[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN113490667B - Imidazopyridine derivatives as dual FGFR and VEGFR inhibitors - Google Patents

Imidazopyridine derivatives as dual FGFR and VEGFR inhibitors Download PDF

Info

Publication number
CN113490667B
CN113490667B CN201980092860.3A CN201980092860A CN113490667B CN 113490667 B CN113490667 B CN 113490667B CN 201980092860 A CN201980092860 A CN 201980092860A CN 113490667 B CN113490667 B CN 113490667B
Authority
CN
China
Prior art keywords
compound
added
mmol
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201980092860.3A
Other languages
Chinese (zh)
Other versions
CN113490667A (en
Inventor
戴美碧
张杨
陈正霞
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cgenetech Suzhou China Co Ltd
Original Assignee
Shengshi Taike Biopharmaceutical Technology Suzhou Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shengshi Taike Biopharmaceutical Technology Suzhou Co ltd filed Critical Shengshi Taike Biopharmaceutical Technology Suzhou Co ltd
Publication of CN113490667A publication Critical patent/CN113490667A/en
Application granted granted Critical
Publication of CN113490667B publication Critical patent/CN113490667B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed are FGFR and VEGFR dual inhibitors, specifically compounds or pharmaceutically acceptable salts of formula (III).

Description

Imidazopyridine derivatives as dual FGFR and VEGFR inhibitors
Citation of related application
The present application claims the following priorities:
CN201811640177.2, filing date: 2018-12-29;
CN201910313237.8, filing date: 2019-04-18;
CN201910802391.1, filing date: 2019-08-28;
CN201911310776.2, filing date: 2019-12-18.
Technical Field
The application relates to a FGFR and VEGFR dual inhibitor, in particular to a compound shown in a formula (III) or pharmaceutically acceptable salt thereof.
Background
FGFR is a bioactive substance with functions of transmitting biological signals, regulating cell growth, participating in tissue repair and the like, and in recent years, a plurality of FGFR family members have been found to play an important role in the processes of tumorigenesis and development. Fibroblast Growth Factor Receptor (FGFR) is a class of receptor proteins that specifically bind to Fibroblast Growth Factor (FGF), and the family of FGFRs includes the following classes: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4. Unlike FGF to which FGFR of different subtypes binds, FGFs binds to FGFs resulting in autophosphorylation of intracellular tyrosine residues, and signaling pathways downstream of activation of phosphorylated FGFRs include MEK/MAPK, PLCy/PKC, PI3K/AKT, STATS, and the like. In tumors, such as liver cancer, bladder cancer, lung cancer, breast cancer, endometrial cancer, brain glioma, prostate cancer and the like, FGFR activation mutation or ligand/receptor overexpression leads to continuous constitutive activation, which is closely related to occurrence, development, poor prognosis and the like of the tumors, and plays an important role in the processes of tumor angiogenesis, invasion and metastasis of the tumors and the like. FGFR is therefore considered an important target for anti-tumor.
Angiogenesis and lymphatic production are important links in tumor formation and metastasis, and the Vascular Endothelial Growth Factor (VEGF) and VEGF receptor (VEGFR) families play a major role in both of these links. The VEGFR family includes three specific tyrosine kinase receptors, VEGFR-1, VEGFR-2 (KDR) and VEGFR-3. VEGFR-2 is an important regulator of VEGF signaling causing endothelial cell proliferation, increasing vascular permeability effects and promoting angiogenesis, and the affinity of VEGFR-2 for VEGF is greater than that of VEGFR-1. Research shows that only VEGFR-2 is expressed in endothelial cells, and the vascular generation can be efficiently stimulated after VEGFR-2 is activated. VEGFR-2 is therefore a major target for the development of anti-angiogenic drugs.
Under specific experimental conditions, VEGF requires the presence of FGF to exert its pro-angiogenic effect, and the VEGFR and FGFR pathways together complete activation and production of endothelial cells in angiogenesis. FGFR and VEGFR can directly inhibit the growth, survival, proliferation and migration of tumor cells; also has the effect of inhibiting tumor angiogenesis, and improving microenvironment. The synergistic effect of FGFR and VEGFR channels can also inhibit tumor immune escape and improve tumor inhibition effect.
Disclosure of Invention
The invention provides a compound shown as a formula (III) or pharmaceutically acceptable salt thereof,
wherein,,
R 1 selected from H, -S (=O) 2 CH 3 、C 1-6 Alkyl, C 1-3 Alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, said C 1-6 Alkyl, C 1-3 Alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl are optionally substituted with 1, 2 or 3R a Substitution;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, B r 、I、OH、NH 2 、CH 3 And OCH 3 ；
R 4 Selected from H, NH 2 、C 1-6 Alkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl radicalsThe C is 1-6 Alkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl and->Optionally by 1, 2 or 3R b Substitution;
m is selected from 1 and 2;
l is selected from-N (R) 5 )C(＝O)-、-N(R 5 )S(＝O) 2 -、-N(R 5 )C(＝O)N(R 5 )-、N(R 5 )S(＝O) 2 N(R 5 ) -and-N (R) 5 )-；
Ring a is selected from phenyl, pyrrolyl, pyrimidinyl and pyridinyl;
ring B is absent;
or, ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl and 3, 6-dihydro-2H-pyranyl;
R 5 are independently selected from H and C 1-3 An alkyl group;
R a and R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、-S(＝O) 2 CH 3 、C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino, said-S (=o) 2 CH 3 、C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino is optionally substituted with 1, 2 or 3R;
r is selected from H, F, cl, B r I, OH and NH 2 。
In some aspects of the invention, R is as described above a And R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、-S(＝O) 2 CH 3 、CH 3 、-OCH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 said-S (=o) 2 CH 3 、CH 3 、-OCH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 Optionally substituted with 1, 2 or 3R, and the other variables are as defined herein.
In some aspects of the invention, R is as described above a And R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 OH、-OCH 3 、-S(＝O) 2 CH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 The other variables are as defined herein.
In some aspects of the invention, R is as described above 1 Selected from H, -S (=O) 2 CH 3 、CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、OCH 2 CH 3 Tetrahydropyranyl, tetrahydrofuranyl and piperidinyl groups, said CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、OCH 2 CH 3 The tetrahydropyranyl, tetrahydrofuranyl and piperidinyl groups are optionally substituted with 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 1 Selected from H, -S (=O) 2 CH 3 、CH 3 、CH 2 OH、CH 2 CH 3 、CH 2 CH 2 OH、OCH 2 CH 3 、 The other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H,NH 2 、CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 、OCH 3 、OCH 2 CH 3 Cyclopropane, azetidine and pyrrolidinyl groups, said CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 、OCH 3 、OCH 2 CH 3 Optionally substituted with 1, 2 or 3R groups b Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H, NH 2 、CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 、CH 2 CH 2 N(CH 3 ) 2 、OCH 3 、 The other variables are as defined herein.
In some aspects of the invention, R is as described above 5 Are respectively and independently selected from H, CH 3 And CH (CH) 2 CH 3 The other variables are as defined herein.
In some embodiments of the invention, the L is selected from the group consisting of-NHC (=O) -, -NHC (=O) NH-, -NHS (=O) 2 -、-NHS(＝O) 2 NH-and-NH-, and other variables are as defined herein.
In some embodiments of the invention, the above-mentioned-L-R 4 Selected from the group consisting of The other variables are as defined herein.
In some embodiments of the invention, the ring A is selected fromThe other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from-> The other variables are as defined herein.
In some embodiments of the invention, the ring B is selected fromThe other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from-> The other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from OCH2CH 3 、 The other variables are as defined herein.
The invention provides a compound shown as a formula (III) or pharmaceutically acceptable salt thereof,
wherein,,
R 1 selected from H, C 1-6 Alkyl and 4-6 membered heterocycloalkyl, said C 1-6 Alkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3R a Substitution;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CH 3 And OCH 3 ；
R 4 Selected from H, NH 2 、C 1-6 Alkyl, C 3-5 Cycloalkyl and 4-6 membered heterocycloalkyl, said C 1-6 Alkyl, C 3-5 Cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3R b Substitution;
l is selected from-N (R) 5 )C(＝O)-、-N(R 5 )S(＝O) 2 -、-N(R 5 )C(＝O)N(R 5 ) -, and-N (R) 5 )-；
Ring a is selected from phenyl and 5-6 membered heteroaryl;
Ring B is selected from the group consisting of 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, and 5-6 membered heterocycloalkenyl;
R 5 are independently selected from H and C 1-3 An alkyl group;
R a and R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、-S(＝O) 2 CH 3 、C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino, said-S (=o) 2 CH 3 、C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino is optionally substituted with 1, 2 or 3R;
r is selected from H, F, cl, br, I, OH and NH 2 ；
The 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl each contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from-NH-, -O-, -S-and N.
In some aspects of the invention, R is as described above a And R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、-S(＝O) 2 CH 3 、CH 3 、-OCH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 said-S (=o) 2 CH 3 、CH 3 、-OCH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 Optionally substituted with 1, 2 or 3R, and the other variables are as defined herein.
In some aspects of the invention, R is as described above a And R is b Are respectively and independently selected from H, F, cl, B r 、I、OH、NH 2 、CN、CH 3 、CH 2 OH、-OCH 3 、-S(＝O) 2 CH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 The other variables are as defined herein.
In some aspects of the invention, R is as described above 1 Selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 Tetrahydropyranyl, tetrahydrofuranyl and piperidinyl groups, said CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 The tetrahydropyranyl, tetrahydrofuranyl and piperidinyl groups are optionally substituted with 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 1 Selected from H, CH 3 、CH 2 OH、CH 2 CH 3 、CH 2 CH 2 OH、 The other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H, NH 2 、CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 Cyclopropane, azetidine and pyrrolidinyl groups, said CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 Optionally substituted with 1, 2 or 3R groups b Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H, NH 2 、CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 、CH 2 CH 2 N(CH 3 ) 2 、The other variables are as defined herein.
In some aspects of the invention, R is as described above 5 Are respectively and independently selected from H, CH 3 And CH (CH) 2 CH 3 The other variables are as defined herein.
In some embodiments of the invention, the L is selected from the group consisting of-NHC (=O) -, -NHC (=O) NH-, -NHS (=O) 2 -and-NH-, the other variables being as defined herein.
In some embodiments of the invention, the above-mentioned-L-R 4 Selected from the group consisting of The other variables are as defined herein.
In some embodiments of the invention, ring A is selected from phenyl, pyrrolyl, pyrimidinyl and pyridinyl, and the other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from-> The other variables are as defined herein.
In some embodiments of the invention, the ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl and 3, 6-dihydro-2H-pyranyl, and the other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from-> The other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from-> The other variables are as defined herein.
The invention provides a compound shown as a formula (II) or pharmaceutically acceptable salt thereof,
wherein,,
R 1 selected from H and optionally substituted with 1, 2 or 3R a Substituted C 1-3 An alkyl group;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, B r I, OH and NH 2 ；
R 4 Selected from H, C 1-6 Alkyl and C 3-5 Cycloalkyl group, the C 1-6 Alkyl and C 3-5 Cycloalkyl is optionally substituted with 1, 2 or 3R b Substitution;
l is selected from-N (R) 5 )C(＝O)-、-N(R 5 )S(＝O) 2 -、-N(R 5 )C(＝O)N(R 5 ) -and-N (R) 5 )-；
R 5 Are independently selected from H and C 1-3 An alkyl group;
ring B is selected from 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;
R a and R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 CN and CH 3 ；
The 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl each contain 1, 2, 3 or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-and N.
In some aspects of the invention, R is as described above 1 Selected from H, CH 3 And CH (CH) 2 CH 3 The CH is 3 And CH (CH) 2 CH 3 Optionally by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 1 Selected from H, CH 3 、CH 2 OH、CH 2 CH 2 OH and CH 2 CH 3 The other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H, cyclopropane, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 And CH (CH) 2 CH 2 CH 3 The cyclopropane group, CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 And CH (CH) 2 CH 2 CH 3 Optionally by 1, 2 or 3R b Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H,CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 And CH (CH) 2 CH 2 CH 3 The other variables are as defined herein.
In some aspects of the invention, R is as described above 5 Are respectively and independently selected from H, CH 3 And CH (CH) 2 CH 3 The other variables are as defined herein.
In some embodiments of the invention, the L is selected from the group consisting of-NHC (=O) -, -NHC (=O) NH-, -NHS (=O) 2 -and-NH-, the other variables being as defined herein.
In some embodiments of the invention, the above-mentioned-L-R 4 Selected from the group consisting of The other variables are as defined herein.
In some embodiments of the invention, ring B is selected from imidazolyl, pyrazolyl, piperidinyl, morpholinyl and tetrahydropyranyl, and the other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from->The other variables are as defined herein.
In some aspects of the invention, the structural units described aboveSelected from->The other variables are as defined herein.
The invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof,
wherein,,
R 1 selected from H and optionally substituted with 1, 2 or 3R a Substituted C 1-3 An alkyl group;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, B r I, OH and NH 2 ；
R 4 Selected from H, cyclopropenyl and optionally substituted with 1, 2 or 3R b Substituted C 1-3 An alkyl group;
l is selected from-N (R) 5 )C(＝O)-、-N(R 5 )S(＝O) 2 -and-NH-;
R 5 are independently selected from H and C 1-3 An alkyl group;
R a and R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 CN and CH 3 。
In some aspects of the invention, R is as described above 1 Selected from H, CH 3 And CH (CH) 2 CH 3 The CH is 3 And CH (CH) 2 CH 3 Optionally by 1, 2 or 3R a Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 1 Selected from H, CH 3 And CH (CH) 2 CH 3 The other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H, cyclopropane, CH 3 And CH (CH) 2 CH 3 The CH is 3 And CH (CH) 2 CH 3 Optionally by 1, 2 or 3R b Instead, the other variables are as defined herein.
In some aspects of the invention, R is as described above 4 Selected from H,CH 3 And CH (CH) 2 CH 3 The other variables are as defined herein.
In some aspects of the invention, R is as described above 5 Are respectively and independently selected from H, CH 3 And CH (CH) 2 CH 3 The other variables are as defined herein.
In some embodiments of the invention, the above L is selected from the group consisting of-NHC (=O) -, -NHS (=O) 2 -and-NH-, the other variables being as defined herein.
In some embodiments of the invention, the above-mentioned-L-R 4 Selected from the group consisting ofThe other variables are as defined herein.
