CN115974872A - Aza-and-ring derivatives, pharmaceutical compositions thereof and uses thereof - Google Patents

Aza-and-ring derivatives, pharmaceutical compositions thereof and uses thereof Download PDF

Info

Publication number
CN115974872A
CN115974872A CN202310039898.2A CN202310039898A CN115974872A CN 115974872 A CN115974872 A CN 115974872A CN 202310039898 A CN202310039898 A CN 202310039898A CN 115974872 A CN115974872 A CN 115974872A
Authority
CN
China
Prior art keywords
radical
compound
alkoxy
alkyl
fluoropropyl
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.)
Pending
Application number
CN202310039898.2A
Other languages
Chinese (zh)
Inventor
李迎君
薛晓纤
王萍
李潮
张绪穆
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.)
Southwest University of Science and Technology
Original Assignee
Southwest University of Science and Technology
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 Southwest University of Science and Technology filed Critical Southwest University of Science and Technology
Publication of CN115974872A publication Critical patent/CN115974872A/en
Pending legal-status Critical Current

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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention belongs to the field of medicines, and relates to a nitrogen heterocyclic compound, a pharmaceutical composition thereof and application thereof in preparing medicines. Specifically, the compound has a structure shown in a formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. The compounds of the invention and medicaments thereofThe composition can be used for preparing medicine for treating HIF-2 alpha mediated related diseases, such as cancer, inflammation, etc.

