WO2022117051A1 - 大环化合物及其制备方法和应用 - Google Patents
大环化合物及其制备方法和应用 Download PDFInfo
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- WO2022117051A1 WO2022117051A1 PCT/CN2021/135154 CN2021135154W WO2022117051A1 WO 2022117051 A1 WO2022117051 A1 WO 2022117051A1 CN 2021135154 W CN2021135154 W CN 2021135154W WO 2022117051 A1 WO2022117051 A1 WO 2022117051A1
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- Prior art keywords
- alkyl
- amino
- cycloalkyl
- alkoxy
- group
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
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- 229910052717 sulfur Inorganic materials 0.000 claims description 218
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 178
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 22
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
Definitions
- the present invention relates to macrocyclic compounds and their preparation methods and applications, in particular to compounds that inhibit, regulate and/or regulate the signal transduction of EGFR kinases, their preparation methods, pharmaceutical compositions containing them and their applications.
- Protein kinases are enzymatic components of signaling pathways that catalyze the transfer of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and/or threonine residues of proteins. Therefore, compounds that inhibit protein kinase function are valuable tools for assessing the physiological consequences of protein kinase activity.
- Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been the subject of extensive research and has been demonstrated in many diseases, including diabetes, angiogenesis, psoriasis, restenosis, eye disease, schizophrenia, It plays an important role in the development of rheumatoid arthritis, atherosclerosis, cardiovascular disease and cancer. Protein kinase inhibitors have particular utility in the treatment of human and animal diseases.
- EGFR is a member of the ErbB receptor family of receptor tyrosine kinases. When EGFR binds to its ligand EGF extracellularly, the receptor undergoes homo- or heterodimerization and autophosphorylation, activating downstream cascade signaling pathways, and ultimately promoting cell growth, proliferation, and division.
- Overexpression (upregulation) or overactivity of EGFR has been shown to be associated with many cancers, including head and neck, ovarian, cervical, bladder, esophageal, gastric, breast, endometrial, colorectal, non- Small cell lung cancer, and glioblastoma.
- EGFR as an oncogene has given rise to targeted therapy against EGFR small molecule inhibitors.
- NSCLC non-small cell lung cancer
- side effects such as rash and diarrhea, and after one year of use, the patient develops drug resistance.
- Clinical data show that about 50% of patients with acquired resistance originate from the T790M (exon 20 position 790 threonine is replaced by methionine) mutant.
- Second-generation inhibitors such as afatinib and dacomitinib have stronger binding activity to EGFR, but have poor selectivity for the T790M mutant, and cannot reach effective concentrations in vivo at tolerable doses.
- the third-generation inhibitor osimertinib can be used as a second-line treatment for patients with T790M mutation after first- and second-generation therapy, or as a first-line treatment for patients with EGFR-sensitive mutations who have not been treated with EGFR-TKIs. After 9.9-18.9 months of treatment with the EGFR inhibitor osimertinib, resistance mutation C797S (C797S mutation at position 797 of exon 20) was inevitable.
- Thress KS first reported that 40% of patients with T790M mutation who took osimertinib developed C797S resistance mutation. In addition, Lee JY et al. also reported that 24% of patients with T790M mutation developed C797S resistance after taking osimertinib. The Papadimitrakopoulou V.A. analysis of 73 patients with disease progression on osimertinib in the AURA3 clinical trial found that 15% of patients developed the C797S resistance mutation.
- osimertinib also showed superior efficacy as first-line treatment compared with the standard treatment of first-generation EGFR inhibitors (gefitinib or erlotinib), in which 91 patients took osimertinib
- the present invention provides a macrocyclic compound, which can overcome both EGFR C797S mutation and EGFR T790M mutation, and has high selectivity.
- the present invention is achieved through the following technical solutions.
- the present invention provides a compound having the structure shown in the following formula I:
- Ring A and Ring B are each independently a 6-10 membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S, or Bicyclic heteroaromatic ring, or 5-10 membered monocyclic heterocycle or bicyclic heterocycle containing 1-4 heteroatoms independently selected from N, O and S, the 6-10 membered monocyclic aromatic ring or Bicyclic aromatic rings, 5-10 membered monocyclic heteroaromatic or bicyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from N, O and S, or containing 1-4 heteroatoms independently selected from N,
- the 5-10 membered monocyclic or bicyclic heterocycle of the O and S heteroatoms may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, halogenated C 1-6
- Ring D is a 6-10-membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S heteroatoms, 5-10 membered monocyclic heterocycle or bicyclic heterocycle, or C 5-7 cycloalkane containing 1-4 heteroatoms independently selected from N, O and S heteroatoms;
- R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged or spirocyclic heterocyclyl-C 0-3 alkyl, amino group containing 1-3 heteroatoms independently selected from N, O or S heteroatoms , C 1-6 alkyl-amino, C 3-6 cycloalkyl-amino, two (C 1-6 alkyl)-amino, C 1-6 alkoxy-C 1-6 alkyl-amino, 4 -6-membered heterocyclyl-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl-amino, hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl , hydroxy-C 1-6 alk
- R3 together with any atom on Ring D other than the atom to which R3 is attached alternatively, R3 and R6 together with the attached atom optionally form a heterocycle consisting of 3-10 atoms
- the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S and the heterocyclic ring is optionally further selected from one or more C 1-6 alkyl groups, halogens, 6-10-membered aryl groups, including 5-10-membered heteroaryl groups containing 1-3 heteroatoms independently selected from N, O or S, 5-10-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O or S , halogenated C 1-6 alkyl, hydroxyl, cyano, halogen, C 1-6 alkoxy, 4-6 membered heterocyclyl alkyl, C 1-6 alkylamino and bis(C 1-6 alkane base) is substituted with amino;
- the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
- R7 is or C 1-6 alkyl C(O);
- Y 1 , Y 2 and Y 3 are each independently a chemical bond, O, NR 8 , S, S(O) 2 , CR 8 R 16 , carbonyl, -amino-acyl, -acyl-amino, -O(CO)- or -(CO)O-;
- M is a chemical bond, -C 1-6 alkyl- substituted or unsubstituted by one or more R m , -C 3-6 cycloalkyl- substituted or unsubstituted by one or more R m , One or more R m substituted or unsubstituted -C 3-6 cycloalkyl-C 1-6 alkyl-, one or more R m substituted or unsubstituted -C 1-6 alkyl- Amino-C 1-6 alkyl-, substituted or unsubstituted by one or more R m -4-7 membered heterocyclyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms-, -4-7 membered heterocyclyl-C 1-6 alkyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms substituted or unsubstituted by one or more R m ;
- R 8 is a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or 5-7 containing 1-2 heteroatoms independently selected from N, O and S and optionally substituted by oxo membered heterocyclic group;
- R 9 and R 10 are independently a hydrogen atom, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, or heterocyclylalkyl;
- R 11 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 Alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1-3 independently selected from N, 4-10-membered heterocyclic group of O or S heteroatom, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1 -6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1- 3 4-10 membered heterocyclyl groups independently selected from N, O or S heteroatoms may be optionally substituted with one or more groups independently selected from the group consisting
- R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a 4-10-membered heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S.
- R 12 and R 13 together with N in NR 12 R 13 form a 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, the C 1-6 alkane group, C 3-7 cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R 12 and R 13 together with N in NR 12 R 13
- Forming a 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S may be optionally substituted with one or more substituents independently selected from the group: C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3 -6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, oxo, C C
- R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
- R 16 is a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group, or a C 3-6 cycloalkoxy group;
- R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
- R a and R b together with the attached carbon atoms form a ring
- R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy.
- Ring E is a 4-7 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or 1-5 heteroatoms independently selected from N, O or S 5-10-membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle, the 4-7-membered saturated or partially unsaturated heterocycle and 5-10-membered bridged or spirocyclic saturated or partially unsaturated heterocycle can be any is independently replaced by one or more Rm ;
- Ring G is a 4-7 membered saturated or partially unsaturated heterocycle, C3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Aromatic ring, or a 5-10-membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle containing 1-5 heteroatoms independently selected from N, O or S, the 4-7 membered saturated or partially unsaturated heterocycle Ring, C 3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic aromatic ring, 5-10 membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle may be optionally independently replaced by one or more R replaced by m ;
- R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino -C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl -Amino-C 1-6 alkyl, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl) -amino, C 3-6 cycloalkyl-amino, C
- q and t are each independently 0, 1, 2 or 3;
- w 1, 2 or 3;
- X is O, S, CR 17 R 18 , NR 17 , CO or S(O) 2 ;
- R 17 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-6 alkoxy-C 1 -6 alkyl, halogenated C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl-carbonyl or C 1-6 alkyl-sulfone;
- R 18 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkane group, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkyl-amino
- Z is N, O, S, CO, S(O) 2 , -amino-acyl, -acyl-amino, -O(CO)-, -(CO)O-, CR 19 , C 3-7 cycloalkyl or 3-7 membered heterocyclyl, the C 3-7 cycloalkyl and 3-7 membered heterocyclyl may be optionally independently substituted with one or more R 18 ;
- R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- n 0, 1, 2, 3 or 4;
- p 0, 1, 2 or 3.
- Ring A and Ring B are each independently a benzene ring, or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, the benzene ring Or the 5-6 membered heteroaromatic ring may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen Substituted C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkane Oxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl
- ring A and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, Isothiazoles, said benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole and isothiazole may be optionally combined with one or more Substituted independently from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycl
- Ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N,O and S, containing 1-2 heteroatoms independently selected from N,O and 5-7 membered heterocycle or cyclohexyl ring of S heteroatom;
- ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole or cyclohexane.
- one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 , When R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or when When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged ring or spirocyclic heterocyclyl-C 0-3 alkyl, hydrogen containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Atom, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy base-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino-C 1-6 alkyl, di(C 1-6 6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino-C 1-6 alkyl, C 1-6 alkoxy, bis(C 1-6 alkyl)-amino-C
- the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
- Y 1 , Y 2 and Y 3 are each independently a chemical bond, O or NR 8 ;
- R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- R 9 and R 10 are independently a hydrogen atom, halogen or cyano
- R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or R 12 and R 13 together with N in NR 12 R 13 form 1-3 independently A 4-7 membered heterocycle selected from N, O or S heteroatoms, the C 1-6 alkyl, C 3-6 cycloalkyl and formed containing 1-3 independently selected from N, O or S
- the 4-7 membered heterocycle of the heteroatom may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, C 1-6 alkyl-amino, bis(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, 3-7 membered heterocyclyl and C 1-6 alkyl-carbonyl containing N, O or S heteroatom
- R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
- R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
- R a and R b together with the attached carbon atoms form a ring
- R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy;
- Ring E is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or a 7-10 membered heteroatom containing 1-5 heteroatoms independently selected from N, O or S Bridged or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, 7-10 membered bridged or spiro saturated heterocycle may be optionally independently substituted by one or more Rm ;
- Ring G is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, a C 3-6 cycloalkane, or contains 1-5 heteroatoms independently selected from N, O or S
- the heteroatom 7-10 membered bridged ring or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, C 3-6 cycloalkane, 7-10 membered bridged ring or spiro saturated heterocycle can be optionally independently replaced by one or more R m ;
- R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy base-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, halogen, hydroxyl, cyano, Amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkane base-OC(O)- or C 3-6 cycloalkyl-OC(O)-;
- q and t are each independently 0, 1, 2 or 3;
- w 1, 2 or 3;
- one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 when R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethyl Oxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxy Methyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinyl Methyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl, piperidine Azin-1-ylmethyl, 4-methylpiperazin-1
- the warhead groups are:
- X is O or S
- Z is N, O, S, -amino-acyl, -acyl-amino, or CR 19 ;
- R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- Z is N, O or CR 19 ;
- R 19 is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl.
- Ring A and Ring B are each independently a benzene ring, or a 5-6-membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, said benzene ring or a 5-6-membered heteroaromatic ring
- the ring may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 Alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino , C 1-6 alkyl
- Ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O and S, a 5-membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S 7-membered heterocycle or cyclohexane;
- R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged ring or spirocyclic heterocyclyl-C 0-3 alkyl, hydrogen containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Atom, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy base-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino-C 1-6 alkyl, di(C 1-6 6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino-C 1-6 alkyl, C 1-6 alkoxy, bis(C 1-6 alkyl)-amino-C
- the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
- Y 1 , Y 2 and Y 3 are each independently a chemical bond, O or NR 8 ;
- R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- R 9 and R 10 are independently a hydrogen atom, halogen or cyano
- R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or R 12 and R 13 together with N in NR 12 R 13 form 1-3 independently A 4-7 membered heterocycle selected from N, O or S heteroatoms, the C 1-6 alkyl, C 3-6 cycloalkyl and formed containing 1-3 independently selected from N, O or S
- the 4-7 membered heterocycle of the heteroatom may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, C 1-6 alkyl-amino, bis(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, 3-7 membered heterocyclyl and C 1-6 alkyl-carbonyl containing N, O or S heteroatom
- R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
- R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
- R a and R b together with the attached carbon atoms form a ring
- R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy;
- Ring E is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or a 7-10 membered heteroatom containing 1-5 heteroatoms independently selected from N, O or S Bridged or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, 7-10 membered bridged or spiro saturated heterocycle may be optionally independently substituted by one or more Rm ;
- Ring G is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, a C 3-6 cycloalkane, or contains 1-5 heteroatoms independently selected from N, O or S
- the heteroatom 7-10 membered bridged ring or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, C 3-6 cycloalkane, 7-10 membered bridged ring or spiro saturated heterocycle can be optionally independently replaced by one or more R m ;
- R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy base-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, halogen, hydroxyl, cyano, Amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkane base-OC(O)- and C 3-6 cycloalkyl-OC(O)-;
- q and t are each independently 0, 1, 2 or 3;
- w 1, 2 or 3;
- X is O or S
- Z is N, O, S, -amino-acyl, -acyl-amino, or CR 19 ;
- R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- n 0, 1, 2, 3 or 4;
- p 0, 1, 2 or 3.
- Ring A and Ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, isothiazole, and the benzene ring , pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole and isothiazole may be optionally replaced by one or more substituents independently selected from the following Substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, hal
- Ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole or hexane;
- R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethyl Oxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxy Methyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinyl Methyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl, piperidine Azin-1-ylmethyl, 4-methylpiperazin-1
- the warhead groups are:
- X is O or S
- Z is N, O or CR 19 ;
- R 19 is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl;
- n 0, 1, 2, 3 or 4;
- p 0, 1, 2 or 3.
- Ring A and Ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, said benzene, pyridine, pyrimidine, pyridazine , pyrazine, pyrazole, imidazole, oxazole, isoxazole, thiazole and isothiazole may be optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, isopropyl , vinyl, ethynyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxy, ethoxy, cyclopropoxy, methoxymethyl, methoxy Ethyl, hydroxyethyl, hydroxypropyl,
- Ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine or piperazine;
- R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
- R3 and R6 are independently hydrogen atom, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl group, ethoxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylamino Ethoxymethyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, nitrogen heterocycle Butylmethyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl base, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acety
- the warhead groups are:
- X is O or S
- Z is N, O or CR 19 ;
- R 19 is independently a hydrogen atom, methyl, ethyl or cyclopropyl
- n 0, 1, 2, 3 or 4;
- p 0, 1, 2 or 3.
- the compound shown in formula I is selected from the following compounds:
- the present application provides a pharmaceutical composition
- a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier or excipient; preferably, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, Injections, solutions, suspensions, ointments, patches, lotions, drops, liniments or sprays.
- the present application provides the use of the above-mentioned compounds and/or pharmaceutical compositions in the preparation of antitumor drugs.
- the antineoplastic drug is used for the following conditions: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovary cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, Cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.
- the tumor is a malignant tumor carrying EGFR gene mutation; preferably, the EGFR gene mutation is selected from one of: Del19EGFR gene mutation, L858R EGFR gene mutation, T790M EGFR gene mutation and C797S EGFR gene mutation or more.
- the present application provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the above-mentioned compound or pharmaceutical composition, the patient is preferably a mammal, and the mammal is preferably a human .
- modes of administration include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal.
- the tumor comprises: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, Pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, intrauterine cancer Membranous carcinoma, multiple myeloma, or mesothelioma.
- the application provides a method for preparing a compound of formula I, the method comprising the following reaction steps:
- the alkali used under alkaline conditions in step (1) is selected from potassium carbonate;
- the base used in the hydrolysis in step (5) is selected from lithium hydroxide.
- the method for preparing a compound of formula I comprises the following reaction steps:
- the alkali used under alkaline conditions in step (1) is selected from potassium carbonate;
- R 22 is a hydrogen atom, -Y 1 (CR a R b ) q NHR 8 , R 20 is R 22 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 21 , R 23 , R 24 and R 25 are R 6 ; when When R 2 is a warhead group, R 23 is -Y 1 (CR a R b ) q NHR 8 , R 21 is R 23 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 20 , R 22 , R 24 and R 25 are R 6 ; when When R 4 is a warhead group, R 24 is -Y 1 (CR a R b ) q NHR 8 , R 18 is R 24 with a protective group, halogen, an oxy group
- protective groups include but are not limited to tert-butoxycarbonyl, benzyloxycarbonyl, benzyl or dimethoxybenzyl;
- L is hydroxyl, halogen or leaving group
- A, B, D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R a , R b , R c , R d , Y 1 , Y 2 , Y 3 , Z, X, p, q, m, n, t, warhead groups are as defined above;
- the present invention relates to compounds of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, nitrogen oxide, prodrug molecule, hydrate or solvate thereof:
- Ring A and Ring B are each independently a 6-10 membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S, or Bicyclic heteroaromatic ring, or 5-10 membered monocyclic heterocycle or bicyclic heterocycle containing 1-4 heteroatoms independently selected from N, O and S, the 6-10 membered monocyclic aromatic ring or Bicyclic aromatic rings, 5-10 membered monocyclic heteroaromatic or bicyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from N, O and S, or containing 1-4 heteroatoms independently selected from N,
- the 5-10 membered monocyclic or bicyclic heterocycle of the O and S heteroatoms may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, halogenated C 1-6
- Ring D is a 6-10-membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S heteroatoms, 5-10 membered monocyclic heterocycle or bicyclic heterocycle, or C 5-7 cycloalkane containing 1-4 heteroatoms independently selected from N, O and S heteroatoms;
- R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged or spirocyclic heterocyclyl-C 0-3 alkyl, amino group containing 1-3 heteroatoms independently selected from N, O or S heteroatoms , C 1-6 alkyl-amino, C 3-6 cycloalkyl-amino, two (C 1-6 alkyl)-amino, C 1-6 alkoxy-C 1-6 alkyl-amino, 4 -6-membered heterocyclyl-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl-amino, hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl , hydroxy-C 1-6 alk
- R3 together with any atom on Ring D except the atom to which R3 is attached alternatively, R3 and R6 together with the attached atom optionally form a heterocycle consisting of 3-10 atoms
- the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S and the heterocyclic ring is optionally further selected from one or more C 1-6 alkyl groups, halogens, 6-10-membered aryl groups, including 5-10-membered heteroaryl groups containing 1-3 heteroatoms independently selected from N, O or S, 5-10-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O or S , halogenated C 1-6 alkyl, hydroxyl, cyano, halogen, C 1-6 alkoxy, 4-6 membered heterocyclyl alkyl, C 1-6 alkylamino and bis(C 1-6 alkane base) is substituted with amino;
- the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
- R7 is or C 1-6 alkyl C(O);
- Y 1 , Y 2 and Y 3 are each independently a chemical bond, O, NR 8 , S, S(O) 2 , CR 8 R 16 , carbonyl, -amino-acyl, -acyl-amino, -O(CO)- or -(CO)O-;
- M is a chemical bond, -C 1-6 alkyl- substituted or unsubstituted by one or more R m , -C 3-6 cycloalkyl- substituted or unsubstituted by one or more R m , One or more R m substituted or unsubstituted -C 3-6 cycloalkyl-C 1-6 alkyl-, one or more R m substituted or unsubstituted -C 1-6 alkyl- Amino-C 1-6 alkyl-, substituted or unsubstituted by one or more R m -4-7 membered heterocyclyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms-, -4-7 membered heterocyclyl-C 1-6 alkyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms substituted or unsubstituted by one or more R m ;
- R 8 is a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or 5-7 containing 1-2 heteroatoms independently selected from N, O and S and optionally substituted by oxo membered heterocyclic group;
- R 9 and R 10 are independently a hydrogen atom, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, or heterocyclylalkyl;
- R 11 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 Alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1-3 independently selected from N, 4-10-membered heterocyclic group of O or S heteroatom, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1 -6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1- 3 4-10 membered heterocyclyl groups independently selected from N, O or S heteroatoms may be optionally substituted with one or more groups independently selected from the group consisting
- R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a 4-10-membered heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S.
- R 12 and R 13 together with N in NR 12 R 13 form a 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, the C 1-6 alkane group, C 3-7 cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R 12 and R 13 together with N in NR 12 R 13
- Forming a 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S may be optionally substituted with one or more substituents independently selected from the group: C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3 -6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, oxo, C C
- R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
- R 16 is a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group, or a C 3-6 cycloalkoxy group;
- R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
- R a and R b together with the attached carbon atoms form a ring
- R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy.
- Ring E is a 4-7 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or 1-5 heteroatoms independently selected from N, O or S 5-10-membered bridged or spiro saturated or partially unsaturated heterocycle, the 4-7-membered saturated or partially unsaturated heterocycle and 5-10-membered bridged or spiro saturated or partially unsaturated heterocycle can be any is independently replaced by one or more Rm ;
- Ring G is a 4-7 membered saturated or partially unsaturated heterocycle, C3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Aromatic ring, or a 5-10-membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle containing 1-5 heteroatoms independently selected from N, O or S, the 4-7 membered saturated or partially unsaturated heterocycle Ring, C 3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic aromatic ring, 5-10 membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle may be optionally independently replaced by one or more R replaced by m ;
- R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino -C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl -Amino-C 1-6 alkyl, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl) -amino, C 3-6 cycloalkyl-amino, C
- q and t are each independently 0, 1, 2 or 3;
- w 1, 2 or 3;
- X is O, S, CR 17 R 18 , NR 17 , CO or S(O) 2 ;
- R 17 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-6 alkoxy-C 1 -6 alkyl, halogenated C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl-carbonyl or C 1-6 alkyl-sulfone;
- R 18 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkane group, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkyl-amino
- Z is N, O, S, CO, S(O) 2 , -amino-acyl, -acyl-amino, -O(CO)-, -(CO)O-, CR 19 , C 3-7 cycloalkyl or 3-7 membered heterocyclyl, the C 3-7 cycloalkyl and 3-7 membered heterocyclyl may be optionally independently substituted with one or more R 18 ;
- R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- n 0, 1, 2, 3 or 4;
- p 0, 1, 2 or 3.
- Ring A and Ring B are each independently a benzene ring, or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, the benzene ring Or the 5-6 membered heteroaromatic ring may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen Substituted C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkane Oxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl
- ring A and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, Isothiazoles, said benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole and isothiazole may be optionally combined with one or more Substituted independently from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycl
- Ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N,O and S, containing 1-2 heteroatoms independently selected from N,O and 5-7 membered heterocycle or cyclohexyl ring of S heteroatom;
- ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole or cyclohexane.
- one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 , When R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or when When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged ring or spirocyclic heterocyclyl-C 0-3 alkyl, hydrogen containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Atom, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy base-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino-C 1-6 alkyl, di(C 1-6 6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino-C 1-6 alkyl, C 1-6 alkoxy, bis(C 1-6 alkyl)-amino-C
- the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
- Y 1 , Y 2 and Y 3 are each independently a chemical bond, O or NR 8 ;
- R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- R 9 and R 10 are independently a hydrogen atom, halogen or cyano
- R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or R 12 and R 13 together with N in NR 12 R 13 form 1-3 independently A 4-7 membered heterocycle selected from N, O or S heteroatoms, the C 1-6 alkyl, C 3-6 cycloalkyl and formed containing 1-3 independently selected from N, O or S
- the 4-7 membered heterocycle of the heteroatom may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, C 1-6 alkyl-amino, bis(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, 3-7 membered heterocyclyl and C 1-6 alkyl-carbonyl containing N, O or S heteroatom
- R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
- R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
- R a and R b together with the attached carbon atoms form a ring
- R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy;
- Ring E is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or a 7-10 membered heteroatom containing 1-5 heteroatoms independently selected from N, O or S Bridged or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, 7-10 membered bridged or spiro saturated heterocycle may be optionally independently substituted by one or more Rm ;
- Ring G is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, a C 3-6 cycloalkane, or contains 1-5 heteroatoms independently selected from N, O or S
- the heteroatom 7-10 membered bridged ring or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, C 3-6 cycloalkane, 7-10 membered bridged ring or spiro saturated heterocycle can be optionally independently replaced by one or more R m ;
- R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy base-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, halogen, hydroxyl, cyano, Amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkane base-OC(O)- or C 3-6 cycloalkyl-OC(O)-;
- q and t are each independently 0, 1, 2 or 3;
- w 1, 2 or 3;
- one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 when R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
- R 3 and R 6 are each independently a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethyl Oxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxy Methyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinyl Methyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl, piperidine Azin-1-ylmethyl, 4-methylpiperazin-1
- the warhead groups are:
- X is O or S
- Z is N, O, S, -amino-acyl, -acyl-amino, or CR 19 ;
- R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
- Z is N, O or CR 19 ;
- R 19 is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl.
