CN112851664B - Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine - Google Patents

Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine Download PDF

Info

Publication number
CN112851664B
CN112851664B CN201911099537.7A CN201911099537A CN112851664B CN 112851664 B CN112851664 B CN 112851664B CN 201911099537 A CN201911099537 A CN 201911099537A CN 112851664 B CN112851664 B CN 112851664B
Authority
CN
China
Prior art keywords
compound
alkyl
pharmaceutically acceptable
acceptable salt
alkoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201911099537.7A
Other languages
Chinese (zh)
Other versions
CN112851664A (en
Inventor
苟俊
何智鹏
邵林江
田园园
叶成
毛利飞
钱文建
胡泰山
陈磊
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.)
Zhejiang Hisun Pharmaceutical Co Ltd
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Hisun Pharmaceutical Co Ltd filed Critical Zhejiang Hisun Pharmaceutical Co Ltd
Priority to CN201911099537.7A priority Critical patent/CN112851664B/en
Priority to PCT/CN2020/127742 priority patent/WO2021093720A1/en
Publication of CN112851664A publication Critical patent/CN112851664A/en
Application granted granted Critical
Publication of CN112851664B publication Critical patent/CN112851664B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof as a therapeutic agent, particularly as a Rearrangement (RET) kinase inhibitor during selective transfection, wherein each substituent in the formula (I) is defined as the specification.

