CN116854678A - RIPK1 inhibitors - Google Patents

RIPK1 inhibitors Download PDF

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CN116854678A
CN116854678A CN202310828345.5A CN202310828345A CN116854678A CN 116854678 A CN116854678 A CN 116854678A CN 202310828345 A CN202310828345 A CN 202310828345A CN 116854678 A CN116854678 A CN 116854678A
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compound
pharmaceutically acceptable
acceptable salts
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compounds
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CN116854678B (en
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朱伟波
曹惠芳
石谷沁
马慧敏
覃华
付家胜
孙大庆
陈波
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

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Abstract

The present invention provides a novel class of compounds having RIPK1 inhibitory activity represented by formula (I'), pharmaceutical compositions containing said compounds, useful intermediates for preparing said compounds and methods of treating cell inflammatory diseases, neurodegenerative diseases, cancer and the like using the compounds of the present invention.

Description

RIPK1 inhibitors
Technical Field
The present invention belongs to the field of pharmaceutical chemistry, and relates to novel compounds having RIPK1 inhibitory activity, pharmaceutical compositions containing said compounds, useful intermediates for preparing said compounds, and methods of treating cell inflammatory diseases, neurodegenerative diseases, cancer and the like using the compounds of the present invention.
Background
Cell necrosis apoptosis (Necroptosis) is a signaling pathway regulating cell necrosis, which is mediated by RIPK1 kinase and its downstream regulatory factors. RIPK1 (receptor-interacting serine/threonine protein kinase 1), an important regulatory molecule in cell survival, inflammation and disease, is involved in innate immune signals and can mediate necrotic apoptosis of cells. The RIPK1 protein contains three domains: an N-terminal kinase domain, an intermediate domain RHIM (cognate interaction motif), a C-terminal death domain. More and more studies confirm that the kinase activity of RIPK1 is involved in necrotic apoptosis of cells. When the cell casepase 8 is inhibited, the presence of TNF- α activates TNF-R1-RIPK1/RIPK3-MIKL related signaling pathways. In this process, TNF- α mediates RIPK1 kinase activation, and activated RIPK1 binds through its RHIM domain to the RHIM domain of downstream RIPK3, thereby recruiting mixed-lineage kinase domain-like proteins (MLKL), leading to necrotic apoptosis, mediating release of intracellular inflammatory cytokines.
RIPK1 mediated apoptosis signaling pathway is closely related to many chronic diseases in humans. Including neurodegenerative diseases, inflammation, hematological and solid organ malignancies, bacterial and viral infections, lysosomal storage disorders, and the like. The use of RIP3 knockout mice (RIPK 1 mediated programmed necrosis is completely blocked) and Necrostatin-1, a tool inhibitor of RIPK1 kinase activity with poor oral bioavailability, has been shown to correlate with inflammatory conditions. RIP3 knockout mice have been shown to have protective effects against inflammatory bowel disease (including ulcerative colitis and crohn's disease), retinal detachment-induced photoreceptor necrosis, retinitis pigmentosa, bombesin-induced acute pancreatitis and sepsis/systemic inflammatory response syndrome. The use of Necrostatin-1 is effective in alleviating ischemic brain injury, retinal ischemia/reperfusion injury, huntington's disease, renal ischemia reperfusion injury, cisplatin-induced kidney injury and traumatic brain injury.
An effective, selective, small molecule inhibitor of RIPK1 kinase activity is capable of blocking RIPK 1-dependent apoptosis and thereby providing therapeutic effects for diseases or events associated with DAMP, cell death and/or inflammation.
Disclosure of Invention
The present invention provides compounds of formula (I') and pharmaceutically acceptable salts thereof:
wherein X is 1 、X 2 Each independently is CR d Or N;
R a 、R b independently is hydrogen, C 1-4 Alkyl orAnd R is a And R is b Are not hydrogen at the same time;
R d is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogen atom,Or R d And R is b Linking to form a 5-6 membered heterocycloalkyl fused with aryl;
ring Q is a 5-6 membered heterocyclyl;
R a1 、R a2 、R a3 each independently is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogen atom, hydroxy, 5-6 membered heterocycloalkyl; or R is a1 、R a2 、R a3 Any two groups and their carbon together provide C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; wherein the heteroatom in the 5-6 membered heterocycloalkyl is O or N, and the heteroatom in the 3-6 membered heterocycloalkyl is O;
R c is unsubstituted or substituted by 1-3R e Substituted 5-6 membered aryl;
R e is a halogen atom.