- (C ab )alkyl means any alkyl group containing "a" to "b” carbon atoms.
- (C 1-6 )alkyl refers to an alkyl group containing from 1 to 6 carbon atoms. Said alkyl group is branched or straight chain.
- Atoms described in the compounds of the present application include isotopes thereof, for example, hydrogen may be deuterium or tritium.
- Alkyl means a straight or branched chain, monovalent, saturated hydrocarbon group including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and other similar groups.
- C 1-8 alkyl groups are preferred. More preferred is C 1-6 alkyl. More preferred is C 1-4 alkyl.
- Cycloalkyl means a saturated monocyclic, bicyclic, spirocyclic, paracyclic, or bridged cycloalkyl, possibly in combination with other groups. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, for example. C 3-8 cycloalkyl is preferred. More preferred is C 3-6 cycloalkyl. More preferred is C 3-4 cycloalkyl.
- Alkenyl refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more double bonds, including but not limited to vinyl, propenyl, (E)-2-methylvinyl, (Z) -2-Methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-ene base.
- C 2-6 alkenyl is preferred. More preferred is C 2-4 alkenyl.
- Alkynyl refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1 -Alkynyl, but-2-ynyl, but-3-ynyl. Preferred is C 2-6 alkynyl. More preferred is C 2-4 alkynyl.
- Alkoxy means a straight or branched chain, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to, for example, methoxy, ethoxy, propoxy, butoxy , isobutoxy, tert-butoxy and other similar groups.
- C 1-8 alkoxy is preferred. More preferred is C 1-6 alkoxy. More preferred is C 1-4 alkoxy.
- Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
- Haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogens have been replaced with the same or different halogen. Including, but not limited to, such as -CH 2 Cl, -CHF 2 , -CH 2 CF 3 , -CH 2 CCl 3 , perfluoroalkyl (eg, -CF 3 ), and the like.
- Aryl refers to a substituted or unsubstituted monocyclic or polycyclic aromatic group including, but not limited to, eg, phenyl, naphthyl. A 6-10 membered monocyclic or bicyclic aromatic group is preferred. More preferred is phenyl or naphthyl. Most preferred is phenyl.
- Heterocyclyl means a substituted or unsubstituted 3-10 membered non-aromatic monocyclic saturated ring system containing 1-3 heteroatoms independently selected from N, O, or S, the remaining ring atoms being carbon atoms .
- heterocyclyl moieties include, but are not limited to: azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxo Piperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazole Alkyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc.
- a 4- to 7-membered heterocyclic group is preferred.
- Heteroaryl means a substituted or unsubstituted 5- or 6-membered mono-heteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or bi-heteroaromatic ring system containing 1-4 independent Selected from N, O, or S heteroatoms, the remaining ring atoms are carbon atoms.
- heteroaryl moieties include, but are not limited to: thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridyl, pyridazine radical, pyrimidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl or benzothiazolyl.
- “Bridged ring” refers to a polycyclic group in which any two rings share two atoms that are not directly connected, may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system, and the ring atoms may be All carbon atoms may also be one or more ring atoms selected from N, O, S, SO or SO2 . 7-10 rings are preferred.
- “Spirocycle” refers to a polycyclic group in which any two rings share carbon atoms, and may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ -electron system, and the ring atoms may be all carbon atoms or One or more of the ring atoms are selected from N, O, S, SO or SO2. 5-10 rings are preferred.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
- a cyclic group can bond to another group in a number of ways. If no bonding method is specified, all possible methods are included. For example, “pyridyl” includes 2-, 3-, or 4-pyridyl, and “thienyl” includes 2- or 3-thienyl.
- “Pharmaceutically acceptable salt” refers to conventional acid addition salts or base addition salts which retain the biological effectiveness and properties of the compounds of formula I, formed from suitable non-toxic organic or inorganic acids or bases.
- acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and those derived from organic acids.
- organic acids such as acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, Hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc.
- base addition salts include those derived from inorganic acids such as ammonium, calcium, iron, aluminum, sodium, potassium, zinc, magnesium, and those derived from organic acids.
- the organic bases include salts of primary, secondary, and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, and the like.
- Chemical modification of pharmaceutical compounds (ie, drugs) into salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, fluidity, and solubility of compounds.
- Prodrug refers to a prodrug that can be converted in vivo to the structure of the compounds involved in the present invention and their pharmaceutically acceptable salts.
- the present application also relates to methods of preparing compounds of formula I.
- the compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds are provided in the Examples. In multistep synthetic routes, the order of the reactions can be adjusted in specific cases.
- the application provides a method for preparing a compound of formula I, the method comprising the following reaction steps:
- the alkali used under alkaline conditions in step (1) is selected from potassium carbonate;
- the base used in the hydrolysis in step (5) is selected from lithium hydroxide.
- the method for preparing a compound of formula I comprises the following reaction steps:
- the alkali used under alkaline conditions in the step (1) is selected from potassium carbonate
- R 22 is a hydrogen atom, -Y 1 (CR a R b ) q NHR 8 , R 20 is R 22 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 21 , R 23 , R 24 and R 25 are R 6 ; when When R 2 is a warhead group, R 23 is -Y 1 (CR a R b ) q NHR 8 , R 21 is R 23 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 20 , R 22 , R 24 and R 25 are R 6 ; when When R 4 is a warhead group, R 24 is -Y 1 (CR a R b ) q NHR 8 , R 18 is R 24 with a protective group, halogen, an oxy group
- protective groups include but are not limited to tert-butoxycarbonyl, benzyloxycarbonyl, benzyl or dimethoxybenzyl;
- L is hydroxyl, halogen or leaving group
- A, B, D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R a , R b , R c , R d , Y 1 , Y 2 , Y 3 , Z, X, p, q, m, n, t, warhead groups are as defined above;
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound as an EGFR kinase inhibitor and a pharmaceutically acceptable carrier or excipient.
- pharmaceutical composition refers to combining one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, with other chemical ingredients, such as pharmaceutical acceptable carriers, excipients or diluents.
- pharmaceutical acceptable carriers such as pharmaceutical acceptable carriers, excipients or diluents.
- the purpose of a pharmaceutical composition is to facilitate the process of administration to an animal.
- “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or potting material, which is involved in carrying out the subject matter of the present invention.
- the compound is loaded or delivered from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part.
- a pharmaceutically acceptable carrier can be a vehicle, diluent, excipient or other material which is not undue toxicity or side effects and which can be used in contact with animal tissue.
- Typical pharmaceutically acceptable carriers include sugars, starches, celluloses, maltose, tragacanth, gelatin, Ringer's solution, alginic acid, physiological saline, buffers and the like.
- Each pharmaceutically acceptable carrier should be compatible with the other ingredients, such as to form formulations with the compounds provided in the present invention, without undue toxicity, irritation, allergic reaction, immunogenicity or other problems to living tissues or organs or complications, and a reasonable benefit-risk ratio.
- Some pharmaceutically acceptable carrier materials include: (1) carbohydrates, such as lactose, glucose, and sucrose; (2) starches, such as cornstarch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate; (4) tragacanth powder; (5) maltose; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppositories Waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitan Alcohols, mannitol, and polyethylene glycols; (12) lipids, such as ethyl oleate, ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) (16)
- compositions may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.
- the pharmaceutical ingredients can be prepared in any suitable dosage form, such as solid dosage forms (eg, tablets, capsules, powders, granules, etc.) and liquid dosage forms (eg, aqueous solutions, emulsions, elixirs, syrups, etc.).
- suitable dosage form such as solid dosage forms (eg, tablets, capsules, powders, granules, etc.) and liquid dosage forms (eg, aqueous solutions, emulsions, elixirs, syrups, etc.).
- liquid dosage forms eg, aqueous solutions, emulsions, elixirs, syrups, etc.
- the preparation methods of pharmaceutical compositions are well known and can be prepared according to conventional techniques, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).
- the compounds or pharmaceutical compositions provided in the present invention can be formulated into dosage forms suitable for drug release and administered by injection route (eg, subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, framed intra-, intra-cardiac, intra-dermal, intra-peritoneal, transtracheal, epidermal, intra-articular, sub-capsular, sub-arachnoid, intra-spinal, intra-sternal, and/or infusion) and non-injection routes (eg, oral, enteral, Oral, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal or epidermal topical administration).
- injection route eg, subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, framed intra-, intra-cardiac, intra-dermal, intra-peritoneal, transtracheal, epidermal, intra-articular, sub-capsular, sub-
- Suitable dosage forms include, but are not limited to, dosage forms for injectable use such as emulsions, solutions and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, topical or transdermal formulations.
- Dosage forms such as sprays, ointments, pastes, creams, lotions, gels, solutions, pharmaceutical patches and inhalants, and those for vaginal or rectal administration such as suppositories.
- These dosage forms can be prepared under suitable conditions depending on the compound and suitable excipients, and the methods and techniques of preparation are well known, for example provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000) .
- the present application provides pharmaceutical compositions comprising the above-described compounds and a pharmaceutically acceptable carrier or excipient.
- the pharmaceutical compositions are tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, sprays agent
- Another aspect of the present invention provides applications of the above compounds and/or pharmaceutical compositions in the preparation of medicines and the treatment of diseases.
- the present invention provides the use of the above-mentioned compounds and/or pharmaceutical compositions in the preparation of anti-tumor drugs.
- the present application provides the use of the above-mentioned compounds and/or pharmaceutical compositions in the preparation of antitumor drugs.
- the antineoplastic drug is used for the following conditions: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovary cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, Cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.
- the present application provides a method of treating a tumor in a patient in need thereof, comprising administering to said patient, preferably a mammal, said mammal an effective amount of a compound or pharmaceutical composition described above People are preferred.
- modes of administration include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal.
- the compounds or pharmaceutical compositions of the present invention may be administered into the organism by any suitable route, such as oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal, or subcutaneous routes.
- suitable route such as oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal, or subcutaneous routes.
- the modes of administration of the compounds or pharmaceutical compositions contemplated by the present invention include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration medicine.
- the compounds or pharmaceutical compositions involved in the present invention can be administered simultaneously with the second active substance, so that an additive or even synergistic effect can be achieved in vivo.
- a compound of the present invention may be combined with a second active substance in a pharmaceutical composition, either administered simultaneously in separate compositions, or administered sequentially in separate compositions.
- Second active substances that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to: fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprolide, goserelin, fluorouracil Tamide, Nilutamide, Finasteride, Dexamethasone, Amglutide, Amacridine, Anastrozole, Asparaginase, BCG, Bicalutamide, Bleomycin, Baixiao Camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin d, danamycin, diethylstilbestrol, diethylstilbestrol, docetaxel, doxorubicin, doxorubicin, epirubicin,
- the compounds provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the compounds provided herein can be administered concurrently with radiation therapy. In certain embodiments, the compounds provided by the present invention can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy, or a combination of the above.
- the compounds provided herein can be used concurrently with steroids.
- Suitable steroids include, but are not limited to: amxicil, beclomethasone, betamethasone, budesonide, cloprednisone, clobetasol, corticosterone, cortisone, hydroxyprednisone, des Oxymethasone, Dexamethasone, Diflurasone, Diflumethasone, Diflugestin, Glycyrrhetinic Acid, Fluzacortisone, Flumethasone, Flunisolide, Fluclonide, Paclolone Acetate, Fluocinolone Acetate, Fluocetide, Fluocinolone, Fludroxolone Acetone, Flupirone Acetate, Fluprednidine Acetate, Fluprednisolone, Fluocinolone, Fluoride Propionate, Aldehydrone, Clobetasol Propionate, Hacecil, Halometasone, Hydrocortisone, Lot
- the compounds provided herein can be used concurrently with immunotherapeutic agents.
- immunotherapeutic agents include tumor cell multidrug resistance reversal agents (such as verapamil), rapamycin, mycophenolate mofetil, thalidomide, cyclophosphamide, cyclosporine, and monocytogenes. cloned antibodies.
- the first step 2,2,2-trifluoro-N-(2-((2-hydroxyethyl)amino)ethyl)acetamide
- tert-butyl (2-hydroxyethyl)(2-(2,2,2-trifluoroacetamido)ethyl)carbamate (20.4g, 0.0677mol) and methanol were successively added to a 500mL round-bottomed flask. (50 mL), water (10 mL) and potassium carbonate (5.0 g), warmed to 60 °C and stirred for 48 h.
- 3,7-Dimethyloct-6-enoic acid (3.5 g, 20.56 mmol) was dissolved in toluene (300 mL), the temperature was raised to 50 °C, triethylamine (2.5 g, 24.67 mmol) was added, and then the stack was slowly added.
- Diphenyl nitrophosphate (5.65g, 20.56mmol) was heated to 70°C and stirred for 12h, 2-methylbutan-2-ol (3.6g, 41.16mmol) was added, the temperature was raised to 110°C and stirred for 2h, then 2-Methylbutan-2-ol (3.6 g, 41.16 mmol) was added. The reaction mixture was stirred at 110 °C for 12 h.
- tert-amyl (2,6-dimethylhept-5-en-1-yl)carbamate 2.5 g, 10.11 mmol
- methanol 20 mL
- ozone was slowly introduced into the reaction system until the reaction system became sky blue, and stirring was continued for 20 min until colorless.
- the temperature was lowered to 0° C., sodium borohydride (0.95 g, 25.1 mmol) was slowly added, and after the addition was completed, the temperature was slowly raised to room temperature and stirred for 12 h.
- tert-amyl (5-hydroxy-2-methylpentyl)carbamate 450 mg, 1.95 mmol
- 4M hydrochloric acid in dioxane 10 mL
- tert-butyl (R)-(2-hydroxypropyl) carbamate 900 mg, 5.1 mmol
- pyridine 5 mL
- Sulfonyl chloride 1.07g, 5.6mmol
- the second step 2-((tert-butoxycarbonyl)amino)ethyl-1,1-dideutero 4-toluenesulfonate
- tert-butyl(2-hydroxyethyl-2,2-dideutero)carbamate 2.5 g, 15.3 mmol
- dichloromethane 25 mL
- p-toluenesulfonyl chloride 4.4 g, 23.0 mmol
- triethylamine 3.1 g, 30.6 mmol
- 1-bromo-2-fluoro-3-nitrobenzene (5.0g, 0.03mol), 1,4-dioxane (50mL), propane- 2-alkyn-1-ylcarbamate tert-butyl ester (4.23g, 0.03mol), N,N-diisopropylethylamine (3.4g, 0.03mol), cuprous iodide (0.04g, 0.2mmol), Bistriphenylphosphonium palladium dichloride (0.64 g, 0.9 mol) and tri-tert-butylphosphine (0.15 g, 1.3 mol), warmed to 45° C. and stirred for 15 h.
- the first step methyl 2-chloro-6-(2-hydroxyphenyl)isonicotinate
- 2-chloro-6-(2-hydroxyphenyl)isonicotinic acid methyl ester (10 g, 0.03 mol), dioxane (100 mL), BocNH 2 (5.32 mol) were added to a 250 mL round-bottomed flask at room temperature. g, 0.04 mol), cesium carbonate (24.0 g, 0.07 mmol), Xphos (3.6 g, 0.0075 mol) and bis(dibenzylideneacetone)palladium (13.3 mg, 0.02 mmol), warmed to 85° C. and stirred for 16 h.
- methyl 2-chloro-6-methylisonicotinate (20.0 g, 0.11 mol) was added to anisole (200 mL) at room temperature, followed by 1-methyl-5-hydroxypyrazole (21.2 g, 0.2156 mol), sodium carbonate (29.4 g, 0.237 mol) and PdCl2 (dppf) (2.36 g, 0.003 mol).
- the first step 2-methyl-6-(1-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)isonicotine methyl ester
- Methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (2.7 g, 10.9 mmol) was dissolved in a 50 mL round bottom flask at room temperature Acetonitrile (30 mL), K 2 CO 3 (2.41 g, 17.44 mmol) and SEMCl (2.91 g, 17.44 mmol) were added successively, and the mixture was stirred at room temperature for 5 h.
- the second step 2-methyl-6-(1-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)isofumine acid
- Step 2 2-(5-(2-((tert-butoxycarbonyl)(2-((2-nitrophenyl)amino)ethyl)amino)ethoxy)-1-methyl-1H- Pyrazol-4-yl)-6-methylisonicotinic acid methyl ester
- the third step 2-(5-(2-((2-aminophenyl)amino)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-1-methyl-1H-pyrazole-4- yl)-6-methylisonicotinic acid methyl ester
- the fourth step 2-(5-(2-((2-(2-amino-1H-benzimidazol-1-yl)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-1-methyl yl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester
- the fifth step 2-(5-(2-((2-(2-amino-1H-benzimidazol-1-yl)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-1-methyl yl-1H-pyrazol-4-yl)-6-methylisonicotinic acid
- intermediates A2-A4 and B1-B7 were prepared using the method for the synthesis of intermediate A1 (Example 31).
- Step 4 1-(5-Hydroxypentyl)-2-(2-methyl-6-(1-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)methoxy )-1H-pyrazol-4-yl)isonicotinamide)-1H-benzo[d]imidazole-6-carboxylate methyl ester
- the fifth step 2-(2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinamide)-1-(5-hydroxypentyl)-1H- Benzo[d]imidazole-6-carboxylate methyl ester
- Example 43 11,26 - Dimethyl-56-(( 4 -methylpiperazin- 1 - yl)methyl)-3-oxo-11H,51H-11-oxo Hetero-4,8-diaza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridyl-1(4,5)-pyrazolecycloundecyl-8 -Synthesis of tert-butyl carboxylate (Intermediate A5)
- Intermediates A6-A11 were prepared by the method for the synthesis of intermediate A5 (Example 43) using intermediate B and nitrogen heterocyclic compound as starting materials.
- intermediate B3 (15.0 g, 0.03 mol), 1,4-dioxane (100 mL), and (2,4-dimethoxyphenyl)methane were successively added to a 100 mL round-bottomed flask at room temperature.
- Amine (7.5 g, 0.045 mol ), Pd2(bda)3 ( 2.75 g, 0.003 mol), BINAP (3.73 g, 0.006 mol) and sodium tert-butoxide (5.77 g, 0.06 mol), stirred at 100°C overnight.
- the third step (E)-(2-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridyl- 1 (4,5)-pyrazolecycloundecan-57-yl)amino) Ethyl) tert-butyl carbamate
- sodium cyanoborohydride (58.25 mg, 0.93 mmol) was added and stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- N-BOC-L-alanine (877 mg, 4.64 mmol) was dissolved in THF (30 mL), NMM (375 mg, 3.7 mmol) was added, the temperature was lowered to -20 °C, and isobutyl chloroformate ( 876.6 mg, 4.64 mmol), stirred at -20 °C for 1 h, then added dropwise (E)-57-amino - 11,26 - dimethyl - 52,53-dihydro - 11H, 51 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridyl-1(4,5)-pyrazolecycloundecane- A solution of 3-keto (200 mg, 0.46 mmol) in THF (15 mL) and NMM (234 mg, 2.32 mmol) was stirred at room temperature overnight.
- Example 62 (E)-(1-((1 1 ,2 6 -Dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza- 5 (2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecan-57-yl)amino)- Synthesis of tert-butyl 6-(dimethylamino)-1-oxohexane-2-yl)carbamate (Intermediate A24)
- the first step (E)-(6-amino-1-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11 -oxa-4-aza- 5 (2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolcycloundecan-57-yl ) amino)-1-oxohexane-2-yl) tert-butyl carbamate
- the second step (E)-(1-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza- 5 (2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecan-57-yl)amino)- 6-(Dimethylamino)-1-oxohexane-2-yl)carbamic acid tert-butyl ester
- the second step (E)-(2-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza-5(2,1)-benzo[d]imidazozol-2(2,4)-pyridyl- 1 (4,5)-pyrazolecycloundecan-56-yl) tert-butyl oxy)ethyl)carbamate
- intermediates A27-A45 were prepared using the method for the synthesis of intermediate A26 (Example 64).
- the first step (S)-2-((tert-butoxycarbonyl)amino)-5-((2-nitrophenyl)amino)pentanoic acid
- intermediate A47 was prepared according to the method for synthesizing intermediate A46 (Example 84).
- the first step methyl 2-(2-(5-bromopentyl)oxy)phenyl)-6-(tert-butoxycarbonyl)amino)isonicotinate
- Step 2 2-(2-((5-(2-Amino-1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-6-((tert-butoxycarbonyl) Amino) methyl isonicotinate
- the third step 2-(2-((5-(2-amino-1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-6-((tert-butoxycarbonyl) amino)isonicotinic acid
- dichloromethane (20 mL) was added to dilute, washed with saturated brine (10 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- intermediate A Using intermediate A as raw material, the final products 4-8, 49, 50, 55, 58, 60, 62, 67-69, 73, 74, 76-78, 80-83, 102, 109, 114, 115, 118-122, 124-126, 131-133, 135, 137-141, 147, 152, 154.
- the final product was prepared according to the method for synthesizing the final product 10 (Example 135) using the amine obtained by the hydrolysis of Intermediate A and a commercially available acid as raw materials.
- the first step methyl 2-methyl-6-(1-methyl-5-(3-(epoxypropan-2-yl)propoxy)-1H-pyrazol-4-yl)isonicotinate
- Step 2 2-(5-((5-(2-Amino-1H-benzo[d]imidazol-1-yl)-4-hydroxypentyl)oxy)-1-methyl-1H-pyridine azol-4-yl)-6-methylisonicotinic acid
- the seventh step (E)-N-(1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4- Aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridyl-1(4,5)-pyrazolecycloundecan-7-yl)acrylamide
- the HTRF KinEASE-TK kit was used to measure its activity by detecting the remaining amount of ATP after the EGFR protein kinase reaction.
- the intensity of the luminescent signal tested was positively correlated with the amount of ATP remaining in the reaction, positively correlated with compound activity, and negatively correlated with kinase activity.
- the enzyme buffer was diluted 5-fold with 5 mM MgCl 2 ; 1 mM DTT; 1 mM MnCl 2 in water.
- Enzyme inhibition percentage (%) 100-(Signal compound -Signal average_PC )/(Signal average_VC -Signal average_PC ) ⁇ 100
- Table 9 shows the inhibitory IC50 of the compounds of the present invention to EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S enzymatic activities.
- the CellTiter-Glo TM live cell detection kit uses luciferase as the detection substance, and luciferase requires the participation of ATP in the process of luminescence.
- Add CellTiter-Glo TM reagent to the cell culture medium measure the luminescence value, the light signal is proportional to the amount of ATP in the system, and ATP is positively correlated with the number of viable cells. Therefore, by using the CellTiter-Glo kit to detect ATP content, the proliferation of cells can be detected.
- the celltiter-Glo (CTG) method was used to measure the compounds prepared above in tumor cell lines NCI-H1975, Ba/F 3 (EGFR-L858R/C797S/T790M), Ba/F 3 (EGFR-Del19/C797S/T790M) and A431, and the 50% inhibitory concentration IC50 was calculated.
- Cell viability (%) (Lum test drug- Lum culture solution control )/(Lum cell control -Lum culture solution control ) ⁇ 100%.
- Table 10 shows the IC50 of the compounds of the present invention for inhibiting proliferation of NCI-H1975, Ba/F3 (EGFR-L858R/C797S/T790M), Ba/F3 (EGFR-Del19/C797S/T790M) and A431 cell lines.
- the compounds of the present invention have positive effects on NCI-H1975 double mutant cell line, Ba/F3 (EGFR-L858R/C797S/T790M) triple mutant cell line and Ba/F3 (EGFR-Del19/C797S/T790M) three
- the mutant cell line has good growth inhibitory activity, and the inhibitory effect on the EGFR wild-type cell line A431 is weak, indicating that the compound of the present invention has good cell inhibitory activity and selectivity.