Description

Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine
Technical Field
The present invention relates to the field of pharmaceutical technology, in particular to a novel pyrazolo [1,5-a ] pyridine-3-carbonitrile compound, a process for its preparation, pharmaceutical compositions containing the derivative and its use as a therapeutic agent, in particular as a selective during-transfection Rearrangement (RET) kinase inhibitor.
Background
RET is a single transmembrane receptor belonging to the superfamily of amino acid kinases, which is required for normal development, maturation and maintenance of several tissues and cells, and unlike other receptor amino acid kinases, RET is linked to the cell surface by glycosyl phosphatidylinositol bonds to the glial cell derived neurotrophic factor (GDNF) family receptor- α (gfrα). Glial derived neurotrophic factor family ligand (GFL) and Glial Derived Neurotrophic Factor (GDNF) family receptor-alpha (gfrα) family members form a binary complex that in turn binds RET and recruits it to the cholesterol-rich, membrane-pressed domain of lipid rafts. In which RET signaling occurs.
Abnormal expression of RET gene is associated with various cancer diseases. The gene is fused with other genes through chromosome rearrangement or mutated at fixed points, and can be in a continuous activation state independent of ligands, so that abnormal signal paths are caused, and cell hyperproliferation and cancer are caused.
In recent years, there is increasing evidence that RET gene fusion and mutation are driving forces for the induction of certain cancers, and are not coincident with other driving genes, with significant specificity. RET gene fusion is most common in papillary thyroid carcinomas and non-small cell lung carcinomas, such as 30% sporadic papillary thyroid carcinomas and 70% radiation induced papillary thyroid carcinomas and about 2% of non-small cell lung carcinomas are driven by RET fusion. RET gene mutations are most common in medullary thyroid cancers, such as more than 50% of medullary thyroid cancers and nearly all congenital medullary cancers and multiple endocrine adenomatosis are caused by site-directed mutations of the RET gene.
Current therapies primarily employ multi-target kinase inhibitors with RET inhibiting activity to treat RET fused or mutated cancer patients. However, under these conditions, the dosage of the drug is insufficient to reach a level sufficient to inhibit aberrant RET gene expression due to off-target effects and drug toxicity. In addition, cancer cells develop resistance through mutation during the course of treatment of cancer. Once resistance develops, the patient's treatment options become very limited. Thus, there is a great need for a selective RET inhibitor for treating patients with RET gene fusion or mutation.
Drugs that selectively target RET targets are not available on the market, and the use of multi-target kinase inhibitors can be therapeutic for RET positive patients. A series of patents for selective RET kinase inhibitors have been disclosed, including WO2016127074, WO2017079140, WO2017011776, WO2017161269, WO2018022761, WO2018136661, WO2018136663, etc., and drugs currently in clinical phase I include Blu-667, loxo-292, GSK-3352589, etc. However, these are far from adequate for anti-tumor studies, and there remains a need to study and develop new selective during-transfection Rearrangement (RET) kinase inhibitors to address unmet medical needs.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a compound shown in a formula (I) or a stereoisomer, a tautomer or pharmaceutically acceptable salt thereof:
wherein:
X 1 、X 2 each independently selected from CH or N;
l is selected from:
wherein the two end points of L are optionally linked with A and R 2 Is connected with each other;
a is selected from 4-6 membered monocyclic heterocyclic group, -NH-4-6 membered heterocyclic group, 7-11 membered bridged heterocyclic group, 7-11 membered spiro heterocyclic group or 7-11 membered condensed ring heterocyclic group, wherein the monocyclic heterocyclic group, -NH-4-6 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or condensed ring heterocyclic group is optionally further selected from C by one or more 1 -C 3 Alkyl, hydroxyalkyl, halo C 1 -C 3 Alkyl, hydroxy, C 3 -C 6 Cycloalkyl or = O;
R 1 selected from: c (C) 3 -C 6 Cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 7-membered heteroaryl or 7-to 11-membered fused heterocyclyl, wherein said cycloalkyl, heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, hydroxyalkyl, amino, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Substituted with alkoxy; the heteroaryl, fused heterocyclyl are optionally further substituted with one or more groups selected from halogen, hydroxy, amino, C 1 -C 3 Alkyl group、C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkoxy, C 3 -C 6 Cycloalkyl, -NHR 3 、-NR 3 R 4 Or = O;
R 2 selected from C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-to 6-membered heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkoxy, C 3 -C 6 Cycloalkyl, -NHR 3 、-NR 3 R 4 Or = O;
R 3 、R 4 each independently selected from C 1 -C 6 An alkyl group;
wherein the above mentioned halogenated C 1 -C 3 Alkyl or halo C 1 -C 3 Alkoxy is preferably 1 to 3 fluoro C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
In some preferred embodiments of the present invention, the compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is a compound of formula (II):
wherein: A. l, R 1 And R is 2 The definition of (a) is as described in formula (I).
In some preferred embodiments of the invention, the compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein a is selected from:
wherein: the 1 and 2 endpoints are optionally connected with L.
In some preferred embodiments of the invention, a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 Selected from:
in some preferred embodiments of the invention, a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1 -C 6 Alkyl, C 4 -C 6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl or 10 membered heteroaryl, wherein said C 4 -C 6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl or 10 membered heteroaryl optionally further substituted with one or more groups selected from cyano, halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkoxy or = O.
In some preferred embodiments of the invention, a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 Selected from:
in a preferred embodiment of the present invention, there is provided a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a method of treating a disorder of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, comprising:
method 1:
reacting the compound (IA) with the compound (IB) under alkaline conditions in the presence of a condensing agent to obtain a compound of formula (I);
wherein:
the condensation reagent is selected from 2- (7-benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, 1-hydroxy-7-azobenzotriazole, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, pentafluorophenyl diphenyl phosphate, benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinyl phosphate; preferably 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine;
The reagent for providing the alkaline condition is an organic base selected from N, N-diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine and 4-dimethylaminopyridine, preferably N, N-diisopropylethylamine or triethylamine;
A、L、X 1 、X 2 、R 1 and R is 2 Is defined as in formula (I); or alternatively
Method 2:
reacting compound (IA) with compound (IB) under basic conditions to obtain a compound of formula (I);
wherein:
the reagent for providing alkaline conditions is an inorganic base, wherein the inorganic base is selected from the group consisting of potassium phosphate, potassium phosphate trihydrate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and potassium hydride, preferably sodium carbonate or potassium carbonate;
g is selected from leaving groups, preferably halogen;
A、L、X 1 、X 2 、R 1 and R is 2 The definition of (a) is as described in formula (I).
Further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
The invention provides an application of a compound shown in a formula (I) or (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines.
The invention also provides the use of a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a Rearrangement (RET) kinase inhibitor during transfection.
The invention further provides the use of a compound of formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease driven by a Rearrangement (RET) gene during transfection, wherein the disease is preferably cancer, wherein the cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
The present invention provides compounds of formula (I) or (II) or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, as selective during transfection Rearrangement (RET) kinase inhibitors. Accordingly, the present invention provides a method of selectively inhibiting a Rearrangement (RET) kinase during transfection comprising contacting the Rearrangement (RET) kinase during transfection with a compound of formula (I) or (II) of the present invention or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Accordingly, the present invention also provides a method of treating a disease driven by a Rearrangement (RET) gene during transfection, comprising administering to a subject in need thereof a compound of formula (I) or (II) of the present invention or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the disease is preferably cancer, wherein the cancer is preferably lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
Detailed description of the invention
Some of the terms used in the description and claims of the present invention are defined as follows:
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 3 -C 6 Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred.
"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged and spiro rings. Preferably having a 5-to 7-membered monocyclic or 7-to 10-membered bicyclic or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, alkenylpiperidinyl, 3, 6-dihydro-2H-pyranyl, 1-methyl-2-oxo-1, 2-dihydropyridine, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferably aryl is C 6 -C 10 Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. Aryl groups may be substituted or unsubstituted. The "aryl" may be fused to a heteroaryl, heterocyclyl, or cycloalkyl group, wherein the aryl ring is attached to the parent structure, non-limiting examples include, but are not limited to:
"heteroaryl" means an aromatic 5-7 membered monocyclic or 9-10 membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, and benzisoxazolyl. Heteroaryl groups may be substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include, but are not limited to:
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Which is a kind ofExamples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to-OH.
"halogen" means fluorine, chlorine, bromine and iodine, preferably chlorine, bromine and fluorine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"benzyl" means-CH 2 -phenyl.
"carboxy" means-C (O) OH.
"carboxylate" refers to-C (O) O (alkyl) or (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"Boc" refers to tert-butoxycarbonyl.