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by R a Is that
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by R a Is that
In some embodiments of the invention, the compounds of formula (I') above andpharmaceutically acceptable salts thereof, R b Is that
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by the structureSelected from->
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized in that ring Q is selected from the group consisting of
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by R c Is that
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by R d is-F, -CF 3 、-CH 3 。
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by R e is-F.
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by R a1 、R a2 、R a3 Each independently is hydroxy, methyl,Methoxy group.
In some embodiments of the present invention, the compounds of formula (I') above and pharmaceutically acceptable salts thereof, are characterized by R a1 、R a2 、R a3 Any two groups and their carbon together provide C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, structural unitsSelected from->
In some embodiments of the present invention, the compound of formula (I') and pharmaceutically acceptable salts thereof, as described above, are characterized in that the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
Wherein X is 1 、X 2 、R a 、R b 、R c As defined above.
In some embodiments of the present invention, the compound of formula (I') and pharmaceutically acceptable salts thereof, as described above, are characterized in that the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
wherein X is 2 、R a 、R b 、R c As defined above.
In some embodiments of the present invention, the compound of formula (I') and pharmaceutically acceptable salts thereof, as described above, are characterized in that the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
wherein R is a 、R b 、R c As defined above.
In some embodiments of the present invention, the compound of formula (I') and pharmaceutically acceptable salts thereof, as described above, are characterized in that the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
wherein R is a 、R b 、R c As defined above.
The invention also provides compounds and pharmaceutically acceptable salts thereof,
the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.
"pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifying agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art according to a number of factors. Including but not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the therapeutic indication of interest. Pharmaceutically acceptable carriers include both aqueous and nonaqueous media and a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients included in the formulation for a variety of reasons (e.g., stabilizing the active agent, adhesive, etc.) are well known to those of ordinary skill in the art.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines for treating RIPK1 mediated diseases, wherein the RIPK1 mediated related diseases comprise cell inflammatory diseases, neurodegenerative diseases and cancers.
The invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the treatment of RIPK1 mediated diseases. Related diseases mediated by RIPK1 include cell inflammatory diseases, neurodegenerative diseases and cancers.
Technical effects
The compound has obvious RIPK1 enzyme inhibition activity and can be used for treating cell inflammatory diseases, neurodegenerative diseases and cancers.
Description and definition of the invention
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present invention prepared with relatively non-toxic acids or bases. These salts may be prepared during synthesis, isolation, purification of the compound, or the purified compound may be used alone in free form to react with a suitable acid or base. When the compound contains relatively acidic functional groups, reaction with alkali metal, alkaline earth metal hydroxides or organic amines gives base addition salts, including salts based on alkali metal and alkaline earth metal cations and non-toxic ammonium, quaternary ammonium and amine cations, as well as amino acid salts and the like. When the compound contains a relatively basic functional group, it is reacted with an organic acid or an inorganic acid to give an acid addition salt.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of the present invention exist as geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic and other mixtures thereof, all of which are within the scope of the present invention.
The term "enantiomer" refers to stereoisomers that are mirror images of each other.
The term "diastereoisomer" refers to a stereoisomer of a molecule having two or more chiral centers and having a non-mirror image relationship between the molecules.
The term "cis-trans isomer" refers to a configuration in which a double bond or a single bond of a ring-forming carbon atom in a molecule cannot rotate freely.
Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute configuration of a solid centre, using straight solid keys +.>And straight dotted bond->Indicating the relative configuration of the stereogenic centers. For example->Representing methyl and amino groups on the same side of cyclopentane. Stereoisomers of the compounds of the invention may be prepared by chiral syntheses or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the invention may be prepared by asymmetric catalytic techniques or chiral auxiliary derivatization techniques. Or by chiral resolution techniques, a single configuration of the compound is obtained from the mixture. Or directly prepared by chiral starting materials. The separation of the optically pure compounds in the invention is usually accomplished by using preparative chromatography, and chiral chromatographic columns are used to achieve the purpose of separating chiral compounds.