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Abstract
一种大环化合物及其制备方法和应用,所述大环化合物具有下式(I) 所示的结构:其中,A、B、D、R1、R2、R3、R4、R5、Z、X、m、n、p 如说明书所定义。所述大环化合物能克服EGFR C797S 和EGFR T790M的突变,选择性高。
Description
相关申请的交叉引用
本申请要求2020年12月3日递交的中国专利申请号为2020114105057的专利申请的权益,在此将其全部内容引入作为参考。
本发明涉及大环化合物及其制备方法和应用,特别涉及抑制、调节和/或调控EGFR激酶的信号转导的化合物、它们的制备方法、含有它们的药物组合物以及它们的应用。
蛋白激酶是信号传导途径的酶组分,它催化末端磷酸盐从ATP迁移至蛋白的酪氨酸、丝氨酸和/或苏氨酸残基的羟基。因此,抑制蛋白激酶功能的化合物是评估蛋白激酶活动的生理学结果的有价值的工具。哺乳动物的正常或突变蛋白激酶的过表达或不适当表达已经成为广泛研究的主题,并已经被证实在许多疾病,包括糖尿病、血管生成、银屑病、再狭窄、眼病、精神***症、类风湿性关节炎、动脉粥样硬化、心血管疾病和癌症的发展中起到重要作用。蛋白激酶抑制剂在治疗人和动物疾病方面具有特别的用途。
EGFR是受体酪氨酸激酶ErbB受体家族成员。当EGFR在胞外与其配体EGF结合后,受体发生同型或异型二聚化和自身磷酸化,激活下游级联信号通路,最终促进细胞生长、增殖和***等。EGFR的过度表达(上调)或过度活动已证实与许多癌症相关,包括头颈部癌、卵巢癌、***、膀胱癌、食道癌、胃癌、乳腺癌、子宫内膜癌、结肠直肠癌、非小细胞肺癌、和胶质母细胞瘤。
EGFR作为一种致癌基因产生了针对EGFR小分子抑制剂的靶向治疗。在非小细胞肺癌(NSCLC)中,50%-80%患者由EGFR突变引起。已经应用于临床的第一代EGFR抑制剂如易瑞沙、特罗凯等,它们对于NSCLC的治疗取得了很大成功。但临床有非常明显的皮疹和腹泻等副作用,而且在使用一年后,患者对药物出现耐药性。临床数 据显示,大约有50%的患者获得性耐药源于T790M(20号外显子第790位点苏氨酸被甲硫氨酸取代)突变体产生。第二代抑制剂如阿法替尼、达可替尼等,它们与EGFR的结合活性更强,但对T790M突变体的选择性差,在可耐受剂量下,无法在体内达到有效浓度。
第三代抑制剂奥希替尼既可作为二线治疗经第一、第二代治疗后T790M突变患者,也可作为一线治疗未经EGFR-TKIs治疗的EGFR敏感突变的患者,但是经第三代EGFR抑制剂奥希替尼治疗9.9-18.9个月后也不可避免产生C797S(20号外显子797位点半胱氨酸突变成丝氨酸)耐药突变。
Thress KS最早报道了服用奥希替尼治疗T790M突变有40%患者发生C797S耐药突变,此外Lee JY等人也报道了对于T790M突变患者服用奥希替尼后会有24%患者产生C797S耐药突变,且Papadimitrakopoulou V.A.对AURA3临床试验中73例服用奥希替尼疾病进展的患者分析发现,有15%患者发生C797S耐药突变。FLAURA研究中奥希替尼作为一线治疗与第一代EGFR抑制剂(吉非替尼或厄洛替尼)标准治疗相比也表现超高的疗效,对该研究中91例服用奥希替尼耐药进展患者研究发现有7%患者发生C797S耐药突变。
耐药突变产生的结果导致EGFR对ATP亲和力大大提高,削弱药物小分子和ATP的竞争结合。Zhu SJ等人[Oncotarget,2018,9(17),13652-13665]发现有3种提高小分子亲和力的方法:共价/不可逆抑制、超高活性非共价/可逆抑制或非ATP竞争性抑制也称变构抑制。
2019年勃林格殷格翰公司在[J.Med.Chem.2019,62,10272-10293]的文章中报道一种既能克服奥希替尼耐药的C797S三突变,同时对野生型wtEGFR具有高度选择性的非共价的大环化合物BI-4020,但是该化合物未进入临床阶段。推测原因可能是非共价化合物的活性不能克服T790M双突变引起的耐药。对于C797S突变,目前市场上还没有有效的药物对其进行治疗,临床中针对C797S突变的药物较少,且主要是针对C797S三突变的可逆抑制剂,这些药物对T790M双突变活性较弱。因此在BI-4020的结构基础上通过引入弹头,形成不可逆抑制,对开发选择性的既能克服C797S突变,又能克服T790M突变的***EGFR抑制剂的具有重要意义。
发明内容
为了解决现有技术的缺陷,本发明提供一种大环化合物,该大环化合物既能克服EGFR C797S突变,又能克服EGFR T790M突变,而且选择性较高。
本发明是通过以下技术方案来实现的。
一方面,本发明提供具有如下式I所示结构的化合物:
其中,
环A和环B各自独立地为6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、或包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环,所述的6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、或包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环可以任选地被一个或多个独立地选自以下的取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、被一个或多个R
m取代或未被取代的包含1-4个独立地选自N,O和S杂原子的5-10元杂芳基、被一个或多个R
m取代或未被取代的6-10元芳基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C
1-6烷基、-S(=O)
2R
a、-S(=O)
2NR
aR
b、-P(=O)R
aR
b、-P(=O)R
aNR
bR
c、-P(=S)R
aR
b、-P(=S)R
aNR
bR
c、R
bS(=O)
2N(R
a)-,其中所述C
1-6烷基、C
2-6烯基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟 基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C
1-6烷基、-S(=O)
2R
a、-S(=O)
2NR
aR
b、-P(=O)R
aR
b、-P(=O)R
aNR
bR
c、-P(=S)R
aR
b、-P(=S)R
aNR
bR
c、R
bS(=O)
2N(R
a)-可选择地和它们所连接的碳原子一起形成环,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、被一个或多个R
m取代或未被取代的包含1-4个独立地选自N,O和S杂原子的5-10元杂芳基、被一个或多个R
m取代或未被取代的6-10元芳基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C
1-6烷基-可以任选地被一个或多个独立地选自以下的取代基所取代:卤素、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、4-7元杂环基和4-7元杂环基-C
1-6烷基;
环D为6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环、或C
5-7环烷;
R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6;当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、氨基、C
1-6烷基-氨基、C
3-6环烷基-氨基、二(C
1-6烷基)-氨基、 C
1-6烷氧基-C
1-6烷基-氨基、4-6元杂环基-C
1-6烷基-氨基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基-氨基、氢原子、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、氰基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷氧基-羰基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基、C
1-6烷基-羰基-C
1-6烷基、C
1-6烷基-氨基酰基-C
1-6烷基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基-C
1-6烷基、C
1-6烷基-OC(O)-C
1-6烷基、或包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、C
1-6烷基-氨基、C
3-6环烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷氧基-C
1-6烷基-氨基、4-6元杂环基-C
1-6烷基-氨基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基-氨基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、氰基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷氧基-羰基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基、C
1-6烷基-羰基-C
1-6烷基、C
1-6烷基-氨基酰基-C
1-6烷基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基-C
1-6烷基、C
1-6烷基-OC(O)-C
1-6烷基、或包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷基-O(O)C-、C
1-6烷基-羰基、氧代、卤素、羟基、C
1-6烷基氨基、二(C
1-6烷基)氨基、被1个或多个C
1-6烷基、C
1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;
或者,R
3与环D上除与R
3连接的原子之外的任意原子一起,或者,R
3和R
6与所连接的原子一起任选地形成由3-10个原子组成的杂环,所述杂环包含1-3个选自N,O或 S杂原子并且杂环上可选地进一步被一个或多个选自C
1-6烷基、卤素、6-10元芳基、包含1-3个独立地选自N,O或S的杂原子的5-10元杂芳基、包含1-3个独立地选自N,O或S的杂原子的5-10元杂环基、卤代C
1-6烷基、羟基、氰基、卤素、C
1-6烷氧基、4-6元杂环基烷基、C
1-6烷基氨基和二(C
1-6烷基)氨基所取代;
Y
1、Y
2和Y
3各自独立地为化学键、O、NR
8、S、S(O)
2、CR
8R
16、羰基、-氨基-酰基、-酰基-氨基、-O(CO)-或-(CO)O-;
M为化学键、被一个或多个R
m取代或未被取代的-C
1-6烷基-、被一个或多个R
m取代或未被取代的-C
3-6环烷基-、被一个或多个R
m取代或未被取代的-C
3-6环烷基-C
1-6烷基-、被一个或多个R
m取代或未被取代的-C
1-6烷基-氨基-C
1-6烷基-、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的-4-7元杂环基-、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的-4-7元杂环基-C
1-6烷基-;
R
8为氢原子、C
1-6烷基、C
3-6环烷基、或包含1-2个独立地选自N,O和S杂原子且任选的被氧代取代的5-7元杂环基;
R
9和R
10独立地为氢原子、卤素、氰基、C
1-6烷基、卤代C
1-6烷基、C
3-6环烷基、或杂环基烷基;
R
11为氢原子、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、氨基、C
1-6烷基氨基、二(C
1-6烷基)氨基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基,所述C
1-6烷基、C
1-6烷氧基、C
3-6环烷 基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷基氨基、二(C
1-6烷基)氨基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基可以任选地被一个或多个独立地选自以下的基团所取代:卤素、羟基、氰基;
R
12和R
13各自独立地为氢原子、C
1-6烷基、C
3-7环烷基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基、或R
12和R
13与NR
12R
13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-10元杂环基,所述C
1-6烷基、C
3-7环烷基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基、或R
12和R
13与NR
12R
13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-10元杂环基可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、卤素、羟基、氰基、氧代、C
1-6烷基-氨基、卤代C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、被一个或多个R
m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C
1-6烷基-羰基;
R
14和R
15独立地为氢原子、C
1-6烷基、或R
14和R
15与所连接的碳原子一起形成C
3-6环烷基;
R
16为氢原子、C
1-6烷基、C
3-6环烷基、C
1-6烷氧基、或C
3-6环烷氧基;
R
a、R
b、R
c和R
d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基,所述的C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基。
或者R
a和R
b与所连接的碳原子一起形成环、R
c和R
d与所连接的碳原子一起形成环,所述的环为C
3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C
3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、 C
3-6环烷基和C
1-6烷氧基。
环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环、或包含1-5个独立地选自N,O或S的杂原子5-10元桥环或螺环饱和或部分不饱和杂环,所述4-7元饱和或部分不饱和杂环和5-10元桥环或螺环饱和或部分不饱和杂环基可以任选独立地被一个或多个R
m所取代;
环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环、C
3-6环烷、6-10元单环芳环或二环芳环、或者包含1-5个独立地选自N,O或S的杂原子5-10元桥环或螺环饱和或部分不饱和杂环,所述4-7元饱和或部分不饱和杂环、C
3-6环烷、6-10元单环芳环或二环芳环、5-10元桥环或螺环饱和或部分不饱和杂环可以任选独立地被一个或多个R
m所取代;
R
m为C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、氧代、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6酰基-氨基、C
1-6烷基-O(CO)-或C
3-6环烷基-O(CO)-;
q和t各自独立地为0、1、2或3;
w为1、2或3;
X为O、S、CR
17R
18、NR
17、CO或S(O)
2;
R
17为氢原子、C
1-6烷基、卤代C
1-6烷基、C
3-6环烷基、卤代C
3-6环烷基、C
1-6烷氧基-C
1-6烷基、卤代C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-羰基或C
1-6烷基-砜基;
R
18为氢原子、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6 环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、C
1-6烷基-O(O)C-、C
1-6烷基-C(O)O-或C
1-6烷基-砜基;
Z为N、O、S、CO、S(O)
2、-氨基-酰基、-酰基-氨基、-O(CO)-、-(CO)O-、CR
19、C
3-7环烷基或3-7元杂环基,所述C
3-7环烷基和3-7元杂环基可以任选独立地被一个或多个R
18所取代;
R
19独立地为氢原子、C
1-6烷基或C
3-6环烷基;
m和n独立地为0、1、2、3或4;
p为0、1、2或3。
在某些实施方式中,环A和环B各自独立地为苯环、或包含1-2个独立地选自N,O和S杂原子的5-6元杂芳环,所述的苯环或5-6元杂芳环可以任选地被一个或多个独立地选自以下的取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基可以任选地被一个或多个独立地选自以下取代基所取代:卤素、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
1-6烷基-氨基和4-7元杂环基;
优选地,在式I中,环A和环B各自独立地为苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑、异噻唑,所述的苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑和异噻唑可以任选地被一个或多个独立地选自以下取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-4烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基和C
3-6环烷基-氨基。
在某些实施方式中,环D为苯环、包含1-3个独立地选自N,O和S杂原子的5-6元杂芳环、包含1-2个独立地选自N,O和S杂原子的5-7元杂环或环己环;
优选地,在式I中,环D为苯环、吡啶、嘧啶、吡嗪、哒嗪、哌啶、哌嗪、吡唑、咪唑或环己烷。
在某些实施方式中,R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6,当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、氢原子、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷基-O(O)C-、C
1-6烷基-羰基、氧代、卤素、羟基、C
1-6烷基氨基、二(C
1-6烷基)-氨基、可被1个或多个C
1-6烷基、C
1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;
Y
1、Y
2和Y
3各自独立地为化学键、O或NR
8;
R
8为氢原子、C
1-6烷基或C
3-6环烷基;
R
9和R
10独立地为氢原子、卤素或氰基;
R
12和R
13各自独立地为氢原子、C
1-6烷基、C
3-6环烷基、或R
12和R
13与NR
12R
13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-7元杂环,所述C
1-6烷基、C
3-6环烷基和形成的包含1-3个独立地选自N,O或S杂原子的4-7元杂环可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、卤素、羟基、氰基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、被一个或多个R
m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C
1-6烷基-羰基;
R
14和R
15独立地为氢原子、C
1-6烷基或R
14和R
15与所连接的碳原子一起形成C
3-6环烷基;
R
a、R
b、R
c和R
d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基,所述的C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基;
或者R
a和R
b与所连接的碳原子一起形成环、R
c和R
d与所连接的碳原子一起形成环,所述的环为C
3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C
3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或 部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基;
环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R
m所取代;
环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、C
3-6环烷、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、C
3-6环烷、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R
m所取代;
R
m为C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、卤素、羟基、氰基、氨基、氧代、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
1-6烷基-OC(O)-或C
3-6环烷基-OC(O)-;
q和t各自独立地为0、1、2或3;
w为1、2或3;
优选地,在式I中,R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6;当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为氢原子、卤素、甲基、乙基、三氟甲基、甲氧基、异丙氧基、氰基、羟基、羟甲基、甲氧基甲基、乙氧基甲基、甲基羰基、甲氧基羰基、4-甲基哌嗪-1-基羰基、二甲氨基甲基、二甲氨基乙氧基、羟基乙氧基、二甲氨基乙氧基甲基、N,N,N’-三甲基乙二氨基甲基、N,N-二甲基乙二氨基甲基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、N,N,N’-三甲基乙二氨基、N,N-二甲基乙二氨基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基,所述4-甲基哌嗪-1-基羰基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、 4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基可以任选地被一个或多个独立地选自下组的取代基所取代:卤素、甲基、乙基、异丙基、环丙基、甲氧基、甲氧基甲基、甲氧基乙基、甲基羰基、甲氧基羰基、氧代和二甲氨基;
弹头基团为:
在某些实施方式中,X为O或S;
Z为N、O、S、-氨基-酰基、-酰基-氨基、或CR
19;
R
19独立地为氢原子、C
1-6烷基或C
3-6环烷基;
优选地,在式I中,Z为N、O或CR
19;
R
19独立地为氢原子、甲基、乙基、异丙基、环丙基或环丁基。
在某些具体实施方案中,式I中:
环A和环B各自独立地为苯环、或包含1-2个独立地选自N,O和S杂原子的5-6元杂芳环,所述的苯环或5-6元杂芳环可以任选地被一个或多个独立地选自以下的取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基可以任选地被一个或多个独立地选自以下取代基所取代:卤素、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
1-6烷基-氨基和4-7元杂环基;
环D为苯环、包含1-3个独立地选自N,O和S杂原子的5-6元杂芳环、包含1-2个独立地选自N,O和S杂原子的5-7元杂环或环己环;
R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立 地为R
6;当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、氢原子、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷基-O(O)C-、C
1-6烷基-羰基、氧代、卤素、羟基、C
1-6烷基氨基、二(C
1-6烷基)-氨基、可被1个或多个C
1-6烷基、C
1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;
Y
1、Y
2和Y
3各自独立地为化学键、O或NR
8;
R
8为氢原子、C
1-6烷基或C
3-6环烷基;
R
9和R
10独立地为氢原子、卤素或氰基;
R
12和R
13各自独立地为氢原子、C
1-6烷基、C
3-6环烷基、或R
12和R
13与NR
12R
13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-7元杂环,所述C
1-6烷基、C
3-6环烷基和形成的包含1-3个独立地选自N,O或S杂原子的4-7元杂环可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、卤素、羟基、氰基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、被一个或多个R
m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C
1-6烷基-羰基;
R
14和R
15独立地为氢原子、C
1-6烷基或R
14和R
15与所连接的碳原子一起形成C
3-6环烷基;
R
a、R
b、R
c和R
d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基,所述的C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基;
或者R
a和R
b与所连接的碳原子一起形成环、R
c和R
d与所连接的碳原子一起形成环,所述的环为C
3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C
3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基;
环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R
m所取代;
环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、C
3-6环烷、或 包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、C
3-6环烷、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R
m所取代;
R
m为C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、卤素、羟基、氰基、氨基、氧代、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
1-6烷基-OC(O)-和C
3-6环烷基-OC(O)-;
q和t各自独立地为0、1、2或3;
w为1、2或3;
X为O或S;
Z为N、O、S、-氨基-酰基、-酰基-氨基、或CR
19;
R
19独立地为氢原子、C
1-6烷基或C
3-6环烷基;
m和n独立地为0、1、2、3或4;
p为0、1、2或3。
在另一些具体实施方案中,在式I中:
环A和环B各自独立地为苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑、异噻唑,所述的苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑和异噻唑可以任选地被一个或多个独立地选自以下取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-4烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基和C
3-6环烷基-氨基;
环D为苯环、吡啶、嘧啶、吡嗪、哒嗪、哌啶、哌嗪、吡唑、咪唑或己烷;
R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6;当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为氢原子、卤素、甲基、乙基、三氟甲基、甲氧基、异丙氧基、氰基、羟基、羟甲基、甲氧基甲基、乙氧基甲基、甲基羰基、甲氧基羰基、4-甲基哌嗪-1- 基羰基、二甲氨基甲基、二甲氨基乙氧基、羟基乙氧基、二甲氨基乙氧基甲基、N,N,N’-三甲基乙二氨基甲基、N,N-二甲基乙二氨基甲基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、N,N,N’-三甲基乙二氨基、N,N-二甲基乙二氨基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基,所述4-甲基哌嗪-1-基羰基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基可以任选地被一个或多个独立地选自下组的取代基所取代:卤素、甲基、乙基、异丙基、环丙基、甲氧基、甲氧基甲基、甲氧基乙基、甲基羰基、甲氧基羰基、氧代和二甲氨基。
弹头基团为:
X为O或S;
Z为N、O或CR
19;
R
19独立地为氢原子、甲基、乙基、异丙基、环丙基或环丁基;
m和n独立地为0、1、2、3或4;
p为0、1、2或3。
在又一些具体实施方案中,在式I中:
环A和环B各自独立地为苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑,所述的苯、吡啶、嘧啶、哒嗪、吡嗪、吡唑、咪唑、噁唑、异噁唑、噻唑和异噻唑可以任选地被一个或多个独立地选自下组的取代基所取代:甲基、乙基、异丙基、乙烯基、乙炔基、氟代乙基、甲氧基、乙氧基、环丙基、环戊基、甲氧基、乙氧基、环丙氧基、甲氧基甲基、甲氧基乙基、羟基乙基、羟基丙基、氨基乙基、氧代、氟、氯、溴、羟基、氰基、氰基乙基、氰基丙基、氨基、甲氨基、乙氨基、二甲基氨基、二乙基氨基、二甲基氨基甲基、二甲基氨基乙基、甲基氨基乙基、环丙氨基;
环D为苯环、吡啶、嘧啶、吡嗪、哒嗪、哌啶或哌嗪;