"Ms" refers to sulfonyl.
"Ts" means 4-methylbenzenesulfonyl.
The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, -OTs, or-OH.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, nhalkyl, N' N-dialkyl substituents or =o.
The definition and use of stereochemistry in the present invention is generally referred to in the following documents:
S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hillbook Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including but in no way limited to diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the invention. Diastereomers can be separated into the individual diastereomers by chromatography, crystallization, distillation, or sublimation, based on their physical-chemical differences. Enantiomers may be converted into diastereomeric mixtures by separation by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers. The intermediates and compounds of the invention may also exist in different tautomeric forms and all such forms are encompassed within the scope of the invention. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to name the sign of the compound plane polarization rotation, where (-) or l means that the compound is left-handed and the prefix (+) or d means that the compound is right-handed. The atoms or groups of atoms of these stereoisomers are connected in the same order but in different steric structures. The particular stereoisomer may be an enantiomer, and the mixture of isomers is commonly referred to as an enantiomeric mixture. The 50:50 enantiomeric mixture is known as a racemic mixture or racemate, which may result in the absence of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
"tautomer" or "tautomeric form" refers to isomers of structures of different energies that can be interconverted by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include tautomerism by proton shift, such as keto-enol and imine-enamine isomerisation. Valency (valence) tautomers include tautomers that reorganize into bond electrons. Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): for example, R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers thereof, are all within the scope of the invention.
By "pharmaceutically acceptable salts" is meant certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound represented by formula (I) may be a metal salt, a salt with a suitable acid.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Examples
The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). 1 H NMR was determined using a Bruker instrument (400 MHz) and chemical shifts were expressed in ppm using tetramethylsilane internal standard (0.00 ppm). 1 H NMR representation method: s=singlet, d=doublet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If a coupling constant is provided, it is in Hz. The mass spectrum was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: thermo, model: finnigan LCQ advantage MAX).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm silica gel plate.
Column chromatography generally uses 200-300 mesh silica gel of yellow sea as a carrier.
The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros organics, aldrich Chemical Company, shaoshima chemical technology (Accela ChemBio Inc), darui chemical, and the like.
In the examples, unless otherwise specified, the reactions were carried out in an open atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume. The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
In the examples, the reaction temperature was room temperature unless otherwise specified.
The room temperature is the most suitable reaction temperature, and the temperature range is 20-30 ℃.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following system of developing agents: a: methylene chloride and methanol systems; b: n-hexane and ethyl acetate systems, the volume ratio of the solvents was adjusted according to the polarity of the compounds.
The system of eluent for column chromatography and the system of developing agent for thin layer chromatography used for purifying the compound include: a: methylene chloride and methanol systems; b: the volume ratio of the solvent in the n-hexane and ethyl acetate system is adjusted according to the polarity of the compound, and can be adjusted by adding a small amount of an acidic or alkaline reagent such as triethylamine.
Preparation of intermediates
Intermediate 1-d
The first step: boc-mesyl hydroxylamine
2,4, 6-Trimethylbenzenesulfonyl chloride (a) (200 g,914.5 mmol), tert-butyl N-hydroxycarbamate (b) (133.0 g,1000 mmol) and methyl tert-butyl ether (1.5L) were placed in a 3L single-necked flask, and after stirring for 30 minutes in an ice bath, triethylamine (170 mL,1371.7 mmol) was slowly added dropwise, and after the addition was completed, the mixture was reacted at 0℃for 30 minutes, followed by stirring at room temperature for 4 hours. The pH of the reaction solution was adjusted to about 4 with dilute HCl (2N), the solution was separated, the organic phase was washed three times with water (30 mL. Times.3), saturated brine was washed once with water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give Boc-mesyl hydroxylamine (1-a) as a white solid 290g. Yield: 74.2%.
MS m/z(ESI):316.2[M+1]
And a second step of: synthesis of mesyl hydroxylamine
Trifluoroacetic acid (500 mL) is added into a 2L single-port bottle, the temperature of the ice salt bath is reduced to minus 15 ℃ to minus 20 ℃, boc-mesyl hydroxylamine (1-a) (290 g,919.5 mmol) is slowly added in batches, the reaction is carried out for 6h under the ice salt bath after the addition, the reaction solution is poured into 6L ice water after the reaction is finished, a large amount of white solid is precipitated, the white solid is filtered, and the filter cake is washed by water until the filtrate is neutral. The filter cake was dissolved in dichloromethane, the solution was separated, the organic phase was dried over anhydrous sodium sulfate, and filtered, and the obtained organic phase was directly subjected to the next reaction.
MS m/z(ESI):216.2[M+1]
And a third step of: synthesis of (3, 5 dichloropyridin-1-yl) ((trimesoyl) hydroxylamine
A2L single vial was charged with a dichloromethane solution (197g, 915.1 mmol) of mesyl hydroxylamine (1-b), the ice bath was cooled to 0℃and 3, 5-dichloropyrimidine (1-b) (135.4 g,915.1 mmol) was added and stirred overnight at room temperature. After completion of the reaction, filtration was carried out, and the cake was washed with methylene chloride and dried to obtain 210g of a white solid (1-c), yield: 63.2%.
MS m/z(ESI):362.02[M+1]
Fourth step: synthesis of 4, 6-dichloropyrazoline [1,5-a ] pyridine-3-carbonitrile
To a 1L single-necked flask was added (1-c) (105 g,290.7 mmol), triethylamine (84 mL,481.4 mmol), ethanol 300mL, stirring, 3-methoxypolyacrylonitrile (d) (25 g,290.7 mmol), reacting at 80℃for 4h, cooling the reaction solution to room temperature, pouring into 3L ice water, filtering, purifying the filter cake by silica gel column chromatography (n-hexane: ethyl acetate=3:1) to obtain a tan product of 4, 6-dichloropyrazoline [1,5-a ] pyridine-3-carbonitrile (1-d) 25g, yield: 40.6%. MS m/z (ESI): 213.2[ M+1]
The first step: synthesis of 4- (5-bromopyridin-2-yl) piperazine-1-carbonic acid tert-butyl ester
In a 200mL single vial was added 2-fluoro-5-bromopyridine (e) (20 g,113.6 mmol), boc-piperazine (f) (32 g,170.5 mmol), K 2 CO 3 (37 g,113.6 mmol), 100mL of N, N-dimethylacetamide, at 110 ℃ C. For 4h, after the reaction has ended and the reaction solution cooled to room temperature, poured into 1L of water, extracted three times (300 mL. Times.3) with an organic solvent (MeOH/DCM=10:1), the organic phase washed with water (300 mL. Times.3), saturated aqueous sodium chloride solution (300 mL) and dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (n-hexane: ethyl acetate=2:1) to give 29.9g of the product 4- (5-bromopyridin-2-yl) piperazine-1-t-butyl carbonate (1-e), yield: 77.3%. MS m/z (ESI): 342.2[ M+1] ]
And a second step of: 6- (4-Boc-1-piperazinyl) pyridine-3-boronic acid pinacol ester
To a 100mL single vial was added 4- (5-bromopyridin-2-yl) piperazine-1-carbon tert-butyl ester (1-e) (29.9 g,87.3 mmol), bipropylalcohol ester (33.3 g,131.0 mmol), bis [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (3.2 g,4.37 mmol), potassium acetate (17.2 g,174.5 mmol) and 400mL of 1, 4-dioxane, nitrogen blanket, and reacted overnight at 100 ℃. The reaction solution was cooled to room temperature, concentrated, and purified by silica gel column chromatography (n-hexane: ethyl acetate=2:1) to give 24.2g of the product 6- (4-Boc-1-piperazinyl) pyridine-3-boronic acid pinacol ester (1-f), yield: 71.2%.
Intermediate 2-f
The first step: 3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester
The first step of synthesis of intermediate 1-f was repeated except that starting material 2-a was substituted for f to give intermediate 3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-tert-butyl carbonate 2-e.
MS m/z(ESI):354.07[M+1]
And a second step of: tert-butyl-3- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonate
The second step of synthesis of intermediate 1-f was repeated except that 1-e was replaced with starting material 2-e to give intermediate tert-butyl-3- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonate 2-f.
MS m/z(ESI):402.25[M+1]
Intermediate 3-f
The first step: synthesis of 3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.2.1] octane-8-carbonic acid tert-butyl ester
The first step of synthesis of intermediate 1-f was repeated except that the starting material 3-a was used instead of f to give intermediate 3- (5-bromopyridin-2-yl) -3, 6-diazabicyclo [3.2.1] octane-8-tert-butyl carbonate 3-e.
MS m/z(ESI):368.09[M+1]
And a second step of: 3- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonic acid tert-butyl ester
The second step of synthesis of intermediate 1-f was repeated except that 1-e was replaced with starting material 3-e to give intermediate 3- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-tert-butyl carbonate 3-f.
MS m/z(ESI):416.25[M+1]
Intermediate 4-f
The first step: synthesis of tert-butyl 3- (5-bromopyridin-2-yl) piperidin-4-yl) carbonate
The first step of the synthesis of intermediate 1-f was repeated except that the starting material 4-a was used instead of f to give intermediate 3- (5-bromopyridin-2-yl) piperidin-4-yl) carbonate tert-butyl 4-e.
MS m/z(ESI):368.09[M+1]
And a second step of: 3- (5- (4, 5-tetramethyl-1, 3, 2-dioxaboran-2-yl) pyridin-2-yl) piperidin-4-yl) carbonate tert-butyl ester
The second step of synthesis of intermediate 1-f was repeated except that starting material 4-e was substituted for 1-e to give intermediate 3- (5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridin-2-yl) piperidin-4-yl) carbonate tert-butyl 4-f. MS m/z (ESI): 416.25[ M+1]
Intermediate 1-i
The first step: synthesis of tert-butyl 4- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine-1-carbonate