Still other embodiments of the present invention are derived from any combination of the variables described above.
In some embodiments of the invention, the above compound or a pharmaceutically acceptable salt thereof is selected from
Wherein,,
R 1 、R 2 、R 3 、L、T 1 and R is 4 As defined herein.
In some embodiments of the invention, the above compound or a pharmaceutically acceptable salt thereof is selected from
Wherein,,
R 1 、R 2 、R 3 、T 1 and R is 4 As defined herein.
The invention also provides a compound shown in the following formula or pharmaceutically acceptable salt thereof,
the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof or the composition in preparing medicines related to FGFR and VEGFR dual inhibitors.
In some aspects of the invention, the use as described above, wherein the dual FGFR and VEGFR inhibitor related agent is an agent for solid tumors.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
Certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine). The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, and may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
When the number of one linking group is 0, such as- (CRR) 0 -, indicating that the linking group is monoA key.
When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.
When a substituent is absent, it is meant that the substituent is absent, e.g., X in A-X is absent, meaning that the structure is actually A. When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring. When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The linking group L is-M-W-, in which case-M-W-may be a group in which the linking rings A and B are linked in the same direction as the reading order from left to right>It is also possible to connect the ring A and the ring B in the opposite direction to the reading order from left to right>Combinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, the term "C 1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is 1-6 Alkyl includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 And C 5 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and isopropyl)t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.
Unless otherwise specified, the term "C 1-3 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C is 1-3 Alkyl includes C 1-2 And C 2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
Unless otherwise specified, the term "C 1-3 Alkoxy "means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-3 Alkoxy includes C 1-2 、C 2-3 、C 3 And C 2 Alkoxy groups, and the like. C (C) 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
Unless otherwise specified, the term "C 1-3 Alkylamino "means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. The C is 1-3 Alkylamino includes C 1-2 、C 3 And C 2 Alkylamino, and the like. C (C) 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-NHCH 2 CH 2 CH 3 、-NHCH 2 (CH 3 ) 2 Etc.
Unless otherwise specified, the term "4-6 membered heterocycloalkyl" alone or in combination with other terms, refers to a saturated cyclic group consisting of 4 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O) p P is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, with respect to the "4-6 membered heterocycloalkyl group", Heteroatoms may occupy the attachment position of the heterocycloalkyl group to the remainder of the molecule. The 4-6 membered heterocycloalkyl group includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups and the like. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.
Unless otherwise specified, "C 3-5 Cycloalkyl "denotes a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 Cycloalkyl includes C 3-4 And C 4-5 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) 3-5 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
Unless otherwise specified, the term "5-6 membered heterocycloalkyl" alone or in combination with other terms, refers to a saturated cyclic group consisting of 5 to 6 ring atoms, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O) p P is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, in the case of the "5-6 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 5-6 membered heterocycloalkyl group includes 5-and 6-membered heterocycloalkyl groups. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl)Group, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.
The terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably herein unless otherwise specified, the term "5-6 membered heteroaryl" meaning a monocyclic group having a conjugated pi-electron system consisting of 5 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. Wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p P is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl, etc.
Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" alone or in combination with other terms, respectively, denotes a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p P is 1 or 2). It comprises a sheetRing and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings, any ring of which is non-aromatic. In addition, with respect to the "5-6 membered heterocycloalkenyl", the heteroatom may occupy the position of attachment of the heterocycloalkenyl to the remainder of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-and 6-membered heterocycloalkenyl groups and the like. Examples of 5-6 membered heterocycloalkenyl groups include, but are not limited to
The term "leaving group" refers to a functional group or atom that may be substituted with another functional group or atom by a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromophenylsulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl groups such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and t-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The solvent used in the present invention is commercially available. The invention adopts the following abbreviations: aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC represents N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE stands for PE; DIAD stands for diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide; etOAc represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents that tert-butoxycarbonyl is an amine protecting group; HOAc stands for acetic acid; naCNBH 3 Represents sodium cyanoborohydride; rt represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc 2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 Represents thionyl chloride; CS (circuit switching) 2 Represents carbon disulphide; tsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (benzenesulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione N-chlorosuccinimide; n-Bu 4 NF represents tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp represents the melting point; LDA represents lithium diisopropylamide; liHMDS represents lithium hexamethyldisilazide; xantphos represents 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; liAlH 4 Represents lithium aluminum hydride; pd (dba) 2 represents tris (dibenzylideneacetone) dipalladium; mCPBA stands for m-chloroperoxybenzoic acid; pd (dppf) Cl 2 Represents [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; DBU represents 1, 8-diazabicyclo [5.4.0]Undec-7-ene; NIS represents N-iodineSubstituted succinimides; pd (Pd) 2 (dba) 3 Represents tris (dibenzylideneacetone) dipalladium; BINAP stands for (±) -2, 2-bis (diphenylphosphino) -11-binaphthyl; k (K) 3 PO 4 Representing potassium phosphate.
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
Technical effects
Compared with Example 5 in patent WO2013053983 (comparative Example 1 in this patent), the imidazopyridine parent nucleus of the present invention is improved by nearly 4 to 10 times on FGFR1 or FGFR2 kinase, nearly 3 to 10 times on FGFR4 and nearly 3 to 20 times on VEGFR2 kinase activity, and nearly 3 to 6 times on cell activity, which is highly likely to show more excellent therapeutic effect at lower doses clinically. The tumor inhibition effect on the FGFR abnormality is obviously better than that of the single-target selective FGFR inhibitor, and the treatment effect of the patient with the clinical FGFR abnormality is expected to be improved.
Drawings
FIG. 1 is a tumor growth inhibition curve;
figure 2 is a graph of mice body weight during dosing.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.
Comparative example 1
Step one
3, 5-dinitrobromobenzene (10 g,40.49 mmol) and (2, 4-difluoro) phenylboronic acid (6.39 g,40.49 mmol) were dissolved in water (2 mL) and acetonitrile (120 mL), palladium acetate (454.46 mg,2.02 mmol) and triethylamine (12.29 g,121.46mmol,16.91 mL) were added, the reaction mixture was stirred at 85℃for 16 hours, the reaction mixture was directly dried to obtain a crude solid product, and the crude solid product was purified by column chromatography with PE: EA=5:1 to obtain compound a.
1 H NMR(400MHz，CDCl 3 )δ9.06(t，J＝2.00Hz，1H)，8.72(dd，J＝1.92，1.10Hz，2H)，7.54(td，J＝8.74，6.32Hz，1H)，7.00-7.15(m，2H).
Step two
Compound a (6.5 g,23.20 mmol) was dissolved in EtOAc (65 mL) in a hydrogenation flask, pd/C (1 g,23.20mmol,10% purity) was added and the reaction stirred at 45℃for 16 hours in a hydrogen bottle (46.77 mg,23.20mmol,1 eq) at 50Psi pressure. The reaction solution is filtered, and the filtrate is dried by spin to obtain the compound b.
LCMS(ESI)m/z：220.9[M+1] +
1 H NMR(400MHz，DMSO-d 6 ，)：δ7.36-7.45(m，1H)，7.20-7.30(m，1H)，7.10(td，J＝8.52，2.44Hz，1H)，5.92(d，J＝1.52Hz，2H)，5.86(d，J＝1.82Hz，1H)，4.84(s，4H).
Step three
To a solution of compound b (2.37 g,10.76 mmol) in DMSO (15 mL) was added DIEA (417.28 mg,3.23mmol, 562.37. Mu.L), ethoxytrimethylsilane (2.29 g,19.37 mmol), 4-bromo-1-fluoro-2-nitro-benzene (2.37 g,10.76mmol,1.32 mL) and stirred at 100deg.C for 16 h. The reaction solution is added into 100mL of water for stirring, a large amount of solids are separated out, a filter cake is collected after decompression and suction filtration, and the filter cake is dried by 20mL of anhydrous toluene with water in a spinning way to obtain the compound c.
LCMS(ESI)m/z：419.9[M+3] + ，421.9[M+3] +
1 H NMR(400MHz，CDCl 3 )δ9.40(s，1H)，8.33(d，J＝2.26Hz，1H)，7.33-7.46(m，2H)，7.21-7.25(m，2H)，7.11-7.19(m，1H)，6.86-6.97(m，2H)，6.76(d，J＝1.52Hz，1H)，6.68(d，J＝1.76Hz，1H)，6.56(t，J＝2.02Hz，1H)，
Step four
To a suspension of compound c (4.5 g,10.71 mmol) in pyridine (30 mL) under nitrogen was added cyclopropylsulfonyl chloride (1.66 g,11.78 mmol). Stirred at 20℃for 2 hours. Acetic acid (34.6 mL) was added to the reaction solution, followed by addition of water (250 mL), extraction was performed by addition of ethyl acetate (150 mL x 2), and the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound d.
LCMS(ESI)m/z：523.8[M+1] + ，525.8[M+3] +
Step five
To a solution of compound d (5.6 g,10.68 mmol), 1-methyl-4-pyrazole-boronate (2.78 g,13.35 mmol) in dimethyl sulfoxide (110 mL) and water (30 mL) was added triphenylphosphine (1.40 g,5.34 mmol), palladium acetate (359.67 mg,1.60 mmol) and potassium carbonate (3.84 g,27.77 mmol). Stirring at 100℃for 16 hours under nitrogen. The reaction solution was added with water (200 mL) containing stirring, solids were precipitated, the filter cake was collected by suction filtration under reduced pressure, the filter cake was transferred to a single-necked flask via methylene chloride, and then the crude product was obtained by concentration under reduced pressure. The crude product was purified by column chromatography (flash silica gel column chromatography) with petroleum ether/ethyl acetate=0/1 to give compound e.
LCMS(ESI)m/z：526.4[M+3] +
1 H NMR(400MHz，CDCl 3 )δ9.45(s，1H)，8.29(d，J＝2.02Hz，1H)，7.73(s，1H)，7.62(s，1H)，7.53-7.58(m，1H)，7.37-7.48(m，2H)，7.16-7.24(m，3H)，6.90-7.01(m，2H)，6.71(s，1H)，3.96(s，3H)，2.52-2.65(m，1H)，1.22-1.26(m，2H)，0.98-1.11(m，2H).
Step six
To a solution of compound e (2.8 g,5.33mmol,1 eq) in formic acid (30 mL) was added Pd/C (1 g,5.33mmol,10% purity) and stirred at 30℃under an atmosphere of hydrogen balloon (15 psi) for 16 hours. After the reaction, the mixture is filtered through diatomite, and the filtrate is decompressed and concentrated to obtain a crude product. The crude product was subjected to high performance liquid chromatography (column: YMC-Triart Prep C18 150X 40mm X7 μm; mobile phase: [ water (0.1% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 35% -50%,10 min) to give control 1.
LCMS(ESI)m/z：506.0[M+1] +
1 H NMR(400MHz，DMSO-d 6 )δ10.25(br s，1H)，8.65(s，1H)，8.19(s，1H)，7.99(s，1H)，7.94(s，1H)，7.71-7.81(m，1H)，7.64-7.70(m，1H)，7.55-7.63(m，3H)，7.40-7.51(m，2H)，7.27(br t，J＝7.53Hz，1H)，3.88(s，3H)，2.81-2.93(m，1H)，0.98-1.08(m，4H).
The trifluoroacetate salt of comparative example 1 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give comparative example 1.
Example 1
Step one
3, 5-dinitrobromobenzene (20 g,80.97 mmol) was dissolved in glacial acetic acid (120 mL), the temperature was raised to 90℃and reduced iron powder (11.30 g,202.43 mmol) was slowly added to the reaction mixture in portions over 30 minutes, and the reaction was completed. Crushed ice is added into the reaction liquid, solid is separated out, and the reaction liquid is filtered and washed 3 times. The filter cake was collected and toluene was used to carry water to give compound 1a.
1 H NMR(400MHz，DMSO-d 6 )δ7.09-7.32(m，3H)，6.13(br s，2H).
Step two
Acetic anhydride (16.02 g,156.95mmol,14.7 mL) was added to 1a (14.7 g,67.74 mmol) at 0deg.C and stirring was continued for 30 min at 15deg.C. 140mL of crushed ice is added into the reaction liquid, solid is separated out, the reaction liquid is filtered, the reaction liquid is washed twice by ice water, a filter cake is collected, and the compound 1b is obtained by spin drying. 1 H NMR(400MHz，DMSO-d 6 )δ8.46(s，1H)，8.19(s，1H)，8.02(s，1H)，2.10(s，3H).
Step three
Compound 1b (16 g,61.76 mmol) and 2, 4-difluorophenylboronic acid (11.70 g,74.12 mmol) were dissolved in ethylene glycol dimethyl ether (160 mL) and H 2 To O (60 mL), pd (dppf) Cl was added 2 (4.52 g,6.18 mmol) and sodium carbonate (19.64 g,185.29 mmol), stirred at 90℃for 2 hours. The reaction solution was filtered, water (200 mL) was added, dichloromethane (300 mL x 2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying to give crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=1:1 to 0:1) to give compound 1c.
1 H NMR(400MHz，DMSO-d 6 )δ8.63(s，1H)，8.09(s，1H)，8.01(s，1H)，7.60-7.70(m，1H)，7.45-7.49(m，1H)，2.12(s，3H).
Step four
Compound 1C (4 g,13.69 mmol) was dissolved in ethyl acetate (25 mL) and methanol (50 mL), dry Pd/C (0.5 g,13.69mmol,50% purity) was added, after 2 nitrogen substitutions, hydrogen substitutions 2 times, and finally the reaction was stirred at 30℃for 8 hours at 50 psi. The reaction solution is filtered, and the filtrate is dried by spin to obtain the product 1d.
1 H NMR(400MHz，DMSO-d 6 )δ9.75(s，1H)，7.14-7.48(m，3H)，6.98(s，1H)，6.85(s，1H)，6.38(s，1H)，5.31(s，2H)，2.01(s，3H).
Step five
To a solution of compound 1d (1 g,3.81 mmol) in acetonitrile (30 mL) was added tert-butyl nitrite (786.41 mg,7.63 mmol), stirred at 0℃for 30 minutes, and further added cuprous bromide (1.09 g,7.63 mmol), stirred at 25℃for 30 minutes, and stirred at 60℃for 1 hour. To the reaction solution was added water (50 mL), followed by extraction with ethyl acetate (50 mL x 2), and the organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give compound 1e.
Step six
To a solution of Compound 1e (100 mg, 306.62. Mu. Mol) in pinacol biboronate (116.79 mg, 459.93. Mu. Mol) in dioxane (5 mL) was added Pd (dppf) Cl 2 (22.44 mg, 30.66. Mu. Mol), potassium acetate (60.18 mg, 613.24. Mu. Mol). Stirring for 3 hours at 100 ℃ under the protection of nitrogen. Filtering and spin-drying to obtain a crude compound 1f.
LCMS(ESI)m/z：374.2[M+1] +
Step seven
Chloroacetaldehyde (8.51 g,43.35mmol,6.97 mL) was added dropwise to 4-bromo-2-aminopyridine (5 g,28.90 mmol) in EtOH (60 mL) and stirred at 80℃for 16 h. The reaction solution was dried under reduced pressure to give 1g of a crude compound.
1 H NMR(400MHz，DMSO-d 6 )δ8.89-8.96(m，1H)，8.40-8.45(m，1H)，8.30(d，J＝1.52Hz，1H)，8.19(d，J＝2.02Hz，1H)，7.70(dd，J＝1.76，7.28Hz，1H).
Step eight
1g (10 g,50.75 mmol) of the compound and 1-methyl-4-pyrazole borate (11.62 g,55.83 mmol) were dissolved in dioxane (155 mL) and H 2 To O (75 mL), pd (dppf) Cl was added 2 (3.71 g,5.08 mmol) and K 3 PO 4 (21.55 g,101.51 mmol) was stirred at 100deg.C for 16 hours, the reaction mixture was extracted with water (150 mL), ethyl acetate (150 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spun dry to give crude product. The crude product was purified by column chromatography (flash silica gel column chromatography) with petroleum ether/ethyl acetate=3/1 to give compound 1h. LCMS (ESI) m/z:198.8[ M+1 ]] +
