-6) in 66% yield. LCMS (ESI) M/z [ M+H] + :575.0.
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)
10 mg of 45-6 was dissolved in methylene chloride, 35 mg of iodotrimethylsilane was slowly added dropwise under an argon atmosphere ice-bath condition, and the mixture was stirred at room temperature for 2 hours after the addition. Methanol and water were added to the reaction mixture, which was stirred for 4 hours and filtered to obtain 6 mg of a gray solid (I-45) in 66% yield. 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)
EXAMPLE 46 preparation of prodrugs
N- (1- (4- (4- (3-chlorophenyl) -2-oxo-1, 3, 2-dioxaphosphorinane-2-yl) benzyl) -5-cyano-1H-benzo [ d ] imidazol-2-yl) -1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (I-46)
A mixture of 30 mg of I-9, 37 mg of (S) -1- (3-chlorophenyl) -1, 3-propanediol, 117. Mu.l of pyridine, 40 mg of N, N' -dicyclohexylcarbodiimide and 1 ml of N, N-dimethylformamide was heated to 80℃in a lock tube and stirred for 10 hours under argon. The reaction mixture was prepared as a thin layer (dichloromethane: methanol=15:1) to give 13 mg of an off-white solid (I-46) in 34% yield. 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).
(4- ((5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) bis (2, 2-trifluoroethyl) phosphonate (I-47)
A mixture of 50 mg of I-9, 87 mg of 2, 2-trifluoroethanol, 222. Mu.l of pyridine, 133 mg of N, N' -dicyclohexylcarbodiimide and 1 ml of N, N-dimethylformamide was heated to 80℃in a closed tube under argon atmosphere and stirred for 10 hours. The reaction mixture was prepared as a thin layer (dichloromethane: methanol=15:1) to give an off-white solid (I-47) 20 mg in 30% yield. 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).
((4- ((5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) phosphoryl guanidino) bis (oxo)) bis (methylene) bis (2, 2-dimethylpropyl ester) (I-48)
50 mg of I-9, 113. Mu.l of N, N-diisopropylethylamine and 1 ml of acetonitrile were stirred under argon for 10 minutes in an ice bath, 156 mg of iodomethyl pivalate was slowly added and the reaction was allowed to react at room temperature for 6 hours, and the reaction mixture was concentrated to dryness to prepare a thin layer (dichloromethane: methanol=20:1) to give 14 mg of an off-white solid (I-48) in 19% yield. 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).
Diethyl 2,2' - ((4- ((5-cyano-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) phosphorylguanidino) bis (azadialkyl)) diacetate (I-49)
A mixture of 20 mg of I-9, 16 mg of ethyl 2-aminoacetate, 68 mg of 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 60. Mu.l of N, N-diisopropylethylamine and 1 ml of N, N-dimethylformamide was stirred at room temperature for 5 hours under argon. The reaction mixture was prepared as a thin layer (dichloromethane: methanol=12:1) to give 5 mg of an off-white solid (I-49) in 19% yield. LCMS (ESI) M/z [ M+H] + :635.3.
1- (4- ((4- (3-chlorophenyl) -2-oxo-1, 3, 2-dioxaphosphorinane-2-yl) oxo) phenethyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ] imidazole-5-carboxamide (I-50)
A mixture of 20 mg of I-16, 21 mg of (S) -1- (3-chlorophenyl) -1, 3-propanediol, 67. Mu.l of pyridine, 23 mg of N, N' -dicyclohexylcarbodiimide and 1 ml of N, N-dimethylformamide was heated to 80℃in a closed tube under argon atmosphere and stirred for 10 hours. The reaction solution was prepared as a thin layer (dichloromethane: methanol=15:1) to give 8 mg of a white solid (I-50) in 32% yield. 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).
((4- ((2- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) ethyl) phenyl) phosphorylguanidino) bis (oxo)) bis (methylene) bis (2, 2-dimethylpropyl) ester (I-51)
100 mg of I-16, 195. Mu.l of N, N-diisopropylethylamine and 2 ml of acetonitrile were stirred under argon for 10 minutes in an ice bath, 166 mg of iodomethyl pivalate was slowly added and the reaction was allowed to proceed to room temperature for 6 hours, and the reaction mixture was concentrated to dryness to prepare a thin layer (dichloromethane: methanol=20:1) to give 28 mg of an off-white solid (I-51) in 20% yield. LCMS (ESI) M/z [ M+H] + :771.5.