In a 100mL single port flask were added 4, 6-dichloropyrazoline [1,5-a ] pyridine-3-carbonitrile (1-d) (2.0 g,9.4 mmol), 6- (4-Boc-1-piperazinyl) pyridine-3-boronic acid pinacol ester (1-f) (4.04 g,10.3 mmol), potassium phosphate (4.0 g,18.8 mmol), tris (dibenzylideneacetone) dipalladium (0.8 g,0.94 mmol), tricyclohexylphosphine (0.53 g,1.88 mmol) and 60mL of solvent (1, 4-dioxane: water=10:1), and reacted under nitrogen at 70℃for 5H, a 1, 4-dioxane solution of 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (H) (2.96 g,14.1 mmol) was added, and refluxed overnight. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, and purified by silica gel column chromatography (n-hexane: ethyl acetate=1:1) to give the product of tert-butyl 4- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine-1-carbonate (1-H) 1.4g, yield: 30.7%.
MS m/z(ESI):486.2[M+1]
And a second step of: synthesis of 4- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine.
In a 100mL single vial was added 4- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl-pyrazoline [1, 5-a)) ]Pyridin-4-yl) pyridin-2-yl piperazine-1-carbonate (1-h) (1.4 g,2.88 mmol) and 25mL ethanol, 5mL concentrated hydrochloric acid, were reacted overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in water (100 mL) using saturated NaHCO 3 The pH of the aqueous solution is adjusted to 8-9, the aqueous solution is extracted three times with methylene chloride (30 mL. Times.3), the organic phases are combined, the organic phase is washed by water (30 mL. Times.3) and saturated sodium chloride aqueous solution (30 mL) and then dried by anhydrous sodium sulfate, and the product 4- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1, 5-a) is obtained after filtration and concentration]Pyridin-4-yl) pyridin-2-yl piperazine (1-i) 1.1g, yield: 99.1%.
MS m/z(ESI):386.2[M+1]
Intermediate 2-i
The first step: synthesis of tert-butyl 3- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonate
The first step of the synthesis of intermediate 1-i was repeated except that 1-f was replaced with starting material 2-f to give intermediate 3- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-tert-butyl carbonate 2-H.
MS m/z(ESI):499.2[M+1]
And a second step of: synthesis of 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 2-H was substituted for 1-H to give intermediate 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 2-i.
MS m/z(ESI):399.2[M+1]
Intermediate 3-i
The first step: synthesis of tert-butyl 3- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonate
The first step of synthesis of intermediate 1-i was repeated except that starting material 3-f was substituted for 1-f to give intermediate 3- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-tert-butyl carbonate 3-H.
MS m/z(ESI):513.2[M+1]
And a second step of: synthesis of 4- (6- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 3-H was substituted for 1-H to give intermediate 4- (6- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 3-i.
MS m/z(ESI):413.2[M+1]
Intermediate 4-i
The first step: synthesis of tert-butyl (1- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperidin-4-amino) carbonate
The first step of the synthesis of intermediate 1-i was repeated except that starting material 4-f was substituted for 1-f to give intermediate tert-butyl (1- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperidin-4-amino) carbonate for 4-H.
MS m/z(ESI):501.2[M+1]
And a second step of: synthesis of 4- (6- (4-aminopiperidin-1-yl) pyridin-3-yl) -6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 4-H was substituted for 1-H to give intermediate 4- (6- (4-aminopiperidin-1-yl) pyridin-3-yl) -6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 4-i. MS m/z (ESI): 401.2[ M+1]
Intermediate 5-i
The first step: synthesis of tert-butyl 4- (5- (3-cyano-6- (2-methylpyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine-1-carbonate
The first step of synthesis of intermediate 1-i was repeated except that starting material j was substituted for starting material h to give intermediate 4- (5- (3-cyano-6- (2-methylpyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine-1-tert-butyl carbonate 5-h.
MS m/z(ESI):496.2[M+1]
And a second step of: synthesis of 6- (2-methylpyridin-4-yl) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 5-h was substituted for 1-h to give intermediate 6- (2-methylpyridin-4-yl) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 5-i.
MS m/z(ESI):396.2[M+1]
Intermediate 6-i
The first step: synthesis of tert-butyl 3- (5- (3-cyano-6- (2-methylpyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonate
The first step of synthesis of intermediate 1-i was repeated except that starting material 3-f was substituted for 1-f and starting material j was substituted for starting material h to give intermediate 3- (5- (3-cyano-6- (2-methylpyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-tert-butyl carbonate 6-h.
MS m/z(ESI):522.2[M+1]
And a second step of: synthesis of 4- (6- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -6- (2-methylpyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 6-h was substituted for 1-h to give intermediate 4- (6- (3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridin-3-yl) -6- (2-methylpyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 6-i.
MS m/z(ESI):422.2[M+1]
Intermediate 7-i
The first step: synthesis of tert-butyl 3- (5- (3-cyano-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine-1-carbonate
The first step of synthesis of intermediate 1-i was repeated except that starting material k was substituted for starting material h to give intermediate 3- (5- (3-cyano-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine-1-tert-butyl carbonate 7-h.
The synthesis method is shown in the first step of the intermediate 1-i.
MS m/z(ESI):512.2[M+1]
And a second step of: synthesis of 6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 7-h was substituted for 1-h to give intermediate 6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) -4- (6- (piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 7-i.
MS m/z(ESI):412.2[M+1]
Intermediate 8-i
The first step: synthesis of tert-butyl 3- (5- (3-cyano-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbonate
The first step of the synthesis of intermediate 1-i was repeated except that starting material 2-f was substituted for 1-f and starting material k was substituted for starting material h to give intermediate 3- (5- (3-cyano-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-tert-butyl carbonate 8-h.
MS m/z(ESI):524.2[M+1]
And a second step of: synthesis of 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 8-h was substituted for 1-h to give intermediate 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 8-i.
MS m/z(ESI):424.2[M+1]
Intermediate 9-i
The first step: synthesis of tert-butyl 3- (5- (3-cyano-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carbonate
The first step of synthesis of intermediate 1-i was repeated except that starting material 3-f was substituted for 1-f and starting material k was substituted for starting material h to give intermediate 3- (5- (3-cyano-6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane-8-tert-butyl carbonate 9-h.
MS m/z(ESI):538.2[M+1]
And a second step of: synthesis of 4- (6- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile.
The second step of synthesis of intermediate 1-i was repeated except that starting material 9-h was substituted for 1-h to give intermediate 4- (6- (3, 8-diazabicyclo [3.2.1] oct-3-yl) pyridin-3-yl) -6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile 9-i.
MS m/z(ESI):438.2[M+1]
Intermediate 1-m
The first step: synthesis of (6-methoxypyridin-3-yl) methanol
6-methoxy nicotinic acid (1-j) (15 g,97.95 mmol) and 150mL tetrahydrofuran were added into a 100mL single-port bottle, stirred in an ice bath for 30min, lithium aluminum hydride (5.58 g,146.93 mmol) was slowly added in portions, reacted under ice bath for 1h, ice bath was removed, then reacted at room temperature for 2h, sodium sulfate pentahydrate was slowly added until no bubbles emerged after the reaction was completed, filtered, the filter cake was washed with dichloromethane (200 mL), and the filtrate was concentrated to give 13g of the product in the yield: 93.4%. And a second step of: synthesis of 5- (chloromethyl) -2-methoxypyridine
In a 100mL single-necked flask, (6-methoxypyridin-3-yl) methanol (1-k) (13 g,93.42 mmol) and 150mL of methylene chloride were added, and stirred in an ice bath for 30min, thionyl chloride (13.5 mL,186.84 mmol) was added dropwise, and the ice bath was removed and reacted overnight at room temperature. After the reaction, saturated sodium bicarbonate aqueous solution is added to the reaction solution to adjust the pH to 7-8, the solution is separated, the organic phase is dried with anhydrous sodium sulfate, filtered and concentrated, and silica gel column chromatography (n-hexane: ethyl acetate=10:1) is used for purification to obtain 2.7g of a product, and the yield is: 18.3%.
Example 1
Preparation of Compound I-1
Synthesis of (R) -6- (3, 6-dihydro-2H-pyran-4-yl) -4- (6- (4- (2-hydroxy-3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
To a 100mL single vial was added 4- (5- (3-cyano-6- (3, 6-dihydro-2H-pyran-4-yl) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) piperazine (1-i) (100 mg,0.26 mmol), (R) -2-hydroxy-3-methylbutanoic acid (61.3 mg,0.52 mmol), N, N-diisopropylethylamine (134 mg,1.03 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (536.0 mg,1.03 mmol) and 10mL N, N-dimethylformamide, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted three times with methylene chloride (30 ml×3), the organic phases were combined, washed with water (30 ml×3), saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (methylene chloride: methanol=30:1) to give the product (R) -6- (3, 6-dihydro-2H-pyran-4-yl) -4- (6- (4- (2-hydroxy-3-methylbutanoyl) piperazin-1-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (I-1) 42mg, yield: 33.3%.
1 H NMR(400MHz,DMSO-d 6 )δ8.89(s,1H),8.68(s,1H),8.40(d,J＝2.4Hz,1H),7.86(dd,J＝8.9,2.4Hz,1H),7.72(s,1H),7.01(d,J＝8.9Hz,1H),6.61(s,1H),4.77(d,J＝7.0Hz,1H),4.26(d,J＝3.3Hz,2H),4.10(d,J＝6.1Hz,1H),3.85(t,J＝5.5Hz,2H),3.74-3.55(m,8H),2.55(s,2H),1.89(q,J＝6.6Hz,1H),0.91(d,J＝6.7Hz,3H),0.85(d,J＝6.7Hz,3H).
MS m/z(ESI):487.6[M+1]
Example 2-example 36
Preparation of Compounds I-2 to I-36
Reference example 1 preparation of compound I-1 by reaction of 1I, 2I, 3I, 4I, 5I, 6I, 7I, 8I and 9I, respectively, with the appropriate carboxylic acid gave compounds I-2 to I-36, their structure and characterization data are as follows: i-2
1H NMR(400MHz,Chloroform-d)δ8.49(s,1H),8.35(s,1H),8.27(s,1H),7.78(s,1H),7.57(s,1H),7.42(s,1H),6.90(d,J＝32.1Hz,2H),6.66(s,1H),6.31(s,1H),4.80(s,1H),4.54(s,1H),4.34(d,J＝25.8Hz,3H),3.98(s,2H),3.70(d,J＝43.6Hz,3H),2.92(s,1H),2.81(d,J＝4.6Hz,1H),2.54(s,2H),1.77(s,1H).
MS m/z(ESI):539.2[M+1]
I-3
1 H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.65(d,J＝5.2Hz,1H),8.43(d,J＝2.4Hz,1H),8.37-8.29(m,2H),7.82(dd,J＝8.7,2.4Hz,1H),7.74(dd,J＝8.6,2.2Hz,1H),7.56(s,1H),7.43(s,1H),7.37(d,J＝5.3Hz,1H),6.83(dd,J＝8.7,5.4Hz,2H),4.00(s,3H),3.78(d,J＝23.8Hz,8H),2.68(s,3H).
MS m/z(ESI):531.2[M+1]
I-4
1 H NMR(400MHz,Chloroform-d)δ8.83(s,1H),8.64(s,1H),8.35(d,J＝12.7Hz,2H),7.76(d,J＝8.5Hz,1H),7.58-7.18(m,8H),6.72(d,J＝8.7Hz,1H),4.76(s,1H),4.25-3.16(m,9H),2.97(d,J＝11.9Hz,1H),2.67(d,J＝5.5Hz,3H).
MS m/z(ESI):530.2[M+1]
I-5
1 H NMR(400MHz,Chloroform-d)δ8.52(d,J＝1.6Hz,1H),8.38(d,J＝2.5Hz,1H),8.29(s,1H),7.81(dd,J＝8.9,2.5Hz,1H),7.45(d,J＝1.6Hz,1H),7.28-7.23(m,1H),7.19-7.07(m,2H),6.69(d,J＝8.9Hz,1H),6.34(dd,J＝3.2,1.8Hz,1H),4.85(s,1H),4.58(s,1H),4.40(q,J＝2.8Hz,2H),4.31(d,J＝11.3Hz,1H),4.01(t,J＝5.4Hz,2H),3.81(t,J＝14.2Hz,2H),3.69(d,J＝12.0Hz,1H),2.95(q,J＝7.0Hz,1H),2.61-2.53(m,2H),1.82(d,J＝8.8Hz,1H).