Description

Aza-and-ring derivatives, pharmaceutical compositions thereof and uses thereof
Technical Field
The invention belongs to the field of medicines, and relates to a nitrogen heterocyclic compound, a pharmaceutical composition thereof and application thereof in preparing medicines. Specifically, the compound and the pharmaceutical composition thereof can be used as HIF-2 alpha regulator, and can be used for preparing medicaments for treating related diseases such as cancer, inflammation, pulmonary hypertension, atherosclerosis or ischemic diseases.
Background
HIFs are a class of nuclear transcription complexes that mediate the intracellular hypoxic response, and are widely expressed in tissue cells to promote the adaptation process of organisms to the hypoxic response. HIFS mainly include HIF-1, HIF-2 and HIF-3, which are heterodimers composed of an oxygen-sensitive alpha subunit (HIF-1 alpha, HIF-2 alpha and HIF-3 alpha) and a constitutive beta subunit HIF-1 beta (also known as aromatic Hydrocarbon Receptor Nuclear Transporter, ARNT). Of the three alpha subunits, HIF-2 α is the primary regulator of pathological hypoxia response. When oxygen concentration is normal, the half-life of HIF-2 α is short, and two specific prolines Pro405 and Pro531 in the ODDD domain of HIF-2 α are rapidly recognized and hydroxylated by hydroxylating enzymes. The hydroxylated HIF-2 alpha is combined with VHL protein, and then is ubiquitinated by E3 ubiquitin ligase, and finally is rapidly degraded by protease; meanwhile, in a plurality of malignant tumors, a large number of Hypoxia regions or VHL with function defect exist, HIF-2 alpha accumulates in cells, forms heterodimer with ARNT which is continuously expressed, and is finally combined with Hypoxia Response Elements (HRE) of different molecules, thereby regulating the transcription of a plurality of target genes.
HIF-2 alpha subunitAnd ARNT subunits belong to the Per-ARNT-Sim (PAS) subfamily of the basic helix-loop-helix (bHLH) family, both subunits being structurally similar, comprising mainly an N-terminal bHLH (DNA binding Domain, DBD, DNA binding Domain), and two adjacent PASA and PASB domains (Ligand binding Domain, LBD, ligand binding Domain); the C terminal is combined with a transcription accessory factor to regulate the transcription of downstream genes. The internal existence of an approximation of the PASB domain of the HIF-2 alpha subunit was found
Figure BDA0004050562950000011
And (c) the cavity, upon binding of the modulator, is capable of affecting heterodimerization of the HIF-2. Alpha. Subunit and the ARNT subunit, thereby blocking or activating DNA binding and transcription of the target gene. HIF-2 alpha downstream target genes such as Vascular Endothelial Growth Factor (VEGF), erythropoietin (EPO) and glycolytic enzymes are related to tumor, inflammation and blood diseases, so the development of HIF-2 alpha regulator has important clinical significance.
Disclosure of Invention
The invention provides a novel aza-cyclo derivative, a pharmaceutical composition thereof and application thereof. The compound or the pharmaceutical composition thereof can be effectively used for preparing medicaments for preventing, treating or relieving HIF-2 alpha-mediated related diseases, such as cancers, inflammations, pulmonary hypertension, atherosclerosis or ischemic diseases, and the like.
Specifically, in one aspect, the invention provides a compound having a structure shown as formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure BDA0004050562950000021
wherein, the first and the second end of the pipe are connected with each other,
X1is N or CR1；
X2And X5Each independently is N or CH;
X3is CR5Or N;
X4is CR4Or N;
a is C6-14Aryl or 5-12 membered heteroaryl;
R1is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkoxy radical C1-6Alkyl, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy and C1-6Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、-C(＝O)R8、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
R2is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkoxy radical C1-6Alkyl, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy and C1-6Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO 2、NH2、COOH、CF3、NRcRd、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C6-12Aryl and 5-12 membered heteroaryl;
R3is H, D, F, cl, br, I, OH, CN, NO2、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、-NRcC(＝O)NRcRd、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C6-12Aryl or 5-12 membered heteroaryl, wherein said C6-12Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with a substituent of haloalkoxy;
each R4And R5Independently H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkoxy radical C1-6An alkyl group;
each R6And R7Independently F, cl, br, I, OH, CN, NH2、NO2、C(＝O)OR8、C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-C(＝O)R8、C1-6Alkyl radical, C1-6Haloalkyl or C1-6A haloalkoxy group;
each R8Independently is C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, and R8Optionally selected from 1, 2, 3 or 4 selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
each RaAnd RbIndependently H, F, cl, br, I, OH, CN, NH2、C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
Each RcAnd RdIndependently is C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl;
m is 1,2 or 3; and
each n1 and n2 is independently 0, 1,2,3 or 4;
provided that R is2And R3Not both being H, and the compounds of formula (I) do not comprise compounds
Figure BDA0004050562950000031
Figure BDA0004050562950000032
In some embodiments, a is C6-12Aryl or 5-10 membered heteroaryl. In some embodiments, a is C6Aryl radical, C7Aryl radical, C8Aryl radical, C9Aryl radical, C10Aryl radical, C11Aryl radical, C12Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl.
In some embodiments, the 5-10 membered heteroaryl contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments , the 5-to 10-membered heteroaryl group includes 2-furyl , 3-furyl radical , n-imidazolyl , 2-imidazolyl group , 4-imidazolyl , 5-imidazolyl , 3-isoxazolyl , 4-isoxazolyl , 5-isoxazolyl , 2-oxazolyl radical , 4-oxazolyl radical , 5-oxazolyl radical , n-pyrrolyl , 2-pyrrolyl , 3-pyrrolyl , 2-pyridyl radical , 3-pyridyl group , 4-pyridyl radical , 2-pyrimidinyl radicals , 4-pyrimidinyl radicals , 5-pyrimidinyl radicals , pyridazinyl (e.g. 3-pyridazinyl) , 2-thiazolyl radical , 4-thiazolyl radical , 5-thiazolyl radical , tetrazolyl (e.g. 5-tetrazolyl) , triazolyl radicals (e.g. 2-triazolyl and 5-triazolyl) , 2-thienyl radical , 3-thienyl radical , pyrazolyl (e.g. 2-pyrazolyl) , isothiazolyl group , 1 , 2 , 3-oxadiazolyl , 1 , 2 , 5-oxadiazolyl , 1 , 2 , 4-oxadiazolyl , 1 , 2 , 3-triazolyl , 1 , 2 , 3-thiadiazolyl radicals , 1 , 3 , 4-thiadiazolyl radicals , 1 , 2 , 5-thiadiazolyl radicals , pyrazinyl radical , 1 , 3 , 5-triazinyl group , benzimidazolyl radicals , benzofuranyl radical , benzothienyl , indolyl (such as 2-indolyl) , purine radical , quinolyl radicals (e.g. 2-quinolyl radicals) , 3-quinolyl radicals , 4-quinolyl) , isoquinolinyl (e.g. 1-isoquinolinyl) , 3-isoquinolinyl or 4-isoquinolinyl) , imidazo [ 1) , 2-a ] pyridinyl , Pyrazolo [1,5-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl or [1,2,4] triazolo [1,5-a ] pyridinyl.
In some embodiments, the C1-6Haloalkyl being C1-6One or more H in the alkyl is independently selected from F, cl, br. In some embodiments, the C1-6Haloalkyl is trifluoromethyl, trifluoroethyl, monofluoromethyl, difluoromethyl, monofluoroethyl, 1, 2-difluoroethyl, 1-difluoroethyl, 2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, 1-dichloroethyl, 2-dichloroethyl or 1, 1-dibromoethyl.
In some embodiments, the C1-4Haloalkyl being C1-4One or more H in the alkyl is independently selected from F, cl, br. In some embodiments, the C1-4Haloalkyl is trifluoromethyl, trifluoroethyl, monofluoromethyl, difluoromethyl, monofluoroethyl, 1, 2-difluoroethyl, 1-difluoroethyl, 2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, 1-dichloroethyl, 2-dichloroethyl or 1, 1-dibromoethyl.
In some embodiments, the heterocyclyl contains 1,2, or 3 heteroatoms selected from O, N, S. In some embodiments, the heterocyclyl group comprises an oxirane group, azetidinyl group, oxetanyl group, thietanyl group, pyrrolidinyl group, 2-pyrrolinyl group, 3-pyrrolinyl group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, tetrahydrofuryl group, dihydrofuranyl group, tetrahydrothienyl group, dihydrothienyl group, 1, 3-dioxocyclopentyl group, dithiocyclopentyl group, tetrahydropyranyl group, dihydropyranyl group, 2H-pyranyl group, 4H-pyranyl group, tetrahydrothiopyranyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, dioxanyl group, dithianyl group, thioxanyl group, homopiperazinyl group, homopiperidinyl group, 1-dioxo-1, 3-thiomorpholine, 2-oxopyrrolidinyl group, oxo-1, 3-thiazolidinyl group, 2-piperidinonyl group, 3, 5-dioxopiperidinyl group, or 1, 1-dioxo-1, 3-thiomorpholine.
In some embodiments, a is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, benzofurazan, or pyrazolyl.
In some embodiments, R1Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Alkoxy radical C1-4Alkyl, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy and C1-4Alkoxy radical C1-4Each alkyl is independently optionally substituted by 1,2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、-C(＝O)R8、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C3-12Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 5-6 membered heteroaryl; wherein R isa、Rb、Rc、RdN1 and R8Each having a definition as set forth in the present invention.
In some casesIn the embodiment, R1Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8Methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl or ethoxyethyl, wherein said methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, tert-butyl, allyl, ethynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, allyl, 2-hydroxypropyl, 4-hydroxypropyl, 2-hydroxypropyl, etc 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl and ethoxyethyl each independently being optionally substituted by 1,2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO 2、COOH、CF3、NRcRd、-C(＝O)R8、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRdCyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl, and imidazolyl; wherein R isa、Rb、Rc、RdN1 and R8Each having a definition as set forth in the present invention.
In some embodiments, R2Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Alkoxy radical C1-4Alkyl, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy and C1-4Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1,2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、NH2、COOH、CF3、NRcRd、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C6-12Aryl and 5-6 membered heteroaryl; wherein R isa、Rb、Rc、RdN2 and R8Each having a definition as set forth in the present invention.
In some embodiments, R2Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8Methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl or ethoxyethyl, wherein said methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl or ethoxyethyl are each independently optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of F, cl, br, I, OH, CN, NO, N 2、NH2、COOH、CF3、NRcRd、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRdPhenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl; wherein R isa、Rb、Rc、RdN2 and R8Each having a definition as described herein.
In some embodiments, R3Is H, D, F, cl, br, I, OH, CN, NO2、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、-NRcC(＝O)NRcRdMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, triazolyl or pyrazolyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, triazolyl and pyrazolyl are each independently optionally substituted with 1,2, 3 or 4 substituents selected from the group consisting of F, cl, br, I, OH, CN, NO2COOH, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl and ethoxyethyl; wherein R is a、Rb、Rc、RdN1 and R8Each having a definition as described herein.
In some embodiments, each R is4And R5Independently H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Alkoxy radical C1-4An alkyl group;
each R6And R7Independently F, cl, br, I, OH, CN, NH2、NO2、C(＝O)OR8、C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-C(＝O)R8Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C1-4Haloalkyl or C1-4A haloalkoxy group;
wherein R isa、Rb、Rc、RdN1 and R8Each having a definition as set forth in the present invention.
In some embodiments, each R is8Independently is C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl or 5-6 membered heteroaryl, and R8Optionally selected from 1, 2, 3 or 4 selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 5-6 membered heteroaryl; wherein R iscAnd RdEach having a definition as described herein.
In some embodiments, each R is8Independently is methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, propyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuryl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl or imidazolyl, and R is 8Optionally selected from 1,2, 3 or 4 selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRdMethyl, ethyl, n-propyl, isopropyl, tert-butylButyl, -fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl, wherein R is substituted by a substituent selected from the group consisting ofcAnd RdEach having a definition as set forth in the present invention.
In some embodiments, each R isaAnd RbIndependently H, F, cl, br, I, OH, CN, NH2Methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
Each RcAnd RdIndependently methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl.
In some embodiments, the compounds of the present invention are of formula (IX), or a stereoisomer, tautomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
Figure BDA0004050562950000081
wherein A is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl,Imidazolyl, thienyl, benzofurazan or pyrazolyl, R1、R2、R3、R6And R7Each having a definition as set forth in the present invention.
In some embodiments, the compounds of the present invention are of formula (II), or a stereoisomer, tautomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
Figure BDA0004050562950000082
wherein R is1、R2、R3、R6And R7Each having a definition as set forth in the present invention.
In some embodiments, the compounds of the present invention are structures of formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), or stereoisomers, tautomers, nitrogen oxides, metabolites, pharmaceutically acceptable salts, or prodrugs thereof,
Figure BDA0004050562950000083
wherein R1, R2, R3, R6 and R7 each have the definitions as described herein.
In some embodiments, the compounds of the present invention are of formula (II-1), or a stereoisomer, tautomer, nitrogen oxide, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
Figure BDA0004050562950000091
wherein R is1、R2、R8、R6And R7Each having a definition as described herein.
In some embodiments, the compounds of the present invention have one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
Figure BDA0004050562950000092
/>
Figure BDA0004050562950000101
/>
Figure BDA0004050562950000111
/>
Figure BDA0004050562950000121
in another aspect, the invention provides a pharmaceutical composition comprising a compound described herein.
In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable adjuvant.
In some embodiments, the adjuvant of the present invention includes, but is not limited to, a carrier, excipient, diluent, vehicle, or combination thereof.
In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
In another aspect, the present invention provides a use of a compound or pharmaceutical composition of the present invention in the manufacture of a medicament for preventing, treating, or ameliorating a HIF-2 α -mediated associated condition.
In some embodiments, the HIF-2 alpha-mediated associated condition is cancer, inflammation, pulmonary hypertension, atherosclerosis, or an ischemic condition.
In some embodiments, the cancer is renal cancer, glioblastoma, breast cancer, non-small cell lung cancer, prostate cancer, hepatocellular carcinoma, and head and neck squamous cell carcinoma.
In some embodiments, the inflammation is of the digestive system, optionally, the inflammation of the digestive system is crohn's disease or ulcerative colitis. In another aspect, the invention relates to intermediates for preparing compounds of formula (I), formula (II-1), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX).
In another aspect, the invention relates to methods of preparing, isolating and purifying compounds of formula (I), formula (II-1), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX). Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically compatible, in relation to the other components making up the formulation and the mammal being treated.
Detailed description of the invention
Definition of terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
Unless otherwise indicated, the structural formulae depicted herein and the compounds depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds that are individual stereochemically isomeric forms, enantiomeric forms, diastereomeric forms, geometric forms, conformational forms, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are also within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae for the compounds described herein include isotopically enriched versions of one or more different atoms.
As described herein, a compound of the present invention may be independently optionally substituted with one or more substituents, it being understood that the term "independently optionally substituted with ... substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The description mode adopted in the invention is that each of \8230, independently and interchangeably can be understood in a broad sense, and the description mode can mean that specific options expressed among the same symbols in different groups do not influence each other, and can also mean that the specific options expressed among the same symbols in the same groups do not influence each other.
In the compounds of the invention, when any variable (e.g. R)c、RdEtc.) occur more than one time in any combination, their definition on each occurrence is independent of its definition on every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. It is to be understood that substituents of the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and readily synthesized from starting materials that are readily available by those of skill in the art and methods set forth below.
The term "room temperature" means ambient temperature and may be from 10 ℃ to 35 ℃, alternatively from 15 ℃ to 30 ℃ or alternatively from 20 ℃ to 30 ℃.
"C" in the inventionq1-q2"denotes the number of carbon atoms of the group described, e.g. C1-6Alkyl represents an alkyl group having 1 to 6 carbon atoms; c 3-6Cycloalkyl means cycloalkyl containing 3 to 6 carbon atoms.
The term "q3-q4 membered" or "q3-q4 atom composed" denotes the number of ring-forming atoms of the ring depicted, e.g. a 3-6 membered heterocyclyl denotes a heterocyclyl group containing 3-6 ring-forming atoms.
The term "alkyl" denotes a saturated straight or branched chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms. In another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl (s-Bu, -CH (CH)3)CH2CH3) T-butyl, n-pentyl, 2-pentyl, etc.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 10 carbon atoms; in one embodiment, alkenyl groups The group contains 2 to 6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH)2) Allyl (-CH)2CH＝CH2) Propenyl (-C = CHCH)3) Isopropenyl (-C (CH))3)＝CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-10 carbon atoms; alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH)2C.ident.CH), 1-propynyl (-C.ident.C-CH)3) And so on.
The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxyl groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1, 2, 3, or 4 hydroxy groups. In some embodiments, hydroxyalkyl represents alkyl substituted with 1 or 2 hydroxy groups. In some embodiments, hydroxyalkyl represents C 1-6Hydroxyalkyl, i.e. C1-6Alkyl in which the alkyl group is substituted by 1 or more hydroxyl groups, preferably, C1-6Hydroxyalkyl denotes, i.e. C1-6Alkyl in which the alkyl group is substituted with 1 hydroxyl group. In some embodiments, hydroxyalkyl represents C1-4A hydroxyalkyl group. In some embodiments, hydroxyalkyl represents C1-3A hydroxyalkyl group. Examples of hydroxyalkyl include, but are not limited to, CH2OH-、CH2OHCH2CH2CH2-、CH2OHCH2-、CH2OHCH2CHOHCH2-、CH(CH3)OHCH2CHOHCH2-, etc.