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) phosphorylguanidino) bis (aminooxy)) diacetate (I-52)
A mixture of 20 mg of I-16, 13 mg of ethyl 2-aminoacetate, 58 mg of 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 52. Mu.l of N, N-diisopropylethylamine and 1 ml of N, N-dimethylformamide was stirred at room temperature for 5 hours under argon. The reaction mixture was prepared as a thin layer (dichloromethane: methanol=12:1) to give 5 mg of an off-white solid (I-52) in 19% yield. LCMS (ESI) M/z [ M+H ] + :713.3.
Test of inhibitory Activity of Compounds of example 47 against EnPP1 enzyme
1. Experimental method
384 well plates were placed on ice, 5 μl l Reaction buffer (20 mM Tris (pH 7.4), 250nM NaCl,500 μM CaCl2,1 μM ZnCl 2) and 1 μl compound solution (diluted with PBS solution), 2 μl ENPP1 protein solution (150 nM, formulated with PBS solution) were mixed well, 2 or 3 wells each, and negative and positive compound controls were set. Sealing the membrane, shaking and mixing uniformly, centrifuging 500g for 1 minute, and placing the membrane in an incubator at room temperature or 37 ℃ for incubation for 1 hour; after 1 hour, 2. Mu.l of 2', 3' -cGAMP solution (5. Mu.M, LAL water dilution) was added to each well, membrane sealed, mixed by shaking, and centrifuged at 500g1 minute, and placing the mixture in an incubator at room temperature or 37 ℃ for incubation for 1 hour; after the incubation was completed, 384 well plates were heated in a 95 ℃ water bath for 10 minutes to terminate the enzyme activity reaction. Detection of product AMP fluorescence reaction: according to AMP-Glo TM The Assay kit shows that 10 μl Reagent I is added to each well, gently mixed, centrifuged to keep the liquid at the bottom, and placed in an incubator at room temperature or 37 ℃ for 1 hour; after 1 hour, 20 mu l AMPDetection Solution%One Solution: reagent II = 1ml:10 μl; preparing on ice, preparing on site), shaking, mixing, slightly centrifuging to keep the liquid at the bottom, and incubating at room temperature or 37 ℃ in an incubator in the absence of light for 1 hour; after 1 hour, the fluorescence value (luminescence: lum) was measured using a microplate reader. Wherein the screening concentration of the compounds was 10. Mu.M and 1. Mu.M.
Analysis of results: inhibition (%) =100× (AMP average negative control -AMP sample )/AMP averagenegative control 。
2. Experimental results
The test results show that the inhibition rate of 8 compounds such as compounds I-8, I-9, I-10, I-11, I-12, I-13, I-15, I-16 and the like on ENPP1 at the concentration of 10 mu M is 86-93%, which is obviously better than that of a positive drug ENPP1-IN-1 (WO 2019046778A 1 example 55) (Table 1); and compounds I-9, I-11, I-12, I-13, I-16 inhibit IC on ENPP1 activity 50 The value is 86-647nM, which shows that the inhibition rate of ENPP1 is obviously higher than that of the positive medicine ENPP1-IN-1 (Table 2).
Structure of ENPP 1-IN-1:
TABLE 1 inhibition activity of compounds on ENPP1 (10. Mu.M)
TABLE 2 Compounds inhibit EnPP1 Activity 50
Example 49 activation of the type I Interferon pathway (ISG) in human THP1-Dual cells by Compounds
1. Experimental method
200 μl (96 well plate, transparent flat bottom) per well contains 2 μl 2'3' -cGAMP solution or compound solution or solvent (negative control), 10 ten thousand human THP1-Dual cells. The final concentration of 2'3' -cGAMP was 10 μm (solvent was LAL water), the final concentration of compound was 10 μm, and 1 μm was two concentrations (solvent was DMSO), each concentration was 3 duplicate wells. The positive control compound is ENPP1-IN-1, and the negative control compound is DMSO. The final concentration of DMSO in the system was 1%. Setting solvent group, compound group, 2'3' -cGAMP group, 2'3' -cgamp+ compound group and blank group, and regulating cell concentration to 5.05X10 + 5 Per ml, 198. Mu.l of cell suspension was added to each well, and 200. Mu.l of culture medium was added to the blank. Mu.l of solvent or 2'3' -cGAMP solution or compound solution was added to each well, and the cells were incubated in a cell incubator for 24 hours for detection. Detecting the color reaction: after 24 hours, 20. Mu.l of the cell supernatant culture was taken into a new 96-well plate (black, transparent bottom) and 50. Mu.l of the chromogenic solution Quanti-Lucia was added to each well, and the fluorescence value was measured immediately on the machine, and the experiment was repeated 2 times.