MS m/z(ESI):539.2[M+1].
I-6
1 H NMR(400MHz,DMSO-d 6 )δ8.88(d,J＝1.5Hz,1H),8.67(s,1H),8.39(d,J＝2.5Hz,1H),8.02(d,J＝2.4Hz,1H),7.84(dd,J＝8.8,2.6Hz,1H),7.71(d,J＝1.6Hz,1H),7.56(dd,J＝8.5,2.5Hz,1H),7.00(d,J＝8.8Hz,1H),6.77(d,J＝8.5Hz,1H),6.62-6.55(m,1H),4.25(q,J＝2.8Hz,2H),3.83(d,J＝8.9Hz,5H),3.74(s,2H),3.69-3.56(m,8H),2.54(s,2H).
MS m/z(ESI):536.2[M+1]
I-7
1 H NMR(400MHz,Chloroform-d)δ8.52(d,J＝1.6Hz,1H),8.38(d,J＝2.5Hz,1H),8.29(s,1H),7.80(d,J＝8.7Hz,1H),7.73-7.66(m,2H),7.44(d,J＝1.6Hz,1H),7.13(t,J＝8.6Hz,2H),6.70(d,J＝9.1Hz,1H),6.33(dd,J＝3.5,1.9Hz,1H),4.77(s,2H),4.40(q,J＝2.8Hz,2H),4.01(t,J＝5.4Hz,2H),3.75(s,4H),2.96(q,J＝7.1Hz,1H),2.57(s,2H),1.80(d,J＝8.8Hz,1H).
MS m/z(ESI):521.2[M+1]
I-8
1 H NMR(400MHz,DMSO-d 6 )δ8.89(s,1H),8.68(s,1H),8.37(d,J＝2.4Hz,1H),8.17(s,2H),7.87-7.77(m,1H),7.70(s,1H),7.45-7.35(m,2H),7.32(d,J＝7.1Hz,1H),6.95(d,J＝8.9Hz,1H),6.61(s,1H),4.26(s,2H),3.86(t,J＝5.5Hz,2H),3.70–3.54(m,6H),3.15(dt,J＝12.2,5.7Hz,4H),2.55(s,2H).
MS m/z(ESI):521.2[M+1]
I-9
1 H NMR(400MHz,DMSO-d 6 )δ8.89(s,1H),8.68(d,J＝1.6Hz,1H),8.40(d,J＝2.5Hz,1H),8.34(d,J＝2.3Hz,1H),7.85(td,J＝8.1,2.3Hz,2H),7.72(s,1H),7.00(d,J＝8.9Hz,1H),6.90(s,1H),6.61(s,1H),4.26(d,J＝3.1Hz,2H),3.91(s,3H),3.85(t,J＝5.5Hz,2H),3.70(s,4H),3.34(s,4H),2.55(s,2H).
MS m/z(ESI):522.2[M+1]
I-10
1 H NMR(400 MHz,DMSO-d 6 )δ9.50(d,J＝1.6 Hz,1H),8.77(d,J＝1.7 Hz,1H),8.55(d,J＝5.3 Hz,1H),8.45(t,J＝2.5 Hz,3H),7.96–7.84(m,3H),7.77(d,J＝5.4 Hz,1H),7.62(d,J＝8.1 Hz,1H),7.41–7.33(m,1H),6.97(d,J＝8.9 Hz,1H),3.50(d,J＝81.3Hz,8H),2.55(s,3H),1.42(d,J＝5.2 Hz,2H),1.32(s,2H).
MS m/z(ESI):541.2[M+1]
I-11
1 H NMR(400 MHz,DMSO-d 6 )δ8.90(s,1H),8.69(s,1H),8.42(dd,J＝16.1,2.4 Hz,2H),7.98-7.89(m,1H),7.86(dd,J＝8.8,2.5 Hz,1H),7.73(s,1H),6.92(dd,J＝8.9,3.2 Hz,2H),6.62(s,1H),4.81(s,1H),4.23(d,J＝31.4 Hz,4H),3.94(d,J＝5.8 Hz,4H),3.86(t,J＝5.6 Hz,2H),3.15(d,J＝12.2 Hz,2H),2.56(s,2H),1.94(s,2H),1.74(d,J＝8.9 Hz,2H).
MS m/z(ESI):548.2[M+1]
I-12
1 H NMR(400 MHz,DMSO-d 6 )δ9.44(s,1H),8.78(s,1H),8.48(d,J＝2.5 Hz,1H),8.35(d,J＝2.3 Hz,1H),7.93(d,J＝8.9 Hz,1H),7.85(d,J＝8.8 Hz,3H),7.02(d,J＝8.3 Hz,2H),6.93(d,J＝8.6 Hz,1H),6.85(d,J＝7.2 Hz,1H),3.92(s,3H),3.72(s,8H),3.48(s,3H).
MS m/z(ESI):547.2[M+1]
I-13
1 H NMR(400 MHz,DMSO-d 6 )δ9.50(s,1H),8.78(s,1H),8.56(d,J＝5.3 Hz,1H),8.45(d,J＝2.4 Hz,1H),7.94(s,1H),7.90(d,J＝7.6 Hz,2H),7.78(d,J＝5.3 Hz,1H),7.26(t,J＝8.0 Hz,1H),6.98(d,J＝8.9 Hz,1H),6.81(d,J＝7.6 Hz,2H),6.70(t,J＝2.0Hz,1H),3.75(s,3H),3.59(d,J＝37.7 Hz,8H),2.56(s,3H),1.36(d,J＝2.4 Hz,2H),1.25-1.20(m,2H).
MS m/z(ESI):570.2[M+1]
I-14
1 H NMR(400 MHz,DMSO-d 6 )δ8.89(s,1H),8.69(s,1H),8.37(d,J＝2.5 Hz,1H),7.81(dd,J＝8.8,2.5 Hz,1H),7.71(s,1H),7.64(d,J＝8.2 Hz,1H),6.99(d,J＝9.0 Hz,1H),6.62(s,1H),5.28(d,J＝5.7 Hz,1H),4.42–4.31(m,2H),4.27(d,J＝3.2 Hz,2H),3.98-3.76(m,3H),3.66(t,J＝4.8 Hz,1H),3.02(t,J＝12.4 Hz,2H),2.56(s,2H),2.09-1.91(m,1H),1.79(d,J＝12.6 Hz,2H),1.52(p,J＝13.6,13.2 Hz,2H),1.27(dd,J＝
13.6,6.7 Hz,1H),0.91(d,J＝6.9 Hz,3H),0.79(d,J＝6.8 Hz,3H).
MS m/z(ESI):501.2[M+1]
I-15
1 H NMR(400 MHz,DMSO-d 6 )δ8.91(s,1H),8.71(s,1H),8.41(d,J＝2.4 Hz,1H),8.34(d,J＝7.7 Hz,1H),7.84(dd,J＝8.8,2.5 Hz,1H),7.72(s,1H),7.46(d,J＝7.6 Hz,1H),7.40(dd,J＝14.2,5.8 Hz,2H),7.10(dd,J＝8.0,2.5 Hz,1H),7.04(d,J＝8.9 Hz,1H),6.64(s,1H),4.47(d,J＝13.2 Hz,2H),4.29(d,J＝3.3 Hz,2H),4.14(s,1H),3.88(t,J＝5.5 Hz,2H),3.82(s,3H),3.07(t,J＝12.6 Hz,2H),2.58(s,2H),1.98-1.82(m,2H),1.60(q,J＝12.0 Hz,2H).
MS m/z(ESI):535.2[M+1]
I-16
1 H NMR(400 MHz,DMSO-d 6 )δ8.91(s,1H),8.70(s,1H),8.40(d,J＝2.5 Hz,1H),7.86(dd,J＝8.8,2.4 Hz,1H),7.74(s,1H),6.93(d,J＝8.8 Hz,1H),6.63(s,1H),4.75(d,J＝32.4 Hz,2H),4.28(d,J＝3.2 Hz,2H),4.18(t,J＝11.9 Hz,2H),3.98(d,J＝6.4 Hz,1H),3.90-3.82(m,2H),3.12-2.88(m,2H),2.57(s,2H),1.83(dd,J＝57.4,28.5 Hz,6H),0.90(d,J＝7.0 Hz,6H).
MS m/z(ESI):513.2[M+1]
I-17
1 H NMR(400 MHz,DMSO-d 6 )δ9.52(d,J＝1.7 Hz,1H),8.79(s,1H),8.53(dd,J＝
28.9,3.9 Hz,2H),8.01–7.84(m,2H),7.79(d,J＝5.3 Hz,1H),7.04(d,J＝8.9 Hz,1H),4.79(d,J＝7.1 Hz,1H),4.13(t,J＝6.5 Hz,1H),3.77–3.53(m,8H),2.56(s,3H),1.91(q,J＝6.6 Hz,1H),0.89(dd,J＝22.5,6.6 Hz,6H).
MS m/z(ESI):496.2[M+1]
I-18
1 H NMR(400 MHz,DMSO-d 6 )δ9.53(d,J＝1.7 Hz,1H),8.80(s,1H),8.58(d,J＝5.3Hz,1H),8.50(d,J＝2.5 Hz,1H),8.00-7.89(m,3H),7.81(d,J＝5.3 Hz,1H),7.05(d,J＝8.8 Hz,1H),4.82(d,J＝7.0 Hz,1H),4.15(s,1H),3.67(dt,J＝28.8,8.5 Hz,7H),2.58(s,3H),1.65(dd,J＝50.6,12.3 Hz,7H),1.17(ddt,J＝35.9,23.9,12.2 Hz,2H).
MS m/z(ESI):536.2[M+1]
I-19
1 H NMR(400 MHz,DMSO-d 6 )δ9.51(s,1H),8.78(s,1H),8.55(d,J＝5.3 Hz,1H),8.44(d,J＝2.5 Hz,1H),7.97-7.82(m,3H),7.78(d,J＝5.3 Hz,1H),7.35(d,J＝4.4 Hz,4H),7.27(q,J＝4.3 Hz,1H),6.97(d,J＝8.9 Hz,1H),4.76(t,J＝5.4 Hz,1H),4.18(t,J＝6.9 Hz,1H),4.02(dt,J＝14.5,7.1 Hz,1H),3.78-3.38(m,8H),3.09(s,1H),2.56(s,3H).
MS m/z(ESI):544.2[M+1]
I-20
1H NMR(400 MHz,DMSO-d 6 )δ9.81(s,1H),8.87(d,J＝6.2 Hz,2H),8.60-8.47(m,1H),8.47-8.36(m,1H),8.12(s,1H),8.02(dd,J＝8.8,2.4 Hz,1H),7.94(t,J＝6.8 Hz,1H),7.80(d,J＝7.7 Hz,1H),7.44(t,J＝6.5 Hz,2H),7.14(d,J＝8.9 Hz,1H),4.46(s,2H),3.54(d,J＝62.9 Hz,8H),2.77(s,3H).
MS m/z(ESI):522.2[M+1]
I-21
1 H NMR(400 MHz,DMSO-d 6 )δ8.90(s,1H),8.69(s,1H),8.39(d,J＝2.4 Hz,1H),7.85(dd,J＝8.9,2.5 Hz,1H),7.73(s,1H),7.61-7.43(m,4H),6.92(d,J＝8.9 Hz,1H),6.62(s,1H),4.84(s,1H),4.32-4.07(m,5H),3.86(t,J＝5.5 Hz,2H),3.13(s,2H),2.56(s,2H),1.93(s,2H),1.75(s,2H).
MS m/z(ESI):517.2[M+1]
I-22
1 H NMR(400 MHz,DMSO-d 6 )δ8.90(s,1H),8.69(s,1H),8.39(d,J＝2.4 Hz,1H),7.89-7.78(m,2H),7.72(s,1H),6.91(d,J＝8.9 Hz,1H),6.62(s,1H),6.47(s,1H),6.31(dd,J＝6.9,1.8 Hz,1H),4.78(d,J＝5.8 Hz,1H),4.32-4.06(m,5H),3.86(t,J＝5.5 Hz,2H),3.47(s,3H),3.09(dd,J＝20.1,12.1 Hz,2H),2.56(s,2H),1.94(d,J＝9.7 Hz,2H),1.73(dd,J＝10.5,4.4 Hz,2H).
MS m/z(ESI):548.2[M+1]
I-23
1 H NMR(400 MHz,DMSO-d 6 )δ8.89(s,1H),8.68(s,1H),8.36(d,J＝2.4 Hz,1H),7.83(dd,J＝8.8,2.5 Hz,1H),7.72(s,1H),7.62(q,J＝7.5 Hz,5H),6.87(d,J＝8.9 Hz,1H),6.62(s,1H),4.85-4.76(m,1H),4.42(s,1H),4.30-4.18(m,3H),4.08(d,J＝12.5Hz,1H),3.86(t,J＝5.6 Hz,2H),3.00(d,J＝12.3 Hz,1H),2.59(d,J＝29.0 Hz,4H),1.85(s,1H),1.71(d,J＝9.1 Hz,3H).
MS m/z(ESI):567.2[M+1]
I-24
1 H NMR(400 MHz,DMSO-d 6 )δ8.89(s,1H),8.69(s,1H),8.39(d,J＝2.4 Hz,1H),7.85(dd,J＝8.6,2.4 Hz,1H),7.72(s,1H),7.41(t,J＝8.2 Hz,1H),7.16-7.04(m,3H),6.91(d,J＝8.9 Hz,1H),6.62(s,1H),4.83(s,1H),4.23(d,J＝34.3 Hz,5H),3.84(d,J＝16.4 Hz,4H),3.13(s,2H),2.70(s,3H),2.56(s,2H),1.93(s,2H),1.74(s,2H).MS m/z(ESI):547.2[M+1]
I-25
1 H NMR(400 MHz,DMSO-d 6 )δ9.43(s,1H),8.78(s,1H),8.46(s,1H),7.97-7.78(m,3H),7.03(s,1H),6.97-6.89(m,1H),6.87-6.81(m,1H),4.71(d,J＝22.1 Hz,2H),4.16(t,J＝12.8 Hz,2H),3.99(s,1H),3.48(s,3H),3.09-2.87(m,2H),1.96-1.46(m,10H),1.28-0.97(m,6H).
MS m/z(ESI):578.2[M+1]
I-26
1 H NMR(400 MHz,DMSO-d 6 )δ9.44(s,1H),8.79(s,1H),8.51-8.41(m,2H),7.92(d,J＝8.7 Hz,2H),7.85(d,J＝8.0 Hz,2H),7.03(s,1H),6.93(d,J＝8.7 Hz,2H),6.85(d,J＝7.2 Hz,1H),4.21(s,4H),3.93(s,3H),3.48(s,3H),3.16(d,J＝12.1 Hz,2H),1.94(s,2H),1.75(d,J＝9.0 Hz,2H).
MS m/z(ESI):573.2[M+1]
I-27
/>
1 H NMR(400 MHz,Chloroform-d)δ8.50(s,1H),8.37(d,J＝2.4 Hz,1H),8.27(s,1H),7.93(s,2H),7.76(dd,J＝8.8,2.4 Hz,1H),7.42(s,1H),6.75(d,J＝8.9 Hz,1H),6.31(s,1H),5.03(s,1H),4.65(s,1H),4.37(d,J＝3.6 Hz,2H),4.14(d,J＝45.4 Hz,2H),3.98(t,J＝5.5 Hz,2H),3.29(d,J＝12.0 Hz,2H),2.55(d,J＝5.2 Hz,2H),2.09-1.84(m,4H).MS m/z(ESI):507.2[M+1]
I-28
1 H NMR(400 MHz,Chloroform-d)δ8.47(s,1H),8.34(s,1H),8.25(s,1H),7.74(s,2H),7.65(s,1H),7.40(s,1H),7.24(d,J＝7.4 Hz,1H),6.72(s,1H),6.35-6.16(m,1H),4.35(s,2H),4.14(s,2H),3.96(s,2H),3.31(s,2H),2.54(s,2H),1.99(d,J＝46.3 Hz,4H),1.24(s,2H).
MS m/z(ESI):507.2[M+1]
I-29
1 H NMR(400 MHz,Chloroform-d)δ8.88(s,1H),8.68(d,J＝5.3 Hz,1H),8.41(d,J＝18.9 Hz,2H),7.83(t,J＝8.6 Hz,1H),7.58(s,1H),7.47(d,J＝18.0 Hz,2H),6.78(dd,J＝16.5,8.9 Hz,1H),5.05(s,0.5H),4.88(s,0.5H),4.32(q,J＝12.5 Hz,2H),4.21-4.02(m,2H),3.37-3.07(m,2H),2.74(s,3H),2.10-1.13(m,15H).
MS m/z(ESI):562.2[M+1]
I-30
1 H NMR(400 MHz,Chloroform-d)δ8.87(s,1H),8.68(d,J＝5.3 Hz,1H),8.45(s,2H),8.38(s,1H),7.84(t,J＝8.1 Hz,2H),7.58(s,1H),7.50-7.38(m,2H),6.82(dd,J＝24.4,8.7 Hz,2H),5.03(s,1H),4.40(s,1H),4.18(s,2H),4.03(s,3H),3.32(s,2H),2.72(s,3H),2.13-1.85(m,4H).
MS m/z(ESI):557.2[M+1]
I-31
1 H NMR(400 MHz,Chloroform-d)δ8.84(d,J＝1.6 Hz,1H),8.65(d,J＝5.3 Hz,1H),8.42(d,J＝2.5 Hz,1H),8.36(s,1H),7.80(dd,J＝8.8,2.6 Hz,1H),7.56(d,J＝1.6 Hz,1H),7.44(d,J＝1.8 Hz,1H),7.38(dd,J＝5.2,1.8 Hz,1H),6.75(d,J＝8.9 Hz,1H),4.40(d,J＝6.7 Hz,1H),4.31-4.26(m,1H),4.11-3.93(m,2H),3.72-3.47(m,4H),3.37(s,3H),3.32(dd,J＝11.9,2.4 Hz,1H),3.22(dd,J＝12.0,2.4 Hz,1H),2.69(s,3H),1.99(tdd,J＝21.1,9.7,4.4 Hz,4H),1.84(t,J＝8.9 Hz,2H).
MS m/z(ESI):549.2[M+1]
I-32
1 H NMR(400 MHz,Chloroform-d)δ8.53(d,J＝1.6 Hz,1H),8.40(d,J＝2.5 Hz,1H),8.30(s,1H),7.80(dd,J＝8.9,2.5 Hz,1H),7.46(d,J＝1.6 Hz,1H),7.23(t,J＝7.8 Hz,1H),6.90-6.78(m,3H),6.65(d,J＝8.8 Hz,1H),6.35(p,J＝1.6 Hz,1H),4.67(d,J＝5.9 Hz,1H),4.54(s,1H),4.41(q,J＝2.8 Hz,2H),4.22-4.14(m,1H),4.02(t,J＝5.4 Hz,2H),3.84(s,2H),3.77(s,3H),3.68(d,J＝11.3 Hz,1H),3.55(d,J＝6.8 Hz,2H),2.80(p,J＝7.0 Hz,1H),2.58(dt,J＝7.0,3.7 Hz,2H),1.71(d,J＝8.8 Hz,1H).
MS m/z(ESI):547.2[M+1]
I-33
1 H NMR(400 MHz,Chloroform-d)δ8.78(d,J＝1.6 Hz,1H),8.41-8.34(m,2H),8.13(d,J＝2.3 Hz,1H),7.75(dd,J＝8.9,2.6 Hz,1H),7.51-7.41(m,2H),6.87(d,J＝2.1Hz,1H),6.79(d,J＝8.5 Hz,1H),6.70(d,J＝8.8 Hz,1H),6.44(dd,J＝7.1,2.1 Hz,1H),3.97(s,5H),3.64(s,5H),3.38(s,2H),2.13-2.03(m,2H),1.86-1.67(m,2H).MS m/z(ESI):556.2[M+1]
I-34
1 H NMR(400 MHz,Chloroform-d)δ8.52(d,J＝1.5 Hz,1H),8.38(d,J＝2.5 Hz,1H),8.29(s,1H),7.81(d,J＝8.8 Hz,1H),7.44(d,J＝1.5 Hz,1H),7.35(t,J＝7.9 Hz,1H),7.25-7.20(m,2H),7.08-6.99(m,1H),6.70(d,J＝9.1 Hz,1H),6.34(s,1H),4.78(s,2H),4.40(q,J＝2.8 Hz,2H),4.01(t,J＝5.5 Hz,2H),3.86(s,3H),3.76(s,4H),2.96(q,J＝7.1 Hz,1H),2.57(s,2H),1.80(d,J＝8.8 Hz,1H).
MS m/z(ESI):533.2[M+1]
I-35
1 H NMR(400 MHz,Chloroform-d)δ8.52(s,1H),8.38(d,J＝2.2 Hz,1H),8.29(s,1H),7.80(s,0H),7.66(d,J＝8.7 Hz,2H),7.44(s,1H),6.94(d,J＝8.6 Hz,2H),6.70(s,1H),6.33(s,1H),4.77(d,J＝6.2 Hz,2H),4.40(q,J＝2.7 Hz,2H),4.01(t,J＝5.4 Hz,2H),3.88(s,3H),3.73(d,J＝27.9 Hz,4H),2.95(d,J＝7.7 Hz,1H),2.57(s,2H),1.78(d,J＝8.8 Hz,1H).
MS m/z(ESI):533.2[M+1]
I-36
1 H NMR(400 MHz,Chloroform-d)δ8.55-8.49(m,2H),8.38(d,J＝2.5 Hz,1H),8.29(s,1H),7.92(dd,J＝8.6,2.4 Hz,1H),7.81(d,J＝8.7 Hz,1H),7.44(d,J＝1.6 Hz,1H),6.80(dd,J＝8.6,0.7Hz,1H),6.70(d,J＝9.0Hz,1H),6.34(s,1H),4.79(d,J＝6.2Hz,2H),4.40(q,J＝2.8Hz,2H),4.01(s,5H),3.81(d,J＝15.1Hz,4H),2.98(q,J＝7.2Hz,1H),2.57(d,J＝1.8Hz,2H),1.81(d,J＝8.9Hz,1H).
MS m/z(ESI):534.2[M+1]
Example 37
Preparation of Compound I-37
4- (6- (8- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazole [1,5-a ] pyridine-3-carbonitrile
In a 100mL single vial was added 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (8-i) (100 mg,0.24 mmol), 5- (chloromethyl) -2-methoxypyridine 1-m (55.8 mg,0.35 mmol), potassium carbonate (65.3 mg,0.47 mmol) and 10mL acetonitrile, and reacted at 60℃overnight. After the reaction was completed, the reaction mixture was poured into water (100 mL), extracted three times with dichloromethane (30 ml×3), the organic phases were combined, the organic phases were washed with water (30 ml×3), saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by column chromatography on silica gel (dichloromethane: methanol=30:1) to give the product 4- (6- (8- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (I-37) 67mg, yield: 52.1%.
1 H NMR(400MHz,Chloroform-d)δ8.80(d,J＝1.6Hz,1H),8.47(d,J＝2.4Hz,1H),8.37(s,1H),8.14(s,1H),7.84(dd,J＝8.9,2.4Hz,1H),7.72(s,1H),7.52(d,J＝1.7Hz,1H),7.47(d,J＝7.1Hz,1H),6.89(d,J＝2.1Hz,1H),6.74(dd,J＝8.6,5.9Hz,2H),6.45(dd,J＝7.0,2.1Hz,1H),3.91(d,J＝27.9Hz,7H),3.64(s,6H),2.79(s,1H)1.52(m,2H).
MS m/z(ESI):545.2[M+1]
Examples 38 to 40
Preparation of Compounds I-38 to I-40