R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6;当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6独立地为氢原子、氟、氯、溴、甲基、乙基、三氟甲基、甲氧基、异丙氧基、氰基、羟基、羟甲基、甲氧基甲基、乙氧基甲基、甲基羰基、甲氧基羰基、4-甲基哌嗪-1-基羰基、二甲氨基甲基、二甲氨基乙氧基、羟基乙氧基、二甲氨基乙氧基甲基、N,N,N’-三甲基乙二氨基甲基、N,N-二甲基乙二氨基甲基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、N,N,N’-三甲基乙二氨基、N,N-二甲基乙二氨基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基,所述4-甲基哌嗪-1-基羰基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基可以任选地被一个或多个独立地选自下组的取代基所取代:氟、氯、溴、甲基、乙基、异丙基、环丙基、甲氧基、甲氧基甲基、甲氧基乙基、甲基羰基、甲氧基羰基、氧代和二甲氨基;
弹头基团为:
X为O或S;
Z为N、O或CR
19;
R
19独立地为氢原子、甲基、乙基或环丙基;
m和n独立地为0、1、2、3或4;
p为0、1、2或3。
在一个更具体的具体实施方案中,式I所示的化合物选自下列的化合物:
另一方面,本申请提供包含上述化合物以及药学上可接受的载体或赋形剂的药物组合物;优选地,所述药物组合物为片剂、胶囊剂、丸剂、颗粒剂、散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、洗剂、滴剂、擦剂或喷雾剂。
再一方面,本申请提供包含上述化合物和/或药物组合物在制备抗肿瘤药物中的应 用。在某些实施方式中,所述抗肿瘤药物应用于以下病症:头颈部癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾细胞癌、乳腺癌、结肠直肠癌、卵巢癌、***、胰腺癌、胶质瘤、胶质母细胞瘤、***癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道基质瘤、甲状腺癌、胆管癌、子宫内膜癌、多发性骨髓瘤或间皮瘤。
在某些实施方式中,所述肿瘤为携带EGFR基因突变的恶性肿瘤;优选地,EGFR基因突变选自:Del19EGFR基因突变、L858R EGFR基因突变、T790M EGFR基因突变和C797S EGFR基因突变中的一种或多种。
又一方面,本申请提供一种治疗有需要的患者中肿瘤的方法,包括向所述患者给予治疗有效量的上述化合物或药物组合物,所述的患者优选哺乳动物,所述哺乳动物优选为人。
在某些实施方式中,给药方式包括口腔、粘膜、舌下、眼部、局部、肠道外、直肠、脑池、***、腹膜、膀胱、鼻部给药。
在某些实施方式中,所述肿瘤包括:头颈部癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾细胞癌、乳腺癌、结肠直肠癌、卵巢癌、***、胰腺癌、胶质瘤、胶质母细胞瘤、***癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道基质瘤、甲状腺癌、胆管癌、子宫内膜癌、多发性骨髓瘤或间皮瘤。
在某些实施方式中,本申请提供一种制备式I化合物的方法,该方法包括如下反应步骤:
(1)使化合物1与化合物2在碱性条件下反应,形成化合物3;
(2)使化合物3与化合物4发生Mitsunobu反应或亲核取代反应或偶联反应形成化合物5;
(3)将化合物5还原为化合物6;
(4)使化合物6与BrCN反应,形成化合物7;
(5)将化合物7水解为化合物8;
(6)使化合物8发生分子内缩合反应,形成化合物9;
(7)将化合物9脱保护基或者使化合物9先偶联或取代再脱保护基为化合物10;
(8)使化合物10与化合物11反应,形成式I所示化合物;
优选地,步骤(1)中碱性条件下使用的碱选自碳酸钾;
步骤(5)中水解使用的碱选自氢氧化锂。
在某些实施方式中,所述制备式I化合物的方法包括如下反应步骤:
(1)使化合物1与化合物2在碱性条件下反应,形成化合物3;
(2)将化合物3还原为化合物11;
(3)使化合物11与BrCN反应,形成化合物12;
(4)使化合物12与化合物13发生反应,形成化合物14;
(5)将化合物14关环形成化合物9;
(6)将化合物9脱保护基或者使化合物9先偶联或取代再脱保护基为化合物10;
(7)使化合物10与化合物11反应,形成式I所示化合物;
优选地,步骤(1)中碱性条件下使用的碱选自碳酸钾;
其中,当R
1为弹头基团时,R
22为氢原子、-Y
1(CR
aR
b)
qNHR
8、
R
20为带有保护基团的R
22、卤素、带保护基的氧基、带保护基的氨基等,R
18、R
19、R
21、R
23、R
24和R
25为R
6;当R
2为弹头基团时,R
23为-Y
1(CR
aR
b)
qNHR
8、
R
21为带有保护基团的R
23、卤素、带保护基的氧基、带保护基的氨基等,R
18、R
19、R
20、R
22、R
24和R
25为R
6;当R
4为弹头基团时,R
24为-Y
1(CR
aR
b)
qNHR
8、
R
18为带有保护基团的R
24、卤素、带保护基的氧基、带保护基的氨基等,R
19、R
20、R
21、R
22、R
23和R
25为R
6;或当R
5为弹头基团时,R
25为-Y
1(CR
aR
b)
qNHR
8、
R
19为带有保护基团的R
25、卤素、带保护基的氧基、带保护基的氨基等,R
18、R
20、R
21、R
22、R
23和R
24为R
6;
上述的带保护基的基团中,保护基团包括但不限于叔丁氧羰基、苄氧羰基、苄基或二甲氧基苄基;
L为羟基、卤素或离去基团;
此外,A、B、D、E、G、R
1、R
2、R
3、R
4、R
5、R
6、R
8、R
a、R
b、R
c、R
d、Y
1、Y
2、Y
3、Z、X、p、q、m、n、t、弹头基团如前述所定义;
本发明的其它特点和优势可见下面的详细叙述。以下实施例和具体实施方式旨在清楚说明本发明的技术方案及其技术效果和优势,并非限制本发明的范围。
作为EGFR激酶抑制剂的大环化合物的结构
本发明涉及式I化合物或者其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子、水合物或溶剂化物:
其中,
环A和环B各自独立地为6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、或包含1-4个独立地选自N,O和S 杂原子的5-10元单环杂环或二环杂环,所述的6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、或包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环可以任选地被一个或多个独立地选自以下的取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、被一个或多个R
m取代或未被取代的包含1-4个独立地选自N,O和S杂原子的5-10元杂芳基、被一个或多个R
m取代或未被取代的6-10元芳基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C
1-6烷基、-S(=O)
2R
a、-S(=O)
2NR
aR
b、-P(=O)R
aR
b、-P(=O)R
aNR
bR
c、-P(=S)R
aR
b、-P(=S)R
aNR
bR
c、R
bS(=O)
2N(R
a)-,其中所述C
1-6烷基、C
2-6烯基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C
1-6烷基、-S(=O)
2R
a、-S(=O)
2NR
aR
b、-P(=O)R
aR
b、-P(=O)R
aNR
bR
c、-P(=S)R
aR
b、-P(=S)R
aNR
bR
c、R
bS(=O)
2N(R
a)-可选择地和它们所连接的碳原子一起形成环,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基) -氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、被一个或多个R
m取代或未被取代的包含1-4个独立地选自N,O和S杂原子的5-10元杂芳基、被一个或多个R
m取代或未被取代的6-10元芳基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C
1-6烷基-可以任选地被一个或多个独立地选自以下的取代基所取代:卤素、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、4-7元杂环基和4-7元杂环基-C
1-6烷基;
环D为6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环、或C
5-7环烷;
R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6;当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、氨基、C
1-6烷基-氨基、C
3-6环烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷氧基-C
1-6烷基-氨基、4-6元杂环基-C
1-6烷基-氨基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基-氨基、氢原子、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、氰基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷氧基-羰基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基、C
1-6烷基-羰基-C
1-6烷基、C
1-6烷基-氨基酰基-C
1-6烷基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基-C
1-6烷基、C
1-6烷基-OC(O)-C
1-6烷基、或包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、C
1-6烷基-氨基、C
3-6环烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷氧基-C
1-6烷基-氨基、4-6元杂环基-C
1-6烷基-氨基、二(C
1-6 烷基)-氨基-C
1-6烷基-氨基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基-氨基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、氰基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
3-6环烷基-羰基、C
1-6烷氧基-羰基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基、C
1-6烷基-羰基-C
1-6烷基、C
1-6烷基-氨基酰基-C
1-6烷基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基-C
1-6烷基、C
1-6烷基-OC(O)-C
1-6烷基、或包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷基-O(O)C-、C
1-6烷基-羰基、氧代、卤素、羟基、C
1-6烷基氨基、二(C
1-6烷基)氨基、被1个或多个C
1-6烷基、C
1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;
或者,R
3与环D上除与R
3连接的原子之外的任意原子一起,或者,R
3和R
6与所连接的原子一起任选地形成由3-10个原子组成的杂环,所述杂环包含1-3个选自N,O或S杂原子并且杂环上可选地进一步被一个或多个选自C
1-6烷基、卤素、6-10元芳基、包含1-3个独立地选自N,O或S的杂原子的5-10元杂芳基、包含1-3个独立地选自N,O或S的杂原子的5-10元杂环基、卤代C
1-6烷基、羟基、氰基、卤素、C
1-6烷氧基、4-6元杂环基烷基、C
1-6烷基氨基和二(C
1-6烷基)氨基所取代;
Y
1、Y
2和Y
3各自独立地为化学键、O、NR
8、S、S(O)
2、CR
8R
16、羰基、-氨基-酰基、-酰基-氨基、-O(CO)-或-(CO)O-;
M为化学键、被一个或多个R
m取代或未被取代的-C
1-6烷基-、被一个或多个R
m取代或未被取代的-C
3-6环烷基-、被一个或多个R
m取代或未被取代的-C
3-6环烷基-C
1-6烷基-、被一个或多个R
m取代或未被取代的-C
1-6烷基-氨基-C
1-6烷基-、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的-4-7元杂环基-、被一个或多个R
m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的-4-7元杂环基-C
1-6烷基-;
R
8为氢原子、C
1-6烷基、C
3-6环烷基、或包含1-2个独立地选自N,O和S杂原子且任选的被氧代取代的5-7元杂环基;
R
9和R
10独立地为氢原子、卤素、氰基、C
1-6烷基、卤代C
1-6烷基、C
3-6环烷基、或杂环基烷基;
R
11为氢原子、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、氨基、C
1-6烷基氨基、二(C
1-6烷基)氨基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基,所述C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷基氨基、二(C
1-6烷基)氨基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基可以任选地被一个或多个独立地选自以下的基团所取代:卤素、羟基、氰基;
R
12和R
13各自独立地为氢原子、C
1-6烷基、C
3-7环烷基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基、或R
12和R
13与NR
12R
13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-10元杂环基,所述C
1-6烷基、C
3-7环烷基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基、或R
12和R
13与NR
12R
13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-10元杂环基可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、卤素、羟基、氰基、氧代、C
1-6烷基-氨基、卤代C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、被一个或多个R
m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C
1-6烷基-羰基;
R
14和R
15独立地为氢原子、C
1-6烷基、或R
14和R
15与所连接的碳原子一起形成C
3-6环烷基;
R
16为氢原子、C
1-6烷基、C
3-6环烷基、C
1-6烷氧基、或C
3-6环烷氧基;
R
a、R
b、R
c和R
d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基,所述的C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基。
或者R
a和R
b与所连接的碳原子一起形成环、R
c和R
d与所连接的碳原子一起形成环,所述的环为C
3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C
3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基。
环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环、或包含1-5个独立地选自N,O或S的杂原子5-10元桥环或螺环饱和或部分不饱和杂环,所述4-7元饱和或部分不饱和杂环和5-10元桥环或螺环饱和或部分不饱和杂环基可以任选独立地被一个或多个R
m所取代;
环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环、C
3-6环烷、6-10元单环芳环或二环芳环、或者包含1-5个独立地选自N,O或S的杂原子5-10元桥环或螺环饱和或部分不饱和杂环,所述4-7元饱和或部分不饱和杂环、C
3-6环烷、6-10元单环芳环或二环芳环、5-10元桥环或螺环饱和或部分不饱和杂环可以任选独立地被一个或多个R
m所取代;
R
m为C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6 环烷基-氨基-C
1-6烷基、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、氧代、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6酰基-氨基、C
1-6烷基-O(CO)-或C
3-6环烷基-O(CO)-;
q和t各自独立地为0、1、2或3;
w为1、2或3;
X为O、S、CR
17R
18、NR
17、CO或S(O)
2;
R
17为氢原子、C
1-6烷基、卤代C
1-6烷基、C
3-6环烷基、卤代C
3-6环烷基、C
1-6烷氧基-C
1-6烷基、卤代C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-羰基或C
1-6烷基-砜基;
R
18为氢原子、C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
1-6烷基-氨基-酰基、二(C
1-6烷基)-氨基-酰基、C
3-6环烷基-氨基-酰基、C
1-6烷基-酰基-氨基、C
1-6烷基-O(O)C-、C
1-6烷基-C(O)O-或C
1-6烷基-砜基;
Z为N、O、S、CO、S(O)
2、-氨基-酰基、-酰基-氨基、-O(CO)-、-(CO)O-、CR
19、C
3-7环烷基或3-7元杂环基,所述C
3-7环烷基和3-7元杂环基可以任选独立地被一个或多个R
18所取代;
R
19独立地为氢原子、C
1-6烷基或C
3-6环烷基;
m和n独立地为0、1、2、3或4;
p为0、1、2或3。
在某些实施方式中,环A和环B各自独立地为苯环、或包含1-2个独立地选自N,O和S杂原子的5-6元杂芳环,所述的苯环或5-6元杂芳环可以任选地被一个或多个独立地选自以下的取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨 基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基,所述的C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、氰基-C
1-6烷基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基可以任选地被一个或多个独立地选自以下取代基所取代:卤素、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
1-6烷基-氨基和4-7元杂环基;
优选地,在式I中,环A和环B各自独立地为苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑、异噻唑,所述的苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑和异噻唑可以任选地被一个或多个独立地选自以下取代基所取代:C
1-6烷基、C
2-6烯基、C
2-6炔基、卤代C
1-4烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、卤代C
3-6环烷基、C
3-6环烷氧基、卤代C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、氧代、卤素、羟基、氰基、氰基-C
1-6烷基、氨基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基和C
3-6环烷基-氨基。
在某些实施方式中,环D为苯环、包含1-3个独立地选自N,O和S杂原子的5-6元杂芳环、包含1-2个独立地选自N,O和S杂原子的5-7元杂环或环己环;
优选地,在式I中,环D为苯环、吡啶、嘧啶、吡嗪、哒嗪、哌啶、哌嗪、吡唑、咪唑或环己烷。
在某些实施方式中,R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6,当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、氢原子、卤素、羟基、氰基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基 -羰基、C
1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C
0-3烷基、C
1-6烷基、卤代C
1-6烷基、羟基-C
1-6烷基、羟基-C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷氧基-C
1-6烷基、二(C
1-6烷基)-氨基-C
1-6烷基-氨基-C
1-6烷基、C
1-6烷氧基、二(C
1-6烷基)-氨基-C
1-6烷氧基、C
1-6烷基-羰基、C
1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷基-O(O)C-、C
1-6烷基-羰基、氧代、卤素、羟基、C
1-6烷基氨基、二(C
1-6烷基)-氨基、可被1个或多个C
1-6烷基、C
1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;
Y
1、Y
2和Y
3各自独立地为化学键、O或NR
8;
R
8为氢原子、C
1-6烷基或C
3-6环烷基;
R
9和R
10独立地为氢原子、卤素或氰基;
R
12和R
13各自独立地为氢原子、C
1-6烷基、C
3-6环烷基、或R
12和R
13与NR
12R
13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-7元杂环,所述C
1-6烷基、C
3-6环烷基和形成的包含1-3个独立地选自N,O或S杂原子的4-7元杂环可以任选地被一个或多个独立地选自下组的取代基所取代:C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、卤素、羟基、氰基、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、被一个或多个R
m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C
1-6 烷基-羰基;
R
14和R
15独立地为氢原子、C
1-6烷基或R
14和R
15与所连接的碳原子一起形成C
3-6环烷基;
R
a、R
b、R
c和R
d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基,所述的C
1-6烷基、C
3-6环烷基、C
3-6环烷基-C
1-6烷基、C
1-6烷氧基、C
1-6烷氧基-C
1-6烷基、C
1-6烷基-氨基、C
1-6烷基-氨基-C
1-6烷基、二(C
1-6烷基)-氨基、二(C
1-6烷基)-氨基-C
1-6烷基、C
3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C
1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基;
或者R
a和R
b与所连接的碳原子一起形成环、R
c和R
d与所连接的碳原子一起形成环,所述的环为C
3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C
3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C
1-6烷基、C
3-6环烷基和C
1-6烷氧基;
环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R
m所取代;
环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、C
3-6环烷、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、C
3-6环烷、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R
m所取代;
R
m为C
1-6烷基、卤代C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、C
3-6环烷氧基、C
1-6烷氧基-C
1-6烷基、羟基-C
1-6烷基、氨基-C
1-6烷基、C
1-6烷基-氨基-C
1-6烷基、卤素、羟基、氰基、氨基、氧代、C
1-6烷基-氨基、二(C
1-6烷基)-氨基、C
3-6环烷基-氨基、C
1-6烷基-羰基、C
1-6烷基-OC(O)-或C
3-6环烷基-OC(O)-;
q和t各自独立地为0、1、2或3;
w为1、2或3;
优选地,在式I中,R
1、R
2、R
4和R
5其中1个为弹头基团,当R
1为弹头基团时,R
2、R
4和R
5各自独立地为R
6;当R
2为弹头基团时,R
1、R
4和R
5各自独立地为R
6;当R
4为弹头基团时,R
1、R
2和R
5各自独立地为R
6;或当R
5为弹头基团时,R
1、R
2和R
4各自独立地为R
6;
R
3和R
6各自独立地为氢原子、卤素、甲基、乙基、三氟甲基、甲氧基、异丙氧基、氰基、羟基、羟甲基、甲氧基甲基、乙氧基甲基、甲基羰基、甲氧基羰基、4-甲基哌嗪-1-基羰基、二甲氨基甲基、二甲氨基乙氧基、羟基乙氧基、二甲氨基乙氧基甲基、N,N,N’-三甲基乙二氨基甲基、N,N-二甲基乙二氨基甲基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、N,N,N’-三甲基乙二氨基、N,N-二甲基乙二氨基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基,所述4-甲基哌嗪-1-基羰基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基可以任选地被一个或多个独立地选自下组的取代基所取代:卤素、甲基、乙基、异丙基、环丙基、甲氧基、甲氧基甲基、甲氧基乙基、甲基羰基、甲氧基羰基、氧代和二甲氨基;
弹头基团为:
在某些实施方式中,X为O或S;
Z为N、O、S、-氨基-酰基、-酰基-氨基、或CR
19;
R
19独立地为氢原子、C
1-6烷基或C
3-6环烷基;
优选地,在式I中,Z为N、O或CR
19;
R
19独立地为氢原子、甲基、乙基、异丙基、环丙基或环丁基。
除非另外指出,阐明下列定义以举例说明和定义用于描述本发明的各种术语的含义和范围。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(C
a-b)烷基表示任何含“a”至“b”个碳原子的烷基。因此,例如,(C
1-6)烷基是指包含1至6个碳原子的烷基。所述的烷基是支链的或直链的。
本申请化合物中所述的原子包括其同位素,例如,氢可以是氘或氚。
“烷基”是指直链或带有支链的,单价的,饱和烃基,包括但不限于如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基以及其它类似基团。优选C
1-8烷基。更优选C
1-6烷基。更优选C
1-4烷基。
“环烷基”是指饱和的单环、联环、螺环、并环或桥环烷基,可能与其它基团组合。环烷基包括但不限于如环丙基、环丁基、环戊基、环己基、环庚基。优选C
3-8环烷基。更优选C
3-6环烷基。更优选C
3-4环烷基。
“烯基”指直链、带有支链或环状的含有一个或多个双键的烃基,包括但不限于乙烯基、丙烯基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基。优选C
2-6烯基。更优选C
2-4烯基。
“炔基”指直链、带有支链或环状的含有一个或多个三键的烃基,包括但不限于乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基。优选C
2-6炔基。更优选C
2-4炔基。
“烷氧基”是指与一氧原子键合的直链或带有支链的,单价的,饱和烷基,包括但不限于如甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、叔丁氧基以及其它类似基团。优选C
1-8烷氧基。更优选C
1-6烷氧基。更优选C
1-4烷氧基。
“卤素”是指氟,氯,溴或碘,优选氟,氯和溴。
“卤代烷基”是指本文定义的烷基,其中一个或多个氢已经被相同或不同卤素取代。包括但不限于如-CH
2Cl,-CHF
2,-CH
2CF
3,-CH
2CCl
3,全氟烷基(例如,-CF
3)等。
“芳基”是指取代或未取代的单环或多环芳香基团,包括但不限于如苯基、萘基。优选6-10元单环或双环芳香基团。更优选苯基或萘基。最优选苯基。
“杂环基”是指取代或未取代的3-10元非芳香族单环饱和环系,其中包含1-3个独立地选自N,O,或S杂原子,其余环原子是碳原子。杂环基部分的实例包括但不限于:氮杂环丁烷基、氧杂环丁烷基、吡咯烷基,哌啶基,哌嗪基,高哌嗪基,氧代哌啶基、氧代哌嗪基、氧代高哌嗪基、四氢呋喃基、咪唑啉基,***啉基,噁唑烷基,异噁唑烷基,噻唑烷基,异噻唑烷基,奎宁环基,噻二唑烷基,二氢呋喃基,四氢呋喃基,二氢吡喃基,四氢吡喃基,硫代吗啉基,硫代吗啉基亚砜,硫代吗啉基砜等。优选4-7元杂环基。更优选4-6元杂环基。
“杂芳基”是指取代或未取代的5元或6元单杂芳环系,或取代或未取代的9元或10元稠合或双杂芳环系,其中包含1-4个独立选自N,O,或S杂原子,其余环原子是碳原子。杂芳基部分的实例包括但不限于:噻吩基,呋喃基,咪唑基,异噁唑基,噁唑基,吡唑基,吡咯基,噻二唑基,***基,吡啶基,哒嗪基,嘧啶基,吲哚基,吲唑基,喹啉基,异喹啉基,苯并咪唑基或苯并噻唑基。
“桥环”是指任意两个环共用两个不直接连接的原子的多环基团,可以含有一个或多个双键,但是没有一个环具有完全共轭的π电子体系,环原子可以是全碳原子也可以其中一个或多个环原子选自N,O,S,SO或SO