The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, examples of which include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, 1, 2-difluoroethyl, 1-difluoroethyl, 2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1, 2-dichloroethyl, 1-dichloroethyl, 2-dichloroethyl, 1-dibromoethyl, and the like.
The term "halogen" denotes F (fluorine), cl (chlorine), br (bromine) or I (iodine).
The term "alkoxy" means that the alkyl group is attached to the rest of the molecule through an oxygen atom. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) And so on.
The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, 1, 2-difluoroethoxy, 1-difluoroethoxy, 2-difluoroethoxy, and the like.
The term "alkoxyalkyl" denotes an alkyl group substituted with one alkoxy group, wherein alkoxy and alkyl have the definitions as described herein. In some embodiments, alkoxyalkyl represents C1-6Alkoxy radical C1-6An alkyl group; in other embodiments, alkoxyalkyl represents C1-4Alkoxy radical C1-4An alkyl group; in other embodiments, alkoxyalkyl represents C1-4Alkoxy radical C1-3An alkyl group; in some embodiments, alkoxyalkyl represents C1-3Alkoxy radical C1-3An alkyl group. Examples of alkoxy groups include, but are not limited to, methoxymethyl,Ethoxymethyl, propoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, and the like.
The terms "cycloalkyl" or "cycloalkane" are used interchangeably and both represent monovalent, saturated, monocyclic carbocyclic ring systems of 3 to 12 carbon atoms. Of carbocyclic ring-CH2The-group may optionally be replaced by-C (O) -. In one embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, i.e., C3-6A cycloalkyl group; in another embodiment, the cycloalkyl group contains 3 to 5 carbon atoms, i.e., C3-5A cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Of carbocyclic ring-CH2Examples of groups that can be replaced by-C (O) -include, but are not limited to: cyclopentanone, cyclobutanone, and the like.
The term "heterocyclyl" denotes a monovalent, non-aromatic, saturated or partially unsaturated monocyclic ring system having 3 to 12 ring atoms and comprising at least 1 carbon atom and comprising 1, 2 or 3 heteroatoms selected from O, N, S. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2The-group may optionally be replaced by-C (O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide and the nitrogen atom of the ring may optionally be oxidized to the N-oxygen compound. In some embodiments, the heterocyclic ring contains 4 to 7 ring atoms, i.e., represents a 4-7 membered heterocyclic ring; in other embodiments, the heterocyclic ring contains 4 to 7 ring atoms, i.e., represents a 4-7 membered heterocyclic ring. Examples of heterocycles include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, 1-dioxo-1, 3-thiomorpholine, and the like. In heterocyclic radicals of-CH 2Examples of-groups substituted with-C (O) -include, but are not limited to2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of heterocyclic nitrogen atoms that are oxidized to the N-oxygen compound include, but are not limited to, 1-dioxo-1, 3-thiomorpholine.
The term "aryl" refers to a monovalent aromatic ring radical formed by the removal of one hydrogen atom from a ring carbon atom of an aromatic ring. Examples of the aryl group may include phenyl, naphthyl, and anthracenyl, and the like.
The term "heteroaromatic ring" denotes monovalent monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms. In one embodiment, the 5-10 membered heteroaryl group contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In some embodiments, the term "heteroaryl" denotes a heteroaryl ring group or a 5-membered heteroaryl group containing 5 ring atoms, wherein 1,2,3 or 4 heteroatoms independently selected from O, S and N are contained. Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1, 3-thiadiazolyl, 1,2, 5-thiadiazolyl, 1, 5-triazinyl; the following bicyclic rings are also included, but by no means limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and can be phenyl ester, aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, which can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those phosphate esters which are phosphorylated via the parent hydroxy group.
"metabolite" refers to the product of a particular compound or salt thereof that is metabolized in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: S.M. Berge et al, describe the descriptor of the pharmacological acceptable salts in detail in J.pharmaceutical Sciences,1977, 66. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate,perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or these salts can be obtained by other methods described in the literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N +(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulphonates and aromatic sulphonates.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
By "nitroxide" herein is meant that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxides (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxide may be prepared by the method of l.w. ready (syn.comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to mitigating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of the disease or disorder.
The "cancer" of the present invention includes, but is not limited to, the following diseases: kidney, glioblastoma, breast, lung, prostate, hepatocellular, and head and neck squamous cell carcinoma, ovarian, bladder, brain, colon, rectal, pancreatic, gastric, vaginal, cervical, endometrial, thyroid, and skin cancers, and the like; lymphohematopoietic tumors including acute lymphocytic leukemia, B cell lymphoma, burketts lymphoma, and the like; myeloid hematopoietic tumors including acute and chronic myelogenous leukemia and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, neuroblastoma, glioma, and the like.
The cyclized compounds provided by the invention can effectively regulate the activity of HIF-2 alpha protein. Modulation as used herein means that some of the compounds are inhibitors and some of the compounds are agonists. The terms "inhibitor" and "antagonist" are used interchangeably and refer to a compound that has the ability to inhibit a target protein or enzyme (e.g., HIF-2. Alpha.). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological effects of the target protein. Although the preferred antagonists herein specifically interact with the target (e.g., bind to HIF-2 α), compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway to which the target protein belongs are also specifically included within this scope. The term "agonist" as used herein refers to a compound having the biological function of initiating or enhancing a target protein by binding to the target protein. Thus, the term "agonist" is defined in the context of the biological effect of a target protein. While preferred agonists herein specifically interact with the target (e.g., bind to HIF-2 α), compounds that initiate or enhance the biological activity of the target by interacting with other members of the signal transduction pathway are also specifically included. "Signal transduction" is a process in which a stimulatory or inhibitory signal is transmitted into a cell and an intracellular response is initiated within the cell. A "modulator of a signal transduction pathway" refers to a compound that modulates the activity of one or more cellular proteins localized to the same particular signal transduction pathway. Modulators may enhance (agonists) or inhibit (antagonists) the activity of signaling molecules.
Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention
The present invention provides compounds of the present invention or pharmaceutical compositions thereof that have a modulating effect on HIF-2 α. The pharmaceutical compositions of the present invention include compounds of formula (I), (II) or (II-1), compounds listed herein, or compounds of the examples. The amount of the compound in the compositions of the invention is effective to treat or ameliorate a HIF-2 α -associated disease or condition in the subject, including cancer, inflammation, pulmonary hypertension, atherosclerosis, or ischemic disease.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like, as appropriate for the particular target dosage form. As described in: in Remington, the Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, lippincott Williams and Wilkins, philadelphia, and Encyclopedia of Pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, marcel Dekker, new York, taken together with The disclosure of this document, indicate that different adjuvants may be used In The formulation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.
When useful in therapy, a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (II) or (II-1), and pharmaceutically acceptable salts thereof, may be administered as a raw chemical, and may also be provided as the active ingredient of a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (II) or (II-1), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents, or excipients, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show meaningful patient benefit (e.g., cancer cell reduction). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that, when combined, administered sequentially or simultaneously, result in a therapeutic effect. The compounds of the invention, especially the compounds of formula (I), (II) or (II-1) and pharmaceutically acceptable salts thereof, are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of the present invention, especially a compound of formula (I), (II) or (II-1) or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
The amount of active ingredient that may be combined with one or more adjuvants to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The amount of active ingredient mixed with the compound of formula (I), (II) or (II-1)) and the carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the time of treatment and the age, sex, body weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose, or a suitable fraction thereof, of an active ingredient as described herein above. Treatment can be initiated with small doses that are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at a concentration level that generally provides an effective result against tumors without causing any harmful or toxic side effects.
The pharmaceutical compositions are suitable for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.
The compounds and compositions according to the methods of the invention can be in any amount administered and by any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents.
The invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for preventing, treating, or ameliorating a HIF-2 α -mediated associated condition.
The compounds of the invention or pharmaceutical compositions thereof can act as HIF-2 α modulators, and are useful for treating or lessening the severity of a disease, condition, or disorder when HIF-2 α activation and/or one or more downstream processes associated with HIF-2 α activation or overactivation are associated with the disease, condition, or disorder. In addition, the present invention provides methods for treating or lessening the severity of a disease, condition, or disorder, wherein HIF-2 α activation or overactivation is associated with the disease state.
Wherein the HIF-2 alpha mediated associated condition includes, but is not limited to, cancer, inflammation, pulmonary hypertension, atherosclerosis, or ischemic condition.
Wherein said "cancer" includes but is not limited to the following diseases: kidney, glioblastoma, breast, lung, prostate, hepatocellular, and head and neck squamous cell carcinoma, ovarian, bladder, brain, colon, rectal, pancreatic, gastric, vaginal, cervical, endometrial, thyroid, and skin cancers, and the like; lymphohematopoietic tumors including acute lymphocytic leukemia, B cell lymphoma, burketts lymphoma, and the like; myeloid hematopoietic tumors including acute and chronic myelogenous leukemia and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, neuroblastoma, glioma, and the like. Preferably, the compounds of the present invention or the pharmaceutical compositions of the present invention can be prepared for the prevention, treatment or alleviation of renal, glioblastoma, breast, lung, prostate, hepatocellular, and head and neck squamous cell carcinoma-related cancers in a patient.
Where the inflammation is of the digestive system, including but not limited to, crohn's disease or ulcerative colitis, the compounds of the present invention are preferably prepared for use in preventing, treating or reducing inflammation of the digestive system of a patient.
General Synthesis of Compounds of the invention
In general, the compounds of the invention may be prepared by the methods described herein. The following reaction schemes and examples serve to further illustrate the context of the invention. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Unless otherwise stated, the reagents are conventional and commercially available. The column chromatography is performed using a silica gel column. Nuclear magnetic resonance spectroscopy with CDC13Or DMSO-d6As solvent (reported in ppm) TMS (0 ppm) or chloroform (7.25 ppm) was used as reference standard. Coupling constant J, expressed in Hertz (Hz).
The following acronyms are used throughout the invention:
Figure BDA0004050562950000211
the following synthetic schemes describe the steps for preparing the compounds disclosed herein.
Synthesis scheme 1
Figure BDA0004050562950000212
The compound (Ia), wherein R is2、R3、R6、R7And R8Each having a definition as described herein. Reacting the compound (Ia-1) with the compound (Ia-2) under suitable conditions (such as refluxing in a 1, 2-dichloroethane solution under the action of zinc chloride and N, N-diisopropylethylamine) to obtain a compound (Ia-3); the compound (Ia-3) is subjected to reduction reaction under proper conditions (such as the action of palladium hydroxide and hydrogen) to obtain a compound (Ia-4); reacting the compound (Ia-4) with formic acid to obtain a compound (Ia-5); compound (Ia-5) and POCl3Reacting under appropriate conditions (such as reflux) to obtain a compound (Ia-6); reacting the compound (Ia-6) with NBS to obtain a compound (Ia-7); compound (Ia-7) with Compound (Ia-8) under suitable conditions (e.g., pd (dppf) Cl2Under the action of the reaction, simultaneously adding alkali such as sodium carbonate) to carry out coupling reaction to obtain the compound (Ia).
Synthesis scheme 2
Figure BDA0004050562950000221
Compound (Ib) can be prepared by the synthetic methods of scheme 2, wherein R2、R3、R6And R7Each having a definition as set forth in the present invention. Reacting the compound (Ib-1) under appropriate conditions (such as under the action of borane and in a tetrahydrofuran solvent under reflux) to obtain a compound (Ib-2); carrying out amidation reaction on the compound (Ib-2) and the compound (Ib-3) under appropriate conditions (such as HATU and DIPEA in dichloromethane solution) to obtain a compound (Ib-4); compound (Ib-4) with POCl 3Under appropriate conditions (e.g., reflux), the reaction affords compound (Ib).
Synthesis scheme 3
Figure BDA0004050562950000222
Compound (Ib) can be prepared by the synthetic methods of scheme 3, wherein R2、R3、R6And R7Each having a definition as set forth in the present invention. Reacting the compound (Ib-5) with the compound (Ib-6) under an alkaline condition (such as sodium hydride) to obtain a compound (Ib-4); compound (Ib-4) with POCl3Under appropriate conditions (e.g., reflux), the reaction affords compound (Ib).
The preparation of the other compounds of the invention is carried out analogously to the synthesis schemes described above or analogously to the examples below.
Examples
Example 1: synthesis of ethyl 2- (3, 5-difluorophenyl) -7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) acetate (Compound 1)
Figure BDA0004050562950000231
/>
Step 1: preparation of 4- (methylsulfonyl) pyridine-2-carbonitrile
4-bromopyridine-2-carbonitrile (5.0 g, 27.3mmol), sodium methanesulfinate (3.3g, 32.7mmol) and cuprous iodide (15.6g, 81.9mmol) were taken and added to 100mL of dimethyl sulfoxide under argon. The reaction is carried out for 3h at 100 ℃. After cooling to room temperature, 200mL of water was added, extraction was performed three times with ethyl acetate, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic solution was removed by spinning, and the residue was subjected to silica gel column chromatography (PE: EA (v: v) = 4) to obtain 4.2g of the objective compound (yield 84%). 1H NMR(400MHz,CDCl3):δ9.04(d,J＝5.0Hz,1H),8.19(s,1H),8.03(d,J＝5.0Hz,1H),3.15(s,3H).
And 2, step: preparation of ethyl 3-amino-3- (4- (methylsulfonyl) pyridin-2-yl) acrylate
4- (methylsulfonyl) pyridine-2-carbonitrile (4.2 g, 23.1mmol), sodium 3-ethoxy-3-oxopropionate (5.7g, 36.9mmol) and zinc chloride (1.6g, 11.5mmol) were added to a solution of 200mL 1, 2-dichloroethane, N-diisopropylethylamine (300mg, 2.3mmol) and refluxed over 120 ℃ water trap for 10h. Cooling to room temperature, adding 200mL of water, extracting with dichloromethane for three times, combining organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and removing organic solutionColumn chromatography (PE: EA (v; v) = 3).1H NMR(400MHz,CDCl3):δ8.94(d,J＝5.0Hz,1H),8.26(s,1H),7.86(d,J＝5.0Hz,1H),5.49(s,1H),4.24(q,J＝7.1Hz,2H),3.13(s,3H),1.35(t,J＝7.1Hz,3H).
And 3, step 3: preparation of ethyl 3-amino-3- (4- (methylsulfonyl) pyridin-2-yl) propionate
Ethyl 3-amino-3- (4- (methylsulfonyl) pyridin-2-yl) acrylate (3g, 11.1mmol), palladium hydroxide (450 mg) and acetic acid (7 mL) were added to 100mL of methanol solution, reacted at room temperature for 5 hours under the action of hydrogen gas, filtered, and the filtrate was spin-dried to obtain 2.5g (yield 83%) of ethyl 3-amino-3- (4- (methylsulfonyl) pyridin-2-yl) propionate.1H NMR(400MHz,CDCl3):δ8.77(d,J＝5.0Hz,1H),7.87(s,1H),7.61(d,J＝5.0Hz,1H),4.48(m,1H),4.17(q,J＝7.1Hz,2H),3.02(s,3H),2.86(m,1H),2.69(m,1H),1.20(t,J＝7.1Hz,3H).
And 4, step 4: preparation of ethyl 3-carboxamido-3- (4- (methylsulfonyl) pyridin-2-yl) propionate
Ethyl 3-amino-3- (4- (methylsulfonyl) pyridin-2-yl) propionate (2.5g, 9.2mmol) was added to 20mL of formic acid and refluxed at 100 ℃ for 12h. After cooling to room temperature, formic acid was removed by rotary evaporation to obtain 2.5g of the objective compound (yield 91%). 1H NMR(400MHz,CDCl3):δ8.75(d,J＝5.0Hz,1H),8.26(s,1H),7.99(s,1H),7.81(s,1H),7.66(d,J＝5.0Hz,1H),5.72–5.48(m,1H),4.03(q,J＝7.1Hz,2H),3.16–3.11(m,1H),3.02(s,3H),2.88–2.83(m,1H).
And 5: preparation of ethyl 2- (7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) acetate
Ethyl 3-carboxamido-3- (4- (methylsulfonyl) pyridin-2-yl) propionate (2.5g, 8.3mmol) was added to a 50mL toluene solution, phosphorus oxychloride (5.1g, 33.3mmol) was added, and the mixture was refluxed at 100 ℃ for 12 hours. After cooling to room temperature, toluene was removed by rotation, a saturated sodium bicarbonate solution was added, the pH was adjusted to 8, ethyl acetate was extracted three times, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was subjected to silica gel column chromatography (PE: EA (v: v) = 4) to obtain 2- (7- (methylsulfonyl) imidazo [1, 5-a)]Pyridin-1-yl) acetic acid ethyl ester 1.4g (yield 59%).1H NMR(400MHz,CDCl3):δ8.21(s,1H),8.12(s,1H),7.94(d,J＝7.4Hz,1H),6.87(d,J＝7.4Hz,1H),4.13(q,J＝7.2Hz,2H),3.94(s,2H),3.02(s,3H),1.22(t,J＝7.2Hz,3H).
And 6: preparation of ethyl 2- (3-bromo-7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) acetate
Taking 2- (7- (methylsulfonyl) imidazo [1, 5-a)]Pyridin-1-yl) acetic acid ethyl ester (1.4 g, 4.9mmol) was added to 20mL of DMF solution, NBS (1.1g, 5.4mmol) was added, and reaction was carried out at 55 ℃ for 2h. After cooling to room temperature, 100mL of water was added, ethyl acetate was extracted three times, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was subjected to silica gel column chromatography (PE: EA (v: v) = 4) to obtain 2- (3-bromo-7- (methylsulfonyl) imidazo [1,5-a ]Pyridin-1-yl) acetic acid ethyl ester 1.3g (yield 72%).1H NMR(400MHz,CDCl3):δ8.13–8.07(m,1H),7.87(d,J＝7.5Hz,1H),6.97(d,J＝7.5Hz,1H),4.13(q,J＝7.1Hz,2H),3.92(s,2H),3.03(s,3H),1.22(t,J＝7.1Hz,3H).
And 7: preparation of ethyl 2- (3, 5-difluorophenyl) -7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) acetate