Analysis of results: ISG Fold change (Normalize to Control): lum sample /Lum Control ；Foldchange(Normalized to cGAMP):Lum compound+cGAMP /Lum cGAMP
2. Experimental results
Experimental results indicate that a single compound has no direct activating effect on STING in cells, and STING pathway is activated in cells after exogenous 2'3' -cGAMP is added. I-9, I-11, I-12, I-16 have a certain enhancement effect on the activation of 2'3' -cGAMP at a concentration of 10 mu M; compounds I-11 and I-12 have better activating effect on ISG than the positive medicine ENPP1-IN-1 at the concentration of 1 mu M.
TABLE 3 activation of ISG by Compounds (10. Mu.M)
TABLE 4 activation of ISG by Compounds (1. Mu.M)
EXAMPLE 50 preparation of pharmaceutical compositions
Tablet
The above materials are mixed uniformly, and 1000 tablets are prepared by conventional process. Suitable aqueous or non-aqueous coatings may be used to enhance palatability, improve appearance and stability, or delay absorption.
Capsule
Compound I-16 g
Starch 135 g
Microcrystalline cellulose 85 g
Mixing the above materials according to conventional method, and making into 1000 capsules.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from: n or C-R 1 ；
Y is selected from: n or C-R 2 ；
Z is selected from: n or C-R 3 ；
W is selected from: n or C-R 4 ；
R 1 Selected from: hydrogen, halogen, cyano, C 1 ～C 6 Alkyl OR-OR f ；
R 2 Selected from: hydrogen, halogen, cyano, substituted with 0-4R h 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 or-NR f C(O)R g ；
R 3 、R 4 Each independently selected from: hydrogen, halogen, 0-4R h 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 or-NR f C(O)R g ；
Alternatively, R 3 And R is 4 Cyclizing the atoms to which they are attached to form 0 to 4R i Substituted saturated or unsaturated 4-to 6-membered carbocycle or heterocycle;
l is selected from: c (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 means that the substituted chain is substituted by 1-4R n Substitution; each R is n Independently selected from: hydrogen, halogen, cyano, 0-4R h 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 ；
R t 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 Selected from: substituted C5-C12 aryl, substituted 5-12 membered heteroaryl, substituted 5-12 membered heterocyclyl; wherein the substitution means that the substituted chain is substituted by 1-4R L Substitution;
each R is L 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’ The method comprises the steps of carrying out a first treatment on the surface of the Or in- (CH) 2 ) m’ P(＝O)(OR j’ ) 2 Two OR's in (2) j’ Together with the P atoms to which they are attached form 0 to the maximum4R m Substituted saturated or unsaturated 4-6 membered heterocyclic ring;
m, m' and n are each independently 0, 1, 2, 3, 4, 5 or 6;
R f 、R g 、R f’ and R is g’ Each independently selected from: hydrogen, 0-4R h Substituted C 1 ～C 6 Alkyl, 0-4R h Substituted C 2 ～C 6 Alkynyl, 0-4R h Substituted C 2 ～C 6 Alkenyl, 0 to 4R i Substituted 3-6 membered cycloalkyl or 0-4R i Substituted 3-6 membered heterocycloalkyl;
R j’ 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’ The method comprises the steps of carrying out a first treatment on the surface of the m "are each independently 1, 2, 3, 4, 5 or 6;
R h 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 0 to 4R i Substituted 3-6 membered cycloalkyl or 0-4R i Substituted 3-6 membered heterocycloalkyl;
R i selected from: halogen, hydroxy, 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 selected from: halogen, hydroxy, 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 is k’ Each independently selected from: hydrogen, halogen, C 1 ～C 6 Alkyl or halo C 1 ～C 6 An alkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein a is selected from the group consisting of: hydrogen, substituted C5-C6 aryl, substituted 5-6 membered heteroaryl, substituted [5+6 ]]Aryl, substituted [5+6 ]]Heteroaryl; preferably, a is selected from the following groups substituted: phenyl, pyrrolyl, imidazolyl, pyrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, morpholinyl, piperazinyl, piperidinyl, benzimidazolyl, benzopyrazolyl, indolyl,The substitution means being 1-4R n Substitution; r is R n Is defined in claim 1.