1 H NMR(400MHz，CDCl 3 )δ8.11(brd，J＝7.04Hz，1H)，7.79(s，1H)，7.54-7.71(m，3H)，7.37(br s，1H)，6.90(d，J＝6.78Hz，1H)，3.96(s，3H).
Step nine
To a solution of Compound 1h (0.48 g,2.42 mmol) in acetonitrile (10 mL) was added bromosuccinimide (517.19 mg,2.91 mmol), and the mixture was stirred at 30℃for 2 hours. The reaction liquid is filtered by suction to obtain filtrate, and the filtrate is decompressed and concentrated to obtain crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1, r f =0.59) to give compound 1i.
LCMS(ESI)m/z：276.7[M+1] +
Step ten
To a solution of 1h (2.7 g,13.62 mmol) in dichloromethane (27 mL) was added NIS (3.68 g,16.35 mmol) and stirred at 30℃for 16 h. To the reaction solution was added water (100 mL), and dichloromethane (100 ml×3) was added for extraction, and the organic phases were combined and concentrated under reduced pressure. The crude product was isolated by flash column chromatography on silica gel (DCM: meoh=10:1, rf=0.13) to give compound 1j.
LCMS(ESI)m/z：324.9[M+1] +
Step eleven
To compound 1i (80 mg, 288.68. Mu. Mol), dioxane (6 mL) of compound 1f (107.74 mg, 288.68. Mu. Mol) and H 2 K was added to the O (3 mL) mixture 3 PO 4 (122.56mg，577.37μmol)，Pd(dppf)Cl 2 (21.12 mg, 28.87. Mu. Mol). The reaction was carried out at 100℃for 2 hours under nitrogen protection. The reaction was separated and the organic phase was concentrated and purified by column on silica gel (DCM: meoh=10:1) to give crude product. Subjecting the crude product to high performance liquid chromatography (chromatographic column: YMC-actual Triart C) 18 100X 30mm X5 μm; mobile phase: [ Water (0.05% hydrochloric acid) -acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 25% -55%,10 min) to obtain the hydrochloride of the compound 1.
LCMS(ESI)m/z：444.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.72(d，J＝7.28Hz，1H)，8.41(s，1H)，8.11-8.17(m，3H)，8.07(s，1H)，7.81(d，J＝1.52Hz，1H)，7.75(dd，J＝1.52，7.28Hz，1H)，7.59-7.67(m，1H)，7.57(d，J＝1.00Hz，1H)，7.07-7.14(m，2H)，4.00(s，3H)，2.20(s，3H).
The hydrochloride of compound 1 was added to sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 1.
Example 2
Step one
To compound 3-bromo-5-nitro-phenol (1 g,4.59 mmol), 2, 4-difluorophenylboronic acid (869.21 mg,5.50 mmol) in THF (10 mL) and H 2 Pd (dppf) Cl was added to the O (5 mL) solution 2 (335.64mg，458.71μmol)，K 3 PO 4 (2.43 g,11.47 mmol). Stirring at 90 ℃ for 16 hours under the protection of nitrogenWhen (1). To the reaction solution was added water (50 mL), extracted with ethyl acetate (50 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (PE: EA=5:1, rf=0.12) to give compound 2a.
1 H NMR(400MHz，DMSO-d 6 )δ10.69(br s，1H)，7.77(d，J＝1.52Hz，1H)，7.68(dt，J＝6.54，8.92Hz，1H)，7.59(t，J＝2.14Hz，1H)，7.38-7.47(m，1H)，7.35(d，J＝1.76Hz，1H)，7.23(dt，J＝2.14，8.48Hz，1H).
Step two
To a solution of compound 2a (4 g,15.92 mmol) in DMF (50 mL) was added DIEA (6.17 g,47.77mmol,8.32 mL), N-phenylbis (trifluoromethanesulfonyl) imide (8.53 g,23.89 mmol) and stirred at 15℃for 16 h. To the reaction solution was added 50mL of water, extracted with ethyl acetate (50 ml×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (PE: EA=3:1, rf=0.76) to give compound 2b.
1 H NMR(400MHz，DMSO-d 6 )δ8.42-8.50(m，2H)，8.25(s，1H)，7.79(dt，J＝6.54，8.92Hz，1H)，7.41-7.54(m，1H)，7.22-7.36(m，1H).
Step three
To a solution of compound 2b (6 g,15.66 mmol) in dioxane (40 mL) was added Pd (dppf) Cl 2 (1.15 g,1.57 mmol), duplex pinacol borate (4.77 g,18.79 mmol), potassium acetate (3.07 g,31.31 mmol). Stirring for 16 hours at 90 ℃ under the protection of nitrogen. TLC showed new spots generated. Filtering through diatomite and concentrating to obtain a compound 2c.
Step four
To compound 2c (4.68 g,12.96 mmol), 1j (3.5 g,10.80 mmol) dioxane (30 mL) and H 2 Pd (dppf) Cl was added to an O (10 mL) solution 2 (790.13mg，1.08mmol)，K 3 PO 4 (4.58 g,21.60 mmol). Stirring for 3 hours at 100 ℃ under the protection of nitrogen. To the reaction solution was added water (200 mL), extracted with ethyl acetate (200 ml×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1, rf=0.71) to give compound 2d.
LCMS(ESI)m/z：432.0[M+1] +
Step five
To a solution of compound 2d (2.0 g,4.64 mmol) in MeOH (20 mL) was added Pd/C (0.2 g,10% purity) and stirred under a balloon atmosphere of hydrogen (15 psi) at 15℃for 5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1, rf=0.62) to give compound 2e.
LCMS(ESI)m/z：402.2[M+1] +
Step six
To a solution of compound 2e (50.00 mg, 124.56. Mu. Mol) in pyridine (2 mL) was added ethylsulfonyl chloride (38.44 mg, 298.95. Mu. Mol, 28.26. Mu.L) and stirred at 15℃for 2 hours. The reaction was adjusted to pH 5 with acetic acid (3 mL), water (8 mL) was added, ethyl acetate (8 mL. Times.2) was added for extraction, and the combined organic phases were concentrated under reduced pressure. Purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 25% -55%,8 min) to obtain the trifluoroacetate of compound 2.
LCMS(ESI)m/z：494.0[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.70(d，J＝6.78Hz，1H)，8.38(s，1H)，8.15(s，2H)，8.05(d，J＝0.76Hz，1H)，7.76(dd，J＝1.76，7.28Hz，1H)，7.60-7.68(m，3H)，7.55-7.59(m，1H)，7.09-7.18(m，2H)，4.00(s，3H)，3.25(q，J＝7.36Hz，2H)，1.37(t，J＝7.40Hz，3H).
The trifluoroacetate salt of compound 2 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 2.
The preparation of the compounds of examples in Table 1 can be carried out by referring to the procedure analogous to the procedure of preparation example 2 described above, except that starting material A used in step six is substituted for ethyl sulfonyl chloride to give the trifluoroacetate salt of the corresponding compound, the trifluoroacetate salt of the obtained compound is added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the corresponding compound.
TABLE 1
Example 4
Step one
To a solution of compound 2e (30 mg, 74.74. Mu. Mol), cyclopropylacetic acid (9.65 mg, 112.10. Mu. Mol, 8.85. Mu. L) in DMF (2 mL) was added HATU (42.63 mg, 112.10. Mu. Mol), DIEA (19.32 mg, 149.47. Mu. Mol, 26.04. Mu. L). Stirred at 15℃for 16 hours. The reaction solution was filtered. Purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 27% -57%,8 min) to obtain the trifluoroacetate of the compound 4.
LCMS(ESI)m/z：470.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.73(d，J＝7.54Hz，1H)，8.36(s，1H)，8.07-8.19(m，3H)，8.02(s，1H)，7.78(d，J＝1.52Hz，1H)，7.71(dd，J＝1.64，7.16Hz，1H)，7.59-7.67(m，1H)，7.57(d，J＝1.26Hz，1H)，7.06-7.18(m，2H)，3.99(s，3H)，1.74-1.89(m，1H)，0.96-1.03(m，2H)，0.88-0.96(m，2H).
The trifluoroacetate salt of compound 4 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 4.
Example 5
Step one
To a solution of compound 2e (9.88 mg, 112.10. Mu. Mol, 10.40. Mu.L) in DMF (2 mL) was added HATU (42.63 mg, 112.10. Mu. Mol), DIEA (19.32 mg, 149.47. Mu. Mol, 26.04. Mu.L). Stirred at 15℃for 16 hours. The reaction solution was directly filtered and concentrated. Purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 28% -58%,8 min) to obtain the trifluoroacetate of the compound 5.
LCMS(ESI)m/z：472.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.75(d，J＝7.28Hz，1H)，8.38(s，1H)，8.20(s，1H)，8.15(d，J＝7.04Hz，2H)，8.05(s，1H)，7.80(s，1H)，7.75(d，J＝7.28Hz，1H)，7.57-7.68(m，2H)，7.05-7.18(m，2H)，4.00(s，3H)，2.70(td，J＝6.88，13.62Hz，1H)，1.24(d，J＝6.78Hz，6H).
The trifluoroacetate salt of compound 5 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 5.
Example 7
Step one
To compound 2e (30 mg, 74.74. Mu. Mol) was dissolved in DCM (1 mL), DIEA (28.98 mg, 224.21. Mu. Mol) was added and stirred at 0deg.C for 5 min; while cyclopropylamine (4.27 mg, 74.74. Mu. Mol) was dissolved in DCM (1 mL), DIEA (28.98 mg, 224.21. Mu. Mol) and triphosgene (11.09 mg, 37.37. Mu. Mol) were added and stirred at 0deg.C for 5 min; then, the reaction solution containing cyclopropylamine was added to the reaction solution of compound 2e, and stirring was continued at 0℃for 5 minutes. The reaction solution was directly dried by spin drying. Purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 23% -53%,10 min) to obtain the trifluoroacetate of the compound 7.
LCMS(ESI)m/z：485.2[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.76(d，J＝7.54Hz，1H)，8.16(s，1H)，8.38(s，1H)，8.10(s，1H)，8.02(m，2H)，7.72(d，J＝7.28Hz，1H)，7.60-7.68(m，2H)，7.49(s，1H)，7.08-7.18(m，2H)，4.02(s，2H)，3.98-4.05(m，1H)，2.64(dt，J＝7.04，3.52Hz，1H)，0.76-0.84(m，2H)，0.57(br s，2H).
The trifluoroacetate salt of compound 7 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 7.
Example 8
Step one
To a solution of 7-bromoimidazo [1,2-a ] pyridine (10 g,50.75 mmol), morpholine (6.63 g,76.13 mmol) in toluene (100 mL) was added tris (dibenzylideneacetone) dipalladium (4.65 g,5.08 mmol), (+ -) -2, 2-bis (diphenylphosphino) -11-binaphthyl (6.32 g,10.15 mmol), sodium t-butoxide (9.76 g,101.51 mmol). Stirring for 3 hours at 95 ℃ under the protection of nitrogen. LCMS indicated the formation of product. The reaction liquid is filtered by suction to obtain filtrate, and the filtrate is decompressed and concentrated to obtain crude product. The crude product was purified by column chromatography on silica gel (EA: meoh=10:1) to give compound 8a.
LCMS(ESI)m/z：204.1[M+1] +
Step two
To a solution of compound 8a (500 mg,2.46 mmol) in DCM (10 mL) was added NIS (664.19 mg,2.95 mmol) and stirred at 20℃for 16 h. To the reaction solution was added water (10 mL), the separated solution was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 8b.
LCMS(ESI)m/z：329.9[M+1] +
Step three
To compound 8b (0.9 g,2.73 mmol), 2c (1.19 g,3.28 mmol) dioxane (9 mL) and H 2 Pd (dppf) Cl was added to the O (3 mL) solution 2 (200.08mg，273.44μmol)，K 3 PO 4 (1.16 g,5.47 mmol) was stirred at 90℃for 16 hours under nitrogen. The reaction solution was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1) to give compound 8c.
LCMS(ESI)m/z：437.1[M+1] +
Step four
Compound 8C (0.8 g,1.83 mmol) was dissolved in MeOH (30 mL), pd/C (0.8 g,10% purity) was added, after 2 nitrogen substitutions, hydrogen substitutions 2 times, and finally the reaction was stirred at 30℃for 16 hours at 50 psi. The reaction solution is filtered, and the filtrate is dried by spin to obtain the compound 8d.
LCMS(ESI)m/z：407.1[M+1] +
Step five
To a solution of compound 8d (0.16 g, 393.67. Mu. Mol) in pyridine (2 mL) was added cyclopropylsulfonyl chloride (100 mg, 711.30. Mu. Mol). Stirred at 20℃for 3 hours. The reaction was adjusted to pH 5 by the addition of acetic acid, 10mL of water was added, extracted with ethyl acetate (10 mL x 2), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 30% -60%,10 min) to obtain the trifluoroacetate of the compound 8.
LCMS(ESI)m/z：511.2[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.44(d，J＝7.78Hz，1H)，7.86(s，1H)，7.54-7.66(m，4H)，7.28(dd，J＝2.26，8.04Hz，1H)，7.07-7.17(m，2H)，6.92(d，J＝2.02Hz，1H)，3.80-3.91(m，4H)，3.51-3.58(m，4H)，2.66-2.75(m，1H)，1.11(brd，J＝3.76Hz，2H)，0.98-1.06(m，2H).
The trifluoroacetate salt of compound 8 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 8.
Example 9
Step one
3, 4-dihydro-2H-pyran (500.00 g,5.94mol,543.48 mL), concentrated hydrochloric acid (1.02 g,10.35mmol,1.00 mL) was added to bromoethanol (500 g,4.00mol,284.09 mL) at 0deg.C, and stirred at 19℃for 1 hour. After the reaction was completed, 100g of sodium hydrogencarbonate was added and stirred for 30 minutes, and insoluble matter was removed by filtration to obtain a crude product. Distilling under reduced pressure of 0.09MPa, and collecting fraction at 80deg.C to obtain compound 9f.
1 H NMR(400MHz，CDCl 3 )δ4.66-4.60(m，1H)，4.00-3.76(m，3H)，3.50-3.47(m，1H)，1.83-1.50(m，6H).
Step two
Compound 9f (600.78 g,2.87mol,435.35 mL) and 4-boronate-1H-pyrazole (280 g,1.44 mol) were dissolved in DMF (1120 mL), and potassium carbonate (397.12 g,2.87 mol) was added and stirred at 60℃for 48 hours. Insoluble materials are removed by filtration, washing is carried out by ethyl acetate, the filtrates are combined, and the solvent is removed by rotation to obtain crude products. The crude product was chromatographed on a column of silica gel (n-heptane: ethyl acetate=8:1) to give 9g of the compound.
1 H NMR(400MHz，CDCl 3 )δ7.84-7.78(m，1H)，4.52-4.51(m，1H)，4.35-4.32(m，2H)，4.05-4.04(m，1H)，3.79-3.45(m，3H)，1.79-1.47(m，6H)，1.32(s，12H).
Step three
To 7-bromoimidazo [1,2-a ]]Pyridine (8 g,40.60 mmol), compound 9g (15.70 g,48.72 mmol) dioxane (80 mL) and H 2 Pd (dppf) Cl was added to an O (40 mL) solution 2 (2.97g，4.06mmol)，K 3 PO 4 (17.24 g,81.21 mmol). Stirred at 95℃for 16 hours. The reaction solution was separated, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a column of silica gel (DCM: meOH=10:1) to give compound 9a.
LCMS(ESI)m/z：313.0[M+1] +
Step four
To a solution of compound 9a (3.7 g,11.85 mmol) in DCM (30 mL) was added NIS (3.20 g,14.21 mmol) and stirred at 20deg.C for 16 h. To the reaction solution was added water (100 mL), the separated solution was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 9b.
LCMS(ESI)m/z：439.0[M+1] +
Step five
To compound 9b (2.5 g,5.70 mmol), 2c (2.47 g,6.85 mmol) dioxane (50 mL) and H 2 Pd (dppf) Cl was added to an O (15 mL) solution 2 (417.39mg，570.44μmol)，K 3 PO 4 (2.42 g,11.41 mmol). Stirring for 16 hours at 90 ℃ under the protection of nitrogen. The reaction mixture was separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=20:1) to give 9c.
LCMS(ESI)m/z：546.3[M+1] +
Step six
To compound 9c (0.2 g, 366.61. Mu. Mol) EtOH (10 mL) and H 2 Zinc powder (239.73 mg,3.67 mmol) and ammonium chloride (196.11 mg,3.67 mmol) were added to a solution of O (2 mL). Stirred at 20℃for 16 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to give compound 9d.
LCMS(ESI)m/z：516.1[M+1] +
Step seven
To a solution of compound 9d (0.19 g, 368.54. Mu. Mol) in pyridine (2 mL) was added cyclopropylsulfonyl chloride (62.17 mg, 442.24. Mu. Mol), and the mixture was stirred at 20℃for 4 hours. To the reaction solution was added 20mL ice water, then 6mL acetic acid was added to adjust pH to 5, ethyl acetate (20 mL x 3) was added for extraction, and the organic phase was concentrated under reduced pressure to give compound 9e.
LCMS(ESI)m/z：620.1[M+1] +
Step eight
To a single vial of compound 9e (0.19 g, 306.61. Mu. Mol) was added hydrogen chloride/ethyl acetate (4M, 28.50 mL) and stirred at 20℃for 16 hours. The reaction solution was concentrated under reduced pressure. Purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 28% -58%,10 min) to obtain the trifluoroacetate of the compound 9.
LCMS(ESI)m/z：536.3[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.67-8.74(m，1H)，8.44(s，1H)，8.18(d，J＝14.06Hz，2H)，8.06(s，1H)，7.79(dd，J＝1.64，7.16Hz，1H)，7.55-7.72(m，4H)，7.07-7.21(m，2H)，4.33(t，J＝5.14Hz，2H)，3.95(t，J＝5.14Hz，2H)，2.65-2.81(m，1H)，1.09-1.17(m，2H)，0.98-1.07(m，2H).
The trifluoroacetate salt of compound 9 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 9.
Example 11
Step one
To a suspension of 4-borate-1H-pyrazole (0.13 g, 669.97. Mu. Mol) and oxaisobutylene (633.36 mg,8.78mmol, 780.00. Mu.L) was added cesium carbonate (32.74 mg, 100.50. Mu. Mol) and stirred in a microwave reactor at 120℃for 16 hours. Directly used in the next step without treatment. Compound 11a was obtained.
LCMS(ESI)m/z：267.0[M+1] +
Step two
To a solution of compound 1g (0.11 g, 558.29. Mu. Mol), 11a (178.30 mg, 669.94. Mu. Mol) in dioxane (3 mL) and water (1 mL) was added Pd (dppf) Cl 2 (40.85mg，55.83μmol)，K 3 PO 4 (237.01 mg,1.12 mmol). Stirring for 16 hours at 90 ℃ under the protection of nitrogen. The reaction solution is layered, and the organic phase is concentrated and dried to obtain a crude product. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1) to give compound 11b.
LCMS(ESI)m/z：256.9[M+1] +
Step three
To a solution of compound 11b (0.12 g, 468.20. Mu. Mol) in DCM (3 mL) was added NIS (126.40 mg, 561.84. Mu. Mol) and stirred at 25℃for 16 h. The reaction mixture was extracted with water (20 mL) and the separated solution was extracted with dichloromethane (15 ml×3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 11c.
LCMS(ESI)m/z：383.0[M+1] +
Step four
Compound 2b (17.71 g,46.21 mmol) was dissolved in EtOH (150 mL) and H 2 To O (50 mL) was added ammonium chloride (24.72 g,462.10 mmol) and mixed well, followed by slow addition of zinc powder (15.11 g,231.05 mmol). The reaction was stirred at 80℃for 16 hours. The reaction solution is filtered by diatomite, and the filtrate is decompressed and concentrated to obtain crude products. The crude product was chromatographed on a column of silica gel (PE: EA=10:1) to give compound 11d.
LCMS(ESI)m/z：353.9[M+1] +