Taking 2- (3-bromo-7- (methylsulfonyl) imidazo [1, 5-a)]Pyridin-1-yl) acetic acid ethyl ester (150mg, 0.43mmol), (3, 5-difluorophenyl) boronic acid (82mg, 0.52mmol), (1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (31mg, 0.043mmol) and sodium carbonate (91mg, 0.86mmol) were added to 20mL of toluene and 1mL of water under argon. The reaction was refluxed for 3h. Cooling to room temperature, adding 50mL of water, extracting with ethyl acetate three times, combining organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, removing the organic solution by spinning, and purifying the residue by silica gel column chromatography (PE: EA (v: v) =4]Pyridin-1-yl) acetic acid ethyl ester 160mg (yield 94%).1H NMR(400MHz,CDCl3):δ8.34–8.19(m,2H),7.39–7.30(m,2H),7.02–7.00(m,1H),6.98–6.91(m,1H),4.22(q,J＝7.1Hz,2H),4.05(s,2H),3.11(s,3H),1.31(t,J＝7.1Hz,3H).
Example 2: synthesis of 2- (3, 5-difluorophenyl) -7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) acetic acid (Compound 2)
Figure BDA0004050562950000251
Lithium hydroxide (55mg, 1.3 mmol) was added to a mixture of 0.7mL of water and 0.7mL of ethanol, and 2- (3, 5-difluorophenyl) -7- (methylsulfonyl) imidazo [1,5-a ] was added]Pyridin-1-yl) acetic acid ethyl ester (50mg, 0.13mmol). The reaction was carried out at room temperature for 1 hour. The ethanol was removed by rotation, the pH was adjusted to 6 with 1N HCl until a solid precipitated, which was filtered, the filter cake was washed with water and dried to give 42mg of the title compound (88% yield). 1H NMR(400MHz,Methanol-d4):δ8.53–8.51(m,1H),8.34(s,1H),7.60–7.41(m,2H),7.24–7.05(m,2H),4.09(s,2H),3.18(s,3H).
Example 3: synthesis of 2- (3, 5-difluorophenyl) -7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) ethan-1-ol (Compound 3)
Figure BDA0004050562950000261
Taking 2- (3, 5-difluorophenyl) -7- (methylsulfonyl) imidazo [1, 5-a)]Pyridin-1-yl) acetic acid ethyl ester (50mg, 0.13mmol) was added to a solution of 5mL of tetrahydrofuran, and 1N of lithium tri-sec-butylborohydride (0.26 mL) was slowly added dropwise. After the reaction was carried out at room temperature for 1 hour, the reaction was quenched with saturated ammonium chloride, 20mL of water was added, extraction was carried out three times with ethyl acetate, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v; v) = 1) to obtain 32mg of the objective compound (yield 70%).1H NMR(400MHz,CDCl3):δ8.24(d,J＝7.5Hz,1H),8.21(s,1H),7.35–7.32(m,2H),7.01–6.90(m,2H),4.24(s,1H),4.07(t,J＝5.7Hz,2H),3.18(t,J＝5.7Hz,2H),3.09(s,3H).
Example 4: synthesis of ethyl 2- (3- (3-cyano-5-fluorophenyl) -7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) acetate (Compound 4)
Figure BDA0004050562950000271
Synthetic method referring to example 1, the starting material (3, 5-difluorophenyl) boronic acid of step 7 in example 1 was replaced with (3-cyano-5-fluorophenyl) boronic acid.1H NMR(400MHz,CDCl3):δ8.31–8.22(m,2H),7.93(s,1H),7.82–7.79(m,1H),7.479–7.45(m,1H),7.09–7.07(m,1H),4.22(q,J＝7.2Hz,2H),4.05(s,2H),3.12(s,3H),1.31(t,J＝7.2Hz,3H).
Example 5: synthesis of ethyl 2- (3, 5-difluorophenyl) -7- (thiophen-2-yl) imidazo [1,5-a ] pyridin-1-yl) acetate (Compound 5)
Figure BDA0004050562950000272
Figure BDA0004050562950000281
Step 1: preparation of ethyl 3-amino-3- (4-bromopyridin-2-yl) acrylate
Synthetic methods 4- (methylsulfonyl) pyridine-2-carbonitrile was replaced with 4-bromopyridinecarbonitrile with reference to step 2 of example 1. 1HNMR(400MHz,CDCl3):δ8.44(d,J＝5.3Hz,1H),7.92(s,1H),7.51(d,J＝5.3Hz,1H),5.30(s,1H),4.20(q,J＝6.9Hz,2H),1.31(t,J＝7.1Hz,3H).
And 2, step: preparation of ethyl 3-amino-3- (4-bromopyridin-2-yl) propionate
Ethyl 3-amino-3- (4-bromopyridin-2-yl) acrylate (11.2g, 41.3mmol) was added to 50mL of glacial acetic acid, and sodium borohydride (4.7g, 124mmol) was added portionwise. After the reaction is carried out at room temperature for 12 hours, saturated sodium bicarbonate solution is added to quench the reaction, 200mL of water is added, ethyl acetate is extracted for three times, organic layers are combined, saturated sodium chloride solution is washed once, anhydrous sodium sulfate is dried, the organic solution is removed by spinning, and the residue is purified by silica gel column chromatography (PE: EA (v/v) = 1) to obtain 9.4g (84%) of the target compound ethyl 3-amino-3- (4-bromopyridin-2-yl) propionate.1H NMR(400MHz,CDCl3):δ8.36(d,J＝5.2Hz,1H),7.59(s,1H),7.34(d,J＝5.3Hz,1H),4.41–4.38(m,1H),4.13(q,J＝7.1Hz,2H),2.88–2.83(m,1H),2.79–2.67(m,1H),1.23(t,J＝7.1Hz,3H).
And 3, step 3: preparation of ethyl 3- (4-bromopyridin-2-yl) -3-carboxamide propionate
Synthetic method referring to step 4 of example 1, ethyl 3-amino-3- (4- (methylsulfonyl) pyridin-2-yl) propionate was replaced with ethyl 3-amino-3- (4-bromopyridin-2-yl) propionate.1H NMR(400MHz,CDCl3)δ8.07(s,1H),7.55–7.46(m,2H),7.46–7.37(m,1H),4.12(q,J＝7.1Hz,2H),3.73–3.55(m,1H),3.40–3.34(m,1H),2.79–2.61(m,1H),1.33(t,J＝7.1Hz,3H).
And 4, step 4: preparation of ethyl 2- (7-bromoimidazo [1,5-a ] pyridin-1-yl) acetate
Synthetic methods referring to step 5 of example 1, ethyl 3-carboxamido-3- (4- (methylsulfonyl) pyridin-2-yl) propionate was replaced with ethyl 3- (4-bromopyridin-2-yl) -3-carboxamidopropionate.1H NMR(400MHz,CDCl3):δ8.03(s,1H),7.73(d,J＝7.4Hz,1H),7.63(s,1H),6.59(d,J＝7.4Hz,1H),4.18(q,J＝7.1Hz,2H),3.87(s,2H),1.27(t,J＝7.1Hz,3H).
And 5: preparation of ethyl 2- (7- (thien-2-yl) imidazo [1,5-a ] pyridin-1-yl) acetate
Taking 2- (7-bromoimidazole [1,5-a ]]Pyridin-1-yl) acetic acid ethyl ester (283mg, 1mmol), 2-thiopheneboronic acid (192mg, 1.5mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (73mg, 0.1mmol) and sodium carbonate (106mg, 2mmol) were added to a mixture of 30mL of toluene and 3mL of water under argon. The reaction was refluxed for 2h. Cooling to room temperature, adding 50mL of water, extracting with ethyl acetate for three times, combining organic layers, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, removing the organic solution by spinning, and purifying the residue by column chromatography (PE: EA =2]Pyridin-1-yl) acetic acid ethyl ester 267mg (yield 93%).1H NMR(400MHz,CDCl3):δ8.11(s,1H),7.88(d,J＝7.4Hz,1H),7.60(s,1H),7.32–7.29(m,2H),7.10–7.06(m,1H),6.86(d,J＝7.4Hz,1H),4.19(q,J＝7.1Hz,2H),3.94(s,2H),1.28(t,J＝7.3Hz,3H).
And 6: preparation of ethyl 2- (3-bromo-7- (thiophen-2-yl) imidazo [1,5-a ] pyridin-1-yl) acetate
Synthetic method referring to step 6 of example 1, 2- (7- (methylsulfonyl) imidazo [1, 5-a)]Replacement of pyridin-1-yl) acetic acid ethyl ester by 2- (7- (thiophen-2-yl) imidazo [1,5-a]Pyridin-1-yl) acetic acid ethyl ester.1HNMR(400MHz,CDCl3):δ7.75(d,J＝7.5Hz,1H),7.51(s,1H),7.27–7.24(m,2H),7.07–7.01(m,1H),6.88(d,J＝7.5Hz,1H),4.12(q,J＝7.1Hz,2H),3.87(s,2H),1.21(t,J＝7.2Hz,3H).
And 7: preparation of ethyl 2- (3, 5-difluorophenyl) -7- (thiophen-2-yl) imidazo [1,5-a ] pyridin-1-yl) acetate
Synthetic method referring to step 7 of example 1, 2- (3-bromo-7- (methylsulfonyl) imidazo [1, 5-a)]Replacement of pyridin-1-yl) acetic acid ethyl ester by 2- (3-bromo-7- (thiophen-2-yl) imidazo [1,5-a ]Pyridin-1-yl) acetic acid ethyl ester.1HNMR(400MHz,CDCl3):δ8.15(d,J＝7.5Hz,1H),7.60(s,1H),7.29–7.24(m,4H),7.05–7.02(m,1H),6.86(d,J＝7.5Hz,1H),6.82–6.76(m,1H),4.14(q,J＝7.1Hz,2H),3.93(s,2H),1.22(d,J＝7.1Hz,3H).
Example 6: synthesis of 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] pyridin-1-ol (Compound 6)
Figure BDA0004050562950000301
Step 1: preparation of 4-bromo-3-methylpyridine 1-oxide
4-bromo-3-methylpyridine hydrochloride (10g, 48mmol) was added to 200mL of a dichloromethane solution, and m-chloroperoxybenzoic acid (12.4g, 72mmol) was added in portions. After 12 hours of reaction at room temperature, the reaction was quenched with a saturated sodium bicarbonate solution, 200mL of water was added, dichloromethane was extracted three times, organic layers were combined, a saturated sodium chloride solution was washed once, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was subjected to silica gel column chromatography (DCM to DCM: EA (v: v = 1)) to obtain 6.4g of the objective compound (yield 71%). MS (ESI), M/z: M+189.1。
And 2, step: preparation of 4-bromo-3-methylpyridine-2-carbonitrile
4-bromo-3-methylpyridine 1-oxide (6.4 g, 34mmol) was dissolved in 100mL of DMF, and trimethylsilyl chloride (4.0 g, 41mmo) was added theretol), triethylamine (6.9g, 68mmol) and dimethylcarbamoyl chloride (3.8g, 36mmol), heating to 100 ℃, and reacting for 5h. After cooling to room temperature, the reaction was quenched with a saturated sodium bicarbonate solution, 200mL of water was added, extraction was performed with ethyl acetate three times, organic layers were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was subjected to silica gel column chromatography (PE: EA (v: v) = 10). 1H NMR(400MHz,CDCl3):δ8.32(d,J＝5.1Hz,1H),7.71(d,J＝5.1Hz,1H),2.66(s,3H).
And 3, step 3: preparation of (4-bromo-3-methylpyridin-2-yl) methylamine
The prepared 4-bromo-3-methoxypyridine-2-carbonitrile (3.5g, 17.8mmol) was dissolved in 100mL of anhydrous THF, a borane-tetrahydrofuran solution (1N, 53mL, 53mmol) was slowly added dropwise at 0 ℃ and reacted at room temperature for 12 hours. Slowly dropping methanol to quench the reaction, stirring at room temperature for 1h, and removing the organic solution to obtain 3.5g (yield 99%) of the target compound (4-bromo-3-methylpyridin-2-yl) methylamine. MS (ESI), M/z: M+202.1。
And 4, step 4: preparation of N- ((4-bromo-3-methylpyridin-2-yl) methyl) -3, 5-difluorobenzamide
(4-bromo-3-methylpyridin-2-yl) methylamine (740mg, 3.7mmol) was dissolved in 100mL of dichloromethane, and 3, 5-difluorobenzoic acid (701mg, 4.4mmol), N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluoro (2.8g, 7.4mmol) and N, N-diisopropylethylamine (1.9g, 14.8mmol) were added, respectively. The reaction is carried out for 12h at room temperature. 100mL of water was added, dichloromethane was extracted three times, organic layers were combined, the mixture was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 7) to obtain 341mg (yield 27%) of the target compound N- ((4-bromo-3-methylpyridin-2-yl) methyl) -3, 5-difluorobenzamide.1H NMR(400MHz,CDCl3)δ8.32(d,J＝5.2Hz,1H),8.21(d,J＝5.2Hz,1H),7.45–7.42(m,2H),7.30(d,J＝5.3Hz,1H),7.00–6.94(m,1H),4.70(s,2H),2.41(s,3H).
And 5: preparation of 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] pyridine
Taking N- ((4-bromo-3-methylpyridine-2-yl) methyl) -3, 5-difluorobenzamide(341mg, 1mmol) was added to 50mL of the toluene solution, phosphorus oxychloride (1.53g, 10mmol) was added, and the mixture was refluxed at 100 ℃ for 12 hours. Cooling to room temperature, removing toluene by rotation, adding a saturated sodium bicarbonate solution, adjusting the pH to 8, adding 50mL of water, extracting with ethyl acetate three times, combining the organic layers, washing with a saturated sodium chloride solution, drying over anhydrous sodium sulfate, removing the organic solution by rotation, and purifying the residue by column chromatography (PE: EA (v: v) = 10) to obtain 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a]Pyridine 270mg (yield 83%).1H NMR(400MHz,CDCl3):δ8.07(d,J＝7.5Hz,1H),7.53(s,1H),7.37–7.29(m,2H),6.91–6.86(m,1H),6.64(d,J＝7.5Hz,1H),2.50(s,3H).
And 6: preparation of 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazol [1,5-a ] pyridin-1-ol
Taking 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ]]Pyridine (100mg, 0.31mmol) was added to a solution of 20mL1, 4-dioxane, selenium dioxide (344mg, 3.1mmol) and t-butyl hydroperoxide (70% in water, 400mg, 3.1mmol) were added, and the reaction was carried out at 50 ℃ for 5 hours. The reaction was cooled to room temperature and quenched by pouring 10mL of ice water. Suction-filtering with celite pad, washing the filter cake with ethyl acetate three times, extracting, combining the organic layers, washing with saturated sodium chloride solution once, drying with anhydrous sodium sulfate, removing the organic solution by rotation, and performing column chromatography (PE: EA (v: v) = 5) to obtain 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazole [1,5-a ]Pyridin-1-ol 58mg (yield 55%).1H NMR(400MHz,CDCl3):δ11.69(s,1H),8.39(d,J＝5.1Hz,1H),7.61(d,J＝5.1Hz,1H),7.53–7.42(m,2H),7.10–7.05(m,1H),2.90(s,3H).
Example 7: synthesis of (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 7)
Figure BDA0004050562950000321
/>
Step 1: synthesis of 1, 7-dibromo-8- (bromomethyl) -3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine
Taking 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ]]Pyridine (32mg, 0.1mmol) was added to 20mL of carbon tetrachloride solution, andadding N-bromosuccinimide (40mg, 0.2mmol) and benzoyl peroxide (2.4mg, 0.01mmol), and reacting under reflux for 2h under the protection of argon. After cooling to room temperature, 10mL of water was added, dichloromethane was extracted three times, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 10) to obtain the objective compound 1, 7-dibromo-8- (bromomethyl) -3- (3, 5-difluorophenyl) imidazo [1,5-a]Pyridine 21mg (yield 55%).1H NMR(400MHz,CDCl3):δ8.10(d,J＝7.6Hz,1H),7.28–7.25(m,2H),6.98–6.90(m,1H),6.68(d,J＝7.6Hz,1H),5.09(s,2H).
And 2, step: synthesis of methyl (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) acetate
1, 7-dibromo-8- (bromomethyl) -3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine (21mg, 0.043mmol) was added to a 3mL acetonitrile solution, acetic acid (5mg, 0.081mmol) and triethylamine (10mg, 0.1mmol) were added, and the mixture was reacted at 60 ℃ for 1 hour. The organic solution was spun off. Crude methyl (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) acetate was obtained.
And 3, step 3: synthesis of (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol
Reacting (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ]]The crude methyl pyridin-8-yl) acetate was dissolved in 3mL of methanol, sodium hydroxide (42mg, 1.04mmol) and refluxed for 1h. Cooling to room temperature, adding a saturated ammonium chloride solution, extracting with dichloromethane three times, combining organic layers, washing with a saturated sodium chloride solution, drying over anhydrous sodium sulfate, removing the organic solution by spinning, and subjecting the residue to silica gel column chromatography (PE: EA (v: v) = 5) to obtain a target compound (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazole [1,5-a]Pyridin-8-yl) methanol (Compound 7) 10mg (yield 56%).1H NMR(400MHz,MeOH-d4):δ8.36(d,J＝7.6Hz,1H),7.42–7.39(m,2H),7.18–7.09(m,1H),6.82(d,J＝7.6Hz,1H),5.18(s,2H).
Example 8: synthesis of 2- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridine (Compound 8)
Figure BDA0004050562950000331
Taking 7-bromo-8- (bromomethyl) -3- (3, 5-difluorophenyl) imidazo [1,5-a]Pyridine (210mg, 0.52mmol) was added to 20mL of dimethyl sulfoxide solution, sodium methanesulfinate (80mg, 0.78mmol) and cuprous iodide (494mg, 2.6 mmol) were added, and the mixture was reacted at 100 ℃ for 12 hours under argon protection. Cooled to room temperature and quenched by pouring ice water. The celite pad was filtered by suction, the filter cake was washed three times with ethyl acetate, extraction was performed, the organic layers were combined, a saturated sodium chloride solution was washed once, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 3) ]Pyridine (compound 8) 160mg (yield 76%).1H NMR(400MHz,CDCl3):δ8.19(d,J＝7.6Hz,1H),7.94(s,1H),7.37–7.32(m,2H),7.22(d,J＝7.6Hz,1H),6.97–6.93(m,1H),3.13(s,3H),2.91(s,3H).
Example 9: synthesis of 1-bromo-3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridine (Compound 9)
Figure BDA0004050562950000332
Figure BDA0004050562950000341
Taking 2- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridine (100mg, 0.32mmol) is added into 20mL carbon tetrachloride solution, N-bromosuccinimide (68mg, 0.34mmol), benzoyl peroxide (3.8mg, 0.015mmol) and argon protection are added, and reflux reaction is carried out for 2h. Cooling to room temperature, adding 20mL of water, extracting with dichloromethane three times, combining organic layers, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, removing the organic solution by spinning, and purifying the residue by silica gel column chromatography (PE: EA (v: v) = 3)]Pyridine (compound 9) 50mg (yield 40%).1H NMR(400MHz,Methanol-d4):δ8.39(d,J＝7.8Hz,1H),7.45(d,J＝6.3Hz,2H),7.28–7.07(m,2H),3.20(s,3H),3.16(s,3H).
Example 10: synthesis of 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-ol (Compound 10)
Figure BDA0004050562950000342
Synthesis method referring to step 6 of example 6, 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] is reacted]Substitution of pyridine for 2- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridine. 1H NMR(400MHz,CDCl3)δ11.47(s,1H),8.78(d,J＝4.9Hz,1H),8.26(d,J＝4.9Hz,1H),7.53–7.43(m,2H),7.11–7.07(m,1H),3.22(s,3H),3.19(s,3H).
Example 11: synthesis of 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridine-1-carbaldehyde (Compound 11)
Figure BDA0004050562950000343
Figure BDA0004050562950000351
Phosphorus oxychloride (742mg, 4.5 mmol) is taken into a 10mL sealed tube, and the sealed tube is placed in an ice-water bath. 2- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridine (100mg, 0.32mmol) was dissolved in N, N-dimethylformamide (330mg, 4.5 mmol), and the mixture was slowly dropped into the sealed tube. Heated to 100 ℃ and reacted for 3h. After cooling to room temperature, 20mL of water was added to quench the reaction, ethyl acetate was extracted three times, the organic layers were combined, the mixture was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) =4]Pyridine-1-carbaldehyde (Compound 11) 98mg (yield 87%).1H NMR(600MHz,CDCl3):δ10.41–10.14(m,1H),8.27(d,J＝8.3Hz,1H),7.55(d,J＝7.1Hz,1H),7.39–7.31(m,2H),7.04(t,J＝8.3Hz,1H),3.32(s,3H),3.23(s,3H).
Example 12: synthesis of (3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) methanol (Compound 12)
Figure BDA0004050562950000352
/>
Taking 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridine-1-carbaldehyde (50mg, 0.14mmol) was added to 5mL of ultra-dry tetrahydrofuran, and sodium borohydride (27mg, 0.71mmol) was added slowly. Reacting at room temperature for 1h, and slowly dropwise adding saturated ammonium chloride to quench the reaction. 10mL of water was added, extraction was performed with ethyl acetate for three times, organic layers were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and column chromatography (PE: EA (v: v) = 2) was performed to obtain a target compound (3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1, 5-a) ]Pyridin-1-yl) methanol (Compound 12) 44mg (yield 89%).1H NMR(400MHz,CDCl3):δ8.13(d,J＝7.6Hz,1H),7.37–7.28(m,2H),7.24(s,1H),7.03–6.92(m,1H),5.15(s,2H),3.14(s,3H),3.09(s,3H).
Example 13: synthesis of 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridine-1-carboxylic acid (Compound 13)
Figure BDA0004050562950000361
Taking 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridine-1-carbaldehyde (50mg, 0.14mmol) was added to 2mL t-butanol and 1mL 2-methyl-2-butene. Sodium hypochlorite (66mg, 0.78mmol) and sodium hydrogen phosphate monohydrate (94mg, 0.78mmol) were dissolved in 2mL of water, and the mixture was slowly dropped thereto and reacted at room temperature for 12 hours. Adding 10mL of water, extracting with ethyl acetate for three times, combining organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, removing organic solution by spinning, and performing silica gel column chromatography on the residue(PE: EA = 1-DCM: meOH = 20) to give the target compound 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazole [1, 5-a)]Pyridine-1-carboxylic acid (compound 13) 27mg (yield 53%).1H NMR(400MHz,Methanol-d4):δ8.28(s,1H),7.45–7.34(s,3H),7.12(t,J＝9.0Hz,1H),3.23(s,3H),3.17(s,3H).
Example 14: synthesis of methyl 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridine-1-carboxylate (Compound 14)
Figure BDA0004050562950000362
Figure BDA0004050562950000371
Taking 2- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazole [1,5-a]Pyridine-1-carboxylic acid (25mg, 0.07mmol) was added to 1mL DCM and 0.5mL MeOH, and trimethylsilylated diazomethane (39mg, 0.34mmol) was slowly added dropwise under ice bath, and reacted at room temperature for 2h. 10mL of water was added, dichloromethane was extracted three times, organic layers were combined, the mixture was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA =2 ]Pyridine-1-carboxylic acid methyl ester (compound 14) 9mg (yield 34%).1H NMR(400MHz,CDCl3):δ8.21(d,J＝7.5Hz,1H),7.46(d,J＝7.5Hz,1H),7.36–7.30(m,2H),7.04–6.96(m,1H),4.03(s,3H),3.23(s,3H),3.20(s,3H).
Example 15: synthesis of 7-bromo-3- (3, 5-difluorophenyl) -8-methyl-1- (methylsulfonyl) imidazo [1,5-a ] pyridine (Compound 15)
Figure BDA0004050562950000372
Step 1: preparation of 1, 7-dibromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] pyridine
Synthesis ofProcess referring to step 1 of example 7, 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] is reacted]Pyridine substitution to 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ]]Pyridine.1H NMR(600MHz,CDCl3):δ8.02(d,J＝7.5Hz,1H),7.30–7.27(m,2H),6.92–6.89(m,1H),6.64(d,J＝7.5Hz,1H),2.80(s,3H).