Reference compound I-37 was prepared by reacting 3I, 5I, and 9I with the appropriate halide, respectively, to give compound I-38, compound I-39, and compound I-40, the structure and characterization data of which are as follows:
I-38
1 H NMR(400MHz,Chloroform-d)δ8.83(d,J＝1.6Hz,1H),8.65(d,J＝5.2Hz,1H),8.41(d,J＝2.5Hz,1H),8.35(s,1H),8.10(d,J＝2.3Hz,1H),7.78(dd,J＝8.8,2.6Hz,1H),7.64(dd,J＝8.5,2.4Hz,1H),7.55(d,J＝1.6Hz,1H),7.42(d,J＝1.7Hz,1H),7.36(dd,J＝5.3,1.8Hz,1H),6.78(dd,J＝12.0,8.6Hz,2H),3.96(s,3H),3.68(t,J＝5.1Hz,4H),3.52(s,2H),2.68(s,3H),2.58(t,J＝5.1Hz,4H).
MS m/z(ESI):517.2[M+1]
I-39
1 H NMR(400MHz,Chloroform-d)δ8.51(d,J＝1.5Hz,1H),8.37–8.34(m,1H),8.29(s,1H),7.75(dd,J＝8.8,2.6Hz,1H),7.51(s,1H),7.43(d,J＝1.6Hz,1H),6.70(d,J＝8.8Hz,1H),6.33(d,J＝3.4Hz,1H),4.40(q,J＝2.8Hz,2H),4.06–3.88(m,6H),3.72–3.29(m,3H),2.57(d,J＝6.2Hz,2H),2.10(s,2H),1.79(d,J＝70.8Hz,6H).
MS m/z(ESI):507.2[M+1]
I-40
1H NMR(400MHz,Chloroform-d)δ8.78(d,J＝1.6Hz,0H),8.41–8.36(m,0H),8.36(s,0H),8.13(d,J＝2.3Hz,0H),7.84–7.78(m,1H),7.75(dd,J＝8.9,2.6Hz,0H),7.51–7.40(m,1H),6.87(d,J＝2.1Hz,0H),6.79(d,J＝8.5Hz,0H),6.70(d,J＝8.8Hz,0H),6.44(dd,J＝7.1,2.1Hz,0H),3.64(s,1H),3.60(s,1H),3.38(s,1H),3.26(s,1H),2.15–2.01(m,1H),1.82(d,J＝8.1Hz,1H).
biological evaluation
Test example 1 measurement of RET kinase Activity by the Compounds of the invention
The method uses Cisbio companyKinEASE-TK tyrosine kinase kit (cat. No. 62TK0 PEB) for determining the degree of phosphorylation of a biotinylated polypeptide substrateThe time-resolved fluorescence energy resonance transfer method (TR-FRET) was used for the measurement. Human RET protein (RET kinase) was purchased from Carna bioscience (Japan, cat. No. 08-159-5. Mu.g).
The experimental procedure was as follows:
(1) Test compounds were dissolved in 100% DMSO to a final concentration of 10mM.
(2) The test compound solution prepared in step (1) was dissolved in 46uL of 100% DMSO, and the solution obtained in this step was designated as No. 2.
(3) The solution No. 2 was subjected to subsequent gradient dilutions at 5-fold (i.e., 20 μl of 100% DMSO plus 5 μl of compound) for a total of 9 gradients, numbered 3 to 11.
Note that: no. 2 is not used for the dilution in step (4).
(unless otherwise specified, the following steps are all required to be performed on ice)
(4) The solutions 3 to 11 were further subjected to a gradient dilution with the buffer provided in the kit (Cisbio, cat. No. 62TK0 PEB) at a dilution factor of 20 (i.e.19. Mu.L buffer was added to 1. Mu.L solution 3 to 11), numbered 12-20, respectively. At this time, the final concentration of the test compound in the system No. 12-20 was 3200nM to 0.008nM (9 gradients), and the final concentration of DMSO was 2%.
(5) Adding the 9 compound solutions to be tested with gradient concentration in the step (4) into 384-well plates according to the concentration, wherein each well is 4 mu L, and two compound wells are arranged.
(6) mu.L of human RET protein was added to each well, and incubated on ice for 10 minutes.
(7) The phosphorylation reaction was initiated by adding 2. Mu.L of ATP (Sigma #A7699) and 2. Mu.L of biotinylated polypeptide substrate (Cisbio, cat. No. 62TK0 PEB) per well. Incubate at 37℃for half an hour.
(8) mu.L of an anti-phosphotyrosine antibody conjugated with europium-based element compound (supplied in the kit under the trade name 62TK0 PEB) and 5. Mu.L of streptavidin conjugated with modified allophycocyanin XL665 (Cisbio under the trade name 62TK0 PEB) were added to each well.
(9) Incubation was continued for 1 hour at room temperature. After the incubation, the TF-FRET pattern of the microplate reader (BMG Labtech, model: FLUOStar Omega) was used to measure the fluorescence intensity of each well at excitation wavelength of 304nM, and the ratio was automatically calculated by reading the fluorescence intensity of each well at emission wavelengths of 615nM and 665 nM.
(10) Calculating the inhibition rate of the compound at each concentration by comparing with the fluorescence intensity ratio of the control group, and further calculating the IC of the compound by performing curve fitting on the inhibition rate by using the GraphPad Prism5 at logarithmic concentration 50 The values are given in Table 1 below.
The control kinase selected is another receptor tyrosine kinase KDR which is similar to RET kinase in structure. Purchased from Carna bioscience (Japan, cat. No. 08-191-5. Mu.g). The gradient dilution step is the same as RET kinase, so that the final concentration range of the compound to be tested in a reaction system is 16000 nM-0.04 nM, and other reaction conditions (the gradient dilution of the compound to be tested in the step 4) are the same as above, and the final concentration of DMSO is 2%. IC for inhibiting KDR kinase by test compound 50 Value calculation method and RET kinase inhibition IC 50 The value calculation method is the same.
TABLE 1 IC of compounds for RET kinase and KDR kinase inhibition 50 Value of
Remarks:
the structure of LOXO292 is shown below and is prepared as described in example 163 of WO 2018071447.
From the above table, it can be seen that the compounds of the present invention have a significant inhibitory effect on RET kinase activity. The inhibiting activity of the compound of the invention on RET kinase is better than that on KDR kinase. The compounds of the invention are therefore useful as a class of potent and selective RET kinase inhibitors.
Test example 2 measurement of hERG inhibition by the Compounds of the invention
TABLE 2
Abbreviations (abbreviations) Full scale
CHO Chinese hamster ovary cells
DMSO Dimethyl sulfoxide
ECG Electrocardiogram
EGTA Ethylene glycol bis (2-aminoethyl ether) -N, N, N ', N' -tetraacetic acid
FBS Fetal bovine serum
HEPES N- (2-hydroxyethyl) piperazine-N' - (2-ethanesulfonic acid)
hERG Human ether-a-go-go-related gene
QT Time between Q wave and T wave in Electrocardiogram (ECG)
2.1 cell culture
2.1.1 cells used in this assay were CHO cell lines transfected with hERG cDNA and stably expressing the hERG channel (supplied by Denmark Sophion Bioscience company) in cell numbers P13-P14. Cells were cultured in medium containing the following ingredients (all from Invitrogen): ham's F medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/ml hygromycin B,100 μg/ml Geneticin.
2.1.2CHO hERG cells were grown in dishes containing the above medium and cultured at 37℃in an incubator containing 5% CO 2. 24 to 48 hours prior to electrophysiological experiments, CHO hERG cells were transferred to round glass plates placed in petri dishes and grown in the same culture broth and culture conditions as above. The density of CHO hERG cells on each circular slide needs to be such that the vast majority of cells are independent, single.
2.2 Experimental solutions
The following solutions (recommended by Sophion) were used for electrophysiological recording.
TABLE 3 composition of intracellular and extracellular fluids
TABLE 4 detailed information on reagents
Reagent name Goods number Lot number Molecular weight Suppliers (suppliers)
NaCl S1679-1KG WXBC1368V 58.44 Sigma
KCl 31248-100G WXBC2571V 74.55 Sigma
CaCl2(1M solution) 21114-1L BCBM6063V 110.98 Sigma
MgCl2·6H2O M7304-100G V900020-500G 203.30 Sigma
HEPES H3375-1KG SLBP2246V 238.30 Sigma
Glucose G8270-1KG WXBC2393V 180.16 Sigma
EGTA 03777-50G SLBP2807V 380.15 Sigma
Na2-ATP A-7699-5G SLBJ8915V 551.14 Sigma
NaOH(2M solution) 35254-1L BCBG6297V 40.00 Sigma
KOH 232041-50G SLBK9251V 149.91 Sigma
2.3 electrophysiology recording System
The experiment used a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, available from HEKA Electronics, germany) for whole cell current recording. The round slide with CHO hERG cells grown on the surface was placed in an electrophysiological recording well under an inverted microscope. Continuous perfusion (approximately 1 ml per minute) with extracellular fluid was recorded in the tank. The experimental process adopts a conventional whole-cell patch clamp current recording technology. Experiments were performed at conventional room temperature (25 ℃.+ -. 2 ℃), unless otherwise indicated. The cells were clamped at a voltage of-80 mV. The cell clamp voltage depolarized to +20mV to activate the hERG potassium channel, and after 5 seconds again clamped to-50 mV to eliminate inactivation and generate tail current. The tail current peak is used as a value for hERG current magnitude. After the hERG potassium current recorded in the steps is stable under the continuous extracellular fluid perfusion in the recording groove, the medicine to be tested can be subjected to the perfusion in a superimposed mode until the inhibition effect of the medicine on the hERG current reaches a stable state. The most recent coincidence of 3 consecutive current traces is generally used as a criterion for determining whether or not a steady state is present. After reaching the stable state, the extracellular fluid is irrigated and washed until the hERG current returns to the size before the drug is added. One cell may be tested for one or more drugs, or for multiple concentrations of the same drug, but with an extracellular fluid wash between different drugs. Cisapride (Cisapride, available from Sigma) was used in the experiment as a positive control to ensure that the quality of the cells used was normal.
2.4 Compound treatment and dilution
To obtain the IC50 of the compounds, we selected the following concentrations (30,10,3,1,0.3 and 0.1 μm) for testing. Prior to the assay, the stock solutions were diluted in a gradient dilution with DMSO (Cat#: V900090-500ML, lot#, WXBC 66818V, sigma) to 10,3,1,0.3 and 0.1mM, and the extracellular solution was diluted to the final 0.1. Mu.M test concentration. The final concentration of DMSO in each concentration of compound solution was 0.1. Mu.M, and the test concentration of the positive control Cisapride was 0.1. Mu.M. All compound solutions were subjected to conventional 5 to 10 minute sonication and shaking to ensure complete dissolution of the compound.
2.5 data analysis
The test data were analyzed by data analysis software provided by HEKA Patchmaster (V2x73.2), microsoft Excel, and Graphpad Prism 5.0.
2.6 quality control
The test data in the report need to meet the following criteria:
recording parameters
Membrane resistance Rm >500MΩ
Access resistance (Ra) <10mΩ
Tail current amplitude >300pA
Current rundown (spontaneous reduction) per minute <2%
Leakage current <200pA or 10% of hERG current peak (within 90% of recording time)
Pharmacological parameters
Cisapride (C4740-10 mg, sigma) at 0.1. Mu.M blocked hERG current by more than 50% as a positive control.
Table 5 hERG inhibition by the compounds of the invention.
As can be seen from the above table, the compounds of the present invention have a percent of hERG blocking of less than fifty percent at a concentration of 10 μm, and the control LOXO-292 compound has a much greater percent of hERG blocking than fifty percent under the same conditions, and the compounds of the present invention have good hERG safety. The compounds of the invention are therefore useful as a class of safe RET kinase inhibitors.
In conclusion, the compound has remarkable inhibition effect on RET kinase activity, good RET/KDR selectivity and good hERG safety, so that the compound can be used as a selective transfection period Rearrangement (RET) kinase inhibitor and can solve the unmet medical needs.