1 H NMR(400MHz，DMSO-d 6 )δ7.58-7.54(m，1H)，7.38-7.35(m，1H)，7.19-7.18(m，1H)，6.79(s，1H)，6.79-6.62(m，2H)，5.87(s，2H).
Step five
To a solution of compound 11d (16.5 g,46.71 mmol) in pyridine (75 mL) was added methanesulfonyl chloride (8.03 g,70.06 mmol), and the mixture was stirred at 30℃for 3 hours. After the reaction was completed, the reaction mixture was added with water (100 mL), extracted with ethyl acetate (80 ml×3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure with an oil pump to give compound 11e.
Step six
Compound 11e, duplex pinacol borate (8.12 g,31.99 mmol) was dissolved in dioxane (200 mL) and Pd (dppf) Cl was added 2 (1.95 g,2.67 mmol) and potassium acetate (5.23 g,53.32 mmol) were reacted at 100℃for 16 hours with stirring. The reaction solution is filtered by diatomite to collect filtrate, and the filtrate is decompressed and concentrated to obtain crude product. The crude product was chromatographed on a column of silica gel (PE/EA=5:1) to give compound 11f.
LCMS(ESI)m/z：409.13[M+1] +
1 H NMR(400MHz，DMSO-d 6 )δ7.93(s，1H)，7.54-7.55(m，1H)，7.50(s，2H)，7.48-7.46(m，1H)，7.33-7.42(m，1H)，7.20(br d，J＝2.24Hz，1H)，3.01(s，3H)，1.26-1.35(m，12H).
Step seven
To a solution of compound 11c (65 mg, 170.07. Mu. Mol), compound 11f (153.12 mg, 374.15. Mu. Mol) in dioxane (3 mL) and water (1 mL) was added Pd (dppf) Cl 2 (12.44mg，17.01μmol)，K 3 PO 4 (72.20 mg, 340.14. Mu. Mol) was stirred at 90℃for 16 hours under nitrogen. The reaction solution is concentrated to obtain crude products. The crude product is subjected to high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 20% -50%,12 min) and purifying to obtain the trifluoroacetate salt of the compound 11.
LCMS(ESI)m/z：538.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.71(br d，J＝7.03Hz，1H)，8.40(s，1H)，8.17(br d，J＝2.76Hz，2H)，8.08(br s，1H)，7.53-7.83(m，5H)，7.13(br s，2H)，4.20(s，2H)，3.11(s，3H)，1.23(s，6H).
The trifluoroacetate salt of compound 11 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 11.
Step one
Compound 11d (9 g,25.48 mmol) was dissolved in pyridine (10 mL), and ethanesulfonyl chloride (3.93 g,30.57mmol,2.89 mL) was added dropwise and the reaction was stirred at 30℃for 4 hours. The reaction mixture was extracted with 30mL of water and 30mL of ethyl acetate, and the organic phase was washed twice with 30mL of water and dried by spin to give 11g of the compound.
1 H NMR(400MHz，CDCl 3 )：δ7.67(s，1H)，7.27(d，J＝1.52Hz，1H)，7.22(s，1H)，7.11(s，1H)，6.84-6.99(m，2H)，3.06-3.22(m，2H)，1.28-1.39(m，3H).
Step two
Example 11g (9 g,20.21 mmol) and duplex pinacol borate (6.16 g,24.25mmol, 1.2) were dissolved in dioxane (90 mL) and Pd (dppf) Cl was added 2 (1.48 g,2.02 mmol) and KOAc (3.97 g,40.41 mmol) under nitrogen at 90℃for 16 h with stirring. The reaction solution was directly filtered, washed with ethyl acetate, the filtrate was dried by spin to give a crude product, which was purified by column chromatography with PE/ea=5/1 to give 11h.
1 H NMR(400MHz，CDCl 3 )：δ7.68-7.71(m，1H)，7.56(d，J＝2.02Hz，1H)，7.49-7.55(m，1H)，7.41(td，J＝8.54，6.5Hz，1H)，6.84-6.96(m，2H)，3.15(q，J＝7.32Hz，2H)，1.32-1.35(m，12H)，1.24(br s，3H).
Example 12
Step one
To a solution of compound 11d (6.9 g,19.53 mmol) in pyridine (67.62 g,854.87mmol,69.00 mL) was added cyclopropanesulfonyl chloride (3.30 g,23.44 mmol) and stirred at 20℃for 16 hours. Acetic acid (80 mL) was added to the reaction solution, followed by water (250 mL), extraction with ethyl acetate (200 mL x 3), and drying of the combined organic phases over anhydrous sodium sulfate, filtration, and spin-drying of the filtrate to give compound 12a.
Step two
To a solution of compound 12a (8 g,17.49 mmol), duplex pinacol borate (4.44 g,17.49 mmol) in dioxane (80 mL) was added Pd (dppf) Cl 2 (1.28 g,1.75 mmol), potassium acetate (3.43 g,34.98 mmol). Stirring for 16 hours at 90 ℃ under the protection of nitrogen. The reaction solution is filtered by diatomite, and the filtrate is decompressed and concentrated to obtain a crude product. The crude product was purified by column chromatography over flash silica gel (PE: ea=3:1) to give compound 12b.
Step three
To a solution of compound 11c (65 mg, 176.55. Mu. Mol), compound 12b (153.70 mg, 353.10. Mu. Mol) in dioxane (3 mL) and water (1 mL) was added Pd (dppf) Cl 2 (12.92mg，17.65μmol)，K 3 PO 4 (74.95 mg, 353.10. Mu. Mol) under nitrogenStirring was carried out at 90℃for 16 hours. The reaction solution is concentrated to obtain crude products. The crude product is subjected to high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 20% -50%,12 min) and purifying to obtain the trifluoroacetate salt of the compound 12.
LCMS(ESI)m/z：564.2[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.70(d，J＝7.28Hz，1H)，8.40(s，1H)，8.17(d，J＝6.54Hz，2H)，8.07(s，1H)，7.79(dd，J＝1.64，7.16Hz，1H)，7.59-7.72(m，4H)，7.08-7.19(m，2H)，4.20(s，2H)，2.66-2.80(m，1H)，1.14(s，6H)，1.09-1.17(m，2H)，0.99-1.07(m，2H).
The trifluoroacetate salt of compound 12 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 12.
Example 13
Step one
To a solution of 1g (10 g,50.75 mmol) of morpholine (6.63 g,76.13mmol,6.70 mL) in toluene (100 mL) was added Pd 2 (dba) 3 (4.65 g,5.08 mmol), BINAP (6.32 g,10.15 mmol), t-Buona (9.76 g,101.51 mmol). Stirring for 3 hours at 95 ℃ under the protection of nitrogen. The reaction liquid is filtered by suction to collect filtrate, and the filtrate is decompressed and concentrated to obtain crude product. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1) to give compound 13b.
LCMS(ESI)m/z：204.1[M+1] +
Step two
Compound 13b (5.8 g,28.54 mmol) was dissolved in DCM (110 mL) and NIS (7.70 g,34.25 mmol) was added and the reaction stirred at 25℃for 16 h. The reaction mixture was added with water (100 mL), the mixture was separated, the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 13c.
LCMS(ESI)m/z：329.8[M+1] +
Step three
Compound 13c (50 mg, 151.91. Mu. Mol) and compound 11f (93.26 mg, 227.87. Mu. Mol) were dissolved in THF (1.5 mL) and H 2 To O (0.7 mL), pd (dppf) Cl was added 2 (11.12 mg, 15.19. Mu. Mol) and K 3 PO 4 (64.49 mg, 303.83. Mu. Mol) and stirred at 90℃for 16 hours under nitrogen. Concentrating the reaction solution to obtain crude product, subjecting the crude product to high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 21% -51%,12 min) to obtain the trifluoroacetate salt of the compound 13.
LCMS(ESI)m/z：485.0[M+1] +
1 H NMR(400MHz，CD 3 OD)δppm 8.46(d，J＝8.0Hz，1H)，7.86(s，1H)，7.53-7.67(m，4H)，7.29(dd，J＝7.78，2.52Hz，1H)，7.08-7.17(m，2H)，6.95(d，J＝2.26Hz，1H)，3.84-3.93(m，4H)，3.51-3.61(m，4H)，3.11(s，3H).
The trifluoroacetate salt of compound 13 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 13.
Example 14
Step one
Compound 9b (100 mg, 228.17. Mu. Mol) and compound 11f (140.07 mg, 342.26. Mu. Mol) were dissolved in tetrahydrofuran (1.5 mL) and water (0.7 mL), and Pd (dppf) Cl was added 2 (16.70 mg, 22.82. Mu. Mol) and K 3 PO 4 (96.87 mg, 456.35. Mu. Mol) was reacted under nitrogen at 90℃with stirring for 0.5 hours. Water (3 mL) was added to the reaction, extracted with ethyl acetate (3 mL. Times.2), the organic phase was collected, and the organic phase was concentrated and dried to give crude product. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=20:1) to give compound 14a.
LCMS(ESI)m/z：594.1[M+1] +
Step two
Compound 14a (50 mg, 84.23. Mu. Mol) was dissolved in DCM (2 mL), and hydrogen chloride/ethyl acetate (4M, 2 mL) was added and the reaction stirred at 25℃for 1 hour. The reaction solution is directly dried by spin to obtain a crude product. Purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 15% -45%,12 min) to obtain trifluoroacetate of compound 14.
LCMS(ESI)m/z：510.0[M+1] +
1 H NMR(400MHz，CD 3 OD)δppm 8.72(s，1H)，8.45(s，1H)，8.21(s，1H)，8.17(s，1H)，8.08(s，1H)，7.79(dd，J＝7.32，1.6Hz，1H)，7.62-7.71(m，3H)，7.59(d，J＝1.60Hz，1H)，7.11-7.20(m，2H)，4.35(t，J＝5.20Hz，2H)，3.97(t，J＝5.20Hz，2H)，3.13(s，3H).
The trifluoroacetate salt of compound 14 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 14.
Example 15
Step one
To a solution of 4-borate-1H-pyrazole (5 g,25.77 mmol) in acetonitrile (50 mL) was added 1-methanesulfonyl ethylene (4.10 g,38.65mmol,3.39 mL), DBU (1.96 g,12.88mmol,1.94 mL). Stirred at 90℃for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 15a.
LCMS(ESI)m/z：300.9[M+1] +
Step two
To a solution of compound 1g (549.98 mg, 558.29. Mu. Mol), 15a (1.0 g,3.333 mmol) in dioxane (10 mL) and water (5 mL) was added Pd (dppf) Cl 2 (203.13 mg, 277.61. Mu. Mol) and K 3 PO 4 (1.18 g,5.55 mmol) was stirred at 85℃for 16 hours under nitrogen. Water (10 mL) was added to the reaction, extracted with ethyl acetate (10 mL. Times.2), and the organic phase was collected and concentrated to give crude product. Purification of the crude product by flash column chromatography on silica gel (DCM: meOH=20:1) gives the compound15b。
1 HNMR(400MHz，CDCl 3 )δ8.08-8.15(m，1H)，7.92(s，1H)，7.89(s，1H)，7.68(s，1H)，7.56(br d，J＝13.30Hz，2H)，6.93(dd，J＝1.00，7.04Hz，1H)，4.66(t，J＝6.16Hz，2H)，3.65-3.70(m，2H)，2.62(s，3H).
Step three
To compound 15b (100 mg, 344.42. Mu. Mol) was dissolved in DCM (2 mL), NIS (92.99 mg, 413.31. Mu. Mol) was added and the reaction stirred at 30℃for 16 hours. The reaction mixture was extracted with water (3 mL) and methylene chloride (3 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 15c.
LCMS(ESI)m/z：416.8[M+1] +
Step four
Compound 15c (80 mg, 192.20. Mu. Mol) and compound 11f (94.39 mg, 230.64. Mu. Mol) were dissolved in tetrahydrofuran (2 mL) and water (1 mL), and Pd (dppf) Cl was added 2 (14.06 mg, 19.22. Mu. Mol) and K 3 PO 4 (81.59 mg, 384.40. Mu. Mol) and under nitrogen protection, the reaction was stirred at 90℃for 0.5 hours. The reaction mixture was extracted with water (4 mL) and ethyl acetate (4 mL), and the organic phase was concentrated to give crude product. The crude product is subjected to high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 20% -50%,12 min) to obtain the trifluoroacetate salt of the compound 15.
LCMS(ESI)m/z：572.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.73(d，J＝7.28Hz，1H)，8.52(s，1H)，8.25(s，1H)，8.18(s，1H)，8.10(s，1H)，7.79(dd，J＝1.60，7.28Hz，1H)，7.62-7.71(m，3H)，7.60(d，J＝1.76Hz，1H)，7.10-7.19(m，2H)，4.77(t，J＝6.40Hz，2H)，3.81(t，J＝6.40Hz，2H)，3.13(s，3H)，2.91(s，3H).
The trifluoroacetate salt of compound 15 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 15.
Example 16
Step one
1g (0.2 g,1.02 mmol) was dissolved in DCM (4 mL) and NIS (274.05 mg,1.22 mmol) was added at 25℃and the reaction stirred for 2 h. The reaction mixture was extracted with water (5 mL) and methylene chloride (5 mL), and the organic phase was collected and concentrated to give compound 16a.
1 H NMR(400MHz，DMSO-d 6 )δ8.51(d，J＝7.24Hz，1H)，8.18(d，J＝1.24Hz，1H)，8.14(s，1H)，7.51(dd，J＝1.88，7.24Hz，1H).
Step two
Compound 16a (200 mg, 619.33. Mu. Mol) and compound 11f (304.16 mg, 743.20. Mu. Mol) were dissolved in dioxane (1 mL) and water (0.25 mL), and sodium carbonate (164.11 mg,1.55 mmol) and Pd (dppf) Cl were added 2 (45.32 mg, 61.93. Mu. Mol) was stirred for 20 minutes at 110℃under nitrogen. The reaction mixture was extracted with water (3 mL) and ethyl acetate (3 mL x 2), and the organic phase was concentrated to give crude product. The crude product was purified by flash column chromatography (PE/ea=1/1 to 0/1) to give compound 16b.
LCMS(ESI)m/z：479.7[M+1] +
Step three
Compound 16b (120 mg, 250.88. Mu. Mol) and 4-borate-1H-pyrazole (58.42 mg, 301.06. Mu. Mol) were dissolved in dioxane (2 mL) and water (1 mL), and Pd (dppf) Cl was added 2 (18.36 mg, 25.09. Mu. Mol) and K 3 PO 4 (106.51 mg, 501.77. Mu. Mol) and under nitrogen protection, the reaction was stirred at 90℃for 0.5 hours. The reaction mixture was extracted with water (3 mL) and ethyl acetate (4 mL), and the organic phase was concentrated under reduced pressure to give compound 16c.
LCMS(ESI)m/z：466.2[M+1] +
Step four
Compound 16c (100 mg, 214.83. Mu. Mol) and tetrahydropyran-4-yl 4-methylbenzenesulfonic acid (55.07 mg, 214.83. Mu. Mol) were dissolved in DMF (1 mL), cesium carbonate (209.99 mg, 644.50. Mu. Mol) was added, and the mixture was reacted at 90℃with stirring for 16 hours. The reaction solution is filtered, and the filtrate is purified by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 25% -45%,12 min) to obtain the trifluoroacetate of the compound 16.
LCMS(ESI)m/z：550.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.70-8.76(m，1H)，8.54(s，1H)，8.21(s，1H)，8.17(s，1H)，8.09(s，1H)，7.80(dd，J＝1.52，7.28Hz，1H)，7.63-7.71(m，3H)，7.60(s，1H)，7.11-7.21(m，2H)，4.49-4.62(m，1H)，4.12(br d，J＝11.04Hz，2H)，3.59-3.68(m，2H)，3.13(s，3H)，2.15(br d，J＝3.76Hz，2H)，1.26-1.42(m，2H).
The trifluoroacetate salt of compound 16 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 16.
Example 17
Step one
To a solution of 3-bromo-5-nitro-phenol (3 g,13.76 mmol), pinacol borate (4.19 g,16.51 mmol) in dioxane (50 mL) was added Pd (dppf) Cl 2 (1.01 g,1.38 mmol), potassium acetate (2.70 g,27.52 mmol). Stirring at 100℃for 16 hours under nitrogen. The reaction solution was filtered by suction and the filtrate was concentrated to give crude compound 17a, which was used directly in the next step without purification.
Step two
To compound 1j (3 g,9.26 mmol), 17a (3.65 g,13.77 mmol) dioxane (5 mL) and H 2 Pd (dppf) Cl was added to an O (1.5 mL) solution 2 (677.25mg，925.58μmol)，K 3 PO 4 (3.93 g,18.51 mmol). Stirring at 100℃for 16 hours under nitrogen. Water (100 mL) was added to the reaction, extracted with ethyl acetate (100 mL. Times.3), the organic phases combined and driedDrying with sodium sulfate, and concentrating under reduced pressure to obtain crude product. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1) to give compound 17b.
LCMS(ESI)m/z：335.9[M+1] +
Step three
To a solution of compound 17b (0.8 g,2.39 mmol) in DMF (5 mL) was added DIEA (925.05 mg,7.16mmol,1.25 mL), N-phenylbis (trifluoromethanesulfonyl) imide (1.28 g,3.58 mmol). Stirred at 20℃for 16 hours. The reaction mixture was taken up in water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1) to give compound 17c.
LCMS(ESI)m/z：468.0[M+1] +
Step four
To a solution of compound 17c (320 mg, 684.67. Mu. Mol) in EtOH (10 mL) and water (2 mL) was added ammonium chloride (366.24 mg,6.85 mmol) and zinc powder (447.71 mg,6.85 mmol). Stirring for 16 hours at 25 ℃, and stirring for 3 hours at 60 ℃. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to give compound 17d.
LCMS(ESI)m/z：438.0[M+1] +
Step five
Methanesulfonyl chloride (439.98 mg,3.84mmol, 297.29. Mu.L) was added to a solution of 17d (1.4 g,3.20 mmol) in pyridine (15 mL) at 0deg.C, and stirred at 30deg.C for 3 hours. Quenched with water (10 mL) at 0deg.C, extracted with ethyl acetate (20 mL x 3), the organic phase dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, and concentrated under reduced pressure to give crude product. The crude product was purified by flash column chromatography on silica gel (DCM: meoh=10:1) to give compound 17e.
LCMS(ESI)m/z：516.1[M+1] +
Step six
To a solution of 17e (0.05 g, 97.00. Mu. Mol), (2-fluoro-4-methoxy-phenyl) boronic acid (19.78 mg, 116.40. Mu. Mol) in dioxane (3 mL) and water (1 mL) was added Pd (dppf) Cl 2 (7.10mg，9.70μmol)，K 3 PO 4 (41.18 mg, 194.00. Mu. Mol). Stirring was carried out in a microwave reactor at 100℃for 0.5 hour under nitrogen protection. The reaction solution is added with sodium sulfate for drying and filtering,concentrating the filtrate under reduced pressure to obtain crude product. The crude product is subjected to high performance liquid chromatography (chromatographic column: welch Xtime C18:25 mm 5 μm; mobile phase: [ water (0.04% ammonia water) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 20% -50%,8.5 min) to obtain compound 17.
LCMS(ESI)m/z：492.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.54(d，J＝7.04Hz，1H)，8.16(s，1H)，7.99(s，1H)，7.75(s，1H)，7.69(s，1H)，7.39-7.56(m，4H)，7.26(d，J＝7.28Hz，1H)，6.71-6.92(m，2H)，3.96(s，3H)，3.85(s，3H)，3.02(s，3H).
Example 18
Step one
To a solution of 17e (100 mg, 193.99. Mu. Mol) in duplex pinacol borate (54.19 mg, 213.39. Mu. Mol) in dioxane (2 mL) was added Pd (dppf) Cl 2 (14.19 mg, 19.40. Mu. Mol), potassium acetate (38.08 mg, 387.98. Mu. Mol). Stirring was carried out in a microwave reactor at 100℃for 1 hour under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 18a.
LCMS(ESI)m/z：494.2[M+1] +
Step two
To a solution of 18a (45 mg, 91.21. Mu. Mol), 2-bromopyrazine (14.50 mg, 91.21. Mu. Mol) in dioxane (2 mL) and water (0.5 mL) was added Pd (dppf) Cl 2 (6.67mg，9.12μmol)，K 3 PO 4 (38.72 mg, 182.41. Mu. Mol). Stirring was carried out in a microwave reactor at 100℃for 1 hour under nitrogen protection. The reaction liquid is filtered to obtain filtrate, and the filtrate is decompressed and concentrated to obtain crude product. The crude product is subjected to high performance liquid chromatography (chromatographic column: boston Green ODS150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 10% -40%,12 min) to obtain the trifluoroacetate salt of the compound 18.