And 2, step: preparation of 7-bromo-3- (3, 5-difluorophenyl) -8-methyl-1- (methylsulfonyl) imidazo [1,5-a ] pyridine
Synthesis method referring to the synthesis of example 8, 7-bromo-8- (bromomethyl) -3- (3, 5-difluorophenyl) imidazo [1,5-a]Substitution of pyridine for 1, 7-dibromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ]]Pyridine.1H NMR(400MHz,Methanol-d4):δ8.43–8.32(m,1H),7.49(d,J＝6.8Hz,2H),7.24–7.12(m,1H),7.02(d,J＝7.5Hz,1H),3.46(s,3H),2.86(s,3H).
Example 16: synthesis of 3- (3, 5-difluorophenyl) -8-methyl-1, 7-bis (methylsulfonyl) imidazo [1,5-a ] pyridine (Compound 16)
Figure BDA0004050562950000381
Synthesis method referring to the synthesis of example 8, 7-bromo-8- (bromomethyl) -3- (3, 5-difluorophenyl) imidazo [1,5-a]Substitution of pyridine for 1, 7-dibromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ]]Pyridine. By adopting the condition, 7-bromo-3- (3, 5-difluorophenyl) -8-methyl-1, 7-bi (methylsulfonyl) imidazo [1,5-a ] can be obtained simultaneously ]Pyridine (yield 11%).1H NMR(400MHz,CDCl3)δ8.23(dd,J＝7.5,0.9Hz,1H),7.50(d,J＝7.5Hz,1H),7.31–7.29(m,2H),7.06–7.00(m,1H),3.58(s,3H),3.31(s,3H),3.18(s,3H).
Example 17: synthesis of 3-fluoro-5- (1- (hydroxymethyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridin-3-yl) benzonitrile (Compound 17)
Figure BDA0004050562950000382
Synthesis method referring to the synthesis of example 12, 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Replacement of pyridine-1-carbaldehyde with 3-fluoro-5- (1-formyl-8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridin-3-yl) benzonitrile.1H NMR(400MHz,CDCl3):δ8.28(d,J＝7.6Hz,1H),8.01(s,1H),7.89(d,J＝9.4Hz,1H),7.68(d,J＝8.3Hz,1H),6.79(d,J＝7.6Hz,1H),4.96(s,2H),3.34(s,3H),2.75(s,3H).
Example 18: synthesis of (3- (3, 5-difluorophenyl)) -7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-yl) methanol (Compound 18)
Figure BDA0004050562950000391
The starting material was 4-bromopyridine-2-carbonitrile, which was synthesized by sequentially referring to steps 3, 4, and 5 of example 6, example 8, example 11, and example 12.1H NMR(400MHz,CDCl3):δ8.39(s,1H),8.28(d,J＝7.6Hz,1H),7.38–7.32(m,2H),7.15–7.05(m,1H),7.00–6.95(m,1H),5.07(s,2H),3.11(s,3H).
Example 19: synthesis of 3- (3, 5-difluorophenyl) -7- (methylsulfonyl) imidazo [1,5-a ] pyridin-1-ol (Compound 19)
Figure BDA0004050562950000392
The starting material was 4-bromopyridine-2-carbonitrile, and the synthetic procedure was followed with reference to steps 3, 4, and 5 of example 6, step 8, and step 6 of example 6.1H NMR(400MHz,CDCl3):δ11.21(s,1H),8.99(d,J＝5.0Hz,1H),8.79(s,1H),8.15(d,J＝5.0Hz,1H),7.57–7.47(m,2H),7.14–7.09(s,1H),3.18(s,3H).
Example 20: synthesis of (3, 5-difluorophenyl) -8-methyl-7- (methylthio) imidazo [1,5-a ] pyridin-1-ol (Compound 20)
Figure BDA0004050562950000393
/>
Step 1: preparation of 3- (3, 5-difluorophenyl) -8-methyl-7- (methylthio) imidazo [1,5-a ] pyridine
Taking 7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ]]Pyridine (143mg, 0.46mmol) was added to 5mL of N, N-dimethylformamide, and sodium thiomethoxide (39mg, 0.56mmol) was added thereto, followed by reaction at 100 ℃ for 4 hours. After cooling to room temperature, 20mL of water was added, extraction was performed three times with ethyl acetate, the organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was purified by silica gel column chromatography (PE: EA = 10) to give 3- (3, 5-difluorophenyl) -8-methyl-7- (methylthio) imidazo [1,5-a]Pyridine 120mg (yield 89%).1H NMR(400MHz,CDCl3):δ8.06(d,J＝7.5Hz,1H),7.54(s,1H),7.43(s,1H),7.23–7.19(m,1H),7.02–7.00(m,1H),6.63(d,J＝7.5Hz,1H),2.55(s,3H),2.50(s,3H).
And 2, step: preparation of (3, 5-difluorophenyl) -8-methyl-7- (methylthio) imidazo [1,5-a ] pyridin-1-ol
Taking (3, 5-difluorophenyl) -8-methyl-7- (methylthio) imidazo [1,5-a]Pyridin-1-ol (27.5mg, 0.1mmol) was added to 5mL of 1, 4-dioxane, selenium dioxide (27mg, 0.24mmol) was added, and the reaction was carried out at 100 ℃ for 2h. After cooling to room temperature, 10mL of water was added, extraction was performed three times with ethyl acetate, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 3).1H NMR(400MHz,CDCl3):δ11.63(s,1H),8.39(d,J＝5.4Hz,1H),7.60(d,J＝5.4Hz,2H),7.39–7.31(m,1H),7.17–7.15(m,1H),2.89(s,3H),2.55(s,3H).
Example 21: synthesis of 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) -1-nitroimidazo [1,5-a ] pyridine (Compound 21)
Figure BDA0004050562950000401
Taking 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridine (79mg, 0.26mmol) was added to 5mL acetonitrile under argon. Nitrosotetrafluoroborate (90mg, 0.77mmol) was dissolved in 5mL acetonitrile, added dropwise to the mixed system, and reacted at room temperature for 2h. The reaction was quenched with 1mL of ethanol, 20mL of water was added, extraction was carried out three times with ethyl acetate, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 3.1H NMR(400MHz,CDCl3):δ8.18–8.10(m,2H),7.87–7.78(m,2H),7.06(d,J＝7.4Hz,1H),3.15(s,3H),2.85(s,3H).
Example 22: synthesis of 3- (3, 5-difluorophenyl) -1-fluoro-8-methyl-7- (methylsulfonyl) imidazo [1,5-a ] pyridine (Compound 22)
Figure BDA0004050562950000411
Taking 3- (3, 5-difluorophenyl) -8-methyl-7- (methylsulfonyl) imidazo [1,5-a]Pyridine (127mg, 0.41mmol) was added to 5mL of N, N-dimethylformamide under argon. 1-fluoro-2, 4, 6-trimethylpyridine boron tetrafluoride (187mg, 0.82mmol) is dissolved in N, N-dimethylformamide and dripped into a mixed system to react for 2h at 60 ℃. After cooling to room temperature, 2mL of 1N sodium hydroxide solution was added, 20mL of water was added, ethyl acetate was extracted three times, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was purified by silica gel column chromatography (PE: EA = 5). 1H NMR(600MHz,CDCl3):δ8.11(s,1H),7.97(d,J＝7.5Hz,1H),7.75(d,J＝9.0Hz,1H),7.66(d,J＝7.2Hz,1H),6.65–6.64(m,1H),3.12(d,J＝2.6Hz,3H),2.57(s,3H).
Example 23: synthesis of ethyl 3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine-8-carboxylate (Compound 23)
Figure BDA0004050562950000412
Figure BDA0004050562950000421
/>
Step 1: preparation of 3-bromo-2- (bromomethyl) pyridine
Adding 2-methyl-3-bromopyridine (5g, 29mmol) into 100mL of carbon tetrachloride solution, adding N-bromosuccinimide (7.7g, 43.6 mmol) and benzoyl peroxide (1.87g, 5.8 mmol), and refluxing for 12h under the protection of argon. After cooling to room temperature, 100mL of water was added, dichloromethane was extracted three times, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 10) to obtain 2.4g of the objective compound (yield 33%).1H NMR(600MHz,CDCl3):δ8.54(d,J＝3.7Hz,1H),8.01–7.85(m,1H),7.13–7.12(m,1H),4.72(s,2H).
And 2, step: preparation of N- ((3-bromopyridin-2-yl) methyl) -3, 5-difluorobenzamide
3-bromo-2- (bromomethyl) pyridine (2.4 g,9.5 mmol) and 3, 5-difluorobenzamide (1.6 g,10.5 mmol) were added to 100mL of an anhydrous tetrahydrofuran solution, and sodium hydride (60%, 573mg,14.3 mmol) was added in portions and reacted for 24 hours under reflux. Cooling in ice water bath, and slowly dripping saturated ammonium chloride to quench the reaction. 100mL of water was added, extraction was performed three times with ethyl acetate, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 5) to obtain 1.38g of the objective compound (yield 44%). 1H NMR(400MHz,CDCl3):δ8.55–8.54(m,1H),8.01(s,1H),7.93(d,J＝8.0Hz,1H),7.50–7.39(m,2H),7.23–7.16(m,1H),7.03–6.91(m,1H),4.79(d,J＝3.9Hz,2H).
And 3, step 3: preparation of 8-bromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine
N- ((3-bromopyridin-2-yl) methyl) -3, 5-difluorobenzamide (1.38g, 4.2mmol) was added to 50mL of toluene solution, phosphorus oxychloride (6.48g, 42mmol) was added, and the mixture was refluxed at 100 ℃ for 12 hours. Cooling to room temperature, removing toluene by spinning, adding saturated sodium bicarbonate solution, adjusting pH to 8, adding 100mL water, extracting with ethyl acetate for three times, combining organic layers, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, removing organic solution by spinning, and removing residue with siliconGel column chromatography (PE: EA (v: v) = 10) purified to obtain the target compound 1.06g (yield 81%).1H NMR(400MHz,CDCl3):δ8.23(d,J＝7.2Hz,1H),7.68(s,1H),7.35–7.33(m,2H),7.02(d,J＝6.9Hz,1H),6.97–6.82(m,1H),6.55(t,J＝7.1Hz,1H).
And 4, step 4: preparation of ethyl 3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine-8-carboxylate
Taking 8-bromo-3- (3, 5-difluorophenyl) imidazo [1,5-a]Pyridine (1.06g, 3.43mmol), bis (cyanophenyl) palladium dichloride (31mg, 0.082mmol), 1' -bis (di-phenylphosphino) ferrocene (114mg, 0.21mmol) and triethylamine (694mg, 6.86mmol) were added to 50mL ethanol, charged with carbon monoxide (15 bar) and reacted at 140 ℃ for 12h. Cooling to room temperature, and slowly releasing carbon monoxide gas. 100mL of water was added, extraction was performed with ethyl acetate three times, organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v/v) = 5) to obtain 3- (3, 5-difluorophenyl) imidazo [1,5-a ]Pyridine-8-carboxylic acid ethyl ester 0.93g (yield 89%).1H NMR(400MHz,CDCl3):δ8.41(d,J＝7.1Hz,1H),8.11(d,J＝0.9Hz,1H),7.68–7.66(m,1H),7.35–7.33(m,2H),6.94–6.88(m,1H),6.74(t,J＝7.0Hz,1H),4.48(q,J＝7.2Hz,2H),1.48(t,J＝7.2Hz,3H).
Example 24: synthesis of (3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 24)
Figure BDA0004050562950000431
Taking 3- (3, 5-difluorophenyl) imidazo [1,5-a]Pyridine-8-carboxylic acid ethyl ester (400mg, 1.32mmol) was added to 30mL of ultra-dry tetrahydrofuran, and a solution of lithium aluminum hydride in tetrahydrofuran (2.5 mol/L,1mL, 2.64mmol) was slowly added dropwise. The reaction was carried out at room temperature for 1h. The reaction was quenched by slowly dropping an aqueous solution, extracted three times with ethyl acetate, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was spun off, and the residue was purified by silica gel column chromatography (PE: EA = 3.1H NMR(400MHz,CDCl3):δ8.21(d,J＝7.2Hz,1H),7.64(s,1H),7.41–7.30(m,2H),6.91–6.86(m,2H),6.69(t,J＝6.9Hz,1H),4.92(s,2H).
Example 25: synthesis of 3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine-8-carboxylic acid (Compound 25)
Figure BDA0004050562950000441
Taking 3- (3, 5-difluorophenyl) imidazo [1,5-a]Ethyl pyridine-8-carboxylate (52mg, 0.17mmol) was added to 2mL of tetrahydrofuran, 2mL of 2N sodium hydroxide was added dropwise, and the mixture was reacted at room temperature for 1 hour. Removing tetrahydrofuran solution by spinning, adjusting pH to 7 with dilute hydrochloric acid, filtering, washing filter cake with water for three times, and drying to obtain target compound 3- (3, 5-difluorophenyl) imidazole [1,5-a]Pyridine-8-carboxylic acid (Compound 25) 40mg (yield 86%).1H NMR(600MHz,DMSO-d6):δ8.77(d,J＝7.2Hz,1H),7.95(s,1H),7.65(d,J＝6.7Hz,1H),7.59–7.57(m,2H),7.45–7.30(m,1H),6.89(t,J＝7.0Hz,1H).
Example 26: synthesis of 3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine-8-carbaldehyde (Compound 26)
Figure BDA0004050562950000442
Taking (3- (3, 5-difluorophenyl) imidazole [1,5-a ]]Pyridin-8-yl) methanol (220mg, 0.85mmol) was added to 10mL of dichloromethane, dess martin reagent (726 mg,1.7 mmol) was added and the reaction was allowed to proceed for 3h at room temperature. 20mL of water was added, extraction was performed with ethyl acetate for three times, organic layers were combined, the mixture was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 4)]Pyridine-8-carbaldehyde (Compound 26) was added (yield: 93%).1H NMR(600MHz,CDCl3):δ10.06(s,1H),8.46(d,J＝7.2Hz,1H),8.29(s,1H),7.44(d,J＝6.2Hz,1H),7.34(d,J＝5.8Hz,2H),6.96–6.89(m,1H),6.85(t,J＝6.9Hz,1H).
Example 27: synthesis of (1, 7-dibromo-3- (3-chloro-5-fluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 27)
Figure BDA0004050562950000451
Synthetic method referring to steps 1-5 of example 6 and steps 1-3 of example 7, 3, 5-difluorobenzoic acid of step 4 in example 6 was replaced with 3-chloro-5-fluorobenzoic acid.1H NMR(600MHz,Methanol-d4):δ8.36(d,J＝7.5Hz,1H),7.67(d,J＝1.8Hz,1H),7.54–7.52(m,1H),7.41–7.39(m,1H),6.85(d,J＝7.5Hz,1H),5.21(s,3H).
Example 28: synthesis of 3-fluoro-5- (8- (hydroxymethyl) -7-methylimidazo [1,5-a ] pyridin-3-yl) benzonitrile (Compound 28)
Figure BDA0004050562950000452
Synthetic methods referring to steps 1-5 of example 6 and step 6 of example 23, the starting material was 4-methyl-3-bromopyridine. And 7: preparation of 3-fluoro-5- (8- (hydroxymethyl) -7-methylimidazo [1,5-a ] pyridin-3-yl) benzonitrile
Taking 3- (3-cyano-5-fluorophenyl) -7-methylimidazo [1,5-a ] ]Pyridine-8-carboxylic acid ethyl ester (32mg, 0.1mmol) was added to 2mL of anhydrous toluene. Dissolving lithium borohydride (4.4mg, 0.2mmol) in 1mL of anhydrous ether, slowly dropping into the reaction system, raising the temperature from room temperature to 100 ℃, and continuing the reaction for half an hour after the temperature is stable. Cooling to room temperature, extracting with ethyl acetate for three times, combining organic layers, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, removing the organic solution by rotation, and purifying the residue by silica gel column chromatography (PE: EA (v: v) = 3) to obtain the target compound 3-fluoro-5- (8- (hydroxymethyl) -7-methylimidazo [1,5-a]Pyridin-3-yl) benzonitrile (Compound 28) 18mg (yield 64%).1H NMR(600MHz,CDCl3):δ7.83–7.74(m,2H),7.25–7.24(m,2H),7.08–6.99(m,1H),6.62(d,J＝7.3Hz,1H),4.90(s,2H),2.38(s,3H).
Example 29: synthesis of (3- (3, 5-difluorophenyl) -7-methylimidazo [1,5-a ] pyridin-8-yl) methanol (Compound 29)
Figure BDA0004050562950000461
Synthetic method referring to example 28, 3-fluoro-5-cyanobenzoic acid in step 4 was replaced with 3, 5-difluorobenzoic acid.1HNMR(400MHz,CDCl3):δ8.14(d,J＝7.3Hz,1H),7.62(s,1H),7.33–7.30(m,2H),6.95–6.77(m,1H),6.52(d,J＝7.3Hz,1H),4.91(s,2H),2.37(s,3H).
Example 30: synthesis of (1-bromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 30)
Figure BDA0004050562950000462
Step 1: preparation of ethyl 1-bromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine-8-carboxylate
Taking 3- (3, 5-difluorophenyl) imidazo [1,5-a]Ethyl pyridine-8-carboxylate (52mg, 0.17mmol) was added to 5mL of methylene chloride, NBS (36mg, 0.2mmol) was added, and the mixture was reacted at room temperature for 3 hours. The organic layers were extracted three times with dichloromethane, combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 6). MS (ESI), M/z: M +383.0。
Step 2: preparation of (1-bromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol
Synthesis method referring to example 24, starting material 3- (3, 5-difluorophenyl) imidazo [1,5-a]Replacement of pyridine-8-carboxylic acid ethyl ester with 1-bromo-3- (3, 5-difluorophenyl) imidazo [1,5-a]Pyridine-8-carboxylic acid ethyl ester.1H NMR(400MHz,CDCl3):δ8.19(d,J＝7.2Hz,1H),7.33–7.30(m,2H),7.00–6.82(m,2H),6.69(t,J＝6.9Hz,1H),5.14(d,J＝6.0Hz,2H).
Example 31: synthesis of (1-bromo-7-chloro-3- (3-fluoro-5- (trifluoromethyl) phenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 31)
Figure BDA0004050562950000471
The starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referenced in sequence to steps 1-3 in example 6 to obtain the intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine, then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis method referring in turn to steps 4, 5 in example 6 and the synthesis of example 7.1H NMR(400MHz,CDCl3)δ8.85(d,J＝5.1Hz,1H),7.87(s,1H),7.76(d,J＝8.6Hz,1H),7.61(d,J＝5.2Hz,1H),7.54(t,J＝8.0Hz,1H),5.41(s,2H).
Example 32: synthesis of (1-bromo-7-chloro-3- (3, 4-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 32)
Figure BDA0004050562950000472
The starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referenced in sequence to steps 1-3 in example 6 to obtain the intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis referring in turn to steps 4, 5 in example 6 and the synthesis of example 7, wherein step 4 is the reaction of 4-chloro-3-methylpyridin-2-yl) methylamine with 3, 4-difluorobenzoic acid. 1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.6Hz,1H),7.61–7.56(m,1H),7.47–7.50(m,1H),7.38–7.34(m,1H),6.68(d,J＝7.6Hz,1H),5.26(s,2H).
Example 33: synthesis of (1-bromo-7-chloro-3- (3-fluoro-4- (trifluoromethyl) phenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 33)
Figure BDA0004050562950000473
Starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referred to steps 1-3 in example 6 in order to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine, then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis referring in turn to steps 4, 5 and in example 6The synthesis of example 7 wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl) methylamine with 3-fluoro-4-trifluoromethylbenzoic acid.1H NMR(400MHz,CDCl3)δ8.15(d,J＝7.6Hz,1H),7.80(t,J＝7.7Hz,1H),7.65(t,J＝9.0Hz,2H),6.75(d,J＝7.6Hz,1H),5.28(s,2H).
Example 34: synthesis of (1-bromo-7-chloro-3- (2-fluoro-5- (trifluoromethyl) phenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 34)
Figure BDA0004050562950000481
Starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referred to steps 1-3 in example 6 in order to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis method referring in turn to steps 4, 5 in example 6 and the synthesis of example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl) methylamine with 2-fluoro-5-trifluoromethylbenzoic acid.1H NMR(400MHz,CDCl3)δ8.07(dd,J＝6.3,2.3Hz,1H),7.83–7.78(m,1H),7.64(dd,J＝7.6,4.4Hz,1H),7.41(t,J＝9.2Hz,1H),6.74(d,J＝7.5Hz,1H),5.29(s,2H).
Example 35: synthesis of (1-bromo-7-chloro-3- (3- (trifluoromethyl) phenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 35)
Figure BDA0004050562950000482
The starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referenced in sequence to steps 1-3 in example 6 to obtain the intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis method referring in turn to steps 4, 5 in example 6 and the synthesis of example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl) methylamine with 3-trifluoromethylbenzoic acid.1H NMR(400MHz,CDCl3)δ8.08(d,J＝7.7Hz,1H),8.02(d,J＝2.7Hz,1H),7.93(d,J＝7.7Hz,1H),7.76(d,J＝7.9Hz,1H),7.69(t,J＝7.8Hz,1H),6.70(d,J＝7.5Hz,1H),5.27(s,2H).
Example 36: synthesis of (1-bromo-7-chloro-3- (2, 3-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 36)
Figure BDA0004050562950000491
The starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referenced in sequence to steps 1-3 in example 6 to obtain the intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis referring in turn to steps 4, 5 in example 6 and the synthesis of example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl) methylamine with 2, 3-difluorobenzoic acid.1H NMR(400MHz,CDCl3)δ8.03(d,J＝3.9Hz,1H),7.59–7.35(m,3H),7.35–7.30(m,1H),5.36(s,2H).
Example 37: synthesis of (1-bromo-7-chloro-3- (3-fluoro-5-methoxyphenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 37)
Figure BDA0004050562950000492
The starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referenced in sequence to steps 1-3 in example 6 to obtain the intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis method referring in turn to steps 4, 5 in example 6 and the synthesis of example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl) methylamine with 3-fluoro-5-methoxybenzoic acid. 1H NMR(400MHz,CDCl3)δ7.55(d,J＝8.7Hz,1H),7.38(t,J＝2.2Hz,2H),7.16(d,J＝2.5Hz,1H),7.14(d,J＝2.5Hz,1H),5.42(s,2H),4.00(s,3H).
Example 38: synthesis of (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methylamine (Compound 38)
Figure BDA0004050562950000493
Figure BDA0004050562950000501
Step 1: synthesis of (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methylamine
Bis (tert-butoxycarbonyl) amine (186mg, 0.85mmol) was dissolved in 5mL of DMF, and potassium tert-butoxide (128mg, 1.1mmol) was added and reacted at room temperature for 1 hour. 1, 7-dibromo-8- (bromomethyl) -3- (3, 5-difluorophenyl) imidazo [1,5-a]Pyridine (300mg, 0.57mmol) was dissolved in 10mL of tetrahydrofuran solution, and slowly added dropwise to the mixed system to react at 65 ℃ for 12 hours. Cooled to room temperature, 50mL of water was added, ethyl acetate was extracted three times, the organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 5) to obtain an intermediate 85mg (yield 26%). The intermediate was dissolved in 5mL of 1, 4-dioxane solution, 1N HCl was reacted at room temperature for 2h, and the organic solution was removed by spinning. The use of petroleum ether: ethyl acetate =5:1 is recrystallized to obtain (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1, 5-a)]Pyridin-8-yl) methylamine 38mg (69%).1H NMR(400MHz,Methanol-d4)δ8.89(s,1H),7.54–7.44(m,3H),7.28–7.20(m,1H),5.15(s,2H),3.68(s,2H).
Example 39: synthesis of (1-bromo-7-chloro-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 39)