2。优选为7-10环。
“螺环”是指任意两个环共用碳原子的多环基团,可以含有一个或多个双键,但是没有一个环具有完全共轭的π电子体系,环原子可以是全碳原子也可以其中一个或多个环原子选自N,O,S,SO或SO
2。优选为5-10环。
根据组成环的数目可以分为双环、三环、四环或多环基团,优选为双环、三环或四环,更优选为双环或三环。
一个环状基团可通过多种方式与另一基团键合。如果未明确键合方式,则表示包括所有可能的方式。例如,“吡啶基”包括2-、3-、或4-吡啶基,而“噻吩基”包括2-或3-噻吩基。
“药学上可接受的盐”指常规的酸加成盐或碱加成盐,其保留式I化合物的生物有效性 和性质,其由适宜的非毒性有机或无机酸或有机或无机碱形成。酸加成盐的例子包括衍生自无机酸和衍生自有机酸的那些盐,所述无机酸例如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、磷酸和硝酸。所述有机酸例如乙酸、丙酸、乙醇酸、草酸、硬脂酸、抗坏血酸、对甲苯磺酸、水杨酸、甲磺酸、乙磺酸、草酸、琥珀酸、柠檬酸、马来酸、羟基马来酸、乳酸、富马酸、酒石酸、苹果酸、羟乙基磺酸、苯磺酸、三氟乙酸、扁桃酸等。碱加成盐的例子包括衍生自无机酸和衍生自有机酸的那些盐,所述无机碱例如铵盐、钙盐、铁盐、铝盐、钠盐、钾盐、锌盐、镁盐。所述有机碱包括伯胺、仲胺和叔胺的盐,例如三甲胺、三乙胺、三丙胺、二乙醇胺、乙二胺、乙醇胺、等。将药用化合物(即药物)化学改性成盐是药剂师公知的技术,用以获得化合物的改善的物理和化学稳定性、吸湿性、流动性和溶解性。
“前药”指可以在体内转化为本发明所涉及的化合物及其药学可接受的盐的结构的前药。
作为EGFR激酶抑制剂的大环化合物的制备方法
本申请还涉及制备式I化合物的方法。本发明的化合物可以由任何常规手段制备。实施例中提供了合成这些化合物的合适的方法。在多步骤合成路线中,反应的次序在特定情况下是可以调整的。
在某些实施方式中,本申请提供了一种制备式I化合物的方法,该方法包括如下反应步骤:
(1)使化合物1与化合物2在碱性条件下反应,形成化合物3;
(2)使化合物3与化合物4发生Mitsunobu反应或亲核取代反应或偶联反应形成化合物5;
(3)将化合物5还原为化合物6;
(4)使化合物6与BrCN反应,形成化合物7;
(5)将化合物7水解为化合物8;
(6)使化合物8发生分子内缩合反应,形成化合物9;
(7)将化合物9脱保护基或者使化合物9先偶联或取代再脱保护基为化合物10;
(8)使化合物10与化合物11反应,形成式I所示化合物;
优选地,步骤(1)中碱性条件下使用的碱选自碳酸钾;
步骤(5)中水解使用的碱选自氢氧化锂。
在某些实施方式中,所述制备式I化合物的方法包括如下反应步骤:
(1)使化合物1与化合物2在碱性条件下反应,形成化合物3;
(2)将化合物3还原为化合物11;
(3)使化合物11与BrCN反应,形成化合物12;
(4)使化合物12与化合物13发生反应,形成化合物14;
(5)将化合物14关环形成化合物9;
(6)将化合物9脱保护基或者使化合物9先偶联或取代再脱保护基为化合物10;
(7)使化合物10与化合物11反应,形成式I所示化合物;
优选地,所述步骤(1)中碱性条件下使用的碱选自碳酸钾
其中,当R
1为弹头基团时,R
22为氢原子、-Y
1(CR
aR
b)
qNHR
8、
R
20为带有保护基团的R
22、卤素、带保护基的氧基、带保护基的氨基等,R
18、R
19、R
21、R
23、R
24和R
25为R
6;当R
2为弹头基团时,R
23为-Y
1(CR
aR
b)
qNHR
8、
R
21为带有保护基团的R
23、卤素、带保护基的氧基、带保护基的氨基等,R
18、R
19、R
20、R
22、R
24和R
25为R
6;当R
4为弹头基团时,R
24为-Y
1(CR
aR
b)
qNHR
8、
R
18为带有保护基团的R
24、卤素、带保护基的氧基、带保护基的氨基等,R
19、R
20、R
21、R
22、R
23和R
25为R
6;或当R
5为弹头基团时,R
25为-Y
1(CR
aR
b)
qNHR
8、
R
19为带有保护基团的R
25、卤素、带保护基的氧基、带保护基的氨基等,R
18、R
20、R
21、R
22、R
23和R
24为R
6;
上述的带保护基的基团中,保护基团包括但不限于叔丁氧羰基、苄氧羰基、苄基或二甲氧基苄基;
L为羟基、卤素或离去基团;
此外,A、B、D、E、G、R
1、R
2、R
3、R
4、R
5、R
6、R
8、R
a、R
b、R
c、R
d、Y
1、Y
2、Y
3、Z、X、p、q、m、n、t、弹头基团如前述所定义;
作为EGFR激酶抑制剂的大环化合物药物组合物
本发明还提供了包括所述作为EGFR激酶抑制剂的化合物以及药学上可接受的载体或赋形剂的药物组合物。
在此提到的术语“药物组合物”是指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与其他的化学成分,例如药学上可接受的载体、赋形剂或稀释剂混合。药物组合物的目的是促进给药给动物的过程。
“药学上可接受的载体”是指一种药学上可接受的物质,成分或者介质,比如液体或固体填充剂、稀释剂、赋形剂、溶剂或灌封材料,其参与将本发明涉及的化合物从某一位置,体液、组织、器官(内部或外部)、或身体部分装载或传递到另一位置,体液、器官(内部或外部)、或身体部分。药学上可接受的载体可以是介质、稀释剂、赋形剂或者其它没有过度毒性或者副作用并能用于接触动物组织的材料。典型的药学上可接受的载体包括糖类、淀粉、纤维素类、麦芽糖、黄蓍胶、明胶、林格氏溶液、海藻酸、生理盐水、缓冲剂等。
每种药学上可接受的载体应该与其它组成成分相容,例如与本发明中提供的化合物形成制剂,对生物活体组织或者器官没有过度毒性、刺激、过敏性反应、免疫原性或其它问题或并发症,且有较合理的效益风险比。
一些药学上可接受的载体的物质包括:(1)糖类,比如乳糖、葡萄糖和蔗糖;(2)淀粉,比如玉米淀粉和马铃薯淀粉;(3)纤维素和其衍生物,比如羧甲基纤维素钠、乙基纤维素、醋酸纤维素;(4)西黄蓍胶粉;(5)麦芽糖;(6)明胶;(7)滑石粉;(8)赋形剂,比如可可脂和栓剂蜡;(9)油类,比如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇类,比如丙二醇;(11)多元醇类,比如甘油、山梨醇、甘露醇和聚乙二醇;(12)脂类,比如油酸乙酯、月桂酸乙酯;(13)琼脂胶;(14)缓冲剂,比如氢氧化镁和氢氧化铝;(15)海藻酸;(16)灭菌无热原水;(17)生理盐水;(18)林格氏溶液;(19)醇类,比如乙醇和丙醇;(20)磷酸缓冲液;(21)其它在药物剂型中无毒性可相容的物质,比如丙酮。
药物组合物可能包括药学上可接受的辅料,以模拟生理条件,比如pH调节和缓冲剂、毒性调节剂等等,如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
药物成分可制成任何合适的剂型,如固体剂型(例如片剂、胶囊、粉末、颗粒等)和液体剂型(例如水溶液、乳浊液、酏剂、糖浆等)。药物组合物的制备方法工艺已众所周知,可根据常规工艺进行制备,比如在Remington,The Science and Practice of Pharmacy(Gennaro ed.20th edition,Williams&Wilkins PA,USA)(2000)中提供。
在某些实施方式中,本发明中提供的化合物或药物组合物可以被制成适于药物释放的剂型,通过注射途径给药(如皮下、静脉、肌肉、动脉、鞘膜、囊内、框内、心脏内、真皮内、腹膜内、经气管、表皮、关节内、囊下、蛛网膜下、脊柱内、胸骨内、和/或输液)和非注射途径给药(如口服、肠道、口腔、鼻、鼻内、粘膜、表皮、贴膏剂、真皮、眼药、肺部、舌下、直肠、***或表皮局部给药)。
合适的剂型包括(但不局限于)注射用途的剂型比如乳状液、溶液和混悬液,口服用途的剂型如片剂、胶囊、丸剂、糖衣丸、粉末和颗粒,局部用药或经皮肤吸收的剂型如喷剂、软膏、糊剂、乳霜、洗剂、凝胶、溶液、药物贴片和吸入剂,***或直肠给药的剂型如栓剂。这些剂型可根据化合物以及合适的赋形剂在合适条件下制备,制备方法及工艺众所周知,比如由Remington:在The Science and Practice of Pharmacy(Gennaro ed. 20th edition,Williams&Wilkins PA,USA)(2000)提供。
在某些实施方式中,本申请提供了包含上述化合物以及药学上可接受的载体或赋形剂的药物组合物。在某些实施方式中,药物组合物为片剂、胶囊剂、丸剂、颗粒剂、散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、洗剂、滴剂、擦剂、喷雾剂
作为EGFR激酶抑制剂的大环化合物药物组合物的应用
本发明的另一个方面提供了上述化合物和/或药物组合物在制备药物以及治疗疾病中的应用。
在某些实施方式中,本发明提供了上述化合物和/或药物组合物在制备抗肿瘤的药物中的应用。
在某些实施方式中,本申请提供了包含上述化合物和/或药物组合物在制备抗肿瘤药物中的应用。在某些实施方式中,所述抗肿瘤药物应用于以下病症:头颈部癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾细胞癌、乳腺癌、结肠直肠癌、卵巢癌、***、胰腺癌、胶质瘤、胶质母细胞瘤、***癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道基质瘤、甲状腺癌、胆管癌、子宫内膜癌、多发性骨髓瘤或间皮瘤。
在某些实施方式中,本申请提供了一种治疗有需要的患者中肿瘤的方法,包括向所述患者给予有效量的上述化合物或药物组合物,所述患者优选哺乳动物,所述哺乳动物优选人。在某些实施方式中,给药方式包括口腔、粘膜、舌下、眼部、局部、肠道外、直肠、脑池、***、腹膜、膀胱、鼻部给药。
本发明涉及的化合物或药物组合物可通过任何合适的途径进入生物体内,比如通过口服、静脉注射、鼻内、外用、肌注、真皮内注射、经皮给药或皮下途径。在某些实施方式中,本发明涉及的化合物或药物组合物的给药方式包括口腔、粘膜、舌下、眼部、局部、肠道外、直肠、脑池、***、腹膜、膀胱、鼻部给药。
在某些实施方式中,本发明涉及的化合物或药物组合物可以与第二活性物质同时进行施用,这样能在生物体内达到叠加甚至协同的作用。例如,本发明涉及的化合物可以和第二活性物质组合成一个药物组合物,或者以单独的组合物同时施用,或者以单独的组合物依次施用。能与本发明化合物同时施用、用于治疗癌症的第二活性物质包括但不局限于:氟尿嘧啶、阿霉素、柔红霉素、它莫西芬、亮丙瑞林、戈舍瑞林、氟他米特、 尼鲁米特、非那雄胺、***、氨鲁米特、安吖啶、阿那曲唑、天冬酰胺酶、卡介苗、比卡鲁胺、博来霉素、白消安、喜树碱、卡培他滨、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、克拉屈滨、秋水仙碱、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素d、正定霉素、双烯雌酚、己烯雌酚、多西紫杉醇、阿霉素、亚德里亚霉素、表柔比星、***、雌氮芥、依托泊苷、依西美坦、非格司亭、氟达拉滨、氟氢可的松、氟尿嘧啶、氟***、氟他米特、吉西他滨、染料木黄酮、戈舍瑞林、三苯氧胺、替尼泊苷、睾酮、二氯化二茂钛、拓普泰康、曲妥单抗、维甲酸、长春花碱、羟基脲、伊达比星、异环磷酰胺、伊马替尼、干扰素、伊立替康、来曲唑、甲酰四氢叶酸、喷司他丁、光神霉素、甲基苄肼、雷替曲塞、卟菲尔钠、利妥昔、链脲菌素、苏拉明、亮丙瑞林、左旋咪唑、环己亚硝脲、氮芥、甲羟孕酮、甲地孕酮、美法仑、巯嘌呤、巯乙磺酸钠、甲氨蝶呤、丝裂霉素、米托坦、米托蒽醌、尼鲁米特、诺考达唑、奥曲肽、紫杉醇、帕米磷酸、硫鸟嘌呤、三胺硫磷、氯甲烷、拓扑替康二茂钛、曲妥单抗、维甲酸、长春花碱、长春新碱、长春地辛、长春瑞斌。
在某些实施方式中,本发明提供的化合物可与非化学方法同时使用进行癌症治疗。在某些实施方式中,本发明提供的化合物可与放射疗法同时进行。在某些实施方式中,本发明提供的化合物可与外科手术,肿瘤热治疗,超声聚焦疗法,冷冻疗法或以上几种疗法结合使用。
在某些实施方式中,本发明提供的化合物可与类固醇同时使用。合适的类固醇包括但不局限于:安西缩松、倍氯米松、倍他米松、布***、氯***、氯倍他索、皮质甾酮、可的松、羟泼尼缩松、去羟米松、***、双氟拉松、双氟米松、二氟孕甾丁酯、甘草次酸、氟扎可松、氟米松、氟尼缩松、氟氯奈德、肤轻松醋酸酯、氟轻松醋酸酯、氟可丁丁酯、氟可龙、丙酮缩氟氢羟龙、醋酸氟培龙、醋酸氟泼尼定、氟泼尼龙、氟氢缩松、丙酸氟、醛基缩松、丙酸氯倍他索、哈西缩松、卤米松、氢化可的松、氯替泼诺碳酸乙酯、甲哌地强龙、甲羟松、甲***、6-甲氢化***、在任糠酸盐、帕拉米松、***龙、***、和25-二乙胺醋强的松龙。
在某些实施方式中,本发明提供的化合物可与免疫治疗剂同时使用。合适的免疫治疗剂包括:肿瘤细胞多药耐药性逆转剂(比如维拉帕米)、雷帕霉素、霉酚酸酯、沙利度胺、环磷酰胺、环孢霉素、和单克隆抗体类。
实施发明的最佳方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。
实施例1.(2-氨基乙基)(2-羟基乙基)氨基甲酸叔丁酯的合成
第一步:2,2,2-三氟-N-(2-((2-羟基乙基)氨基)乙基)乙酰胺
0℃下,往100mL圆底烧瓶中依次加入2-(2-氨基乙胺)乙醇(10.0g,96.0mmol),干燥的***(30mL)和三氟乙酸乙酯(13.6g,96.0mmol),所得的混合液在室温下搅拌2h,有白色沉淀物形成。过滤,滤饼使用***洗涤2次(20mL×2),干燥得2,2,2-三氟-N-(2-((2-羟基乙基)氨基)乙基)乙酰胺(14.6g,白色固体),产率:74.9%。
第二步:(2-羟乙基)(2-(2,2,2-三氟乙酰氨基)乙基)氨基甲酸叔丁酯
室温下,往干燥的500mL圆底烧瓶中依次加入2,2,2-三氟-N-(2-((2-羟基乙基)氨基)乙基)乙酰胺(13.4g,0.066mol),四氢呋喃(200mL)和Boc
2O(14.5g,0.066mol),混合液在室温下搅拌6h。反应完毕后,减压浓缩,加入水(100mL),用乙酸乙酯萃取(150mL×3),合并有机相,用饱和食盐水洗涤(100mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品(2-羟乙基)(2-(2,2,2-三氟乙酰氨基)乙基)氨基甲酸叔丁酯(20.4g,无色油状物),产率:100.0%。
MS(ESI
+)m/z=323.9[M+Na]
+.
第三步:(2-氨基乙基)(2-羟基乙基)氨基甲酸叔丁酯
室温下,往500mL圆底烧瓶中依次加入(2-羟乙基)(2-(2,2,2-三氟乙酰氨基)乙基)氨基甲酸叔丁酯(20.4g,0.0677mol),甲醇(50mL),水(10mL)和碳酸钾(5.0g),升温至60℃搅拌48h。反应完毕后,减压浓缩,除去甲醇,往剩余物中加入水(30mL),用乙酸乙酯萃取(50mL×2),舍弃乙酸乙酯相,水相减压浓缩,得到粗品(2-氨基乙基)(2-羟基乙基)氨基甲酸叔丁酯(15.8g,无色油状物)。产率:91.4%。
MS(ESI
+)m/z=205.2[M+H]
+.
实施例2. 5-氨基-4-甲基戊烷-1-醇的合成
第一步:(2,6-二甲基庚-5-烯-1-基)氨基甲酸叔戊酯
将3,7-二甲基辛-6-烯酸(3.5g,20.56mmol)溶于甲苯(300mL)中,升温至50℃,加入三乙胺(2.5g,24.67mmol),然后缓慢加入叠氮磷酸二苯酯(5.65g,20.56mmol),升温至70℃并搅拌12h,加入2-甲基丁烷-2-醇(3.6g,41.16mmol),升温至110℃并搅拌2h后,再加入2-甲基丁烷-2-醇(3.6g,41.16mmol)。反应混合液在110℃下搅拌12h。减压浓缩,往所得剩余物中加入水(100mL),用乙酸乙酯(200mL×3)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=6/1~5/1纯化得到(2,6-二甲基庚-5-烯-1-基)氨基甲酸叔戊酯(2.5g,无色油状物),产率:41.5%。
第二步:(5-羟基-2-甲基戊基)氨基甲酸叔戊酯
室温下,在干燥的100mL圆底烧瓶中依次加入(2,6-二甲基庚-5-烯-1-基)氨基甲酸叔戊酯(2.5g,10.11mmol)和甲醇(20mL),降温至-78℃,缓慢通入臭氧至反应体系变为天 蓝色为止,继续搅拌20min至无色。降温至0℃,缓慢加入硼氢化钠(0.95g,25.1mmol),加毕,缓慢升温至室温并搅拌12h。减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=5/1~1/1纯化得到(5-羟基-2-甲基戊基)氨基甲酸叔戊酯(450mg,无色油状物),产率:27.9%。
第三步:5-氨基-4-甲基戊烷-1-醇
室温下,在干燥的100mL圆底烧瓶中依次加入(5-羟基-2-甲基戊基)氨基甲酸叔戊酯(450mg,1.95mmol)和4M盐酸的二氧六环溶液(10mL),室温搅拌2h,减压浓缩得到粗品5-氨基-4-甲基戊烷-1-醇(600mg,无色油状物)。
实施例3.(R)-1-((叔丁氧羰基)氨基)丙烷-2-基4-甲苯磺酸盐的合成
第一步:(R)-(2-羟丙基)氨基甲酸叔丁酯
室温下,在100mL圆底烧瓶中依次加入(R)-1-氨基丙烷-2-醇(1.5g,0.02mol)和DCM(20mL),降温至0℃,缓慢加入Boc
2O(4.8g,0.022mol)和三乙胺(4.0g,0.04mol),升温至室温搅拌2h。加入水(20mL),用二氯甲烷萃取(20mL×3),合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=5/1纯化得到(R)-(2-羟丙基)氨基甲酸叔丁酯(2.4g,白色固体),产率:68.6%。
第二步:(R)-1-((叔丁氧羰基)氨基)丙烷-2-基4-甲苯磺酸盐
室温下,在100mL圆底烧瓶中依次加入叔丁基(R)-(2-羟丙基)氨基甲酸酯(900mg,5.1mmol)和吡啶(5mL),降温至0℃,缓慢加入对甲苯磺酰氯(1.07g,5.6mmol),升温至室温搅拌4-5h。减压浓缩,所得剩余物使用薄层层析法以洗脱剂体系石油醚/乙酸乙酯=10/1纯化得到(R)-1-((叔丁氧羰基)氨基)丙烷-2-基4-甲苯磺酸盐(640mg,白色固体),产率:38.1%。
实施例4-16.对甲苯磺酸盐化合物的合成
以市售Boc保护或不保护的氨基(环)烷基醇或杂环基(烷基)醇为原料,按照合成(R)-1-((叔丁氧羰基)氨基)丙烷-2-基4-甲苯磺酸盐(实施例3)方法制备以下对甲苯磺酸盐化合物。
表1对甲苯磺酸盐化合物
实施例17. 2-((叔丁氧羰基)氨基)乙基-1,1-二氘4-甲苯磺酸盐的合成
第一步:叔丁基(2-羟乙基-2,2-二氘)氨基甲酸酯
室温下,在250mL圆底烧瓶中加入THF(50mL),降温至0℃分批加入氘代四氢铝锂(1.66g,39.6mmol),然后分批加入(叔丁氧羰基)甘氨酸甲酯(5g,26.4mmol),室温搅拌过夜。反应完毕后,加十水合硫酸钠(1.7g)淬灭,过滤,滤液旋干得到粗品叔丁基(2-羟乙基-2,2-二氘)氨基甲酸酯(3.6g,黄色油状物),产率:83.7%。
第二步:2-((叔丁氧羰基)氨基)乙基-1,1-二氘4-甲苯磺酸盐
在100mL圆底烧瓶中加入叔丁基(2-羟乙基-2,2-二氘)氨基甲酸酯(2.5g,15.3mmol)和二氯甲烷(25mL),然后加入对甲苯磺酰氯(4.4g,23.0mmol)和三乙胺(3.1g,30.6mmol),室温搅拌过夜。反应完毕后,缓慢倒入水中,用二氯甲烷萃取(50mL×3),合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品2-((叔丁氧羰基)氨基)乙基-1,1-二氘4-甲苯磺酸盐(3.5g,黄色固体),产率:72.0%。
MS(ESI
+)m/z=218.0[M-100+H]
+.
实施例18. 2-((叔丁氧羰基)(甲基)氨基)乙基4-甲苯磺酸盐的合成
室温下,100mL圆底烧瓶中依次加入(2-羟乙基)(甲基)氨基甲酸叔丁酯(2.5g,15.3mmol)和二氯甲烷(25mL),然后加入对甲苯磺酰氯(4.4g,23.0mmol)和三乙胺(3.1g,30.6mmol),室温搅拌过夜。反应完毕后,倒入水中淬灭,用二氯甲烷萃取(50mL×3),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品2-((叔丁氧羰基)(甲基)氨基)乙基4-甲苯磺酸盐(3.5g,黄色固体),产率:72.0%。
实施例19.N
6-((苄氧基)羰基)-N
2-(叔丁氧基羰基)赖氨酸的合成
在50mL干燥的圆底烧瓶中依次加入(叔丁氧基羰基)赖氨酸(2g,8.13mmol),THF(20mL)和碳酸钠(1.7g,16.26mmol),0℃下滴加CbzCl(1.66g,9.72mmol),室温搅拌过夜。反应完毕后,加水(20mL)稀释,用乙酸乙酯洗涤(20mL×1),水相用2M HCl调节pH=2,用乙酸乙酯(20mL×6)萃取,合并有机相,用饱和食盐水洗一次,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品N
6-((苄氧基)羰基)-N
2-(叔丁氧基羰基)赖氨酸(1.8g,黄色油状),产率:66.7%。
实施例20. 2-甲酰氮杂环丁烷-1-羧酸叔丁酯的合成
在100mL三口圆底烧瓶中加入1-(叔丁基)2-甲基氮杂环丁烷-1,2-二甲酸酯(500mg,2.32mmol)和二氯甲烷(10mL),氮气保护下,-78℃下滴加二异丁基氢化铝(4.65mL,4.65mmol),滴加完毕在-78℃搅拌2h。反应完毕后,加入水(15mL),用二氯甲烷萃取(5mL×3),合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到2-甲酰氮杂环丁烷-1-羧酸叔丁酯(300mg,黄色液体),产率:69.8%。
实施例21. 2-(3-溴丙基)环氧乙烷的合成
冰水浴下,在250mL圆底烧瓶中依次加入5-溴戊烯(10.0g,67.1mmol)和二氯甲烷(200mL),然后分批加入间氯过氧苯甲酸(23.2g,134.2mmol),加毕,室温搅拌16h。反应完毕后,分批加入亚硫酸氢钠(20g)淬灭反应,所得混合液用二氯甲烷萃取(50mL×5),合并有机相,用无水硫酸钠干燥,过滤,滤液浓缩,得到粗品2-(3-溴丙基)环氧乙烷(7.0g,无色透明液体),产率:56.9%。
实施例22. 4-(二甲氧基甲基)-2-氟硝基苯的合成
室温下,将3-氟-4-硝基苯甲醛(8.5g,0.05mol)和原甲酸三甲酯(8.0g,0.075mol)加入 甲醇(100mL)中,然后加入对甲苯磺酸(50mg),升温至70℃并搅拌18h。反应混合液减压浓缩除去甲醇,向所得剩余物中加入水(50mL),用乙酸乙酯(100mL×3)萃取,合并乙酸乙酯相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品4-(二甲氧基甲基)-2-氟-1-硝基苯(10.0g,黑色油状物),产率:83.1%。
实施例23. 4-(苄氧基)-2-氟-1-硝基苯的合成
室温下,在250mL圆底烧瓶中依次加入3-氟-4-硝基苯酚(5.0g,31.8mmol),乙腈(150mL),K
2CO
3(13.2g,95.4mmol)和溴苄(5.98g,35.0mmol),加热至回流搅拌2h。反应完毕后,减压浓缩,剩余物用硅胶柱色谱法以洗脱剂体系乙酸乙酯/石油醚=1/4纯化得到4-(苄氧基)-2-氟-1-硝基苯(6.5g,黄色固体),产率:78.9%。
MS(ESI
+)m/z=248.0[M+H]
+.
实施例24. 3-(苄氧基)-2-氟-1-硝基苯的合成
以2-氟-3-硝基苯酚为原料,按照合成4-(苄氧基)-2-氟-1-硝基苯(实施例23)的方法合成3-(苄氧基)-2-氟-1-硝基苯。
实施例25.(2-氟-3-硝基苄基)(甲基)氨基甲酸叔丁基酯的合成
第一步:1-(2-氟-3-硝基苯基)-N-甲基甲胺
室温下,往250mL圆底烧瓶中依次加入2-氟-3-硝基苯甲醛(1.5g,8.87mmol),甲醇(50mL),醋酸(2mL)和甲胺(0.330g,10.64mmol),室温下搅拌1-2h,然后缓慢加入氰基硼氢化钠(1.12g,17.74mmol),加毕,在室温下搅拌16h。减压浓缩,除去溶剂甲醇,所 得剩余物中加入水(50mL),用乙酸乙酯萃取(50mL×3),舍弃乙酸乙酯相,剩余水相,减压浓缩,得到粗品1-(2-氟-3-硝基苯基)-N-甲基甲胺(3.0g,黄色油状物)。
MS(ESI
+)m/z=185.1[M+H]
+.
第二步:(2-氟-3-硝基苄基)(甲基)氨基甲酸叔丁基酯
室温下,往干燥的500mL圆底烧瓶中依次加入1-(2-氟-3-硝基苯基)-N-甲基甲胺(3.0g,16.3mmol),二氯甲烷(100mL),DIPEA(4.2g,32.58mmol)和Boc
2O(4.26g,16.55mmol),室温下搅拌3-4h。反应完毕后,减压浓缩,剩余物中加入水(100mL),用二氯甲烷萃取(100mL×3),合并有机相,用饱和食盐水洗涤(100mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩所得粗品(2-氟-3-硝基苄基)(甲基)氨基甲酸叔丁基酯(4g,黄色油状物),产率:82.9%。
实施例26.(2-氟-3-硝基苯乙基)氨基甲酸叔丁基酯的合成
第一步:(Z)-2-氟-1-硝基-3-(2-硝基乙烯基)苯
将2-氟-3-硝基苯甲醛(3.0g,17.7mmol)加入乙酸(20mL)中,然后依次加入硝基甲烷(1.3g,21.3mmol)和乙酸铵(0.82g,10.6mmol),升温至120℃搅拌4-5h,反应完毕后,减压浓缩,向剩余物中加入水(50mL),用乙酸乙酯萃取(100mL×3),合并有机相,用饱和食盐水洗涤(100mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系乙酸乙酯/石油醚=1/5纯化得到(Z)-2-氟-1-硝基-3-(2-硝基乙烯基)苯(1.8g,黄色固体),产率:43.1%。
第二步:2-(2-氟-3-硝基苯基)乙烷-1-胺
0℃下,将三氟化硼***(15mL)滴加到硼氢化钠(2.2g,57.7mmol)的干燥四氢呋喃(50mL)悬液中,室温下搅拌0.25h,然后缓慢滴加(Z)-2-氟-1-硝基-3-(2-硝基乙烯基)苯(1.8g,8.5mmol)的四氢呋喃(20mL)溶液,回流下搅拌6.5h,冷却到室温,反应混合液缓慢加入冰水(30mL),用二氯甲烷(20mL)萃取,舍弃有机相,水相用饱和碳酸氢钠溶液调节pH=7~8,然后用二氯甲烷(20mL×3)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品2-(2-氟-3-硝基苯基)乙烷-1-胺(3.0g,黄色固体)。
MS(ESI
+)m/z=185.1[M+H]
+.
第三步:(2-氟-3-硝基苯乙基)氨基甲酸叔丁基酯
室温下,在500mL圆底烧瓶中依次加入2-(2-氟-3-硝基苯基)乙烷-1-胺(3.0g,16.3mmol),二氯甲烷(100mL),Boc
2O(4.3g,19.5mmol)和三乙胺(3.3g,32.6mmol),室温下搅拌12h。反应完毕后,减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系乙酸乙酯/石油醚=1/5纯化得到(2-氟-3-硝基苯乙基)氨基甲酸叔丁基酯(1.3g,黄色油状物),收率:26.6%。
MS(ESI
+)m/z=307.1[M+Na]
+.
实施例27.(3-(2-氟-3-硝基苯基)丙-2-炔-1-基)氨基甲酸叔丁酯的合成
氮气保护下,室温下,往250mL圆底烧瓶中依次加入1-溴-2-氟-3-硝基苯(5.0g,0.03mol),1,4-二氧六环(50mL),丙-2-炔-1-基氨基甲酸叔丁酯(4.23g,0.03mol),N,N-二异丙基乙胺(3.4g,0.03mol),碘化亚铜(0.04g,0.2mmol),双三苯基磷二氯化钯(0.64g,0.9mol)和三叔丁基膦(0.15g,1.3mol),升温至45℃并搅拌15h。反应完毕后,使用硅藻土过滤,滤液加入乙酸乙酯(60mL),用水(20mL×3)和饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=10/1纯化得到(3-(2-氟-3-硝基苯基)丙-2-炔-1-基)氨基甲酸叔丁酯(3.4g,黄色油状物),产率:45.4%。
实施例28. 2-((叔丁氧羰基)氨基)-6-(2-羟基苯基)异烟酸甲酯的合成
第一步:2-氯-6-(2-羟基苯基)异烟酸甲酯
氮气保护下,室温往250mL圆底烧瓶中依次加入2,6-二氯异烟酸甲酯(14.0g,0.068mol),乙二醇二甲醚(140mL),水(30mL),2-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)苯酚(16.5g,0.0748mol),碳酸铯(33.2g,0.102mol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.5g,0.002mmol),升温至90℃并搅拌16h。减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=20/1纯化得到2-氯-6-(2-羟基苯基)异烟酸甲酯(10.0g,黄色固体),产率:50.2%。
MS(ESI
+)m/z=263.7[M+H]
+.
第二步:2-((叔丁氧羰基)氨基)-6-(2-羟基苯基)异烟酸甲酯
氮气保护下,室温往250mL圆底烧瓶中依次加入2-氯-6-(2-羟基苯基)异烟酸甲酯(10g,0.03mol),二氧六环(100mL),BocNH
2(5.32g,0.04mol),碳酸铯(24.0g,0.07mmol),Xphos(3.6g,0.0075mol)和双(二亚芐基丙酮)钯(13.3mg,0.02mmol),升温至85℃搅拌16h。反应完毕后,减压浓缩,用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=20/1纯化得到2-((叔丁氧羰基)氨基)-6-(2-羟基苯基)异烟酸甲酯(5.6g,黄色固体),产率:42.8%。
MS(ESI
+)m/z=344.7[M+H]
+.
实施例29. 2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯的合成
氮气保护下,室温将2-氯-6-甲基异烟酸甲酯(20.0g,0.11mol)加入苯甲醚(200mL),然后加入1-甲基-5-羟基吡唑(21.2g,0.2156mol),碳酸钠(29.4g,0.237mol)和PdCl
2(dppf)(2.36g,0.003mol)。升温至130℃并搅拌16h,减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇=50/1~30/1纯化得到2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(16.5g,***固体),产率:55.7%。
MS(ESI
+)m/z=248.2[M+H]
+.