LCMS(ESI)m/z：445.9[M+1] +
1 H NMR(400MHz，DMSO-d 6 )δ10.37(s，1H)，9.34(s，1H)，8.78(br s，1H)，8.69(s，1H)，8.58(s，1H)，8.32(s，1H)，8.21(br d，J＝12.05Hz，2H)，8.14(s，1H)，8.08(br s，1H)，7.61-7.72(m，2H)，7.10-7.27(m，1H)，3.92(s，3H)，3.33(br s，3H).
The trifluoroacetate salt of compound 18 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 18.
The preparation of the compounds of examples in Table 2 can be carried out by reference to the procedure analogous to the route of preparation example 18, except that starting material A used in step two is used instead of 2-bromopyrazine to give the trifluoroacetate salt of the corresponding compound.
TABLE 2
Example 21
Step one
To water (30 mL) was added 2-amino-4-methoxypyridine (1 g,7.24 mmol) and hydrochloric acid (12M, 60.31. Mu.L), stirred at 25℃for 2.5 hours, then heated to 80℃and stirred for 1.5 hours, cooled to 25℃and then sodium bicarbonate (972.85 mg,11.58 mmol) and bromoacetaldehyde diethyl acetal (2.85 g,14.48 mmol) were added, and the reaction was stirred at 25℃for 12 hours. The reaction was extracted with 100ml of ethyl acetate 3 and the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning. Purification by column (dichloromethane: methanol=1:0 to 10:1) afforded compound 21a.
LCMS(ESI)m/z：163.2[M+1] +
1 H NMR(399MHz，DMSO-d 6 )δ8.37-8.39(d，J＝7.2Hz，1H)，7.74(s，1H)，7.40(s，1H)，6.89-6.90(d，J＝2.8Hz，1H)，6.59-6.62(m，1H)，4.05-4.11(m，2H)，1.34-1.37(t，J＝7.0Hz，3H).
Step two
To anhydrous dichloromethane (5 mL) was added compound 21a (0.5 g,3.08 mmol), N-iodosuccinimide (762.95 mg,3.39 mmol), and the reaction was allowed to react at 25℃for 12 hours. The reaction solution was extracted with 100mL of saturated aqueous sodium bicarbonate solution and 100mL of dichloromethane x 3, and the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying. Purification by column (petroleum ether: ethyl acetate=20:1 to 3:1) afforded compound 21b.
LCMS(ESI)m/z：289.0[M+1] +
1 H NMR(400MHz，DMSO-d 6 )δ8.15-8.18(m，1H)，7.55(s，1H)，7.00(s，1H)，6.73-6.75(d，J＝7.6Hz，1H)，4.08-4.14(m，2H)，1.35-1.38(t，J＝7.0Hz，3H).
Step three
Dioxane (5 mL) and water (2 mL), 21b (0.01 g, 34.71. Mu. Mol), 11f (17.05 mg), anhydrous potassium phosphate (14.74 mg, 69.42. Mu. Mol), 1-bis (diphenylphosphorus) ferrocene palladium chloride (2.54 mg) were added to the reaction, the reaction was replaced with nitrogen, and the reaction was carried out at 65℃for 3 hours. The reaction solution was extracted with 20 ml of water and dichloromethane (20 ml x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spinning. Crude product is obtained, and compound 21 is obtained by purification of a preparative thin layer chromatography silica gel plate.
LCMS(ESI)m/z：444.2[M+1] +
1 H NMR(400MHz，DMSO-d 6 )δ10.04(s，1H)，8.45-8.47(d，J＝7.6Hz，1H)，7.46(s，2H)，7.43-7.45(m，4H)，7.04(s，1H)，6.72(s，1H)，4.12-4.17(m，2H)，3.11(s，1H)，1.38(s，3H).
Example 22
Step one
DIEA (28.98 mg, 224.22. Mu. Mol, 39.05. Mu.L) was added to a solution of 2e (30 mg, 74.74. Mu. Mol) in DCM (1 mL) at 0℃followed by triphosgene (11.09 mg, 37.37. Mu. Mol) and stirred at 0℃for 10 minutes, while DIEA (28.98 mg, 224.22. Mu. Mol, 39.05. Mu. L) was added to a solution of 3-methoxypyrrole (7.56 mg, 54.94. Mu. Mol, HCl) in DCM (1 mL) and stirred for 10 minutes at 0℃and poured into the reaction mixture and stirred for 20 minutes. The reaction was quenched by addition of water (5 mL) at 0 ℃, extracted by addition of DCM (5 mL x 4), the organic phases combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude product. The crude product is purified by preparative high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 23% -53%,8 min) to obtain the trifluoroacetate of compound 22.
LCMS(ESI)m/z：529.1[M+1] +
1 HNMR(400MHz，CD 3 OD)δ8.77(d，J＝7.28Hz，1H)，8.38(s，1H)，8.15(s，1H)，8.12(s，1H)，8.05(d，J＝0.75Hz，1H)，7.97(t，J＝1.76Hz，1H)，7.71-7.78(m，2H)，7.62(dt，J＝6.40，8.85Hz，1H)，7.50(d，J＝1.51Hz，1H)，7.05-7.17(m，2H)，4.00(s，3H)，3.49-3.68(m，5H)，3.37(s，3H)，1.98-2.22(m，2H).
The trifluoroacetate salt of compound 22 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 22.
Example 23
Step one
Compound 2e (50.00 mg, 124.56. Mu. Mol) was dissolved in DCM (1 mL), DIEA (48.29 mg, 373.68. Mu. Mol, 65.09. Mu.L, 3 eq) was added, triphosgene (55.44 mg, 186.84. Mu. Mol) was added, stirred at 0deg.C for 10min, while O-methylhydroxylamine hydrochloride (20.81 mg, 249.12. Mu. Mol HCl) was dissolved in DCM (1 mL) and DIEA (48.29 mg, 373.68. Mu. Mol, 65.09. Mu. L) was added, stirred at 0deg.C for 10min, and then poured into the above reaction solution, and stirred at 0deg.C for 7-10 min. 2ml of water is added into the reaction solution for extraction, and the organic phase is decompressed and concentrated to obtain crude products. Purifying by preparative high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 25% -55%,8 min) to obtain trifluoroacetate of compound 23.
LCMS(ESI)m/z：475.3[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.75(d，J＝7.00Hz，1H)，8.37(s，1H)，8.13(d，J＝12.02Hz，2H)，8.06(t，J＝1.74Hz，1H)，8.02(s，1H)，7.84(d，J＝1.64Hz，1H)，7.73(dd，J＝1.70，7.32Hz，1H)，7.64(dt，J＝6.50，8.82Hz，1H)，7.56(d，J＝1.50Hz，1H)，7.04-7.18(m，2H)，3.99(s，3H)，3.77(s，3H).
The trifluoroacetate salt of compound 23 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 23.
Example 24
Step one
Compound 2e (0.03 g, 74.74. Mu. Mol) was dissolved in DCM (1 mL), DIEA (28.98 mg, 224.21. Mu. Mol, 39.05. Mu. L) was added to triphosgene (33.27 mg, 112.10. Mu. Mol) and stirred at 0deg.C for 10 min, while additionally 2- (dimethylamino) ethanol (13.32 mg, 149.47. Mu. Mol, 15.00. Mu. L) was dissolved in DCM (1 mL) and DIEA (28.98 mg, 224.21. Mu. Mol, 39.05. Mu. L) was added, stirred at 0deg.C for 10 min, poured into the above reaction solution and stirred at 0deg.C for 7-10 min. 2ml of water is added into the reaction solution for extraction, and the organic phase is decompressed and concentrated to obtain crude products. Purifying by preparative high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 25% -55%,8 min) to obtain trifluoroacetate of compound 24.
LCMS(ESI)m/z：517.3[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.69(d，J＝7.54Hz，1H)，8.34(s，1H)，8.12(s，1H)，8.05(d，J＝9.80Hz，2H)，7.96(s，1H)，7.79(s，1H)，7.67(br d，J＝7.54Hz，1H)，7.55(s，1H)，7.35(d，J＝8.28Hz，1H)，7.06-7.20(m，2H)，4.50-4.61(m，2H)，4.00(s，3H)，3.50-3.59(m，2H)，3.01(s，6H).
The trifluoroacetate salt of compound 24 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 24.
Example 25
Step one
Compound 2e (0.04 g, 99.65. Mu. Mol) was dissolved in pyridine (3 mL), and 2-methoxy-1-ethylsulfonyl chloride (79.02 mg, 498.24. Mu. Mol) diluted with pyridine (3 mL) was slowly added thereto and reacted at 25℃with stirring for 2 hours. The reaction solution is quenched by adding water, 10ml of ethyl acetate is added for extracting an organic phase, and the organic phase is decompressed and distilled to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (column: boston Green ODS 150X 30mm X5 μm; mobile phase: [ water (0.1% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile): 26% -%,7 min) to give the trifluoroacetate salt of compound 25.
LCMS(ESI)m/z：524.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.72(d，J＝7.28Hz，1H)，8.39(s，1H)，8.16(d，J＝2.52Hz，2H)，8.07(s，1H)，7.77(dd，J＝1.76，7.28Hz，1H)，7.73-7.81(m，1H)，7.58-7.71(m，4H)，7.14(br d，J＝4.02Hz，2H)，4.01(s，3H)，3.78-3.90(m，2H)，3.47(s，2H)，3.31(br s，3H).
The trifluoroacetate salt of compound 25 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 25.
Example 26
Step one
Compound 2e (0.03 g, 74.74. Mu. Mol) was dissolved in DCM (1 mL), DIEA (28.98 mg, 224.21. Mu. Mol, 39.05. Mu.L) was added, and triphosgene (11.09 mg, 37.37. Mu. Mol) was stirred at 0deg.C for 10 min; while additionally azetidine (6.99 mg, 74.74. Mu. Mol, 8.26. Mu.L, HCl) was dissolved in DCM (1 mL), DIEA (28.98 mg, 224.21. Mu. Mol, 39.05. Mu.L, 3 eq) was added and stirred at 0deg.C for 10 min; pouring into the reaction liquid, and stirring for 7-10 minutes at the temperature of 0 ℃. 2ml of water is added into the reaction solution for extraction, and the organic phase is decompressed and concentrated to obtain crude products. 2ml of water is added into the reaction solution for extraction, and the organic phase is decompressed and concentrated to obtain crude products. The crude product is purified by a preparative high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: water (0.1% trifluoroacetic acid) -acetonitrile ]; B (acetonitrile)%: 20% -60%,7 min) to obtain the trifluoroacetate salt of compound 26.
LCMS(ESI)m/z：485.3[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.74(d，J＝7.04Hz，1H)，8.36(s，1H)，8.14(s，1H)，8.08(s，1H)，7.95-8.04(m，2H)，7.68-7.78(m，2H)，7.61(d，J＝6.54Hz，1H)，7.47(d，J＝1.24Hz，1H)，7.02-7.19(m，2H)，4.14(t，J＝7.64Hz，4H)，4.00(s，3H)，2.34(s，2H).
The trifluoroacetate salt of compound 26 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 26.
The preparation of the compounds of examples in Table 3 can be carried out by reference to the procedure analogous to the route of preparation example 26, except that starting material A used in step six is used instead of cyclobutylamine to give the trifluoroacetate salt of the corresponding compound.
TABLE 3 Table 3
Example 28
Step one
To a solution of 1g (6 g,30.45 mmol), 4-pyrazoleboronic acid pinacol ester (8.86 g,45.68 mmol) in tetrahydrofuran (60 mL) and water (30 mL) was added Pd (dppf) Cl 2 (2.23 g,3.05 mmol) and potassium phosphate (12.93 g,60.90 mmol). Stirring at 80℃for 16 hours under nitrogen. The reaction liquid is separated, the organic phase is collected, and the crude product is obtained by decompression and concentration. The crude product was purified by column chromatography (flash silica gel column chromatography) with dichloromethane/methanol=10/1 to give compound 28a.
LCMS(ESI)m/z：184.9[M+1] +
Step two
To a solution of compound 28a (2.5 g,13.57 mmol) in dichloromethane (25 mL) and DMF (25 mL) was added NIS (3.66 g,16.29 mmol) and stirred at 30℃for 16 h. To the reaction solution was added water (50 mL), followed by extraction with dichloromethane (50 mL x 3), the organic phases were combined and dried under reduced pressure using an oil pump to give compound 28b.
LCMS(ESI)m/z：310.7[M+1] +
Step three
Triethylamine (1.96 g,19.35mmol,2.69 mL), msCl (1.48 g,12.90mmol, 998.40. Mu.L) was added to a solution of compound 28b (2 g,6.45 mmol) in methylene chloride (25 mL) at 0deg.C, and stirred at 30deg.C for 3 hours. The reaction was extracted with water (25 mL), dichloromethane (25 mL x 3), the organic phases combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, which was slurried with DCM: meoh=25:25, and filtered with suction to give compound 28c.
LCMS(ESI)m/z：388.8[M+1] +
Step four
To a solution of compound 28c (0.1 g, 257.61. Mu. Mol), 11f (137.06 mg, 334.89. Mu. Mol) in tetrahydrofuran (5 mL) and water (2.5 mL) was added Pd (dppf) Cl 2 (18.85 mg, 25.76. Mu. Mol), potassium sulfate (109.36 mg, 515.22. Mu. Mol). Stirring for 16 hours at 90 ℃ under the protection of nitrogen. The reaction solution is layered, and then the organic phase is concentrated to obtain a crude product. Crude product warpPreparative HPLC (column: boston Green ODS 150. Mu.m.30 mm. 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 25% -55%,7 min) to obtain the trifluoroacetate salt of the compound 28.
LCMS(ESI)m/z：544.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ9.00(s，1H)，8.77(d，J＝7.28Hz，1H)，8.54(s，1H)，8.26(s，1H)，8.23(s，1H)，7.86(dd，J＝1.25，7.28Hz，1H)，7.56-7.70(m，4H)，7.07-7.18(m，2H)，3.47-3.59(m，3H)，3.05-3.16(m，3H).
The trifluoroacetate salt of compound 28 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 28.
Example 29
Step one
Compound 2e (0.15 g, 373.68. Mu. Mol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C, pyridine (88.67 mg,1.12mmol, 90.48. Mu.L) and methanesulfonyl chloride (58.10 mg, 448.42. Mu. Mol) were added, and the reaction was stirred at 0deg.C for 1 hour. To the reaction mixture were added water (100 mL) and methylene chloride (200 mL) to extract a liquid, and the organic phase was dried, filtered and concentrated to give a crude product. The crude product was purified by high performance liquid chromatography (column: welch Xtimate C18X 25mM X3 μm; mobile phase: [ water (10 mM ammonium bicarbonate) -acetonitrile ]; B (acetonitrile): 27% -57%,10.5 min) to give compound 29.
LCMS(ESI)m/z：495.1[M+1] +
1 H NMR(399MHz，DMSO-d 6 )δ8.53-8.56(m，1H)8.35(s，1H)8.08(s，1H)7.87(s，1H)7.79(s，1H)7.71-7.73(m，2H)7.51-7.56(m，2H)7.49(s，1H)7.41(s，1H)7.33(s，1H)7.23-7.28(m，2H)3.86-3.91(m，3H)3.28-3.32(m，3H).
Example 30
Step one
3-bromo-5-nitro-phenol (20 g,91.74 mmol) and pinacol borate (25.63 g,100.92 mmol) were dissolved in dioxane (200 mL) and KOAc (18.01 g,183.48 mmol) and Pd (dppf) Cl were added 2 (3.36 g,4.59 mmol) was stirred at 90℃for 16 hours under nitrogen. The reaction solution was directly filtered through celite, washed twice with ethyl acetate, the filtrate was collected and dried to give a crude product, which was purified by column chromatography with PE/ea=5/1 to give compound 30a.
1 H NMR(400MHz，CDCl 3 )δ8.17(d，J＝1.52Hz，1H)，7.76(t，J＝2.26Hz，1H)，7.57(d，J＝2.02Hz，1H)，7.00(br s，1H)，1.35(s，12H).
Step two
To compound 30a (3 g,11.32 mmol) and dimethyl t-butylchlorosilane (2.05 g,13.58mmol,1.66 mL) were dissolved in DMF (30 mL), imidazole (1.93 g,28.29 mmol) and DMAP (138.27 mg,1.13 mmol) were added and the reaction was stirred at 30℃for 16 hours at room temperature. The reaction solution is extracted by adding 3mL of water, the organic phase is collected, dried by anhydrous sodium sulfate and spun-dried to obtain a crude product. Compound 30b was obtained directly without purification.
1 H NMR(400MHz，DMSO-d 6 )δ8.01(d，J＝1.24Hz，1H)，7.69(t，J＝2.12Hz，1H)，7.45(d，J＝1.52Hz，1H)，1.32(s，12H)，0.98(s，9H)，0.24(s，6H).
Step three
Compound 30b (2.8 g,7.38 mmol) was dissolved in ethanol (120 mL) and water (20 mL), and ammonium chloride (3.95 g,73.81 mmol) and zinc powder (4.83 g,73.81 mmol) were added and the reaction stirred at 30℃for 16 hours. The reaction solution is directly filtered, washed twice by absolute ethyl alcohol, and the filtrate is dried by spin to obtain a crude product. The crude product was purified by column chromatography with PE/ea=5/1 to give compound 30c.
LCMS(ESI)m/z：350.0[M+1] +
Step four
Compound 30c (1.9 g,5.44 mmol) was dissolved in pyridine (5 mL), and cyclopropanesulfonyl chloride (917.55 mg,6.53 mmol) was added thereto and the reaction was stirred at 30℃for 16 hours. The reaction solution is extracted by adding 10mL of water and 15mL of ethyl acetate, the organic phase is washed twice with 10mL of water, dried by anhydrous sodium sulfate and spin-dried to obtain a crude product. The crude product was purified by column chromatography with PE/ea=5/1 to 1/1 to give compound 30d.
LCMS(ESI)m/z：454.1[M+1] +
Step five
To compound 30d (2.85 g,6.28 mmol), compound 1j (1.36 g,4.19 mmol) dioxane (30 mL) and H 2 Pd (dppf) Cl was added to a solution of O (10 mL) 2 (306.58 mg, 418.99. Mu. Mol), potassium sulfate (1.78 g,8.38 mmol). Stirring at 100℃for 16 hours under nitrogen. The reaction mixture was extracted with water (80 mL), ethyl acetate (50 mL x 3) and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography with DCM/meoh=20/1 to give compound 30e.
LCMS(ESI)m/z：410.1[M+1] +
Step six
To a solution of compound 30e (870 mg,2.12 mmol) in DMF (9 mL) was added DIEA (823.83 mg,6.37 mmol), N-phenylbis (trifluoromethanesulfonyl) imine (1.14 g,3.19 mmol), and the mixture was stirred at 20℃for 16 hours. Water (20 mL) was added to the reaction, ethyl acetate (20 mL. Times.3) was added to the reaction mixture to extract, the organic phases were combined and washed with water (50 mL. Times.3), and the organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography with DCM/meoh=20/1 to give compound 30f.
LCMS(ESI)m/z：542.1[M+1] +
Step seven
To a solution of compound 30f (100 mg, 184.66. Mu. Mol), a borate of bis-pinacolato (56.27 mg, 221.60. Mu. Mol) in dioxane (3 mL) was added Pd (dppf) Cl 2 (13.51 mg, 18.47. Mu. Mol) KOAc (36.25 mg, 369.33. Mu. Mol). Stirring for 16 hours at 90 ℃ under the protection of nitrogen. The reaction solution was concentrated to obtain 30g of a compound.
LCMS(ESI)m/z：520.1[M+1] +
Step eight