3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt or prodrug thereof, wherein a is selected from the group consisting of: hydrogen, hydrogen, R 5 And R is 6 R is as defined in claim 1 n 。
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure shown in (II):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is hydrogen;
R 2 selected from: hydrogen, halogen, cyano, 0-4R h 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 or-NR f C(O)R g ；
R 3 And R is 4 Each independently selected from: hydrogen, halogen, 0-4R h 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 or-NR f C(O)R g ；
Alternatively, R 3 And R is 4 Cyclizing the atoms to which they are attached to form 0 to 4R i Substituted saturated or unsaturated 4-to 6-membered carbocycle or heterocycle;
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, hydrogen,
R 5 And R is 6 Each independently selected from: hydrogen, halogen, cyano, 0-4R h 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 or-NR f C(O)R g ；
R t 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 Selected from: substituted
R u Selected from: - (CH) 2 ) m’ OP(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’ Or- (CH) 2 ) m’ NH 2 SO 2 NR f’ R g’ ；
R v 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 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' and n are each independently 0, 1, 2, 3, 4, 5 or 6;
R f 、R g 、R f’ and R is g’ Each independently selected from: hydrogen, 0-4R h Substituted C 1 ～C 6 Alkyl, 0-4R h Substituted C 2 ～C 6 Alkynyl, 0 to 4R h Substituted C 2 ～C 6 Alkenyl, is covered with 0-4R i Substituted 3-6 membered cycloalkyl, 0-4R i Substituted 3-6 membered heterocycloalkyl;
R j’ 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’ The method comprises the steps of carrying out a first treatment on the surface of the m "are each independently 1, 2, 3, 4, 5 or 6;
R h 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 Is covered with 0-4R i Substituted 3-to 6-membered cycloalkyl or substituted with 0-4R i Substituted 3-6 membered heterocycloalkyl;
R i selected from: halogen, hydroxy, 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 is k’ Each independently selected from: hydrogen or C 1 ～C 6 An alkyl group.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1 Is hydrogen;
R 2 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 is 4 Each independently selected from: hydrogen, halogen, 0-4R h Substituted C 1 ～C 6 Alkyl, -OR f or-C (O) R f 、-CO 2 R f ；
Alternatively, R 3 And R is 4 Cyclizing the atoms to which they are attached to form 0 to 4R i Substituted saturated or unsaturated 4-to 6-membered carbocycle or heterocycle;
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, hydrogen,
R 5 And R is 6 Each independently selected from: hydrogen, halogen, cyano, 0-4R h 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 or-NR f C(O)R g ；
R t 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 Selected from:
R u Selected from: - (CH) 2 ) m’ OP(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’ ；
R v 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 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' and n are each independently 0, 1, 2, 3, 4, 5 or 6;
R f 、R g 、R f’ and R is g’ Each independently selected from: hydrogen, 0-4R h Substituted C 1 ～C 6 Alkyl, 0-4R h Substituted C 2 ～C 6 Alkynyl, 0-4R h Substituted C 2 ～C 6 Alkenyl, 0 to 4R i Substituted 3-6 membered cycloalkyl, 0-4R i Substituted 3-6 membered heterocycloalkyl;
R j’ 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’ The method comprises the steps of carrying out a first treatment on the surface of the m "are each independently 1, 2, 3, 4, 5 or 6;
R h 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 0 to 4R i Substituted 3-6 membered cycloalkyl, 0-4R i Substituted 3-6 membered heterocycloalkyl;
R i selected from: c (C) 1 ～C 6 Alkyl, halogen substituted C 1 ～C 6 An alkyl group;
R a 、R b 、R j 、R k and R is k’ Each independently selected from: hydrogen or C 1 ～C 6 An alkyl group.
6. The process of claim 1A compound, or a pharmaceutically acceptable salt or prodrug thereof, wherein each R L 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(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 is j’ The definition of (1) is as defined in claim 1, preferably each R L 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 。
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound is selected from the group consisting of:
8. a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any one of claims 1-7, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
9. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 8, in the manufacture of an immunoadjuvant or ENPP1 inhibiting medicament.
10. Use of a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment of a disease associated with ENPP1 activity, said disease associated with ENPP1 activity being one or several of a disease associated with inflammatory, autoimmune, infectious, cancer, precancerous syndrome.
CN202210023244.6A 2022-01-10 2022-01-10 Benzimidazole compound and medical application thereof Pending CN116444544A (en)

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BR0214019A (en) * 2001-11-09 2004-10-13 Boehringer Ingelheim Phamaceut Benzimidazoles Useful as Protein Kinase Inhibitors
DE10342503A1 (en) * 2003-09-12 2005-04-14 Merck Patent Gmbh Benzyl-Benzimidazolylderivate
WO2008153701A1 (en) * 2007-05-24 2008-12-18 Schering Corporation Compounds for inhibiting ksp kinesin activity
EP3952995B1 (en) * 2019-04-12 2023-09-20 Riboscience LLC Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors
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