实施例30. 2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酸的合成
第一步:2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酸甲酯
室温下,在50mL圆底烧瓶中将2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(2.7g,10.9mmol)溶于乙腈(30mL),依次加入K
2CO
3(2.41g,17.44mmol)和SEMCl(2.91g,17.44mmol),室温搅拌5h。反应完毕后,将反应混合液倒入水中(20mL),用乙酸乙酯萃取(30mL×3),合并有机相,用食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系乙酸乙酯/石油醚=1/10~1/5纯化得到2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酸甲酯(2.4g,黄色油状物),产率:55.1%。
MS(ESI
+)m/z=377.9[M+H]
+.
第二步:2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酸
室温下,在干燥的100mL圆底烧瓶中依次加入2-甲基-6-(1-甲基-5-((2-(三甲基硅基) 乙氧基)甲氧基)-1H-吡唑-4-基)异烟酸甲酯(2.4g,6.4mmol),THF(10mL)和1M LiOH水溶液(20mL),室温下搅拌5h。反应完毕后,减压除掉有机相,剩余物用0.5M稀盐酸调节pH=3-4,抽滤,滤饼干燥得到2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酸(1.79g,淡黄色固体),产率:73.4%。
MS(ESI
+)m/z=363.9[M+H]
+.
实施例31. 1
1,2
6-二甲基-3-氧代-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-8-甲酸叔丁酯的合成(中间体A1)
第一步:(2-羟乙基)(2-((2-硝基苯基)氨基)乙基)氨基甲酸叔丁酯
室温下,往250mL圆底烧瓶中依次加入(2-氨基乙基)(2-羟基乙基)氨基甲酸叔丁酯(5.79g,0.028mol),DMF(50mL),2-氟硝基苯(4.0g,0.028mol)和DIPEA(7.3g,0.056mol),室温下搅拌16h。反应完毕后,加入水(150mL),用乙酸乙酯萃取(100mL×3),合并有机相,用饱和食盐水洗涤(50mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系乙酸乙酯/石油醚=1/5纯化得到(2-羟乙基)(2-((2-硝基苯基)氨基)乙基)氨基甲酸叔丁酯(8.0g,黄色油状物),产率:99.0%。
MS(ESI
+)m/z=348.2[M+Na]
+.
第二步:2-(5-(2-((叔丁氧羰基)(2-((2-硝基苯基)氨基)乙基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯
冰水浴下,往250mL圆底烧瓶中依次加入(2-羟乙基)(2-((2-硝基苯基)氨基)乙基)氨基甲酸叔丁酯(3.25g,0.01mol),无水四氢呋喃(150mL),2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(2.47g,0.01mol),三苯基膦(3.14g,0.012mol)和偶氮二甲酸二异丙酯(2.4g,0.012mol),升温至室温搅拌4h。反应完毕后,减压浓缩,用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇=20/1纯化得到2-(5-(2-((叔丁氧羰基)(2-((2-硝基苯基)氨基)乙基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(6.5g,黄色油状物),产率:70.0%。
MS(ESI
+)m/z=555.1[M+H]
+.
第三步:2-(5-(2-((2-氨基苯基)氨基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯
室温下,往250mL圆底烧瓶中依次加入2-(5-(2-((叔丁氧羰基)(2-((2-硝基苯基)氨基)乙基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(4.0g,7.2mmol),甲醇(100mL)和钯碳(0.4g,10%),用氢气置换气体3次,室温下搅拌12h。反应完毕后,使用硅藻土过滤,滤液减压浓缩,得到2-(5-(2-((2-氨基苯基)氨基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(5.0g,红色油状物),产率:88.3%。
MS(ESI
+)m/z=525.2[M+H]
+.
第四步:2-(5-(2-((2-(2-氨基-1H-苯并咪唑-1-基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯
室温下,往250mL圆底烧瓶中依次加入2-(5-(2-((2-氨基苯基)氨基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(5.0g,9.5mmol),甲醇(50mL),水(50mL)和溴化氰(1.5g,14.0mmol),升温至70℃搅拌4-5h。反应完毕后,减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇=15/1纯化得到2-(5-(2-((2-(2-氨基-1H-苯并咪唑-1-基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(2.7g,棕色固体),产率:51.5%。
MS(ESI
+)m/z=549.9[M+H]
+.
第五步:2-(5-(2-((2-(2-氨基-1H-苯并咪唑-1-基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸
室温下,往250mL圆底烧瓶中依次加入2-(5-(2-((2-(2-氨基-1H-苯并咪唑-1-基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(1.7g,0.0031mol),四氢呋喃(50mL),水(20mL)和氢氧化锂一水合物(0.25g,0.006mol)。室温搅拌4-5h。反应完毕后,减压除去四氢呋喃,所得剩余物加入水(10mL),并使用1M的盐酸调节pH=6-7,用乙酸乙酯萃取(50mL×5),合并有机相,用饱和食盐水洗涤(50mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品2-(5-(2-((2-(2-氨基-1H-苯并咪唑-1-基)乙基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸(1.0g,棕色固体),产率:54.4%。
MS(ESI
+)m/z=535.9[M+H]
+.
第六步:1
1,2
6-二甲基-3-氧代-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-8-羧酸叔丁酯
室温下,往100mL圆底烧瓶中依次加入2-(5-(2-((2-(2-氨基-1H-苯并咪唑-1-基)乙 基)(叔丁氧羰基)氨基)乙氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸(500mg,0.93mmol),二氯甲烷(15mL),DIPEA(240mg,1.86mmol)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(388mg,1.02mmol),混合液室温搅拌1-2h。反应完毕后,减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇=15/1纯化得到1
1,2
6-二甲基-3-氧代-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-8-羧酸叔丁酯(370mg,淡黄色油状物),产率:76.3%。
MS(ESI
+)m/z=517.9[M+H]
+.
实施例32-41.中间体A2-A4和中间体B1-B7的合成
以市售或合成的取代的2-氟-1-硝基苯和羟基氨为原料,运用合成中间体A1(实施例31)的方法制备中间体A2-A4和B1-B7。
表2中间体A2-A4和中间体B1-B7
实施例42.(E)-5
6-(羟甲基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮的合成(中间体B8)
第一、第二和第三步:2-氨基-1-(5-羟基戊基)-1H-苯并[d]咪唑-6-羧酸甲酯
以3-氟-4-硝基苯甲酸甲酯和5-氨基戊醇为原料,按照合成中间体A1(实施例31)第一、第三和第四步的方法制备2-氨基-1-(5-羟基戊基)-1H-苯并[d]咪唑-6-羧酸甲酯。
MS(ESI
+)m/z=278.1[M+H]
+.
第四步:1-(5-羟基戊基)-2-(2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酰胺)-1H-苯并[d]咪唑-6-羧酸甲酯
室温下,在100mL圆底烧瓶中依次加入2-氨基-1-(5-羟基戊基)-1H-苯并[d]咪唑-6-羧酸甲酯(0.65g,1.8mmol),DMF(20mL),2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酸(0.5g,1.8mmol),HATU(1.03g,2.7mmol)和DIPEA(0.7g,5.4mmol),室温下搅拌3h。反应完毕后,向反应液中加入水(20mL),用乙酸乙酯萃取(50mL×5),合并有机相,用饱和食盐水洗涤(50mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法分离纯化得到1-(5-羟基戊基)-2-(2-甲基-6-(1-甲基 -5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酰胺)-1H-苯并[d]咪唑-6-羧酸甲酯(500mg,浅黄色油状物),产率:38.9%。
MS(ESI
+)m/z=623.0[M+H]
+.
第五步:2-(2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酰胺)-1-(5-羟基戊基)-1H-苯并[d]咪唑-6-羧酸甲酯
冰水浴下,将1-(5-羟基戊基)-2-(2-甲基-6-(1-甲基-5-((2-(三甲基硅基)乙氧基)甲氧基)-1H-吡唑-4-基)异烟酰胺)-1H-苯并[d]咪唑-6-羧酸甲酯(500mg,0.803mmol)溶于4M氯化氢的二氧六环溶液(15mL),室温搅拌1h。减压浓缩,所得剩余物加水(10mL),用饱和碳酸氢钠水溶液调节pH=6-7,减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系甲醇/二氯甲烷=1/6纯化得到2-(2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酰胺)-1-(5-羟基戊基)-1H-苯并[d]咪唑-6-羧酸甲酯(300mg,紫色固体),产率:67.5%。
MS(ESI
+)m/z=493.0[M+H]
+.
第六步:(E)-1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷基-5
6-羧酸甲酯
室温下,将2-(2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酰胺)-1-(5-羟基戊基)-1H-苯并[d]咪唑-6-羧酸甲酯(300mg,0.609mmol)溶于THF(15mL),然后加入DIAD(184mg,0.914mmol)和PPh3(239.64mg,0.914mmol),室温搅拌3h。反应完全后,减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系甲醇/二氯甲烷=1/100~1/20纯化得到(E)-1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑十一烷基-5
6-羧酸甲酯(210mg,淡黄色油状物),产率:69.0%.
MS(ESI
+)m/z=474.8[M+H]
+.
第七步:(E)-5
6-(羟甲基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮
冰水浴下,将(E)-1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷基-5
6-羧酸甲酯(84mg,0.177mmol)溶于THF(3mL),分批加入LiAlH
4(26.7mg,0.708mmol),搅拌1h。反应完全后,向反应液中滴加水(2mL),抽滤,滤液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系甲醇/二氯甲烷=1/100~1/20纯化得到(E)-5
6-(羟甲基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(58mg,白色固体),产率:66.1%。
MS(ESI
+)m/z=447.0[M+H]
+.
实施例43. 1
1,2
6-二甲基-5
6-((4-甲基哌嗪-1-基)甲基)-3-氧代-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷基-8-羧酸叔丁酯的合成(中间体A5)
室温下,在100mL圆底烧瓶中将中间体B1(200mg,0.37mmol)溶于二氯甲烷(20mL),然后加入1-甲基哌嗪(40mg,0.4mmol)和醋酸(110mg,1.83mmol),室温下搅拌1h,缓慢加入三乙酰氧基硼氢化钠(300mg,1.46mmol),在室温下搅拌4-5h。反应完毕后,反应液直接减压浓缩,所得剩余物使用薄层层析法以洗脱剂体系二氯甲烷/甲醇=15/1分离纯化得到1
1,2
6-二甲基-5
6-((4-甲基哌嗪-1-基)甲基)-3-氧代-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷基-8-羧酸叔丁酯(110mg,黄色固体),产率:38.13%。
MS(ESI
+)m/z=630.8[M+H]
+.
实施例44-49.中间体A6-A11的合成
以中间体B和氮杂环化合物为原料,运用合成中间体A5(实施例43)的方法制备中间体A6-A11。
表3中间体A6-A11
实施例50.(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)氨基)乙基)氨基甲酸叔丁酯的合成(中间体A12)
第一步:(E)-5
7-((3,4-二甲氧基苄基)氨基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮
氮气保护下,室温下在100mL圆底烧瓶中依次加入中间体B3(15.0g,0.03mol),1,4-二氧六环(100mL),(2,4-二甲氧基苯基)甲胺(7.5g,0.045mol),Pd
2(bda)
3(2.75g,0.003mol),BINAP(3.73g,0.006mol)和叔丁醇钠(5.77g,0.06mol),100℃搅拌过夜。反应完毕后,降至室温,过滤,滤液加水(100mL)稀释,乙酸乙酯萃取(100mL×3),合并有机相, 用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物使用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇=20/1纯化得到(E)-5
7-((3,4-二甲氧基苄基)氨基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(11.4g,黄色固体),产率:69.0%。
第二步:(E)-5
7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮
室温下,在100mL圆底烧瓶中依次加入(E)-5
7-((3,4-二甲氧基苄基)氨基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(4.0g,7.27mmol)和TFA(20mL),室温下搅拌3h。反应完毕后,减压浓缩得到(E)-5
7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(2.8g,黄色固体),产率:89.2%。
第三步:(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)氨基)乙基)氨基甲酸叔丁酯
氮气保护下,室温下在100mL单口圆底烧瓶中加入(E)-5
7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(200mg,0.46mmol),(2-氧乙基)氨基甲酸叔丁酯(73.78mg,0.46mmol),4-A分子筛(200mg)和甲醇/醋酸混合液(10/1,5.5mL),室温搅拌1h。然后加入氰基硼氢化钠(58.25mg,0.93mmol),室温搅拌过夜。反应完毕后,加入水(10mL),用乙酸乙酯(10mL×3)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,经过薄层层析法以洗脱体系二氯甲烷/甲醇=20/1纯化得到(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)氨 基)乙基)氨基甲酸叔丁酯(90mg,黄色液体),产率:15.2%。
MS(ESI
+)m/z=575.3[M+H]
+.
实施例51.(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)(甲基)氨基)乙基)氨基甲酸叔丁酯的合成(中间体A13)
氮气保护下,室温下在50mL单口圆底烧瓶中加入(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)氨基)乙基)氨基甲酸叔丁酯(330mg,0.58mmol),甲醛(78.23mg,2.61mmol),4A分子筛(300mg)和甲醇/醋酸(10/1,5mL)混合液,室温搅拌1h。向反应液中加入氰基硼氢化钠(72.82mg,1.16mmol),继续搅拌3h。反应完毕后,加入水(20mL),用乙酸乙酯(30mL×3)萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品使用硅胶柱层析色谱法以洗脱剂体系二氯甲烷/甲醇=10/1纯化得到(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)(甲基)氨基)乙基)氨基甲酸叔丁酯(150mg,黄色固体),产率:44.0%.
MS(ESI
+)m/z=589.7[M+H]
+.
实施例52-55.中间体A14-A17的合成
以中间体(E)-5
7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮和烷基醛或酮为原料,运用合成中间体A12(实施例50)第三步的方法制备中间体A14-A17。
表4中间体A14-A17
实施例56.(S,E)-(1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-1-氧代丙-2-基)氨基甲酸叔丁酯的合成(中间体A18)
氮气保护下,将N-BOC-L-丙氨酸(877mg,4.64mmol)溶于THF(30mL),加入NMM(375mg,3.7mmol),降温至-20℃,滴加氯甲酸异丁酯(876.6mg,4.64mmol),-20℃搅拌1h,然后滴加(E)-5
7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(200mg,0.46mmol)的THF(15mL)溶液及NMM(234mg,2.32mmol),室温搅拌过夜。反应完毕后加水(30mL),乙酸乙酯萃取(30mL×3),合并有机相,用饱和食盐水(50mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品(S,E)-(1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-1-氧代丙-2-基)氨基甲酸叔丁酯(70mg,黄色固体),产率:25.1%。
MS(ESI
+)m/z=603.1[M+H]
+.
实施例57-61.中间体A19-A23的合成
以中间体(E)-5
7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮和氨基酸为原料,运用合成中间体A18(实施例56)的方法制备中间体A19-A23。
表5中间体A19-A23
实施例62.(E)-(1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-6-(二甲氨基)-1-氧代己烷-2-基)氨基甲酸叔丁酯的合成(中间体A24)
第一步:(E)-(6-氨基-1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-1-氧代己烷-2-基)氨基甲酸叔丁酯
在氢化瓶中依次加入中间体A23(450mg,0.57mmol),甲醇(10mL)和钯碳(100mg),通入氢气,40℃搅拌4h。过滤,滤液减压浓缩得到粗品(E)-(6-氨基-1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-1-氧代己烷-2-基)氨基甲酸叔丁酯(240mg,黄色油状),产率:64.3%。
MS(ESI
+)m/z=660.2[M+H]
+.
第二步:(E)-(1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-6-(二甲氨基)-1-氧代己烷-2-基)氨基甲酸叔丁酯
室温下,在50mL圆底烧瓶中将(E)-(6-氨基-1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-1-氧代己烷-2-基)氨基甲酸叔丁酯(240mg,0.36mmol)溶于甲醇(10mL),加入醋酸(0.2mL),降温至0℃分批加入氰基硼氢化钠(46mg,0.73mmol),室温搅拌1h。降温至0℃滴加甲醛(137mg,1.82mmol),室温搅拌4h。反应完毕后,加入氯化铵淬灭反应,用乙酸乙酯(20mL×2)萃取,合并有机相,用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物用薄层层析法以洗脱体系二氯甲烷/甲醇=10/1纯化得到 (E)-(1-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)氨基)-6-(二甲氨基)-1-氧代己烷-2-基)氨基甲酸叔丁酯(80mg,黄色固体),产率:32%。
MS(ESI
+)m/z=689.3[M+H]
+.
实施例63.(E)-(1-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)吡咯烷-3-基)氨基甲酸叔丁酯的合成(中间体A25)
氮气保护下,室温下在100mL圆底烧瓶中依次加入中间体B3(200mg,0.4mmol),1,4-二氧六环(10mL),吡咯烷-3-基氨基甲酸叔丁酯(112.78mg,0.6mmol),三(二亚苄基丙酮)二钯(36.97mg,0.04mmol),1,1'-联萘-2,2'-双二苯膦(50.27mg,0.08mmol)和叔丁醇钠(77.59g,0.81mmol),100℃搅拌过夜。反应完毕后,降至室温,过滤,滤液加水(10mL)稀释,乙酸乙酯萃取(30mL×3),合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,所得剩余物经过薄层层析法以洗脱剂体系二氯甲烷/甲醇=20/1纯化得到(E)-(1-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(4,5)-吡唑环十一烷-5
7-基)吡咯烷-3-基)氨基甲酸叔丁酯(100mg,黄色油状物),产率:12.4%。
MS(ESI
+)m/z=601.4[M+H]
+.
实施例64.(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
6-基)氧基)乙基)氨基甲酸叔丁酯的合成(中间体A26)
第一步:(E)-5
6-羟基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d] 咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮
室温下,将中间体B4(200mg,0.38mmol)溶于MeOH/EtOAc(10mL,1/1),然后加入钯碳(10%,30mg),氢气置换气体三次,室温搅拌16h。抽滤,滤液减压浓缩得到粗品(E)-5
6-羟基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(150mg,棕黄色油状物),产率:72.5%。所得粗品未经纯化直接用于下一步反应。
MS(ESI
+)m/z=433.1[M+H]
+.
第二步:(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
6-基)氧基)乙基)氨基甲酸叔丁酯
室温下,将(E)-5
6-羟基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(25mg,0.058mmol)溶于DMF(2mL),然后加入碳酸钾(24mg,0.173mmol)和N-Boc-溴乙胺(39mg,0.174mmol),升温至70℃搅拌2h。反应完毕后,加入水(10mL),用乙酸乙酯萃取(10mL×5),合并有机相,用饱和食盐水洗涤(15mL×3),无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品(E)-(2-((1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
6-基)氧基)乙基)氨基甲酸叔丁酯(31mg,棕黄色油状物)。所得粗品未经纯化直接用于下一步反应。
MS(ESI
+)m/z=576.1[M+H]
+.
实施例65-83.中间体A27-A45的合成
以中间体B和烷基溴代物或合成的对甲苯磺酰基化合物为原料,运用合成中间体A26(实施例64)的方法制备中间体A27-A45。
表6中间体A27-A45
实施例84.(S,E)-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑并唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-9-基)氨基甲酸叔丁酯的合成(中间体A46)
第一步:(S)-2-((叔丁氧羰基)氨基)-5-((2-硝基苯基)氨基)戊酸
室温下,在100mL圆底烧瓶中依次加入(S)-5-氨基-2-((叔丁氧羰基)氨基)戊酸(1.0g,4.3mmol),乙腈(20mL),碳酸钾(770mg,5.59mmol)和2-氟硝基苯(730mg,5.2mmol),升温至70℃搅拌16h。将反应液降温至室温,抽滤,滤液减压浓缩得到粗品(S)-2-((叔丁氧羰基)氨基)-5-((2-硝基苯基)氨基)戊酸(1.53g,红色油状物)。所得粗品未经纯化直接用于下一步反应。
MS(ESI
+)m/z=375.8[M+Na]
+.
第二步:(S)-2-((叔丁氧羰基)氨基)-5-((2-硝基苯基)氨基)戊酸甲酯
室温下,在100mL圆底烧瓶中依次加入(S)-2-((叔丁氧羰基)氨基)-5-((2-硝基苯基)氨基)戊酸(3.0g,8.5mmol),甲醇(50mL)和TMSCH
2N
2(2.91g,25.5mmol),室温搅拌16h,减压浓缩,所得剩余物使用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=0~1/1纯化得到(S)-2-((叔丁氧羰基)氨基)-5-((2-硝基苯基)氨基)戊酸甲酯(1.9g,黄色油状物),产率:57.7%。
MS(ESI
+)m/z=390.0[M+Na]
+.
第三步:(S)-(1-羟基-5-((2-硝基苯基)氨基)戊烷-2-基)氨基甲酸叔丁酯
室温下,在100mL圆底烧瓶中将(S)-2-((叔丁氧羰基)氨基)-5-((2-硝基苯基)氨基)戊酸甲酯(1.0g,2.7mmol)溶于无水四氢呋喃(20mL),降温至0℃,缓慢滴加硼氢化锂(356mg,16.2mmol)的无水四氢呋喃混合液(20mL)。滴加完毕后,升温至室温,搅拌12h,将反应液倒入水(20mL)中,混合液减压浓缩,所得剩余物使用硅胶柱色谱法以洗脱剂体系乙酸乙酯/石油醚=0~1/1纯化得到(S)-(1-羟基-5-((2-硝基苯基)氨基)戊烷-2-基)氨基甲酸叔丁酯(810mg,红色油状物),产率:87%。
MS(ESI
+)m/z=362.0[M+Na]
+.
第四、第五、第六、第七和第八步:(S,E)-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-9-基)氨基甲酸叔丁酯
以(S)-(1-羟基-5-((2-硝基苯基)氨基)戊烷-2-基)氨基甲酸叔丁酯为原料,按照合成中间体A1(实施例31)第二、第三、第四、第五和第六步的方法制备中间体A46。
实施例85.(R,E)-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-9-基)氨基甲酸叔丁酯的合成(中间体A47)
以(R)-5-氨基-2-((叔丁氧羰基)氨基)戊酸和2-氟硝基苯为原料,按照合成中间体A46(实施例84)的方法制备中间体A47。
实施例86.(E)-(3-氧代-5
2,5
3-二氢-5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(1,2)-苯并环十一烷-2
6-基)氨基甲酸叔丁酯(中间体A48)
第一步:2-(2-(5-溴戊基)氧基)苯基)-6-(叔丁氧羰基)氨基)异烟酸甲酯
室温下,在250mL圆底烧瓶中依次加入2-((叔丁氧羰基)氨基)-6-(2-羟基苯基)异烟酸甲酯(5.6g,0.016mol),乙腈(50mL),碳酸钾(2.70g,0.019mol)和1,5-二溴戊烷(4.12g,0.018mol),升温至85℃搅拌16h。反应完毕后,混合液减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=10/1纯化得到2-(2-(5-溴戊基)氧基)苯基)-6-(叔丁氧羰基)氨基)异烟酸甲酯(1.5g,黄色油状物),产率18.8%。
MS(ESI
+)m/z=492.8[M+H]
+.
第二步:2-(2-((5-(2-氨基-1H-苯并[d]咪唑-1-基)戊基)氧基)苯基)-6-((叔丁氧羰基)氨基)异烟酸甲酯
室温下,在100mL圆底烧瓶中依次加入1H-苯并[d]咪唑-2-胺(0.58g,4.3mol),乙腈(15mL),碳酸钾(2.9g,3.9mol)和2-(2-(5-溴戊基)氧基)苯基)-6-(叔丁氧羰基)氨基)异烟酸甲酯(1.5g,3.6mmol),加热回流搅拌24h。反应完毕后,混合液减压浓缩,用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=10/1纯化得到2-(2-((5-(2-氨基-1H-苯并[d]咪唑-1-基)戊基)氧基)苯基)-6-((叔丁氧羰基)氨基)异烟酸甲酯(498mg,黄色固体),产率:27.8%。
MS(ESI
+)m/z=545.9[M+H]
+.
第三步:2-(2-((5-(2-氨基-1H-苯并[d]咪唑-1-基)戊基)氧基)苯基)-6-((叔丁氧羰基)氨基)异烟酸
室温下,在100mL圆底烧瓶中依次加入2-(2-((5-(2-氨基-1H-苯并[d]咪唑-1-基)戊基)氧基)苯基)-6-((叔丁氧羰基)氨基)异烟酸甲酯(498mg,1.07mmol),四氢呋喃和水混合液(6mL,5/1),氢氧化锂一水合物(449mg,10.7mmol),室温搅拌3h。反应完毕后,减压除去四氢呋喃,所得残余物加入水(10mL),并使用1M的盐酸调Ph=6-7,用乙酸乙酯萃取(20mL),有机相减压浓缩得到粗品2-(2-((5-(2-氨基-1H-苯并[d]咪唑-1-基)戊基)氧基)苯基)-6-((叔丁氧羰基)氨基)异烟酸(0.695mg,黄色油状物),产率:31.5%。
MS(ESI
+)m/z=531.8[M+H]
+.