To compound 30g (95 mg, 182.90. Mu. Mol), 2-bromo-3, 5-difluoropyridine (40 mg, 206.21. Mu. Mol) dioxane (3 mL) and H 2 Pd (dppf) Cl was added to the O (1 mL) solution 2 (15.09 mg, 20.62. Mu. Mol), potassium phosphate (87.54 mg, 412.42. Mu. Mol,2 eq). Stirring for 3 hours at 100 ℃ under the protection of nitrogen. The reaction solution is directly dried, and the filtrate is decompressed and concentrated to obtain crude products. Separating the crude product with preparative thin layer chromatography silica gel plate (DCM: meOH=10:1), purifying the crude product with preparative high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 20% -50%,7 min) to obtain the trifluoroacetate salt of the compound 30.
LCMS(ESI)m/z：507.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.73(d，J＝7.03Hz，1H)，8.56(d，J＝2.26Hz，1H)，8.39(s，1H)，8.17(d，J＝5.52Hz，2H)，7.99-8.09(m，3H)，7.74-7.82(m，3H)，4.00(s，3H)，2.68-2.80(m，1H)，1.09-1.19(m，2H)，0.99-1.07(m，2H).
The trifluoroacetate salt of compound 30 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 30.
Example 31
Step one
Compound 33c (20 g,57.25mmol,1 eq) and ethanesulfonyl chloride (8.83 g,68.70 mmol) were dissolved in pyridine (80 mL), reacted for 16 hours at room temperature 25 ℃ with stirring, the reaction solution was extracted 3 times with 100mL of water and 100mL of ethyl acetate x 3, the organic phase was dried over anhydrous sodium sulfate, dried by spin to give crude product, the crude product was purified by column chromatography with PE/ea=5/1, and the crude product was slurried with petroleum ether 25 ℃ for 2 hours after spin-drying to give compound 31a.
LCMS(ESI)m/z：442.2[M+1] +
1 H NMR(400MHz，DMSO-d 6 )：δ9.68-9.78(m，1H)，7.14(d，J＝1.52Hz，1H)，6.94(t，J＝2.12Hz，1H)，6.82(d，J＝1.86Hz，1H)，3.05(q，J＝7.32Hz，2H)，1.29(s，12H)，1.17(t，J＝7.40Hz，3H)，0.95(s，9H)，0.16-0.20(m，6H).
Step two
Compound 31a (11 g,24.92 mmol) and compound 1j (6.73 g,20.76 mmol) were dissolved in dioxane (100 mL) and H 2 To O (50 mL), pd (dppf) Cl was added 2 (1.52 g,2.08 mmol) and potassium sulfate (8.82 g,41.53 mmol) were reacted for 16 hours under nitrogen protection at 90 ℃ with stirring, the reaction solution was extracted with 100mL of water and 100mL x 2 of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, dried to give crude product, and the crude product was purified by column purification with DCM/meoh=20/1 to give compound 31b.
LCMS(ESI)m/z：398.0[M+1] +
Step three
Compound 31b (2.6 g,6.54 mmol) and N-phenylbis (trifluoromethanesulfonyl) imide (3.51 g,9.81 mmol) were dissolved in DMF (20 mL) and DIEA (3.38 g,26.17mmol,4.56 mL) was added and stirred at 25℃for 16 h. Water (20 mL) was added to the reaction, ethyl acetate (50 mL. Times.3) was added to the reaction, the organic phases were combined and washed with water (50 mL. Times.3), the organic phases were dried over anhydrous sodium sulfate, and the crude product was obtained by spin-drying. The crude product was purified by column chromatography with DCM/meoh=20/1 to give compound 31c.
LCMS(ESI)m/z：530.3[M+1] +
Step four
Compound 31c (2.6 g,4.91 mmol) and duplex pinacol borate (1.50 g,5.89 mmol) were dissolved in dioxane (1.5 mL) and Pd (dppf) Cl was added 2 (359.28 mg, 491.02. Mu. Mol) and KOAc (963.79 mg,9.82 mmol) were stirred under nitrogen at 90℃for 16 hours. The reaction solution was directly used for the next reaction. Compound 31d was finally obtained.
LCMS(ESI)m/z：508.2[M+1] +
Step five
Compound 31d (2.2 g,4.34 mmol) and 2-bromo-3, 5-difluoropyridine (1.68 g,8.67 mmol) were dissolved in dioxane (1.5 mL) and H 2 O (0.5 mL) to which P was addedd(dppf)Cl 2 (317.25 mg, 433.57. Mu. Mol) and potassium sulfate (1.84 g,8.67 mmol) were reacted under nitrogen at 100℃for 3 hours with stirring. And adding anhydrous sodium sulfate into the reaction solution for drying, filtering, and spin-drying the filtrate to obtain a crude product. The crude product was purified by column chromatography with DCM/meoh=20/1 to give the crude product, which was then subjected to preparative hplc (column: welch xomate C18 x 40mm x 3 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 15% -45%,7 min) and purifying to obtain the trifluoroacetate salt of the compound 31.
LCMS(ESI)m/z：495.0[M+1] +
1 H NMR(400MHz，CD 3 OD): delta 8.72 (d, j=7.34 hz, 1H), 8.52-8.59 (m, 1H), 8.34-8.44 (m, 1H), 8.17 (d, j=7.56 hz, 2H), 8.08 (s, 1H), 7.98 (s, 2H), 7.69-7.84 (m, 3H), 4.01 (s, 3H), 3.27 (q, j=7.38 hz, 2H), 1.39 (t, j=7.44 hz, 3H). The trifluoroacetate salt of compound 31 was added to a sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 31.
Example 32
Step one
To a solution of 2-bromo-3, 5-difluoro-pyridine (4 g,20.62 mmol), 30a (6.01 g,22.68 mmol) dioxane (40 mL) and water (10 mL) was added Pd (dppf) Cl 2 (1.51 g,2.06mmol,0.1 eq) potassium phosphate (8.75 g,41.24mmol,2 eq). Stirring at 100℃for 16 hours under nitrogen. The reaction mixture was extracted with water (100 mL), ethyl acetate (100 mL x 3) and the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography with PE/ea=10/1 to give compound 32a.
LCMS(ESI)m/z：252.9[M+1] +
Step two
To a solution of compound 32a (3.85 g,15.27 mmol) in DMF (50 mL) was added DIEA (5.92 g,45.80mmol,7.98 mL) followed by N-phenylbis (trifluoromethanesulfonyl) imide (8.18 g,22.90 mmol) and stirred at 20℃for 16 h. The reaction mixture was washed with water (200 mL), extracted with ethyl acetate (200 ml×3), combined with water backwash (300 ml×3) of the organic phase, washed with saturated aqueous sodium chloride solution (300 mL), and the organic phase was collected and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 32b.
LCMS(ESI)m/z：384.8[M+1] +
Step three
Compound 32b (13 g,33.83 mmol) was dissolved in ethanol (130 mL) and water (13 mL), ammonium chloride (18.10 g,338.33 mmol) and zinc powder (22.12 g,338.33 mmol) were added, and the reaction was stirred at room temperature 20℃for 16 hours. The reaction solution is directly filtered, and the filtrate is dried by spin to obtain a crude product, and the compound 32c is obtained without purification.
LCMS(ESI)m/z：354.8[M+1] +
Step four
Compound 32c (5 g,14.11 mmol) was dissolved in pyridine (25 mL), methanesulfonyl chloride (2.43 g,21.17mmol,1.64 mL) was added dropwise, and the reaction was stirred at 20℃for 16 hours. The reaction mixture was quenched with 50mL of water, extracted with 50mL of ethyl acetate, washed with 50mL of 3, the organic phase was dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography with PE/ea=5/1 to give compound 32d.
LCMS(ESI)m/z：432.9[M+1] +
Step five
Compound 32d (2.3 g,5.32 mmol) and duplex pinacol borate (2.03 g,7.98 mmol) were dissolved in dioxane (20 mL) and Pd (dppf) Cl was added 2 (389.26 mg, 531.99. Mu. Mol) and KOAc (1.04 g,10.64 mmol) were reacted under nitrogen at 90℃for 16 hours with stirring. The reaction solution was directly filtered, the filtrate was concentrated to obtain a crude product, and the crude product was purified by column chromatography with PE/ea=5/1 to obtain compound 32e.
LCMS(ESI)m/z：411.0[M+1] +
Step six
1g (50 mg, 154.26. Mu. Mol) and compound 32e (94.93 mg, 231.39. Mu. Mol) were dissolved in dioxySix rings (2 mL) and H 2 To O (0.5 mL), pd (dppf) Cl was added 2 (11.29 mg, 15.43. Mu. Mol) and potassium sulfate (65.49 mg, 308.52. Mu. Mol) were reacted under nitrogen at 90℃for 16 hours with stirring. Adding 3mL of water and 5mL of ethyl acetate into the reaction solution, extracting, carrying out spin drying on an organic phase to obtain a crude product, and purifying the crude product by high performance liquid chromatography (chromatographic column: boston Green ODS 150 x 30mm x 5 μm; mobile phase: [ water (0.075% trifluoroacetic acid) -acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the B (acetonitrile)%: 20% -50%,7 min) to obtain the trifluoroacetate salt of the compound 32.
LCMS(ESI)m/z：480.9[M+1] +
1 H NMR(400MHz，CD 3 OD)：δ8.71-8.76(m，1H)，8.54-8.57(m，1H)，8.38-8.41(m，1H)，8.17-8.21(m，1H)，8.16(s，1H)，8.08(s，1H)，7.97-8.03(m，2H)，7.70-7.81(m，3H)，4.01(s，3H)，3.13(s，3H).
The trifluoroacetate salt of compound 32 was added to a sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 32.
Example 33
Step one
To a solution of compound 16c (50 mg, 107.42. Mu. Mol) in DMF (2 mL) was added 3-bromopropane-1, 2-diol (83.24 mg, 537.09. Mu. Mol, 47.03. Mu. L) cesium carbonate (105.00 mg, 322.25. Mu. Mol). Stirred at 80℃for 16 hours. 3-bromopropane-1, 2-diol (83.24 mg, 537.09. Mu. Mol, 47.03. Mu.L) was added thereto, cesium carbonate (50 mg) was added thereto, and the mixture was stirred at 100℃for 16 hours. The reaction solution was directly filtered, and the filtrate was collected. The filtrate is subjected to preparative high performance liquid chromatography (column: phenomenex Gemini-NX 80X 40mM X3 μm; mobile phase: [ water (0.05% ammonia +10mM ammonium bicarbonate) -acetonitrile ]; B (acetonitrile): 18% -48%,8 min) to obtain compound 33.
LCMS(ESI)m/z：540.1[M+1] +
1 H NMR(400MHz，CD 3 OD)δ8.54(d，J＝7.28Hz，1H)，8.21(s，1H)，8.02(s，1H)，7.77(s，1H)，7.72(s，1H)，7.58-7.68(m，1H)，7.54(dd，J＝1.64，4.90Hz，2H)，7.47(d，J＝1.52Hz，1H)，7.29(dd，J＝1.76，7.28Hz，1H)，7.05-7.18(m，2H)，4.37(dd，J＝4.02，14.06Hz，1H)，4.16-4.24(m，1H)，3.98-4.10(m，1H)，3.52-3.58(m，2H)，3.08(s，3H)
Biological test data:
experimental example 1: in vitro enzyme Activity test of the Compounds of the invention
By using 33 P isotope labeled kinase Activity test (Reaction Biology Corp) determination IC 50 The inhibition ability of the test compounds on human FGFR1, FGFR4, VEGFR2 was evaluated.
Buffer conditions: 20mM Hepes (4-hydroxyethyl piperazine ethanesulfonic acid) (pH 7.5), 10mM MgCl 2 1mM EGTA (ethylene glycol bis (2-aminoethylether) tetraacetic acid), 0.02% BriJ35 (surfactant), 0.02mg/ml BSA (bovine serum Albumin), 0.1mM Na 3 VO 4 ，2mM DTT，1％DMSO。
The test steps are as follows: test compounds were dissolved in DMSO at room temperature to make 10mM solutions for use. The substrate was dissolved in freshly prepared buffer, to which the kinase under test was added and mixed well. The DMSO solution in which the test compound was dissolved was added to the above-mentioned well-mixed reaction solution using an acoustic technique (Echo 550). The concentration of the compound in the reaction solution was 10. Mu.M, 2.50. Mu.M, 0.62. Mu.M, 0.156. Mu.M, 39.1nM,9.8nM,2.4nM,0.61nM,0.15nM,0.038nM or 3. Mu.M, 1. Mu.M, 0.333. Mu.M, 0.111. Mu.M, 37.0nM,12.3nM,4.12nM,1.37nM,0.457nM,0.152nM. After incubation for 15 minutes, add 33 P-ATP (activity 0.01. Mu. Ci/. Mu.l, corresponding concentrations are shown in Table 4) was reacted. FGFR1, FGFR4, KDR and concentration information in the reaction solution are listed in table 2. After the reaction was carried out at room temperature for 120 minutes, the reaction solution was spotted on P81 ion exchange filter paper (Whatman # 3698-915). After repeatedly washing the filter paper with a 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured. Kinase activity data was represented by an alignment of kinase activity containing test compounds and kinase activity of the blank (DMSO only) and was curve fitted by Prism4 software (GraphPad) to give IC 50 The values and experimental results are shown in table 5.
Table 4: information about kinase, substrate and ATP in vitro assays.
TABLE 5 Compound kinase Activity IC of the invention 50 Test results
N/A: and not detected.
Conclusion: the compound of the invention has excellent FGFR1, FGFR2, FGFR4 and VEGFR2 kinase inhibition activity.
Experimental example 2: kinetic solubility data test of the inventive Compounds
The kinetic solubility samples were first filtered and sampled. The final sample contained 2% dmso. Calibration was performed by uv-measurement and by 3 standard curves (1, 20, 200 μm). K.s. shaking time: at room temperature for 24 hours.
TABLE 6 kinetic solubility data for compounds of the invention
Conclusion: the compound of the invention has excellent solubility (pH 2.0) and improved pharmaceutical properties.
Experimental example 3: gastric cancer cell line SNU-16 cell activity test of the Compound of the invention
Purpose of experiment
The compounds were tested for their proliferation inhibitory effect on FGFR 2-expressed human gastric cancer SNU-16 cells.
Experimental method
The compounds used for the test were diluted 3-fold at 9 concentrations, starting from 10. Mu.M, 3-fold serial dilutions, 10. Mu.M, 2.50. Mu.M, 0.62. Mu.M, 0.156. Mu.M, 39.1nM,9.8nM,2.4nM,0.61nM,0.15nM.
Instrument for measuring and controlling the intensity of light
(1) Promega CellTiter-Glo luminous cell viability assay kit (Promega-G7573).
(2) 2104 EnVision multi-tag reader, perkinElmer.
Analysis of results: the Inhibition Rate (IR) of the test compound is determined by the following formula: IR (%) = (1- (RLU compound-RLU blank)/(RLU control-RLU blank)) × 100%. The inhibition rates of the compounds at different doses will be calculated in Excel file and parametric curve fitting (GraphPad Software) will yield compound IC 50 Data.
TABLE 7 Compound kinase Activity IC of the invention 50 Test results
Conclusion: the compounds of the present invention have more excellent SNU-16 cell activity (3-5 fold) than the control.
Experimental example 4: antitumor Activity test on in vivo animal tumor model
Purpose of experiment
Tumor inhibiting effect of the compound in mouse human gastric cancer SNU-16 subcutaneous xenograft tumor model
The experimental method comprises the following steps:
1) Tumor tissue preparation
Tumor tissue preparation: at 5% CO 2 SNU-16 cells were routinely cultured in RPMI-1640 medium containing 10% fetal bovine serum at 37℃and saturated humidity. According to the growth condition of cells, the cells are passaged or rehydrated 1 to 2 times per week, and the passaging ratio is 1:3 to 1:4
2) Tissue inoculation and grouping
Collecting SNU-16 cells in logarithmic growth phase, counting, re-suspending in 50% serum-free RPMI-1640 medium and 50% matrigel, and adjusting cell concentration to 4×10 7 cells/mL; cells were placed in ice boxes, and the cell suspension was aspirated with a 1mL syringe, injected under the anterior right armpit of nude mice, and 200. Mu.L (8X 10) of each animal was inoculated 6 Cell/tumor), a model of SNU-16 graft tumor was established. And periodically observing the state of the animal, measuring the tumor diameter by using an electronic vernier caliper, inputting data into an Excel electronic table, calculating the tumor volume, and monitoring the tumor growth condition. The volume of the tumor to be treated reaches 100-300 mm 3 60 tumor-bearing mice (tumor volume 104-179 mm) with good health condition and similar tumor volume are selected 3 ) The random block method was used to divide into 10 (n=6), and the average tumor volume per group was about 143mm 3 。
3) Tumor diameters were measured 2 times per week, tumor volumes were calculated, and animal weights were measured and recorded.
The Tumor Volume (TV) is calculated as follows: TV (mm) 3 )＝1×w 2 Wherein 1 represents a tumor major diameter (mm); w represents the tumor minor diameter (mm).
The tumor-inhibiting effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C (%) =t RTV /C RTV ×100％(T RTV : treatment group mean RTV; c (C) RTV : average RTV for negative control). Relative tumor volume (relative tumor volume, RTV) is calculated from the result of the tumor measurement, calculated as rtv=v t /V 0 Wherein V is 0 Is the tumor volume obtained by measurement of group administration (D0), V t T is the tumor volume measured for a certain time corresponding to the mouse RTV And C RTV The same day data was taken.
TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [ (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with solvent control group-mean tumor volume at the beginning of the treatment with solvent control group) ]x100%. Experimental results:
on the mouse gastric cancer SNU-16 model, the compound of the invention shows remarkable anti-tumor activity compared with a vehicle group after being continuously dosed for 25 days, and tumor growth inhibition rates (% TGI) are respectively as follows: 76%,80%,76%, relative tumor proliferation rate (% T/C) was: 34%,33%,35%, the compound of the present invention exhibited a superior inhibitory effect compared to comparative example 1. The specific results are shown in Table 8, FIG. 1 and FIG. 2 (QDs in the figures represent once a day).
TABLE 8 SNU-16 summary of tumor growth inhibition and relative tumor proliferation rates
* In all the administration groups, the administration dose was changed to 30 mg/kg/day on day 9 and to 20 mg/kg/day on day 12.
Conclusion of experiment: the compounds of the present invention demonstrate excellent tumor therapeutic effects at lower doses in preclinical animal models.