Claims (14)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 CH;
X 2 is N;
l is selected from:
wherein the two end points of L are optionally linked with A and R 2 Is connected with each other;
a is selected from 4-6 membered monocyclic heterocyclic group or 7-11 membered bridged heterocyclic group, wherein the monocyclic heterocyclic group and bridged heterocyclic group are optionally further selected from C by one or more 1 -C 3 Alkyl, hydroxyalkyl, halo C 1 -C 3 Alkyl, hydroxy, C 3 -C 6 Cycloalkyl or = O;
R 1 Selected from: 3-to 6-membered heterocyclyl or 6-membered heteroaryl, wherein said heterocyclyl is optionally further substituted with one or more groups selected from hydroxy, hydroxyalkyl, amino, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Substituted with alkoxy; the heteroaryl group is optionally further substituted with one or more groups selected from halogen, hydroxy, amino, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkoxy or = O;
R 2 selected from C 1 -C 6 Alkyl, 6-membered aryl or 5-to 6-membered heteroaryl, wherein said alkyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from halogen, hydroxy, cyano, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkoxy or = O.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said halo C 1 -C 3 Alkyl or halo C 1 -C 3 Alkoxy groups are each independently 1 to 3 fluoro C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein a is selected from:
wherein: the 1 and 2 endpoints are optionally connected with L.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from:
5. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C 1 -C 6 Alkyl, phenyl, 5-6 membered heteroaryl, wherein said phenyl, 5-6 membered heteroaryl is optionally further substituted with one or more groups selected from cyano, halogen, hydroxy, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkyl, halogenated C 1 -C 3 Alkoxy or = O.
6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:
7. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
8. a process for preparing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which process comprises:
method 1:
reacting the compound (IA) with the compound (IB) under alkaline conditions in the presence of a condensing agent to obtain a compound of formula (I);
wherein:
the condensation reagent is selected from 2- (7-benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, 1-hydroxy-7-azobenzotriazole, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, pentafluorophenyl diphenyl phosphate, benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinyl phosphate;
The reagent for providing the alkaline condition is an organic base, and the organic base is selected from N, N-diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine and 4-dimethylaminopyridine;
A、L、X 1 、X 2 、R 1 and R is 2 Is defined as in claim 1; or alternatively
Method 2:
reacting compound (IA) with compound (IB) under basic conditions to obtain a compound of formula (I);
wherein:
the reagent for providing alkaline conditions is an inorganic base, wherein the inorganic base is selected from the group consisting of potassium phosphate, potassium phosphate trihydrate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and potassium hydride;
g is selected from leaving groups;
A、L、X 1 、X 2 、R 1 and R is 2 Is defined as in claim 1.
9. The method according to claim 8, wherein:
the condensing agent in method 1 is selected from 2- (7-azobenzotriazole) -N, N '-tetramethylurea hexafluorophosphate, 2- (7-oxybenzotriazole) -N, N' -tetramethylurea hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine; or alternatively
The organic base in the method 1 is selected from N, N-diisopropylethylamine or triethylamine; or alternatively
The inorganic base in the method 2 is selected from sodium carbonate or potassium carbonate; or alternatively
In method 2, G is halogen.
10. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
11. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the preparation of a rearrangement kinase inhibitor during transfection.
12. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for the treatment of a disease driven by rearrangement of genes during transfection.
13. The use according to claim 12, wherein the disease is cancer.
14. The use of claim 13, wherein the cancer is lung cancer, thyroid cancer, colon cancer, breast cancer or pancreatic cancer.
CN201911099537.7A 2019-11-12 2019-11-12 Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine Active CN112851664B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201911099537.7A CN112851664B (en) 2019-11-12 2019-11-12 Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine
PCT/CN2020/127742 WO2021093720A1 (en) 2019-11-12 2020-11-10 Pyrazole[1,5-a]pyridine-3-nitrile compound and pharmaceutical use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911099537.7A CN112851664B (en) 2019-11-12 2019-11-12 Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine

Publications (2)

Publication Number Publication Date
CN112851664A CN112851664A (en) 2021-05-28
CN112851664B true CN112851664B (en) 2024-03-29

Family

ID=75911783

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911099537.7A Active CN112851664B (en) 2019-11-12 2019-11-12 Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine

Country Status (2)

Country Link
CN (1) CN112851664B (en)
WO (1) WO2021093720A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4201936A4 (en) * 2020-08-20 2024-02-21 Jiangsu Chia Tai Fenghai Pharmaceutical Co Ltd Heteroaromatic ring compound as ret kinase inhibitor, and preparation and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827073A (en) * 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 Therapeutically active compositions and application methods thereof
CN108349969A (en) * 2015-07-16 2018-07-31 阵列生物制药公司 Substituted pyrazolo [1,5-a] pyridine compounds as RET kinase inhibitors
CN110267960A (en) * 2017-01-18 2019-09-20 阿雷生物药品公司 Substituted pyrazolo [1,5-a] pyrazine compound as RET kinase inhibitor
CN110382494A (en) * 2016-10-10 2019-10-25 阿雷生物药品公司 Pyrazolo [1,5-A] pyridine compounds being substituted are as RET kinase inhibitor

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020064009A1 (en) * 2018-09-30 2020-04-02 北京志健金瑞生物医药科技有限公司 Substituted pyrazole fused ring derivative, preparation method therefor, and application thereof
EP3878852A4 (en) * 2018-12-06 2021-12-15 Shenzhen TargetRx, Inc. Substituted pyrazolo[1,5-a]pyridine compound, composition containing the same and use thereof
WO2020114487A1 (en) * 2018-12-07 2020-06-11 Sunshine Lake Pharma Co., Ltd. Ret inhibitors, pharmaceutical compositions and uses thereof
CN111635400A (en) * 2019-03-02 2020-09-08 察略盛医药科技(上海)有限公司 Pyrazolo [1,5-a ] pyridine derivative, and preparation method and application thereof
EP3950685A4 (en) * 2019-04-03 2022-12-14 Guangzhou Baiyunshan Pharmaceutical Holdings Co., Ltd. Baiyunshan Pharmaceutical General Factory Pyrazolopyridine compound as ret inhibitor and application thereof
WO2020228756A1 (en) * 2019-05-14 2020-11-19 上海翰森生物医药科技有限公司 Inhibitor containing bicyclic derivative, preparation method therefor and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827073A (en) * 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 Therapeutically active compositions and application methods thereof
CN108349969A (en) * 2015-07-16 2018-07-31 阵列生物制药公司 Substituted pyrazolo [1,5-a] pyridine compounds as RET kinase inhibitors
CN110382494A (en) * 2016-10-10 2019-10-25 阿雷生物药品公司 Pyrazolo [1,5-A] pyridine compounds being substituted are as RET kinase inhibitor
CN110267960A (en) * 2017-01-18 2019-09-20 阿雷生物药品公司 Substituted pyrazolo [1,5-a] pyrazine compound as RET kinase inhibitor

Also Published As

Publication number Publication date
WO2021093720A1 (en) 2021-05-20
CN112851664A (en) 2021-05-28

Similar Documents

Publication Publication Date Title
JP6726677B2 (en) Substituted 2-H-pyrazole derivatives as anticancer agents
AU2023202086A1 (en) Antagonists of the muscarinic acetylcholine receptor M4
CN107614499B (en) Pyrido [3,4-d ] pyrimidine derivatives and pharmaceutically acceptable salts thereof
CA3047580A1 (en) Compounds and methods for cdk8 modulation and indications therefor
AU2019233183B2 (en) Phthalazine isoxazole alkoxy derivatives, preparation method thereof, pharmaceutical composition and use thereof
CA2809557A1 (en) Pyrazolopyridines as inhibitors of the kinase lrrk2
KR102513448B1 (en) CDK4/6 inhibitor
CA3204823A1 (en) Prmts inhibitors
CN110062758A (en) Two ring dihydro-pyrimidins-carboxamides derivatives as RHO- kinase inhibitor
CA2742320A1 (en) Pyrido[4,3-b]indoles containing rigid moieties
TW200821309A (en) Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
CN113631557B (en) JAK kinase inhibitor, preparation method thereof and application thereof in medicine field
TW202216686A (en) Degradation of (egfr) by conjugation of egfr inhibitors with e3 ligase ligand and methods of use
JP7030776B2 (en) Use as aminopyridine derivatives and their selective ALK-2 inhibitors
BR112021015012A2 (en) COMPOUNDS, PHARMACEUTICAL COMPOSITION, METHOD OF MODULATION OF TLR7, AND METHOD OF TREATMENT OF A DISEASE OR DISORDER IN A PATIENT
CA3072081A1 (en) Antagonists of the muscarinic acetylcholine receptor m4
CN114787161A (en) Pyrazolo [1,5-a ] pyridine compound and preparation method and application thereof
CN116546985A (en) Pyridopyrimidine derivative and preparation method and application thereof
US20230136194A1 (en) Triazolopyridazine derivative, preparation method therefor, pharmaceutical composition thereof, and use thereof
CN113365996A (en) Imidazopyridine derivative compounds and uses thereof
CN112851664B (en) Pyrazolo [1,5-a ] pyridine-3-nitrile compound and application thereof in medicine
TW202016116A (en) Pyrazolotriazolopyrimidine derivatives as a2a receptor antagonist
JP6816287B2 (en) Pyridine and 5-membered aromatic ring compounds, their production methods and uses
CN111499613B (en) N-carboxamide derivatives, method for the production thereof and their use in medicine
CN111836819A (en) Arylamine-substituted pyrrolopyrimidine compound, and preparation method and application 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
GR01 Patent grant
GR01 Patent grant