第三步:(E)-(3-氧代-5
2,5
3-二氢-5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(1,2)-苯并环十一烷-2
6-基)氨基甲酸叔丁酯
室温下,在100mL圆底烧瓶中依次加入2-(2-((5-(2-氨基-1H-苯并[d]咪唑-1-基)戊基)氧基)苯基)-6-((叔丁氧羰基)氨基)异烟酸(190mg,0.35mmol),二氯甲烷(3mL),三乙胺(72.2mg,0.71mmol)和2-(1H-苯并三偶氮L-1-基)-1,1,3,3-四甲基脲四氟硼酸酯(137.7mg,0.42mmol),室温搅拌0.5h。反应完毕后,加入二氯甲烷(20mL)稀释,用饱和食盐水(10mL×3)洗涤,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩。所得残余物用硅胶柱色谱法以洗脱剂体系石油醚/乙酸乙酯=10/1纯化得到(E)-(3-氧代-5
2,5
3-二氢-5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(1,2)-苯并环十一烷-2
6-基)氨基甲酸叔丁酯(150mg,黄色固体),产率:65.4%。
MS(ESI
+)m/z=513.9[M+H]
+.
实施例87.(E)-8-丙烯酰-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷-3-酮的合成(终产物1)
第一步:(E)-1
1,2
6-二甲基-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-3-酮
室温下,在100mL圆底烧瓶中依次加入中间体A1(370mg,0.71mmol)和盐酸二氧六环溶液(5mL,4mol/L),混合液室温搅拌2-3h。反应完毕后,滤液减压浓缩得到粗品1
1,2
6-二甲基-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-3-酮(160mg,黄色固体),产率:53.4%。
MS(ESI
+)m/z=418.1[M+H]
+.
第二步:(E)-8-丙烯酰-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷-3-酮(终产物1)
室温下,往100mL圆底烧瓶中依次加入1
1,2
6-二甲基-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-3-酮(83mg,0.2mmol),二氯甲烷(5mL)和DIPEA(51.6mg,2.0mmol),降温至0℃,缓慢加入丙烯酰氯(18mg,0.2mmol),加入完毕,0℃下搅拌30min。反应完毕后,减压浓缩所得剩余物使用薄层层析法以洗脱剂体系二氯甲烷/甲醇=15/1分离纯化得到产物(E)-8-丙烯酰-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷-3-酮(37mg,白色固体),产率:38.9%。
MS(ESI
+)m/z=472.1[M+H]
+.
1H NMR(400MHz,DMSO-d
6)δ12.81(s,1H),8.32(d,J=8.0Hz,1H),7.93-7.92(m,1H),7.71-7.45(m,3H),7.29-7.28(m,2H),7.01-7.00(m,1H),6.35-6.22(m,1H),5.82(t,J=8.0Hz,1H),4.52-4.30(m,4H),4.22-3.91(m,4H),3.79(d,J=23.1Hz,3H),2.57(s,3H).
实施例88-134.终产物4-8、49、50、55、58、60、62、67-69、73、74、76-78、80-83、102、109、114、115、118-122、124-126、131-133、135、137-141、147、152、154的合成
以中间体A为原料,按照合成终产物1(实施例87)的方法制备终产物4-8、49、50、55、58、60、62、67-69、73、74、76-78、80-83、102、109、114、115、118-122、124-126、131-133、135、137-141、147、152、154。
表7终产物4-8、49、50、55、58、60、62、67-69、73、74、76-78、80-83、102、
109、114、115、118-122、124-126、131-133、135、137-141、147、152、154
实施例135.(E)-8-(-4-(二甲氨基)丁-2-烯酰基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷-3-酮的合成(终产物10)
室温下,在100mL圆底烧瓶中依次加入(E)-4-(二甲氨基)丁-2-烯酸盐酸(34mg,0.26mmol),二氯甲烷(5mL),N,N-二异丙基乙胺(62mg,0.48mmol),苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(97mg,0.26mmol)和(E)-1
1,2
6-二甲基-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-3-酮(100mg,0.24mmol),室温搅拌1-2h。反应完毕后,减压浓缩,所得剩余物用制备液相色谱法[色谱柱:Gemini-C18150x 21.2mm,5um;流动相:ACN/H
2O(0.1%TFA),梯度:10-40%]纯化得到产物8-(-4-(二甲氨基)丁-2-烯酰基)-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷-3-酮(10.9mg,黄色固体)。
MS(ESI
+)m/z=528.9[M+H]
+.
1H NMR(400MHz,DMSO-d
6)δ12.83(s,1H)8.34(d,J=11.4Hz,1H),8.15(s,1H),7.88(s,1H),7.64-7.43(m,3H),7.30-7.27(m,2H),6.77-6.72(m,2H),4.48-4.29(m,4H),4.11-4.08(m,2H),4.02-3.89(m,1H),3.79(d,J=24.6Hz,3H),3.20-3.07(m,3H),2.55(d,J=11.3Hz,3H),2.23(s,6H).
实施例136-138.终产物52、92、93的合成
以中间体A水解得到的胺与市售酸为原料,按照合成终产物10(实施例135)的方法 制备终产物。
表8终产物52、92、93
实施例139.(E)-3-(1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷-8-基)-3-氧代丙腈的合成(终产物17)
室温下,在100mL圆底烧瓶中依次加入2-氰基乙酸(33mg,0.4mmol),四氢呋喃(5mL),二环己基碳二亚胺(30mg,0.23mmol),4-二甲氨基吡啶(2mg,0.02mmol)和1
1,2
6-二甲基-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷基-3-酮(80mg,0.2mmol),升温至70℃搅拌12h。反应完毕后,减压除去溶剂,所得剩余物用制备液相色谱法[色谱柱:Gemini-C18 150x 21.2mm,5um;流动相:ACN/H
2O(0.1%TFA),梯度:10-40%]纯化得到产物(E)-3-(1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4,8-二氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑基环十一烷-8-基)-3-氧代丙腈(1.5mg,黄色固体)。
MS(ESI
+)m/z=485.0[M+H]
+.
1H NMR(400MHz,DMSO-d
6)δ12.79(s,1H),8.32-8.29(m,1H),7.88(s,1H),7.78(d,J=7.9Hz,1H),7.64-7.40(m,2H),7.38-7.18(m,2H),4.45-4.34(m,6H),4.03-3.97(m,4H),3.76-3.73(m,3H),2.55(s,3H).
实施例140.(E)-N-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-7-基)丙烯酰胺的合成(终产物18)
第一步:2-甲基-6-(1-甲基-5-(3-(环氧丙烷-2-基)丙氧基)-1H-吡唑-4-基)异烟酸甲酯
室温下,在100mL圆底烧瓶中依次加入2-(5-羟基-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸甲酯(2.5g,10.1mmol),乙腈(50mL),碳酸钾(2.09,15.1mmol)和2-(3-溴丙基)环氧乙烷(2.67g,16.1mmol),加热至70℃搅拌16h。反应完毕后,混合液减压浓缩,所得剩余物使用硅胶柱色谱法以洗脱体系石油醚/乙酸乙酯=1/1纯化得到2-甲基-6-(1-甲基-5-(3-(环氧丙烷-2-基)丙氧基)-1H-吡唑-4-基)异烟酸甲酯(1.7g,淡黄色油状物),产率:50.8%。
MS(ESI
+)m/z=331.9[M+H]
+.
第二步:2-(5-((5-(2-氨基-1H-苯并[d]咪唑-1-基)-4-羟基戊基)氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸酸
室温下,封管中加入2-甲基-6-(1-甲基-5-(3-(环氧丙烷-2-基)丙氧基)-1H-吡唑-4-基)异烟酸甲酯(700mg,2.1mmol),2-氨基苯并咪唑(282mg,2.1mmol),MeOH/H
2O混合液(20mL,2.5/1)和KOH(237mg,4.22mmol),于100℃微波下搅拌1h。反应完毕后,减压浓缩得到粗品2-(5-((5-(2-氨基-1H-苯并[d]咪唑-1-基)-4-羟基戊基)氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸酸(970mg,浅黄色油状物),所得粗品未经纯化直接用于下一步反应。
MS(ESI
+)m/z=451.1[M+H]
+.
第三步:(E)-7-羟基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮
室温下,于100mL茄形瓶中依次加入2-(5-((5-(2-氨基-1H-苯并[d]咪唑-1-基)-4-羟基 戊基)氧基)-1-甲基-1H-吡唑-4-基)-6-甲基异烟酸酸(600mg,1.33mmol),DMF(20mL),HATU(1.52g,4mmol),HOAT(544mg,4mmol),DMAP(163mg,1.33mmol)和DIPEA(1.37g,10.7mmol),室温下搅拌16h。反应完全后向混合液中加入水(15mL),用乙酸乙酯萃取(10mL×5),合并有机相,用饱和食盐水洗涤(15mL×3),有机相减压浓缩,所得剩余物使用制备液相色谱[色谱柱:Gemini-C18 150x 21.2mm,5um;流动相:ACN/H
2O(0.1%FA),梯度:10-40%]纯化得到(E)-7-羟基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(0.2g,淡黄色固体),产率:32.1%。
MS(ESI
+)m/z=433.1[M+H]
+.
第四步:(E)-1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-7-基甲磺酸酯
冰水浴下,在50mL圆底烧瓶中将(E)-7-羟基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(70mg,0.162mmol)溶于二氯甲烷(15mL),然后加入三乙胺(49.1mg,0.49mmol)和甲基磺酰氯(37.1mg,0.32mmol),在该温度下搅拌1h。反应完毕后,减压浓缩,所得剩余物用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇=30/1纯化得到(E)-1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-7-基甲磺酸酯(67mg,黄色油状物),产率:56.8%。
MS(ESI
+)m/z=510.7[M+H]
+.
第五步:(E)-7-叠氮-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮
氮气保护下,室温下,在干燥的100mL圆底烧瓶中依次加入(E)-1
1,2
6-二甲基-3-氧代 -5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-7-基甲磺酸酯(110mg,21.5mmol),DMF(10mL)和叠氮化钠(16.8mg,25.84mmol),加热至100℃搅拌16h。反应完毕后,向反应体系中加入水(50mL),抽滤,收集滤饼并干燥得到(E)-7-叠氮-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(57mg,淡黄色固体),产率:48.6%。
MS(ESI
+)m/z=458.1[M+H]
+.
第六步:(E)-7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮
室温下,在100mL圆底烧瓶中依次加入(E)-7-叠氮-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(72mg,0.157mmol),甲醇(10mL)和钯碳(10%,20mg),氢气置换气体三次,室温下搅拌5h。反应完毕后,过滤,滤液减压浓缩,所得剩余物经薄层层析法以洗脱剂体系二氯甲烷/甲醇=20/1纯化得到(E)-7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(35mg,浅黄色油状物),产率:41.2%。
MS(ESI
+)m/z=431.8[M+H]
+.
第七步:(E)-N-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-7-基)丙烯酰胺
冰水浴下,将(E)-7-氨基-1
1,2
6-二甲基-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-3-酮(35mg,0.081mmol)溶于二氯甲烷(5mL),加入三乙胺(16.4mg,0.16mmol),然后再加入丙烯酰氯(9.53mg,0.11mmol)与二氯 甲烷(4mL)的混合物,加毕,继续搅拌1h。减压浓缩,所得剩余物经制备液相色谱法纯化[色谱柱:Gemini-C18 150x 21.2mm,5um;流动相:ACN/H
2O(0.1%FA),梯度:10-40%]得到(E)-N-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-7-基)丙烯酰胺(6mg,黄色固体)。
MS(ESI
+)m/z=485.8[M+H]
+.
1H NMR(300MHz,CD
3OD)δ8.79(s,1H),8.30(s,1H),8.08(s,1H),7.89(s,1H),7.66-7.37(m,4H),6.10-5.90(m,2H),5.62-5.55(m,1H),4.14-4.10(m,1H),3.98(s,3H),2.82(s,3H),2.71-2.46(m,4H),2.10-1.98(m,2H),1.55-1.45(m,2H).
实施例141.(E)-2-(2-氯-2-氟乙酰胺)-N-(1-((1
1,2
6-二甲基-3氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)丙酰胺的合成(终产物136)
室温下,在100mL圆底烧瓶中依次加入(E)-2-氨基-N-(1
1,2
6-二甲基-3-氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)丙酰胺(40mg,0.08mmol),二氯甲烷(2mL),2-氯-2-氟乙酸钠(12.84mg,0.1mmol),1-丙基磷酸酐(75.98mg,0.12mmol)和N,N-二异丙基乙胺(20.58mg,0.16mmol),室温下搅拌过夜。反应完毕后,加入二氯甲烷(10mL),用水洗,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品用制备液相色谱法[色谱柱:symmetry 7um 19-150mm;流动相:ACN/H
2O(0.1%TFA),梯度:10-40%]纯化得到(E)-2-(2-氯-2-氟乙酰胺)-N-(1-((1
1,2
6-二甲基-3氧代-5
2,5
3-二氢-1
1H,5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶基-1(4,5)-吡唑环十一烷-5
7-基)丙酰胺(5.9mg,白色固体)。
MS(ESI
+)m/z=597.2[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.65(s,1H),8.15(s,1H),7.83(s,1H),7.50-7.48(m,1H),7.29-7.26(m,1H),7.10-7.08(m,1H),6.70-6.30(m,1H),4.60-4.80(m,1H),4.30-4.38(m,4H),3.81(s,3H),2.70(s,3H),2.10-2.13(m,4H),1.88-1.93(m,2H),1.62-1.68(m,3H).
实施例142.(E)-2-氯-2-氟-N-(3-氧代-5
2,5
3-二氢-5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d] 咪唑-2(2,4)-吡啶-1(1,2)-苯并环十一烷-2
6-基)乙酰胺的合成(终产物153)
室温下,在100mL圆底烧瓶中依次加入(E)-2
6-氨基-5
2,5
3-二氢-5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(1,2)-苯并环十一烷-3-酮(30.0mg,0.073mmol),DMF(5mL),DIPEA(46.9mg,0.36mmol),2-氯-2-氟乙酸(19.5mg,0.15mmol),降温至0℃,缓慢加入T
3P(91.9mg,0.29mmol),HOBt(39.24mg,0.29mmol),加入完毕,室温下搅拌16h。反应完毕后,所得粗品用高压制备液相色谱法[色谱柱:Gemini-C18 150x 21.2mm,5um;流动相:ACN/H
2O(0.1%FA),梯度:65-80%]纯化得到(E)-2-氯-2-氟-N-(3-氧代-5
2,5
3-二氢-5
1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑-2(2,4)-吡啶-1(1,2)-苯并环十一烷-2
6-基)乙酰胺(3.3mg,黄色固体)。
MS(ESI
+)m/z=508.0[M+H]
+.
1H NMR(400MHz,DMSO-d
6)δ12.74(s,1H),11.26(s,1H),9.08(s,1H),8.49(s,1H),8.24(dd,J=7.8,1.8Hz,1H),7.54-7.50(m,2H),7.42-7.37(m,1H),7.26-7.21(m,2H),7.15(d,J=8.1Hz,1H),7.08-7.04(m,1H),6.93(d,J=49.6Hz,1H),4.19(dd,J=8.0,5.6Hz,2H),1.98-1.93(m,6H),1.59-1.41(m,2H).
实施例143.
一、体外酶学实验
采用HTRF KinEASE-TK试剂盒,通过检测EGFR蛋白激酶反应后ATP的剩余量来测定其活性。测试的发光信号强度与反应剩余ATP的量正相关,与化合物活性正相关,与激酶活性负相关。
1.实验设计
在所选激酶上测定化合物,并设定溶媒对照,共检测10个浓度,每个浓度2个复孔。
2.试剂和耗材
3.实验过程
3.1配置1x激酶缓冲液
酶缓冲液用5mM MgCl
2;1mM DTT;1mM MnCl
2水溶液稀释到5倍。
3.2化合物筛选
a)用Echo移液器将化合物转移到384孔板中。
b)盖上盖子,在1000g转数下离心1分钟。
c)用激酶缓冲液稀释EGFR L858R/T790M/C797S或EGFR Del19/T790M/C797S一倍。
d)加5μl稀释的EGFR L858R/T790M/C797S或EGFR Del19/T790M/C797S到384孔板中。
e)在1000g转数下离心30秒,室温静置10min。
f)用激酶缓存液稀释TK-substrate-biotin和ATP的混合液一倍。
g)加入5μl TK-substrate-biotin和ATP混合液开始反应。
h)在1000g转数下离心30秒,盖上盖子,室温静置10min。
i)用HTRF稀释Sa-XL 665检测缓冲液4倍。
j)每孔中加入5μl Sa-XL 665和5μl TK-antibody-Cryptate。
e)在1000g转数下离心30秒,室温静置1h。
l)在Envision 2104多标记微孔板检测仪中读取615nm(Cryptate)和665nm(XL665)荧光信号。
4.IC
50计算
使用GraphPad Prism 6.0软件分析数据,利用非线性S曲线回归来拟合数据得出剂量-效应曲线,并由此计算IC
50值。
酶抑制百分率(%)=100-(Signal
化合物-Signal
平均_PC)/(Signal
平均_VC-Signal
平均_PC)×100
5.实验结果
表9化合物对EGFR L858R/T790M/C797S和EGFR Del19/T790M/C797S酶抑制IC
50(nM)
注:LR/TM/CS:L858R/T790M/C797S;EGFR Del/TM/CS:Del19/T790M/C797S;/:未测试
本发明化合物对EGFR L858R/T790M/C797S和EGFR Del19/T790M/C797S酶活性抑制IC
50如表9所示。
从表9中可以看出,本发明化合物对EGFR L858R/T790M/C797S和EGFR Del19/T790M/C797S三突变酶具有较好抑制活性,IC
50值在纳摩尔水平。
二、细胞增殖抑制实验
CellTiter-Glo
TM活细胞检测试剂盒采用萤光素酶作检测物,发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-Glo
TM试剂,测量发光值,光信号和体系中ATP量成正比,而ATP又和活细胞数正相关。因此通过使用CellTiter-Glo试剂盒检测ATP含量,可以检测出细胞的增殖情况。
本实验采用celltiter-Glo(CTG)法测量前述制备的化合物在肿瘤细胞株NCI-H1975、 Ba/F
3(EGFR-L858R/C797S/T790M)、Ba/F
3(EGFR-Del19/C797S/T790M)和A431中增殖抑制作用,并计算50%抑制浓度IC
50。
1.实验设计
在所选细胞上测定化合物,并设定溶媒对照,共检测10个浓度,每个浓度2个复孔。
2.试剂和耗材
3.实验过程
3.1细胞培养和接种
a)收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力,确保细胞活力在90%以上。
b)调整细胞浓度;分别添加30μL细胞悬液至384孔板中。
将384孔板中的细胞置于37℃、5%CO
2、95%湿度条件下培养过夜。
3.2药物稀释和加药
a)配制10倍药物溶液,最高浓度为10mM,10个浓度,3倍稀释,在接种有细胞的384孔板中每孔加入10μL药物溶液,每个药物浓度设置2个复孔。Brigatinib、 Osimertinib或BI4020做阳性对照药,DMSO为空白对照。
b)将已加药的384孔板中的细胞置于37℃、5%CO
2、95%湿度条件下继续培养72小时,之后进行CTG分析。
3.3终点读板
a)融化CTG试剂并平衡细胞板至室温30分钟。
b)每孔加入等体积的CTG溶液。
c)在定轨摇床上振动5分钟使细胞裂解。
d)将细胞板放置于室温20分钟以稳定冷光信号。
e)读取冷光值。
4.数据处理
使用GraphPad Prism 5.0软件分析数据,利用非线性S曲线回归来拟合数据得出剂量-效应曲线,并由此计算IC
50值。
细胞存活率(%)=(Lum
待测药-Lum
培养液对照)/(Lum
细胞对照-Lum
培养液对照)×100%.