Claims (21)

1. A compound represented by the formula (III) or a pharmaceutically acceptable salt thereof,
wherein,,
R 1 selected from H, -S (=O) 2 CH 3 、C 1-6 Alkyl, C 1-3 Alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, said C 1-6 Alkyl, C 1-3 Alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl are optionally substituted with 1, 2 or 3R a Substitution;
R 2 and R is 3 Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CH 3 And OCH 3 ；
R 4 Selected from H, NH 2 、C 1-6 Alkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl radicalsThe C is 1-6 Alkyl, C 1-3 Alkoxy, C 3-5 Cycloalkyl and->Optionally by 1, 2 or 3R b Substitution;
m is selected from 1 and 2;
l is selected from-N (R) 5 )C(＝O)-、-N(R 5 )S(＝O) 2 -、-N(R 5 )C(＝O)N(R 5 )-、N(R 5 )S(＝O) 2 N(R 5 ) -and-N (R) 5 )-；
Ring a is selected from phenyl, pyrrolyl, pyrimidinyl and pyridinyl;
ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl and 3, 6-dihydro-2H-pyranyl;
R 5 are independently selected from H and C 1-3 An alkyl group;
R a and R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、-S(＝O) 2 CH 3 、C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino, said-S (=o) 2 CH 3 、C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino is optionally substituted with 1, 2 or 3R;
r is selected from H, F, cl, br, I, OH and NH 2 。
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R a And R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、-S(＝O) 2 CH 3 、CH 3 、-OCH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 said-S (=o) 2 CH 3 、CH 3 、-OCH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 Optionally substituted with 1, 2 or 3R.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R a And R is b Are respectively and independently selected from H, F, cl, br, I, OH, NH 2 、CN、CH 3 、CH 2 OH、-OCH 3 、-S(＝O) 2 CH 3 、-N(CH 3 ) 2 and-NHCH (CH) 3 ) 2 。
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H, -S (=O) 2 CH 3 、CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、OCH 2 CH 3 Tetrahydropyranyl, tetrahydrofuranyl and piperidinyl groups, said CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、OCH 2 CH 3 The tetrahydropyranyl, tetrahydrofuranyl and piperidinyl groups are optionally substituted with 1, 2 or 3R a And (3) substitution.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H, -S (=O) 2 CH 3 、CH 3 、CH 2 OH、CH 2 CH 3 、CH 2 CH 2 OH、OCH 2 CH 3 、
6. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from H, NH 2 、CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 、OCH 3 、OCH 2 CH 3 Cyclopropane, azetidine and pyrrolidinyl groups, said CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 、OCH 3 、OCH 2 CH 3 Optionally substituted with 1, 2 or 3R groups b And (3) substitution.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from H, NH 2 、CH 3 、CH 2 CH 3 、CH(CH 3 ) 2 、C(CH 3 ) 3 、CH 2 CH 2 CH 3 、CH 2 CH 2 N(CH 3 ) 2 、OCH 3 、
8. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 5 Are respectively and independently selected from H, CH 3 And CH (CH) 2 CH 3 。
9. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein L is selected from-NHC (=o) -, -NHC (=o) NH-, -NHs (=o) 2 -、-NHS(＝O) 2 NH-and-NH-.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein-L-R 4 Selected from the group consisting of
11. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from->
13. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from
14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from->
15. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from->
16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from
Wherein,,
T 1 selected from CH and N;
R 2 and R is 3 As defined in claim 1;
R 1 as defined in claim 1;
R 4 as defined in claim 1;
l is as defined in claim 1.
17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, selected from
Wherein,,
T 1 selected from CH and N;
R 1 、R 2 、R 3 and R is 4 As defined in claim 16.
18. A compound represented by the following formula or a pharmaceutically acceptable salt thereof,
19. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, as an active ingredient together with a pharmaceutically acceptable carrier.
20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a composition according to claim 19, for the preparation of a dual FGFR and VEGFR inhibitor related medicament.
21. The use according to claim 20, wherein the dual FGFR and VEGFR inhibitor related drug is a drug for solid tumors.
CN201980092860.3A 2018-12-29 2019-12-30 Imidazopyridine derivatives as dual FGFR and VEGFR inhibitors Active CN113490667B (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
CN201811640177 2018-12-29
CN2018116401772 2018-12-29
CN2019103132378 2019-04-18
CN201910313237 2019-04-18
CN2019108023911 2019-08-28
CN201910802391 2019-08-28
CN2019113107762 2019-12-18
CN201911310776 2019-12-18
PCT/CN2019/130053 WO2020135878A1 (en) 2018-12-29 2019-12-30 Imidazopyridine derivative as fgfr and vegfr dual inhibitor