Figure BDA0004050562950000502
Starting material was 4-chloro-3-methylpyridine hydrochloride, the synthesis method was referred to steps 1-3 in example 6 in order to obtain an intermediate: (4-chloro-3-methylpyridin-2-yl) methylamine then reacted with 3-fluoro-5- (trifluoromethyl) benzoic acid, the synthesis referring in turn to steps 4,5 in example 6 and the synthesis of example 7, wherein step 4 is the reaction of (4-chloro-3-methylpyridin-2-yl) methylamine with 3, 5-difluorobenzoic acid.1H NMR(600MHz,CDCl3)δ8.09(d,J＝7.6Hz,1H),7.28(d,J＝5.7Hz,2H),7.02–6.85(m,1H),6.68(d,J＝7.6Hz,1H),5.20(s,2H).
Example 40: synthesis of ethyl 1-bromo-7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a ] pyridine-8-carboxylate (Compound 40)
Figure BDA0004050562950000511
Step 1: preparation of (E) -3- ((3-ethoxy-3-oxopropyl) amino) but-2-enoic acid ethyl ester
Ethyl acetoacetate (106.2g, 0.7 mol), ethyl 3-aminopropionate (91.0g, 0.7 mol) and potassium carbonate (232.2g, 1.7 mol) were dissolved in 500mL of toluene, and water was added thereto at 120 ℃ for 12 hours. And cooling to room temperature. Filtered with suction and washed with DCM. Concentration in vacuo afforded a yellow liquid (150.0g, 72.1%).
And 2, step: preparation of 2-methyl-4-oxo-1, 4,5, 6-tetrahydropyridine-3-carboxylic acid ethyl ester
(E) -3- ((3-ethoxy-3-oxopropyl) amino) but-2-enoic acid ethyl ester (150g, 0.6 mol) was dissolved in toluene, and NaH (22.6 g, 0.9mol) was added in portions and the reaction was refluxed for 12 hours. Then cooled to room temperature and the pH adjusted to 4-5 with 15% hydrochloric acid solution. EA extraction, spin-dried to obtain yellow solid (48.0 g, 40.0%).
And 3, step 3: preparation of 2-methyl-4-oxo-1, 4-dihydropyridine-3-carboxylic acid ethyl ester
2-methyl-4-oxo-1, 4,5, 6-tetrahydropyridine-3-carboxylic acid ethyl ester (48g, 0.2mol) and Pb (OAc)4(295.0 g, 0.7mol) in acetic acid and refluxed at 120 ℃ for 12h. Then cooled to room temperature, acetic acid was removed by evaporation, EA extracted, and separated by column chromatography (EA: PE = 1.1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝9.5Hz,1H),6.44(d,J＝9.6Hz,1H),4.33(q,J＝7.1Hz,2H),2.75(s,3H),1.38(t,J＝7.1Hz,3H).
And 4, step 4: preparation of ethyl 4-chloro-2-methylnicotinate
2-methyl-4-oxo-1, 4-dihydropyridine-3-carboxylic acid ethyl ester (12.5g, 70.0 mmol) was dissolved in phosphorus oxychloride and refluxed at 110 ℃ for 12 hours. Then cooled to room temperature, phosphorus oxychloride was removed by rotation, EA extracted, and separated by column chromatography (EA: PE = 1) to give a yellow solid (9.0 g, 62.9%).
And 5: preparation of ethyl 2- (bromomethyl) -4-chloronicotinate
Ethyl 4-chloro-2-methylnicotinate (9.0g, 43.5mmol), NBS (8.4g, 47.7mmol) and BPO (1.05g, 4.2mmol) were dissolved in carbon tetrachloride and reacted at 65 ℃ for 12 hours under the protection of argon. Then cooled to room temperature, carbon tetrachloride was removed by spinning, EA extracted, and separated by chromatography (EA: PE = 1.
Step 6: preparation of ethyl 2- (aminomethyl) -4-chloronicotinate
Bis (tert-butoxycarbonyl) amine (2.28g, 10.5 mmol) and potassium tert-butoxide (1.5 g,13.8 mmol) were dissolved in THF and reacted at room temperature for 1h. Then, ethyl 2- (bromomethyl) -4-chloronicotinate (2.0 g,6.9 mmol) was added to the reaction system and refluxed at 65 ℃ for 12 hours. Then cooled to room temperature, water was added, EA extracted, and chromatographed (EA: PE = 1. The intermediate was dissolved in 5mL of 1, 4-dioxane solution, 1N HCl was reacted at room temperature for 4h, and the organic solution was removed by spinning. Then, the 1, 4-dioxane was removed by spinning and dried to obtain a white solid (0.9g, 96%).
And 7: preparation of ethyl 4-chloro-2- ((3-fluoro-5-methylbenzamide) methyl) nicotinate
Ethyl 2- (aminomethyl) -4-chloronicotinate (500mg, 2.3mmol), 3-fluoro-5-methylbenzoic acid (374mg, 2.3mmol), EDCI (643mg, 3.4mmol) and DMAP (311mg, 2.6mmol) were dissolved in DCM and reacted for 6h at RT. Then water was added, DCM was added, and layer chromatography (EA: PE = 1).1H NMR(400MHz,Chloroform-d)δ8.32(d,J＝8.3Hz,1H),7.50(s,1H),7.39(d,J＝8.3Hz,2H),7.06(d,J＝9.3Hz,1H),5.12(d,J＝4.8Hz,2H),4.47(q,J＝7.1Hz,2H),2.45(s,3H),1.46(t,J＝7.1Hz,3H).
And 8: preparation of ethyl 7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a ] pyridine-8-carboxylate
Ethyl 4-chloro-2- ((3-fluoro-5-methylbenzamide) methyl) nicotinate (240mg, 0.68mmol) was dissolved in toluene, and phosphorus oxychloride (10 ml) was added to react at 110 ℃ for 12 hours. Toluene and phosphorus oxychloride were then removed by rotation, EA extracted, and layer chromatographed (EA: PE =1, 3) to give a yellow solid (160mg, 29.3%).
And step 9: preparation of 1-bromo-7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a ] pyridine-8-carboxylic acid ethyl ester
7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a ]]Pyridine-8-carboxylic acid ethyl ester (160mg, 0.72mmol) and NBS were dissolved in DCM and reacted for 4h at RT. Water was then added, DCM was extracted, and the layers were separated by column chromatography (EA: PE = 1) to give a yellow solid (170mg, 54.1%).1H NMR(400MHz,Chloroform-d)δ7.16(s,1H),7.11(dd,J＝7.2,1.5Hz,1H),7.05–1.03(m,2H),6.74(dd,J＝7.2,1.5Hz,1H),4.51(q,J＝7.2,2H),2.42(s,3H),1.48(t,J＝7.2Hz,3H).
Example 41: synthesis of (1-bromo-7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 41)
Figure BDA0004050562950000531
Synthesis method referring to example 24, the starting material 3- (3, 5-difluorophenyl) imidazo [1,5-a]Replacement of pyridine-8-carboxylic acid ethyl ester with 7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a]Pyridine-8-carboxylic acid ethyl ester.1H NMR(400MHz,CDCl3)δ7.15(s,1H),7.02(t,J＝9.2Hz,2H),6.95–6.82(m,1H),6.73–6.62(m,1H),5.17(s,2H),2.42(s,3H).
Example 42: synthesis of 1-bromo-7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a ] pyridine-8-carboxylic acid (Compound 42)
Figure BDA0004050562950000532
Synthesis method referring to example 25, starting material 3- (3, 5-difluorophenyl) imidazo [1,5-a]Replacement of pyridine-8-carboxylic acid ethyl ester with 7-chloro-3- (3-fluoro-5-methylphenyl) imidazo [1,5-a]Pyridine-8-carboxylic acid ethyl ester.1H NMR(400MHz,CDCl3)δ7.32(d,J＝7.3Hz,1H),7.17(s,1H),7.04(t,J＝8.1Hz,2H),6.76(d,J＝7.2Hz,1H),2.43(s,3H).
Example 43: synthesis of ethyl 3- (benzo [ c ] [1,2,5] oxadiazol-5-yl) -1-bromo-7-chloroimidazo [1,5-a ] pyridine-8-carboxylate (Compound 43)
Figure BDA0004050562950000533
Synthesis method referring to example 40, the starting material 3-fluoro-5-methylbenzoic acid of step 7 in example 40 was replaced with benzo [ c][1,2,5]Oxadiazole-5-carboxylic acid.1H NMR(400MHz,CDCl3)δ8.02(d,J＝1.3Hz,1H),7.90(dd,J＝9.2,1.2Hz,1H),7.64(dd,J＝9.3,1.4Hz,1H),7.20(d,J＝7.1Hz,1H),6.85(d,J＝7.1Hz,1H),4.54(q,J＝7.2Hz,2H),1.49(t,J＝7.1Hz,3H).
Example 44: synthesis of ethyl 1-bromo-7-chloro-3- (naphthalen-2-yl) imidazo [1,5-a ] pyridine-8-carboxylate (Compound 44)
Figure BDA0004050562950000541
Synthetic method referring to example 40, the starting material 3-fluoro-5-methylbenzoic acid of step 7 in example 40 was replaced with 2-naphthoic acid.1H NMR(400MHz,CDCl3)δ8.05(d,J＝1.7Hz,1H),7.96–7.86(m,3H),7.63–7.57(m,3H),7.12(d,J＝7.1Hz,1H),6.72(d,J＝7.1Hz,1H),4.53(q,J＝7.1Hz,2H),1.49(t,J＝7.2Hz,3H).
Example 45: synthesis of (1-bromo-7-chloro-3- (naphthalen-2-yl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 45)
Figure BDA0004050562950000542
Synthesis method referring to example 24, starting material 3- (3, 5-difluorophenyl) imidazo [1,5-a ]Replacement of pyridine-8-carboxylic acid ethyl ester with 1-bromo-7-chloro-3- (naphthalen-2-yl) imidazo [1,5-a]Pyridine-8-carboxylic acid ethyl ester.1H NMR(400MHz,CDCl3)δ8.04(d,J＝1.8Hz,1H),7.92–7.88(m,4H),7.69–7.51(m,3H),6.89(d,J＝7.1Hz,1H),6.69(d,J＝7.1Hz,1H),5.19(s,2H).
Example 46: synthesis of ethyl 1-bromo-7-chloro-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a ] pyridine-8-carboxylate (Compound 46)
Figure BDA0004050562950000543
Synthetic method referring to example 40, the starting material 3-fluoro-5-methylbenzoic acid of step 7 in example 40 was replaced with 3- (methylsulfonyl) benzoic acid.1H NMR(400MHz,CDCl3)δ8.13(d,J＝1.8Hz,1H),8.08(dt,J＝7.9,1.4Hz,1H),7.87(dt,J＝7.9,1.4Hz,1H),7.69(t,J＝7.8Hz,1H),7.17(d,J＝7.2Hz,1H),6.79(d,J＝7.2Hz,1H),4.53(q,J＝7.1Hz,2H),3.11(s,3H),1.48(t,J＝7.2Hz,3H).
Example 47: synthesis of (1-bromo-7-chloro-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 47)
Figure BDA0004050562950000551
Synthesis method referring to example 24, starting material 3- (3, 5-difluorophenyl) imidazo [1,5-a]Replacement of pyridine-8-carboxylic acid ethyl ester with 1-bromo-7-chloro-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a]Pyridine-8-carboxylic acid ethyl ester.1H NMR(400MHz,CDCl3)δ8.17–7.98(m,2H),7.89–7.82(m,1H),7.67(t,J＝7.8Hz,1H),6.96(d,J＝7.1Hz,1H),6.75(d,J＝7.1Hz,1H),5.20(s,2H),3.11(s,3H).
Example 48: synthesis of (7-chloro-1-methyl-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 48)
Figure BDA0004050562950000552
Step 1: preparation of ethyl 7-chloro-1-methyl-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a ] pyridine-8-carboxylate
Ethyl 1-bromo-7-chloro-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a ] pyridine-8-carboxylate (80mg, 0.18mmol) was dissolved in 2mL of DMF. Trimethylcyclotriboroxane (27mg, 0.22mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (22mg, 0.027mol) and potassium carbonate (74mg, 0.54mol) were added, respectively. Reacting for 3 hours at 100 ℃ under the protection of argon. Cooled to room temperature, 20mL of water was added, ethyl acetate was extracted three times, the organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was spun off, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 2) to obtain intermediate 30mg (yield 43%).
Step 2: preparation of (7-chloro-1-methyl-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a ] pyridin-8-yl) methanol
Synthesis method referring to example 24, the starting material 3- (3, 5-difluorophenyl) imidazo [1,5-a]Replacement of pyridine-8-carboxylic acid ethyl ester with 7-chloro-1-methyl-3- (3- (methylsulfonyl) phenyl) imidazo [1,5-a ]]Pyridine-8-carboxylic acid ethyl ester.1H NMR(400MHz,CDCl3)δ8.10–8.02(m,2H),7.84(d,J＝7.7Hz,1H),7.67(t,J＝7.8Hz,1H),7.20–7.06(m,1H),6.72(d,J＝6.6Hz,1H),4.99(s,2H),3.09(d,J＝11.3Hz,3H).
Example 49: synthesis of ethyl 1-bromo-7-chloro-3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a ] pyridine-8-carboxylate (Compound 49)
Figure BDA0004050562950000561
Synthetic method referring to example 40, the starting material 3-fluoro-5-methylbenzoic acid of step 7 in example 40 was replaced with 1-methyl-1H-pyrazole-4-carboxylic acid.1H NMR(400MHz,CDCl3)δ7.68(d,J＝1.3Hz,2H),7.07(dd,J＝10.2,7.1Hz,1H),6.71(dd,J＝7.1,3.9Hz,1H),4.50(q,J＝7.1Hz,2H),4.00(s,3H),1.46(t,J＝7.1Hz,3H).
Example 50: synthesis of (1-bromo-7-chloro-3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 50)
Figure BDA0004050562950000562
Synthetic method referring to example 24, starting material 3- (3, 5-bis)Fluorophenyl) imidazo [1,5-a]Replacement of pyridine-8-carboxylic acid ethyl ester with 1-bromo-7-chloro-3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a]Pyridine-8-carboxylic acid ethyl ester.1H NMR(400MHz,CDCl3)δ7.70–7.65(m,2H),6.83(dd,J＝15.6,7.0Hz,1H),6.67(dd,J＝7.1,4.0Hz,1H),5.13(s,2H),4.00(s,3H).
Example 51: synthesis of ethyl 1-bromo-7-chloro-3- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-a ] pyridine-8-carboxylate (Compound 51)
Figure BDA0004050562950000571
Synthetic method referring to steps 1-8 of example 40, the starting material 3-fluoro-5-methylbenzoic acid of step 7 in example 40 was replaced with benzoic acid. 1H NMR(400MHz,CDCl3)δ8.24(s,1H),7.64–7.52(m,3H),7.49–7.46(m,3H),6.73(d,J＝7.2Hz,1H),4.50(q,J＝7.1Hz,2H),1.49(t,J＝7.1Hz,3H).
Example 52: synthesis of ethyl 1-bromo-7-chloro-3-phenylimidazo [1,5-a ] pyridine-8-carboxylate (Compound 52)
Figure BDA0004050562950000572
Synthetic method referring to example 40, the starting material 3-fluoro-5-methylbenzoic acid of step 7 in example 40 was replaced with benzoic acid. Ethyl 2- (aminomethyl) -4-chloronicotinate and benzoic acid, synthesis method reference example 40.1H NMR(400MHz,CDCl3)δ7.62–7.36(m,5H),7.09(d,J＝7.1Hz,1H),6.70(d,J＝7.1Hz,1H),4.51(q,J＝7.2Hz,2H),1.47(t,J＝7.2Hz,3H).
Example 53: synthesis of methyl (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) acetate (Compound 53)
Figure BDA0004050562950000573
The synthesis is detailed in example 7Step 2, obtaining (1, 7-dibromo-3- (3, 5-difluorophenyl) imidazo [1,5-a]Pyridin-8-yl) acetic acid methyl ester (Compound 53).1H NMR(400MHz,CDCl3)δ8.49(s,1H),7.33–7.28(m,3H),7.02–6.94(m,1H),5.71(s,2H),2.17(d,J＝2.0Hz,3H).
Example 54: synthesis of (7-bromo-1-chloro-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol (Compound 54)
Figure BDA0004050562950000581
Step 1: synthesis of 7-bromo-1-chloro-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] pyridine
7-bromo-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] pyridine (323mg, 1mmol) was added to a 20mL dichloromethane solution, and N-chlorosuccinimide (200mg, 1.5mmol) was added and reacted at room temperature for 12 hours. After extraction with 20mL of water and dichloromethane three times, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by rotation, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 10) to obtain 182mg of the objective compound (yield 51%).
And 2, step: synthesis of 7-bromo-8- (bromomethyl) -1-chloro-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridine
Adding 7-bromo-1-chloro-3- (3, 5-difluorophenyl) -8-methylimidazo [1,5-a ] pyridine (182mg, 0.508mmol) into 20mL of carbon tetrachloride solution, adding N-bromosuccinimide (99mg, 0.559mmol) and benzoyl peroxide (12mg, 0.05mmol), and reacting under reflux for 5h under the protection of argon. After cooling to room temperature, 20mL of water was added, dichloromethane was extracted three times, the organic layers were combined, washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic solution was removed by spinning, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 10) to obtain 56mg of the objective compound (yield 25%).
And 3, step 3: synthesis of (7-bromo-1-chloro-3- (3, 5-difluorophenyl) imidazo [1,5-a ] pyridin-8-yl) methanol
For synthesis see steps 3 and 4 of example 7, but with 7-bromo-8- (bromomethyl) -1-chloro-3- (3, 5-difluorophenyl) imidazo [1, 5-a-]Pyridine compoundIs used as a raw material.1H NMR(400MHz,CDCl3)δ8.11(d,J＝7.6Hz,1H),7.70–7.64(m,1H),7.28(s,1H),6.96–6.91(m,1H),6.69(d,J＝7.6Hz,1H),5.24(s,2H).
Experimental example 1
In vitro activity assay: according to the invention, the inhibition or excitation effect of the compound on HIF-2 alpha gene expression is verified by adopting a Luciferase detection technology.
1. Purpose of the experiment
Determining the inhibitory or agonistic effect of a compound of the invention on HIF-2 α gene expression in 786-O cells.
2. Experimental materials
Human clear cell renal cell (786-O); RPMI-1640 medium (thermoloff, C11875500 BT) containing 10% fetal bovine serum (thermoloff, 10099141C); 96-well plate transparent plates (Corning, polo-00895); double reporter gene detection kit (Promeg, E1960); opti-MEM reagent (Thermofisiher, 31985070); lipo-fectamine2000 transfection reagent (Thermofisiher, 11668019); recombinant plasmid: PGL4.42 HRE-luc2:500ng (MiaoLingBio, P3135), pGL4.75 Renilla:50ng (MiaoLingBio, P0211); inhibitor positive molecule: PT-2385 ((S) -3- ((2, 2-difluoro-1-hydroxy-7- (methylsulfonyl) -2, 3-dihydro-1H-inden-4-yl) oxy) -5-fluorobenzonitrile), agonist positive molecule: ZG2033 (N- (3, 5-dimethoxyphenyl) benzo [ d ] isothiazol-3-amine).
3. Experimental methods
Human clear cell renal cell 786-O cell, containing 10% fetal bovine serum RPMI-1640 culture medium. Cells were prepared in 96-well plates at 7000 cells/well the day before transfection. Transient transfection was performed 24 hours after adherent growth, using a double reporter cotransfection method with Lipo-fectamine2000 as the transfection reagent, and Opti-MEM reagents were used to dilute the transfection reagent and plasmid, respectively. PGL4.42 HRE-luc2 500ng per well; pGL4.75 Renilla with 50ng per well, after 5 hours of cotransfection, adding compounds with different concentrations, incubating for 24 hours, and detecting luminescent signals by using a Luciferase double-reporter gene detection kit, wherein each sample has 3 duplicate wells. Data processing: firstly, the ratio of Firefly luciferase/Renilla luciferase of each tube is calculated, and then the ratio of the control group is taken as a unit 1, so that the relative luciferase activity of different treatment groups, namely the regulation and control activity of gene transcription of the treatment groups can be obtained. Inhibitory or agonistic activity was calculated using Graphpad.
4. Results of the experiment
The results of these compounds, determined using the Luciferase assay, are shown in Table 1 for compounds with inhibitory activity, where "A" refers to IC50Less than or equal to 1 μ M, "B" means IC50Between 1. Mu.M and 5. Mu.M, "C" refers to IC50Greater than 5. Mu.M.
Table 2 lists compounds having agonist activity, where "A" refers to EC50Less than or equal to 1 μ M, "B" means EC50Between 1. Mu.M and 5. Mu.M, "C" means EC50Greater than 5. Mu.M.
Specific results are shown in tables 1 and 2:
TABLE 1
A PT2385,1,10,12,14,19,21,23
B 2,6,11,16,18
C 3,4,5,8,13,15,17,19,20,22,25,26,40,42,44,51
The data in Table 1 show that the compounds of the present invention have good inhibitory activity on HIF-2. Alpha. Protein transcription level.
TABLE 2
A ZG2033,7,27,31,32,33,35,37,39
B 9,24,30,34,45,52,53
C 28,29,36,38,41,43,46,47,48,49,50
The data in Table 2 show that the compounds of the present invention have good HIF-2 alpha protein transcription level agonistic activity.
Experimental example 2
In vitro activity assay: the effect of the compounds on the inhibition or the agonism of HIF-2 alpha protein and ARNT protein combination is verified by adopting a TR-FRET detection technology.
1. Purpose of experiment
Determining the inhibitory or agonistic effect of a compound of the invention on HIF-2. Alpha. Protein and ARNT protein.
2. Experimental materials, as shown in table 3:
TABLE 3
Reagent Suppliers of goods Goods number
ARNT(Recombinant protein),FLAG-tag Sino Biological ME14OC2821
HIF-2αprotein Pharmaron \
PT-2385 MCE HY-12867
ZG-2033 \ \
MAb Anti FLAG M2-Eu cryptate Cisbio 61FG2KLA
Streptavidin-D2 Cisbio 610SADAB
DMSO Sigma D8418
3. Experimental method
FLAG-tagged ARNT (Sino-Biological; ME14OC 2821) and His-tagged HIF-2 α (Pharmaron Inc) purified protein complexes in assay buffer were dispensed into 384-well plates and compounds were added. After adding 5nM MAb Anti FLAG M2-Eu cryptate (Cisbio, 61FG2 KLA) and Streptavidin-D2 (Cisbio, 610 SADAB) to each well, the plates were centrifuged at 1000rpm for 1 minute and the plates were equilibrated at room temperature in the dark for 12h. Plates were read and fluorescence ratios of 665nm/615nm were obtained on an EnVision multi-label plate reader (PerkinElmer). Inhibition/activation rate calculation formula:
Figure BDA0004050562950000601
Figure BDA0004050562950000602
Mean RR values of positive controls.
Figure BDA0004050562950000603
Average RR values for negative controls.
4. Results of the experiment
Table 4 lists compounds having inhibitory activity, where "a" means an inhibitory effect of greater than or equal to 50% at a compound concentration of 100 μ M; "B" means that the inhibitory effect is between 0% and 50% at a compound concentration of 100. Mu.M.
Table 5 lists compounds with agonistic activity, where "A" refers to compounds with an agonistic effect of greater than or equal to 50% at a concentration of 100 μ M; "B" refers to a compound concentration of 100. Mu.M with an agonistic effect of between 20% and 50%. "C" means that the agonistic effect is between 0 and 20% at a compound concentration of 100. Mu.M.
TABLE 4
Figure BDA0004050562950000611
The data in Table 4 show that the compounds of the present invention have good inhibitory activity against HIF-2. Alpha. Protein transcription levels.
TABLE 5
A 7,9,27,31,32,33,34,35,37,39,45,46
B ZG2033,28,29,36,47,52
C 24,30,38,41,43,48,49,50,53
The data in Table 5 show that the compounds of the present invention have good HIF-2 alpha protein transcription level agonistic activity.
The present invention is illustrated by the above examples of the compounds, compositions, methods of preparation and uses of the invention, but the invention is not limited to the above methods, i.e., it is not meant that the invention must rely on the above detailed methods to be practiced. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims (19)