5.实验结果
表10化合物对各个细胞株抑制增殖活性IC
50(nM)
注:LR/TM/CS:L858R/T790M/C797S;EGFR Del/TM/CS:Del19/T790M/C797S;/:未测试
本发明化合物对NCI-H1975、Ba/F3(EGFR-L858R/C797S/T790M)、Ba/F3(EGFR-Del19/C797S/T790M)和A431细胞株抑制增殖活性IC
50如表10所示。
从表10中可以看出,本发明化合物对NCI-H1975双突变细胞株、Ba/F3(EGFR-L858R/C797S/T790M)三突变细胞株和Ba/F3(EGFR-Del19/C797S/T790M)三突变细胞株具有较好增殖抑制活性,对EGFR野生型细胞株A431抑制作用较弱,表明本发明化合物具有较好的细胞抑制活性和选择性。
Claims (11)
- 一种式I所示的大环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子、水合物或溶剂化物:其中,在式I中,环A和环B各自独立地为6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、或包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环,所述的6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、或包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环任选地被一个或多个独立地选自以下的取代基所取代:C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、氧代、卤素、羟基、氰基、氰基-C 1-6烷基、氨基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、C 1-6烷基-羰基、C 3-6环烷基-羰基、C 1-6烷基-氨基-酰基、二(C 1-6烷基)-氨基-酰基、C 3-6环烷基-氨基-酰基、C 1-6烷基-酰基-氨基、被一个或多个R m取代或未被取代的包含1-4个独立地选自N,O和S杂原子的5-10元杂芳基、被一个或多个R m取代或未被取代的6-10元芳基、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C 1-6烷基、-S(=O) 2R a、-S(=O) 2NR aR b、-P(=O)R aR b、-P(=O)R aNR bR c、-P(=S)R aR b、-P(=S)R aNR bR c、R bS(=O) 2N(R a)-,其中所述C 1-6烷基、C 2-6烯基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、氰基-C 1-6烷基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、C 1-6烷基-羰基、C 3-6环烷基-羰基、C 1-6烷基-氨基-酰基、二(C 1-6烷基)-氨基-酰基、C 3-6环烷基-氨基- 酰基、C 1-6烷基-酰基-氨基、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C 1-6烷基、-S(=O) 2R a、-S(=O) 2NR aR b、-P(=O)R aR b、-P(=O)R aNR bR c、-P(=S)R aR b、-P(=S)R aNR bR c、R bS(=O) 2N(R a)-可选择地和它们所连接的碳原子一起形成环,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、氰基-C 1-6烷基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、C 1-6烷基-羰基、C 3-6环烷基-羰基、C 1-6烷基-氨基-酰基、二(C 1-6烷基)-氨基-酰基、C 3-6环烷基-氨基-酰基、C 1-6烷基-酰基-氨基、被一个或多个R m取代或未被取代的包含1-4个独立地选自N,O和S杂原子的5-10元杂芳基、被一个或多个R m取代或未被取代的6-10元芳基、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的4-7元杂环基-C 1-6烷基-可以任选地被一个或多个独立地选自以下的取代基所取代:卤素、氰基、氨基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 3-6环烷基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、4-7元杂环基和4-7元杂环基-C 1-6烷基;环D为6-10元单环芳环或二环芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂芳环或二环杂芳环、包含1-4个独立地选自N,O和S杂原子的5-10元单环杂环或二环杂环、或C 5-7环烷;R 1、R 2、R 4和R 5其中1个为弹头基团,当R 1为弹头基团时,R 2、R 4和R 5各自独立地为R 6;当R 2为弹头基团时,R 1、R 4和R 5各自独立地为R 6;当R 4为弹头基团时,R 1、R 2和R 5各自独立地为R 6;或当R 5为弹头基团时,R 1、R 2和R 4各自独立地为R 6;R 3和R 6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C 0-3烷基、氨基、C 1-6烷基-氨基、C 3-6环烷基-氨基、二(C 1-6烷基)-氨基、C 1-6烷氧基-C 1-6烷基-氨基、4-6元杂环基-C 1-6烷基-氨基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基-氨基、氢原子、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-6烷基、羟基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、氰基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基-C 1-6烷基、C 1-6烷氧基、 二(C 1-6烷基)-氨基-C 1-6烷氧基、C 1-6烷基-羰基、C 3-6环烷基-羰基、C 1-6烷氧基-羰基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基、C 1-6烷基-羰基-C 1-6烷基、C 1-6烷基-氨基酰基-C 1-6烷基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基-C 1-6烷基、C 1-6烷基-OC(O)-C 1-6烷基、或包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C 0-3烷基、C 1-6烷基-氨基、C 3-6环烷基-氨基、二(C 1-6烷基)-氨基、C 1-6烷氧基-C 1-6烷基-氨基、4-6元杂环基-C 1-6烷基-氨基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基-氨基、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-6烷基、羟基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、氰基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基-C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)-氨基-C 1-6烷氧基、C 1-6烷基-羰基、C 3-6环烷基-羰基、C 1-6烷氧基-羰基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基、C 1-6烷基-羰基-C 1-6烷基、C 1-6烷基-氨基酰基-C 1-6烷基、包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基-C 1-6烷基、C 1-6烷基-OC(O)-C 1-6烷基、或包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基可以任选地被一个或多个独立地选自下组的取代基所取代:C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷基-O(O)C-、C 1-6烷基-羰基、氧代、卤素、羟基、C 1-6烷基氨基、二(C 1-6烷基)氨基、被1个或多个C 1-6烷基、C 1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;或者,R 3与环D上除与R 3连接的原子之外的任意原子一起,或者,R 3和R 6与所连接的原子一起任选地形成由3-10个原子组成的杂环,所述杂环包含1-3个选自N,O或S杂原子并且杂环上可选地进一步被一个或多个选自C 1-6烷基、卤素、6-10元芳基、包含1-3个独立地选自N,O或S的杂原子的5-10元杂芳基、包含1-3个独立地选自N,O或S的杂原子的5-10元杂环基、卤代C 1-6烷基、羟基、氰基、卤素、C 1-6烷氧基、4-6元杂环基烷基、C 1-6烷基氨基和二(C 1-6烷基)氨基所取代;Y 1、Y 2和Y 3各自独立地为化学键、O、NR 8、S、S(O) 2、CR 8R 16、羰基、-氨基-酰基、-酰基-氨基、-O(CO)-或-(CO)O-;M为化学键、被一个或多个R m取代或未被取代的-C 1-6烷基-、被一个或多个R m取代或未被取代的-C 3-6环烷基-、被一个或多个R m取代或未被取代的-C 3-6环烷基-C 1-6烷基-、被一个或多个R m取代或未被取代的-C 1-6烷基-氨基-C 1-6烷基-、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的-4-7元杂环基-、被一个或多个R m取代或未被取代的包含1-2个独立地选自N,O和S杂原子的-4-7元杂环基-C 1-6烷基-;R 8为氢原子、C 1-6烷基、C 3-6环烷基、或包含1-2个独立地选自N,O和S杂原子且任选的被氧代取代的5-7元杂环基;R 9和R 10独立地为氢原子、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、或杂环基烷基;R 11为氢原子、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、C 3-6环烷基-C 1-6烷基、氨基、C 1-6烷基氨基、二(C 1-6烷基)氨基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基,所述C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基可以任选地被一个或多个独立地选自以下的基团所取代:卤素、羟基、氰基;R 12和R 13各自独立地为氢原子、C 1-6烷基、C 3-7环烷基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基、或R 12和R 13与NR 12R 13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-10元杂环基,所述C 1-6烷基、C 3-7环烷基、包含1-3个独立地选自N,O或S杂原子的4-10元杂环基、或R 12和R 13与NR 12R 13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-10元杂环基可以任选地被一个或多个独 立地选自下组的取代基所取代:C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、卤素、羟基、氰基、氧代、C 1-6烷基-氨基、卤代C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、被一个或多个R m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C 1-6烷基-羰基;R 14和R 15独立地为氢原子、C 1-6烷基、或R 14和R 15与所连接的碳原子一起形成C 3-6环烷基;R 16为氢原子、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、或C 3-6环烷氧基;R a、R b、R c和R d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C 1-6烷基,所述的C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C 1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C 1-6烷基、C 3-6环烷基和C 1-6烷氧基。或者R a和R b与所连接的碳原子一起形成环、R c和R d与所连接的碳原子一起形成环,所述的环为C 3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C 3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C 1-6烷基、C 3-6环烷基和C 1-6烷氧基。环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环、或包含1-5个独立地选自N,O或S的杂原子5-10元桥环或螺环饱和或部分不饱和杂环,所述4-7元饱和或部分不饱和杂环和5-10元桥环或螺环饱和或部分不饱和杂环基可以任选独立地被一个或多个R m所取代;环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环、C 3-6环烷、6-10元单环芳环或二环芳环、或者包含1-5个独立地选自N,O或S的杂原子5-10元桥环或螺环饱和或部分不饱和杂环,所述4-7元饱和或部分不饱和杂环、C 3-6环烷、6-10元单环芳环或二环芳环、5-10元桥环或螺环饱和或部分不饱和杂环可以任选独立地被一个或多个R m所取代;R m为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基-C 1-6烷基、卤素、羟基、氰基、氰基-C 1-6烷基、氨基、氧代、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、C 1-6烷基-羰基、C 1-6烷基-氨基-酰基、二(C 1-6烷基)-氨基-酰基、C 3-6环烷基-氨基-酰基、C 1-6酰基-氨基、C 1-6烷基-O(CO)-或C 3-6环烷基-O(CO)-;q和t各自独立地为0、1、2或3;w为1、2或3;X为O、S、CR 17R 18、NR 17、CO或S(O) 2;R 17为氢原子、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、卤代C 3-6环烷基、C 1-6烷氧基-C 1-6烷基、卤代C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、氰基-C 1-6烷基、C 1-6烷基-羰基或C 1-6烷基-砜基;R 18为氢原子、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、氧代、卤素、羟基、氰基、氰基-C 1-6烷基、氨基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基、C 1-6烷基-羰基、C 1-6烷基-氨基-酰基、二(C 1-6烷基)-氨基-酰基、C 3-6环烷基-氨基-酰基、C 1-6烷基-酰基-氨基、C 1-6烷基-O(O)C-、C 1-6烷基-C(O)O-或C 1-6烷基-砜基;Z为N、O、S、CO、S(O) 2、-氨基-酰基、-酰基-氨基、-O(CO)-、-(CO)O-、CR 19、C 3-7环烷基或3-7元杂环基,所述C 3-7环烷基和3-7元杂环基可以任选独立地被一个或多个R 18所取代;R 19独立地为氢原子、C 1-6烷基或C 3-6环烷基;m和n独立地为0、1、2、3或4;p为0、1、2或3。
- 根据权利要求1所述的大环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子、水合物或溶剂化物,其中,在式I中:环A和环B各自独立地为苯环、或包含1-2个独立地选自N,O和S杂原子的5-6 元杂芳环,所述的苯环或5-6元杂芳环可以任选地被一个或多个独立地选自以下的取代基所取代:C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、氧代、卤素、羟基、氰基、氰基-C 1-6烷基、氨基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、氰基-C 1-6烷基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基可以任选地被一个或多个独立地选自以下取代基所取代:卤素、氰基、氨基、羟基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 1-6烷基-氨基和4-7元杂环基;优选地,在式I中,环A和环B各自独立地为苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑、异噻唑,所述的苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑和异噻唑可以任选地被一个或多个独立地选自以下取代基所取代:C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-4烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、氧代、卤素、羟基、氰基、氰基-C 1-6烷基、氨基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基和C 3-6环烷基-氨基。
- 根据权利要求1或2所述的大环化合物或者药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子、水合物或溶剂化物,其中,在式I中:环D为苯环、包含1-3个独立地选自N,O和S杂原子的5-6元杂芳环、包含1-2个独立地选自N,O和S杂原子的5-7元杂环或环己环;优选地,在式I中,环D为苯环、吡啶、嘧啶、吡嗪、哒嗪、哌啶、哌嗪、吡唑、咪唑或环己烷。
- 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子或溶剂合物,其中,在式I中:R 1、R 2、R 4和R 5其中1个为弹头基团,当R 1为弹头基团时,R 2、R 4和R 5各自独立 地为R 6,当R 2为弹头基团时,R 1、R 4和R 5各自独立地为R 6;当R 4为弹头基团时,R 1、R 2和R 5各自独立地为R 6;或当R 5为弹头基团时,R 1、R 2和R 4各自独立地为R 6;R 3和R 6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C 0-3烷基、氢原子、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-6烷基、羟基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基-C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)-氨基-C 1-6烷氧基、C 1-6烷基-羰基、C 1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C 0-3烷基、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-6烷基、羟基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基-C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)-氨基-C 1-6烷氧基、C 1-6烷基-羰基、C 1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基可以任选地被一个或多个独立地选自下组的取代基所取代:C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷基-O(O)C-、C 1-6烷基-羰基、氧代、卤素、羟基、C 1-6烷基氨基、二(C 1-6烷基)-氨基、可被1个或多个C 1-6烷基、C 1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;Y 1、Y 2和Y 3各自独立地为化学键、O或NR 8;R 8为氢原子、C 1-6烷基或C 3-6环烷基;R 9和R 10独立地为氢原子、卤素或氰基;R 12和R 13各自独立地为氢原子、C 1-6烷基、C 3-6环烷基、或R 12和R 13与NR 12R 13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-7元杂环,所述C 1-6烷基、C 3-6环烷基和形成的包含1-3个独立地选自N,O或S杂原子的4-7元杂环可以任选地被一个或多个独立地选自下组的取代基所取代:C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、卤素、羟基、氰基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、被一个或多个R m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C 1-6烷基-羰基;R 14和R 15独立地为氢原子、C 1-6烷基或R 14和R 15与所连接的碳原子一起形成C 3-6环烷基;R a、R b、R c和R d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C 1-6烷基,所述的C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C 1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C 1-6烷基、C 3-6环烷基和C 1-6烷氧基;或者R a和R b与所连接的碳原子一起形成环、R c和R d与所连接的碳原子一起形成环,所述的环为C 3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C 3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C 1-6烷基、C 3-6环烷基和C 1-6烷氧基;环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R m所取代;环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、C 3-6环烷、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、C 3-6环烷、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R m所取代;R m为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、卤素、羟基、 氰基、氨基、氧代、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、C 1-6烷基-羰基、C 1-6烷基-OC(O)-或C 3-6环烷基-OC(O)-;q和t各自独立地为0、1、2或3;w为1、2或3;优选地,在式I中,R 1、R 2、R 4和R 5其中1个为弹头基团,当R 1为弹头基团时,R 2、R 4和R 5各自独立地为R 6;当R 2为弹头基团时,R 1、R 4和R 5各自独立地为R 6;当R 4为弹头基团时,R 1、R 2和R 5各自独立地为R 6;或当R 5为弹头基团时,R 1、R 2和R 4各自独立地为R 6;R 3和R 6各自独立地为氢原子、卤素、甲基、乙基、三氟甲基、甲氧基、异丙氧基、氰基、羟基、羟甲基、甲氧基甲基、乙氧基甲基、甲基羰基、甲氧基羰基、4-甲基哌嗪-1-基羰基、二甲氨基甲基、二甲氨基乙氧基、羟基乙氧基、二甲氨基乙氧基甲基、N,N,N’-三甲基乙二氨基甲基、N,N-二甲基乙二氨基甲基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、N,N,N’-三甲基乙二氨基、N,N-二甲基乙二氨基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基,所述4-甲基哌嗪-1-基羰基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基可以任选地被一个或多个独立地选自下组的取代基所取代:卤素、甲基、乙基、异丙基、环丙基、甲氧基、甲氧基甲基、甲氧基乙基、甲基羰基、甲氧基羰基、氧代和二甲氨基;弹头基团为:
- 根据权利要求1至4中任一项所述的大环化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子或溶剂合物,其中,式I中:X为O或S;Z为N、O、S、-氨基-酰基、-酰基-氨基、或CR 19;R 19独立地为氢原子、C 1-6烷基或C 3-6环烷基;优选地,在式I中,Z为N、O或CR 19;R 19独立地为氢原子、甲基、乙基、异丙基、环丙基或环丁基。
- 根据权利要求1至5中任一项所述的大环化合物或者其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子或溶剂合物,其中,式I中:环A和环B各自独立地为苯环、或包含1-2个独立地选自N,O和S杂原子的5-6元杂芳环,所述的苯环或5-6元杂芳环可以任选地被一个或多个独立地选自以下的取代基所取代:C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、氧代、卤素、羟基、氰基、氰基-C 1-6烷基、氨基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、氰基-C 1-6烷基、氨基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基可以任选地被一个或多个独立地选自以下取代基所取代:卤素、氰基、氨基、羟基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 1-6烷基-氨基和4-7元杂环基;环D为苯环、包含1-3个独立地选自N,O和S杂原子的5-6元杂芳环、包含1-2个独立地选自N,O和S杂原子的5-7元杂环或环己环;R 1、R 2、R 4和R 5其中1个为弹头基团,当R 1为弹头基团时,R 2、R 4和R 5各自独立地为R 6;当R 2为弹头基团时,R 1、R 4和R 5各自独立地为R 6;当R 4为弹头基团时,R 1、R 2和R 5各自独立地为R 6;或当R 5为弹头基团时,R 1、R 2和R 4各自独立地为R 6;R 3和R 6各自独立地为包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C 0-3烷基、氢原子、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-6烷基、羟基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基-C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)-氨基-C 1-6烷氧基、C 1-6烷基-羰基、C 1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基,所述包含1-3个独立地选自N,O或S杂原子的3-11元单环或桥环或螺环杂环基-C 0-3烷基、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-6烷基、羟基-C 1-6烷氧基、C 1-6烷氧基-C 1-6 烷基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷氧基-C 1-6烷基、二(C 1-6烷基)-氨基-C 1-6烷基-氨基-C 1-6烷基、C 1-6烷氧基、二(C 1-6烷基)-氨基-C 1-6烷氧基、C 1-6烷基-羰基、C 1-6烷氧基-羰基、或包含1-3个独立地选自N,O或S的杂原子的3-7元杂环基-羰基可以任选地被一个或多个独立地选自下组的取代基所取代:C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷基-O(O)C-、C 1-6烷基-羰基、氧代、卤素、羟基、C 1-6烷基氨基、二(C 1-6烷基)-氨基、可被1个或多个C 1-6烷基、C 1-6烷氧基、氧代、卤素取代的包含1-3个独立地选自N,O或S的杂原子的5-7元杂环基;Y 1、Y 2和Y 3各自独立地为化学键、O或NR 8;R 8为氢原子、C 1-6烷基或C 3-6环烷基;R 9和R 10独立地为氢原子、卤素或氰基;R 12和R 13各自独立地为氢原子、C 1-6烷基、C 3-6环烷基、或R 12和R 13与NR 12R 13中的N一起形成包含1-3个独立地选自N,O或S杂原子的4-7元杂环,所述C 1-6烷基、C 3-6环烷基和形成的包含1-3个独立地选自N,O或S杂原子的4-7元杂环可以任选地被一个或多个独立地选自下组的取代基所取代:C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、卤素、羟基、氰基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、被一个或多个R m取代或未被取代的包含N,O或S杂原子的3-7元杂环基和C 1-6烷基-羰基;R 14和R 15独立地为氢原子、C 1-6烷基或R 14和R 15与所连接的碳原子一起形成C 3-6环烷基;R a、R b、R c和R d各自独立地为氢原子、氘原子、卤素、羟基、氰基、氧代、C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C 1-6烷基,所述的C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-氨基、C 1-6烷基-氨基-C 1-6烷基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基、C 3-6环烷基-氨基、3-7元杂环基、3-7元杂环基-C 1-6烷基可以任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C 1-6烷基、C 3-6环烷基和C 1-6烷氧基;或者R a和R b与所连接的碳原子一起形成环、R c和R d与所连接的碳原子一起形成环,所述的环为C 3-6环烷或包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环,所述的C 3-6环烷、包含1-3个独立地选自N,O或S杂原子的4-7元饱和或部分不饱和杂环任选地被一个或者多个以下基团所取代:卤素、羟基、氰基、C 1-6烷基、C 3-6环烷基和C 1-6烷氧基;环E为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R m所取代;环G为包含1-3个独立地选自N,O或S杂原子的4-7元饱和杂环、C 3-6环烷、或包含1-5个独立地选自N,O或S的杂原子7-10元桥环或螺环饱和杂环,所述4-7元饱和杂环、C 3-6环烷、7-10元桥环或螺环饱和杂环可以任选独立地被一个或多个R m所取代;R m为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、卤素、羟基、氰基、氨基、氧代、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、C 3-6环烷基-氨基、C 1-6烷基-羰基、C 1-6烷基-OC(O)-和C 3-6环烷基-OC(O)-;q和t各自独立地为0、1、2或3;w为1、2或3;X为O或S;Z为N、O、S、-氨基-酰基、-酰基-氨基、或CR 19;R 19独立地为氢原子、C 1-6烷基或C 3-6环烷基;m和n独立地为0、1、2、3或4;p为0、1、2或3;优选地,在式I中,环A和环B各自独立地为苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑、异噻唑,所述的苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、吡咯、噻吩、咪唑、噁唑、异噁唑、呋喃、噻唑和异噻唑可以任选地被一个或多个独立地选自以下取代基所取代:C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-4烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 3-6环烷氧基、卤代C 3-6环烷氧基、C 1-6烷氧基-C 1-6烷基、羟基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷基-氨基-C 1-6烷基、氧代、卤素、羟基、氰基、氰基-C 1-6烷基、氨基、C 1-6烷基-氨基、二(C 1-6烷基)-氨基、二(C 1-6烷基)-氨基-C 1-6烷基和C 3-6环烷基-氨基;环D为苯环、吡啶、嘧啶、吡嗪、哒嗪、哌啶、哌嗪、吡唑、咪唑或己烷;R 1、R 2、R 4和R 5其中1个为弹头基团,当R 1为弹头基团时,R 2、R 4和R 5各自独立地为R 6;当R 2为弹头基团时,R 1、R 4和R 5各自独立地为R 6;当R 4为弹头基团时,R 1、R 2和R 5各自独立地为R 6;或当R 5为弹头基团时,R 1、R 2和R 4各自独立地为R 6;R 3和R 6各自独立地为氢原子、卤素、甲基、乙基、三氟甲基、甲氧基、异丙氧基、氰基、羟基、羟甲基、甲氧基甲基、乙氧基甲基、甲基羰基、甲氧基羰基、4-甲基哌嗪-1-基羰基、二甲氨基甲基、二甲氨基乙氧基、羟基乙氧基、二甲氨基乙氧基甲基、N,N,N’-三甲基乙二氨基甲基、N,N-二甲基乙二氨基甲基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、N,N,N’-三甲基乙二氨基、N,N-二甲基乙二氨基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基,所述4-甲基哌嗪-1-基羰基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基可以任选地被一个或多个独立地选自下组的取代基所取代:卤素、甲基、乙基、异丙基、环丙基、甲氧基、甲氧基甲基、甲氧基乙基、甲基羰基、甲氧基羰基、氧代和二甲氨基;弹头基团为:X为O或S;Z为N、O或CR 19;R 19独立地为氢原子、甲基、乙基、异丙基、环丙基或环丁基;m和n独立地为0、1、2、3或4;p为0、1、2或3;更优选地,在式I中,环A和环B各自独立地为苯环、吡啶、嘧啶、哒嗪、吡嗪、吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑,所述的苯、吡啶、嘧啶、哒嗪、吡嗪、吡唑、咪唑、噁唑、异噁唑、噻唑和异噻唑可以任选地被一个或多个独立地选自下组的取代基所取代:甲基、乙基、异丙基、乙烯基、乙炔基、氟代乙基、甲氧基、乙氧基、环丙基、环戊基、甲氧基、乙氧基、环丙氧基、甲氧基甲基、甲氧基乙基、羟基乙基、羟基丙基、氨基乙基、氧代、氟、氯、溴、羟基、氰基、氰基乙基、氰基丙基、氨基、甲氨基、乙氨基、二甲基氨基、二乙基氨基、二甲基氨基甲基、二甲基氨基乙基、甲基氨基乙基、环丙氨基;环D为苯环、吡啶、嘧啶、吡嗪、哒嗪、哌啶或哌嗪;R 1、R 2、R 4和R 5其中1个为弹头基团,当R 1为弹头基团时,R 2、R 4和R 5各自独立地为R 6;当R 2为弹头基团时,R 1、R 4和R 5各自独立地为R 6;当R 4为弹头基团时,R 1、R 2和R 5各自独立地为R 6;或当R 5为弹头基团时,R 1、R 2和R 4各自独立地为R 6;R 3和R 6独立地为氢原子、氟、氯、溴、甲基、乙基、三氟甲基、甲氧基、异丙氧基、氰基、羟基、羟甲基、甲氧基甲基、乙氧基甲基、甲基羰基、甲氧基羰基、4-甲基哌嗪-1-基羰基、二甲氨基甲基、二甲氨基乙氧基、羟基乙氧基、二甲氨基乙氧基甲基、N,N,N’-三甲基乙二氨基甲基、N,N-二甲基乙二氨基甲基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、N,N,N’-三甲基乙二氨基、N,N-二甲基乙二氨基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基,所述4-甲基哌嗪-1-基羰基、吡咯烷基甲基、吗啉代甲基、氮杂环丁烷基甲基、哌啶基甲基、4-(二甲氨基)哌啶-1-基甲基、4-(3-甲氧基吖啶-1-基)哌啶-1-基甲基、哌嗪-1-基甲基、4-甲基哌嗪-1-基甲基、4-乙酰哌嗪-1-基甲基、2-(二甲氨基)-7-氮杂螺[3.5]壬烷-7-基甲基、吡咯烷基、哌啶基、吗啉基、哌嗪基、六氢吡喃基、四氢呋喃基可以任选地被一个或多个独立地选自下组的取代基所取代:氟、氯、溴、甲基、乙基、异丙基、环丙基、甲氧基、甲氧基甲基、甲氧基乙基、甲基羰基、甲氧基羰基、氧代和二甲氨基;弹头基团为:X为O或S;Z为N、O或CR 19;R 19独立地为氢原子、甲基、乙基或环丙基;m和n独立地为0、1、2、3或4;p为0、1、2或3;最优选地,式I所示的化合物选自下列的化合物:
- 一种制备权利要求1至6中任一项所述的化合物的制备方法,该方法包括如下反应步骤:(1)使化合物1与化合物2在碱性条件下反应,形成化合物3;(2)使化合物3与化合物4发生Mitsunobu反应或亲核取代反应或偶联反应形成化合物5;(3)将化合物5还原为化合物6;(4)使化合物6与BrCN反应,形成化合物7;(5)将化合物7水解为化合物8;(6)使化合物8发生分子内缩合反应,形成化合物9;(7)将化合物9脱保护基或者使化合物9先偶联或取代再脱保护基为化合物10;(8)使化合物10与化合物11反应,形成式I所示化合物;优选地,步骤(1)中碱性条件下使用的碱选自碳酸钾;步骤(5)中水解使用的碱选自氢氧化锂;或者,所述制备式I化合物的方法包括如下反应步骤:(1)使化合物1与化合物2在碱性条件下反应,形成化合物3;(2)将化合物3还原为化合物11;(3)使化合物11与BrCN反应,形成化合物12;(4)使化合物12与化合物13发生反应,形成化合物14;(5)将化合物14关环形成化合物9;(6)将化合物9脱保护基或者使化合物9先偶联或取代再脱保护基为化合物10;(7)使化合物10与化合物11反应,形成式I所示化合物;优选地,步骤(1)中碱性条件下使用的碱选自碳酸钾;其中,当R 1为弹头基团时,R 22为氢原子、-Y 1(CR aR b) qNHR 8、 R 20为带有保护基团的R 22、卤素、带保护基的氧基、带保护基的氨基等,R 18、R 19、R 21、R 23、R 24和R 25为R 6;当R 2为弹头基团时,R 23为-Y 1(CR aR b) qNHR 8、 R 21为带有保护基团的R 23、卤素、带保护基的氧基、带保护基的氨基等,R 18、R 19、R 20、R 22、R 24和R 25为R 6;当R 4 为弹头基团时,R 24为-Y 1(CR aR b) qNHR 8、 R 18为带有保护基团的R 24、卤素、带保护基的氧基、带保护基的氨基等,R 19、R 20、R 21、R 22、R 23和R 25为R 6;或当R 5为弹头基团时,R 25为-Y 1(CR aR b) qNHR 8、 R 19为带有保护基团的R 25、卤素、带保护基的氧基、带保护基的氨基等,R 18、R 20、R 21、R 22、R 23和R 24为R 6;上述的带保护基的基团中,保护基团包括但不限于叔丁氧羰基、苄氧羰基、苄基或二甲氧基苄基;L为羟基、卤素或离去基团;此外,A、B、D、E、G、R 1、R 2、R 3、R 4、R 5、R 6、R 8、R a、R b、R c、R d、Y 1、Y 2、Y 3、Z、X、p、q、m、n、t、弹头基团如权利要求1至6任一项所定义。
- 包含如权利要求1-6中任一项所述的化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子或溶剂合物以及药学上可接受的载体或赋形剂的药物组合物;优选地,所述药物组合物为片剂、胶囊剂、丸剂、颗粒剂、散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、洗剂、滴剂、擦剂、喷雾剂。
- 根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子或溶剂合物和/或权利要求8所述的药物组合物在制备抗肿瘤药物中的应用;优选地,所述抗肿瘤药物应用于以下病症:头颈部癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾细胞癌、乳腺癌、结肠直肠癌、卵巢癌、***、胰腺癌、胶质瘤、胶质母细胞瘤、***癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝 细胞癌、胃肠道基质瘤、甲状腺癌、胆管癌、子宫内膜癌、多发性骨髓瘤或间皮瘤。
- 根据权利要求9所述的应用,其特征在于,所述肿瘤为携带EGFR基因突变的恶性肿瘤;优选的EGFR基因突变选自:Del19 EGFR基因突变、L858R EGFR基因突变、T790M EGFR基因突变和C797S EGFR基因突变中的一种或多种。
- 一种治疗有需要的患者中肿瘤的方法,该方法包括向所述患者给予治疗有效量的权利要求1-6中任一项所述的化合物或其药学上可接受的盐、立体异构体、消旋体、互变异构体、同位素标记物、氮氧化物、前药分子或溶剂合物和/或权利要求8所述的药物组合物;优选地,所述的患者优选哺乳动物,所述哺乳动物优选为人;优选地,所述肿瘤选自:头颈部癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾细胞癌、乳腺癌、结肠直肠癌、卵巢癌、***、胰腺癌、胶质瘤、胶质母细胞瘤、***癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道基质瘤、甲状腺癌、胆管癌、子宫内膜癌、多发性骨髓瘤或间皮瘤。
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WO2024017358A1 (zh) * | 2022-07-21 | 2024-01-25 | 贝达药业股份有限公司 | 大环化合物及其药物组合物和应用 |
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