Publications (2)

Publication Number Publication Date
CN113490667A CN113490667A (en) 2021-10-08
CN113490667B true CN113490667B (en) 2023-10-27

Family

ID=71125872

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201980092860.3A Active CN113490667B (en) 2018-12-29 2019-12-30 Imidazopyridine derivatives as dual FGFR and VEGFR inhibitors

Country Status (2)

Country Link
CN (1) CN113490667B (en)
WO (1) WO2020135878A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110446704B (en) * 2017-03-23 2022-07-05 奥赖恩公司 Process for the preparation of sulfonamide-structured kinase inhibitors
MX2021002524A (en) * 2018-09-06 2021-04-28 Aurigene Discovery Tech Limited Star Novel hydrochloride salt forms of a sulfonamide structured kinase inhibitor.
WO2021018047A1 (en) * 2019-07-26 2021-02-04 南京明德新药研发有限公司 Pyridine derivative as fgfr and vegfr dual inhibitors
EP4286382A1 (en) * 2021-01-26 2023-12-06 CGeneTech (Suzhou, China) Co., Ltd. Crystal form of methylpyrazole-substituted pyridoimidazole compound and preparation method therefor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1852905A (en) * 2003-08-21 2006-10-25 Osi制药公司 N-substituted benzimidazolyl c-kit inhibitors
CN101679409A (en) * 2006-12-22 2010-03-24 Astex治疗学有限公司 New compounds
CN103958500A (en) * 2011-10-10 2014-07-30 奥赖恩公司 Protein kinase inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2015384801B2 (en) * 2015-03-04 2022-01-06 Eisai R&D Management Co., Ltd. Combination of a PD-1 antagonist and a VEGFR/FGFR/RET tyrosine kinase inhibitor for treating cancer
JP6898306B2 (en) * 2015-08-07 2021-07-07 ハルビン チェンバオ ファーマシューティカル カンパニー リミテッド Vinyl compounds that are FGFR and VEGFR inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1852905A (en) * 2003-08-21 2006-10-25 Osi制药公司 N-substituted benzimidazolyl c-kit inhibitors
CN101679409A (en) * 2006-12-22 2010-03-24 Astex治疗学有限公司 New compounds
CN103958500A (en) * 2011-10-10 2014-07-30 奥赖恩公司 Protein kinase inhibitors

Also Published As

Publication number Publication date
CN113490667A (en) 2021-10-08
WO2020135878A1 (en) 2020-07-02

Similar Documents

Publication Publication Date Title
CN113490667B (en) Imidazopyridine derivatives as dual FGFR and VEGFR inhibitors
US10519137B2 (en) Pyrazolyl quinoxaline kinase inhibitors
JP7041070B2 (en) Amine-substituted aryl or heteroaryl compounds as EHMT1 and EHMT2 inhibitors
RU2629194C2 (en) Derivatives of 1,5- and 1,7-naphthyridine useful in treatment of fgfr-mediated diseases
KR101862493B1 (en) Ring-fused bicyclic pyridyl derivatives as fgfr4 inhibitors
BR112014010177B1 (en) COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND
KR20130132509A (en) Substituted benzopyrazin derivatives as fgfr kinase inhibitors for the treatment of cancer diseases
BR112014010206B1 (en) compound derived from pyridopyrazine, pharmaceutical composition, and, use of a compound
JP2014530203A (en) Cyanomethylpyrazole carboxamides as Janus kinase inhibitors
JP2022530383A (en) Quinazoline compounds and their pharmaceutical uses
CN116888108B (en) Novel EGFR degradation agent
JP6283688B2 (en) Novel pyrazole-substituted imidazopyrazine as casein kinase 1D / E inhibitor
WO2013056015A1 (en) Isoindolinone and pyrrolopyridinone derivatives as akt inhibitors
JP2017519821A (en) Pyrido [1,2-a] pyrimidone analogs as PI3K inhibitors
EP4393916A1 (en) Nitrogen-containing heterocyclic derivative inhibitor, and preparation method therefor and use thereof
JP2023523863A (en) A novel macrocyclic LRRK2 kinase inhibitor
JP7343622B2 (en) Fused ring compounds as dual FGFR and VEGFR inhibitors
CN112300154B (en) Nitrogen-containing heterocyclic compound, preparation method and application thereof
CN114195771B (en) Multi-kinase inhibitors and uses thereof
CN114072402B (en) Pyridine derivatives as dual FGFR and VEGFR inhibitors
JP7584623B2 (en) Compounds with kinase inhibitory activity
TWI690528B (en) Ring-fused bicyclic pyridyl derivatives

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40052635

Country of ref document: HK

TA01 Transfer of patent application right
TA01 Transfer of patent application right

Effective date of registration: 20220706

Address after: 215123 Room 101, C11 / F, bio nano Park, 218 Xinghu street, Suzhou Industrial Park, Suzhou City, Jiangsu Province

Applicant after: CGENE TECH (SUZHOU, CHINA) Co.,Ltd.

Address before: 210032 room 218, business office building, No.9 Gaoxin Road, Jiangbei new district, Nanjing City, Jiangsu Province

Applicant before: Nanjing Mingde New Drug Development Co.,Ltd.

CB02 Change of applicant information
CB02 Change of applicant information

Address after: 215123 units 101 and 102, C11 building, phase I project of biomedical industrial park, No. 218 Xinghu street, Suzhou Industrial Park, China (Jiangsu) pilot Free Trade Zone, Suzhou, Jiangsu Province

Applicant after: CGENE TECH (SUZHOU, CHINA) Co.,Ltd.

Address before: 215123 Room 101, C11 / F, bio nano Park, 218 Xinghu street, Suzhou Industrial Park, Suzhou City, Jiangsu Province

Applicant before: CGENE TECH (SUZHOU, CHINA) Co.,Ltd.

CB02 Change of applicant information
CB02 Change of applicant information

Address after: 215123 units 101 and 102, C11 building, phase I project of biomedical industrial park, No. 218 Xinghu street, Suzhou Industrial Park, China (Jiangsu) pilot Free Trade Zone, Suzhou, Jiangsu Province

Applicant after: Shengshi Taike Biopharmaceutical Technology (Suzhou) Co.,Ltd.

Address before: 215123 units 101 and 102, C11 building, phase I project of biomedical industrial park, No. 218 Xinghu street, Suzhou Industrial Park, China (Jiangsu) pilot Free Trade Zone, Suzhou, Jiangsu Province

Applicant before: CGENE TECH (SUZHOU, CHINA) Co.,Ltd.

GR01 Patent grant
GR01 Patent grant