1. A compound having a structure as shown in formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,
Figure FDA0004050562930000011
wherein, the first and the second end of the pipe are connected with each other,
X1is N or CR1；
X2And X5Each independently is N or CH;
X3is CR5Or N;
X4is CR4Or N;
a is C6-14Aryl or 5-12 membered heteroaryl;
R1is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、
-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkoxy radical C1-6Alkyl, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy and C1-6Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、-C(＝O)R8、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
R2is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、
-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkoxy radical C1-6Alkyl, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy and C1-6Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO 2、NH2、COOH、CF3、NRcRd、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C6-12Aryl and 5-12 membered heteroaryl;
R3is H, D, F, cl, br, I, OH, CN, NO2、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、
-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、-NRcC(＝O)NRcRd、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C6-12Aryl or 5-12 membered heteroaryl, wherein said C6-12Aryl and 5-12 membered heteroaryl are each independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6HaloalkoxySubstituted with a substituent of the group;
each R4And R5Independently H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-6Hydroxyalkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Alkoxy radical C1-6An alkyl group;
each R6And R7Independently F, cl, br, I, OH, CN, NH2、NO2、C(＝O)OR8、C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-C(＝O)R8、C1-6Alkyl radical, C1-6Haloalkyl or C1-6A haloalkoxy group;
each R8Independently is C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, and R8Optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
each RaAnd RbIndependently H, F, cl, br, I, OH, CN, NH2、C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
Each RcAnd RdIndependently is C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl;
m is 1, 2 or 3; and
each n1 and n2 is independently 0, 1, 2, 3 or 4;
provided that R is2And R3Not both being H, and the compounds of formula (I) do not comprise compounds
Figure FDA0004050562930000031
Figure FDA0004050562930000032
2. The compound of claim 1, wherein a is C6-12Aryl or 5-10 membered heteroaryl.
3. A compound according to claim 1 or 2, wherein a is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, benzofurazan or pyrazolyl.
4. A compound according to any one of claims 1 to 3, wherein R1Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Alkoxy radical C1-4Alkyl, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy and C1-4Alkoxy radical C1-4Each alkyl is independently optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、-C(＝O)R8、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C3-12Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl and 5-6 membered heteroaryl.
5. The compound of any one of claims 1-4, wherein R 1Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8Methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxyOxymethyl or ethoxyethyl, wherein said methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl and ethoxyethyl are each independently optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of F, cl, br, I, OH, CN, NO, and ethoxyethyl 2、COOH、CF3、NRcRd、-C(＝O)R8、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRdCyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuryl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl, and imidazolyl.
6. The compound of any one of claims 1-5, wherein R2Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Alkoxy radical C1-4Alkyl, wherein said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Hydroxy radicalAlkyl radical, C1-4Haloalkyl, C1-4Alkoxy and C1-4Alkoxy radical C1-6Each alkyl is independently optionally substituted by 1,2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、NH2、COOH、CF3、NRcRd、-C(＝O)R8、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRd、C6-12Aryl and 5-6 membered heteroaryl.
7. The compound of any one of claims 1-6, wherein R2Is H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8Methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl or ethoxyethyl, wherein said methyl, ethyl, n-propyl, isopropyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxypropyl, methoxy-hydroxypropyl, 3-hydroxybutyl, trifluoromethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy-fluoropropyl, 3-hydroxyethyl, 4-hydroxybutyl, trifluoromethyl, etc The radical, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl or ethoxyethyl radical is each independently optionally substituted by 1,2, 3 or 4 radicals selected from F, cl, br, I, OH, CN, NO2、NH2、COOH、CF3、NRcRd、-C(＝O)R8、-S(＝O)2R8、C(＝O)NRcRdPhenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl.
8. The compound of any one of claims 1-7, wherein R3Is H, D, F, cl, br, I, OH, CN, NO2、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)OR8、-(CRaRb)n1C(＝O)OH、-CH(＝O)、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、-NRcC(＝O)NRcRdMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, triazolyl or pyrazolyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, thiazolyl, triazolyl and pyrazolyl are each independently optionally substituted with 1,2, 3 or 4 substituents selected from the group consisting of F, cl, br, I, OH, CN, NO2COOH, methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methoxymethyl, ethoxymethyl and ethoxyethyl.
9. The compound of any one of claims 1-8, wherein each R4And R5Independently H, D, F, cl, br, I, OH, CN, NO2、-(CRaRb)n2C(＝O)OR8、-(CRaRb)n2C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、-(CRaRb)n1C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-NRcRd、-NRcS(＝O)2NRcRd、-C(＝O)R8、C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Alkoxy radical C1-4An alkyl group;
each R6And R7Independently F, cl, br, I, OH, CN, NH2、NO2、C(＝O)OR8、C(＝O)OH、-CH(＝O)、-S(＝O)2R8、-OR8、-SR8、-S(＝O)R8、C(＝O)NRcRd、-NRcC(＝O)NRcRd、-S(＝O)2NRcRd、-C(＝O)R8Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, C1-4Haloalkyl or C1-4A haloalkoxy group.
10. The compound of any one of claims 1-9, wherein each R8Independently is C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-12Aryl or 5-6 membered heteroaryl, and R8Optionally substituted by 1, 2, 3 or 4 substituents selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRd、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl,C6-12Aryl and 5-6 membered heteroaryl.
11. The compound of any one of claims 1-10, wherein each R8Independently is methyl, ethyl, n-propyl, isopropyl, t-butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, propyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuryl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl or imidazolyl, and R is 8Optionally selected from 1,2, 3 or 4 selected from F, cl, br, I, OH, CN, NO2、COOH、CF3、NRcRdMethyl, ethyl, n-propyl, isopropyl, tert-butyl, -fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl.
12. The compound according to any one of claims 1 to 11,
each RaAnd RbIndependently H, F, cl, br, I, OH, CN, NH2Methyl, ethyl, n-propyl, isopropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
each RcAnd RdIndependently of one another, methyl, ethyl, n-propyl, isopropyl, tert-butyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2-dichloroethyl Alkyl, 2-fluoropropyl, 3-fluoropropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuryl, pyrazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, thienyl, pyrazolyl and imidazolyl.
13. The compound of any one of claims 1-12, which is a structure of formula (II), formula (II-1), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure FDA0004050562930000061
Figure FDA0004050562930000071
wherein A is phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, thienyl, benzofurazan or pyrazolyl.
14. The compound of any one of claims 1-13, having one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof,
Figure FDA0004050562930000072
/>
Figure FDA0004050562930000081
/>
Figure FDA0004050562930000091
/>
Figure FDA0004050562930000101
15. a pharmaceutical composition comprising a compound of any one of claims 1-14, optionally further comprising pharmaceutically acceptable adjuvants.
16. Use of a compound of any one of claims 1-14 or a pharmaceutical composition of claim 15 for the manufacture of a medicament for preventing, treating, or ameliorating a HIF-2 α -mediated associated condition.
17. The use of claim 16, wherein the HIF-2 α -mediated associated condition is cancer, inflammation, pulmonary hypertension, atherosclerosis, or ischemic disease.
18. The use of claim 17, wherein the cancer is renal cancer, glioblastoma, breast cancer, lung cancer, prostate cancer, hepatocellular carcinoma, and head and neck squamous cell carcinoma.
19. The use of claim 17, wherein the inflammation is inflammation of the digestive system, optionally crohn's disease or ulcerative colitis.
CN202310039898.2A 2022-01-12 2023-01-12 Aza-and-ring derivatives, pharmaceutical compositions thereof and uses thereof Pending CN115974872A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2022100327107 2022-01-12
CN202210032710 2022-01-12

Publications (1)

Publication Number Publication Date
CN115974872A true CN115974872A (en) 2023-04-18

Family

ID=85962916

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310039898.2A Pending CN115974872A (en) 2022-01-12 2023-01-12 Aza-and-ring derivatives, pharmaceutical compositions thereof and uses thereof

Country Status (2)

Country Link
CN (1) CN115974872A (en)
WO (1) WO2023134713A1 (en)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07112984A (en) * 1993-10-15 1995-05-02 Lederle Japan Ltd Imidazo(1, 5-a)pyridine derivative
WO2012170439A1 (en) * 2011-06-06 2012-12-13 The Ohio State University Methods for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
EP3203991A4 (en) * 2014-10-10 2018-06-20 The Board of Regents of The University of Texas System Hif-2 inhibitors for treating iron overload disorders
WO2016144826A1 (en) * 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Substituted pyridines and uses thereof
WO2019040102A1 (en) * 2017-08-22 2019-02-28 Gilead Sciences, Inc. Therapeutic heterocyclic compounds
CN113861187A (en) * 2020-06-30 2021-12-31 辽宁医学诊疗科技研发中心有限公司 Application of HIF-2 alpha inhibitor in preparing medicine for treating glioma
CN112979659B (en) * 2021-02-22 2022-07-08 中国医科大学 Preparation and application of HIF-2 alpha small molecule inhibitor
CN113264900B (en) * 2021-06-07 2023-05-26 南京中医药大学 Preparation method and medical application of benzisothiazole and benzothiophene

Also Published As

Publication number Publication date
WO2023134713A1 (en) 2023-07-20

Similar Documents

Publication Publication Date Title
CN107849040B (en) Tricyclic derivative compound, preparation method thereof, and pharmaceutical composition containing the same
WO2022247760A1 (en) Heterocyclic compounds as kras inhibitor, and preparation therefor and use thereof in treatment
JP5349462B2 (en) Spiroidalon
KR20100093552A (en) [1h-pyrazolo[3,4-b]pyridine-4-yl]-phenyle or -pyridin-2-yle derivatives as protein kinase c-theta
KR20160132041A (en) Azaspiro derivatives as trpm8 antagonists
CA2683758A1 (en) Novel 1,8-naphthyridine compounds
JP2022532758A (en) Inhibitors containing bicyclic derivatives, their production methods and uses
JP7046827B2 (en) Imidazo [1,5-a] pyrimidinylcarboxamide compounds and their use in the treatment of medical disorders
WO2021249057A1 (en) Heterocyclic compound and use thereof
CN113195471B (en) Polysubstituted pyridone derivative and application thereof in medicine
KR20190017959A (en) The α, β-unsaturated amide compound derived from benzotriazole, which is a TGF-βRI inhibitor
JP2022510689A (en) RET Inhibitors, Pharmaceutical Compositions and Their Use
JP2011513221A (en) Tetrahydroflopyridone
CN112661754A (en) Polycyclic compound for inhibiting RNA helicase DHX33
CN113072551A (en) Nitrogen-containing biphenyl derivative inhibitor, preparation method and application thereof
CN110520416A (en) Polysubstituted pyridine ketones derivant, preparation method and its medical usage
WO2023028564A1 (en) Spiro indoline inhibitors of kif18a
WO2022127199A1 (en) Polycyclic compounds for inhibiting rna helicase dhx33 and use thereof
US8492398B2 (en) Spiroazaindoles
WO2020046975A1 (en) Methods of treating neurodegenerative diseases
KR20210018915A (en) ERK inhibitors and uses thereof
WO2022089406A1 (en) Nitrogen-containing fused heterocyclic compound, and preparation method therefor and use thereof
CN114650993A (en) PD-1/PD-L1 inhibitor and preparation method and application thereof
CN112969694A (en) Rho-related protein kinase inhibitor, pharmaceutical composition containing same and application thereof
CN115974872A (en) Aza-and-ring derivatives, pharmaceutical compositions thereof and uses thereof

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