The absolute steric configuration of the compounds can be confirmed by means of conventional techniques in the art. Such as single crystal X-ray diffraction, absolute configuration of the compounds can also be confirmed by chiral structure of the starting materials and reaction mechanism of asymmetric synthesis. Or after resolution, determining the three-dimensional configuration by comparing the product with the absolute configuration. Compounds labeled herein as "unknown absolute configuration" are typically resolved from a racemate compound into the individual isomers by chiral preparation SFC, and then characterized and tested.
The invention also includes isotopically-labeled compounds comprising isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, e.g. 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Compounds of the present invention containing the above isotopes and/or other isotopes of other atoms are within the scope of this invention.
The term "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating and dispersing agents, depending on the mode of administration and nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art according to a number of factors. Including but not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the therapeutic indication of interest. Pharmaceutically acceptable carriers include both aqueous and nonaqueous media and a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients included in the formulation for a variety of reasons (e.g., stabilizing the active agent, adhesive, etc.) are well known to those of ordinary skill in the art.
The term "excipient" generally refers to the carrier, diluent, and/or medium required to make an effective pharmaceutical composition.
The term "prophylactically or therapeutically effective amount" refers to a sufficient amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to treat a disorder at a reasonable effect/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated that the total daily amount of the compounds of formula I or pharmaceutically acceptable salts and compositions of the present invention will be determined by the physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dose level will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment; a medicament for use in combination with or simultaneously with the particular compound employed; and similar factors well known in the medical arts. For example, it is common in the art to start doses of the compound at levels below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
The term "halogen" means a fluorine, chlorine, bromine or iodine atom unless otherwise specified.
Unless otherwise specified, the term "C 1-4 Alkyl "of (C) is used to represent C 1-4 A linear or branched saturated hydrocarbon group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and the like.
Unless otherwise specified, the term "C 1-4 Haloalkyl "refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms, examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2-trifluoroethyl, 2 trichloroethyl, and the like.
Unless otherwise specified, the term "C 1-4 Alkoxy "means C linked through an oxygen bridge 1-4 Alkyl groups, compounds include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy.
Unless otherwise specified, "5-6 membered heterocycloalkyl" refers to a 5-6 membered substituted or unsubstituted mono-heterocycloalkyl, examples of which include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrrole, tetrahydrofuranyl, 3, 4-dihydroxytetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1, 3-dioxolane, 1, 4-dioxane, and the like.
Unless otherwise specified, the term "heterocyclyl" means a stable heteroatom-or heteroatom-group-containing mono-, bi-or tricyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which contains carbon atoms and 1, 2, 3 are independently selected from N, O, S, NO, SO, S (O) 2 Or NR, wherein any of the above-mentioned heterocyclic rings may be fused to one or more aromatic rings, heteroaromatic rings to form a bicyclic, tricyclic or like polycyclic ring, examples include, but are not limited toEtc.
Unless otherwise specified, "C 3-6 Cycloalkyl "refers to 3-6 membered monocyclic alkyl groups, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
Unless otherwise specified, "3-6 membered heterocycloalkyl" refers to 3-6 membered substituted or unsubstituted mono-heterocycloalkyl, examples of which include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrrole, tetrahydrofuranyl, 3, 4-dihydroxytetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1, 3-dioxolane, 1, 4-dioxane, oxetanyl, and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The solvent used in the present invention is commercially available.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using Bruker Neo 400M or Bruker Assend 400 nuclear magnetic instruments with deuterated dimethyl sulfoxide (DMSO-d 6) and deuterated methanol (CD) 3 OD) and/or deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
LC-MS was performed using an Agilent 1260-6125B single quadrupole mass spectrometer or a Waters H-Class SQD2 mass spectrometer (electrospray ionization as the ion source). HPLC determinations used Waters 2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
The HPLC was performed using Waters 2555-2489 (10 μm, ODS 250 cm. Times.5 cm) or GILSON Trilution LC, and the column was a Welch XB-C18 column (5 um, 21.2. Times.150 mm).
The thin layer chromatography silica gel plate uses smoke table Jiang You silica gel to develop a GF254 silica gel plate of a limited company or a GF254 silica gel plate of a new material limited company on the market of the nissan, the specification adopted by TLC is 0.15-0.20 mm, the preparation size is 20x20cm, and column chromatography is generally used for forming 200-300 mesh silica gel as a carrier.
Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
1. Preparation method
Example 1:
(5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (6- (3-hydroxy-3-methylbut-1-yn-1-yl) pyrimidin-4-yl) piperidin-4-yl) methanone
The reaction route is as follows:
the operation steps are as follows:
step A: 4, 6-dichloropyrimidine (3.0 g,20.1 mmol) was dissolved in ethanol (60 mL) at room temperature, triethylamine (3.0 g,30.1 mmol) was slowly added under ice-bath, and the reaction was stirred at 0deg.C for 1 hour.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated and purified by silica gel column chromatography to give ethyl 1- (6-chloropyrimidin-4-yl) piperidine-4-carboxylate (5.0 g).
MS(ESI)M/Z:270.1[M+H] + .
And (B) step (B): 1- (6-Chloropyrimidin-4-yl) piperidine-4-carboxylic acid ethyl ester (500.0 mg,1.8 mmol), 2-methylbutan-3-yn-2-ol (374.2 mg,4.4 mmol), triethylamine (1.1 g,11.1 mmol), cuprous iodide (141.2 mg,0.7 mmol) and ditolylphosphine palladium dichloride (130.1 mg,0.2 mmol) were dissolved in N, N-dimethylformamide (10 mL) at room temperature. The reaction system was stirred under nitrogen at 95℃for 16 hours.
LCMS monitoring showed the disappearance of starting material followed by extraction with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give ethyl 1- (6- (3-hydroxy-3-methylbut-1-yn-1-yl) pyrimidin-4-yl) piperidine-4-carboxylate (500 mg).
MS(ESI)M/Z:318.2[M+H] + .
Step C: 1- (6- (3-hydroxy-3-methylbut-1-yn-1-yl) pyrimidin-4-yl) piperidine-4-carboxylic acid ethyl ester (500.0 mg,1.5 mmol) and potassium hydroxide (265.1 mg,4.7 mmol) were dissolved in a mixed solvent (THF/MeOH/H) at room temperature 2 O=10/10/3, 23 mL). The reaction was stirred at room temperature for 1 hour.
After LCMS monitoring showed the disappearance of starting material, the reaction was adjusted to pH 5 with dilute hydrochloric acid and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (2X 50 mL). The aqueous phases were combined and lyophilized to give the crude 1- (6- (3-hydroxy-3-methyl-1-butyn-1-yl) pyrimidin-4-yl) piperidine-4-carboxylic acid (500.0 mg).
MS(ESI)M/Z:290.2[M+H] + .
Step D: 1- (6- (3-hydroxy-3-methylbut-1-yn-1-yl) pyrimidin-4-yl) piperidine-4-carboxylic acid (280.0 mg,0.9 mmol) and 5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazole (141.0 mg,0.7 mmol) were dissolved in dichloromethane (30 mL) at room temperature, and triethylamine (391.7 mg,3.8 mmol) and 1-propylphosphoric anhydride (1.5 g,4.8 mmol) were added thereto. The reaction was stirred at room temperature for 1 hour.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated directly under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The purification conditions were as follows, column: xbridge 5u C18X 19mm; mobile phase: water (containing 0.1% fa) and acetonitrile; the flow rate is 20mL/min; gradient: acetonitrile rose from 47% to 100% in 13 minutes; detection wavelength: 214nm. And collecting the product. 12.81mg of Compound 1 was obtained.
MS(ESI)M/Z:454.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.46(s,1H),7.25(s,1H),7.13-7.09(m,1H),6.93(s,1H),6.83(d,J＝6.4Hz,2H),5.33(dd,J＝12.0,4.8Hz,1H),4.45–4.35(m,2H),3.51-3.43(m,4H),3.03-2.98(m,2H),2.74(dd,J＝18.4,4.4Hz,1H),1.91-1.75(m,2H),1.46(s,6H).
Example 2:
(R) - (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3-hydroxy-3-methyl-1-butyn-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone
(S) - (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3-hydroxy-3-methyl-1-butyn-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone
The reaction route is as follows:
the operation steps are as follows:
step A: 2, 4-dichloropyrimidine (1.0 g,6.7 mmol), ((1, 1-dimethyl-2-propynyl) oxy) trimethylsilane (1.3 g,8.3 mmol), triethylamine (4.1 g,40.2 mol), cuprous iodide (0.3 g,1.3 mmol) and ditolylphosphine palladium dichloride (0.5 g,0.6 mmol) were dissolved in tetrahydrofuran (30 mL) at room temperature. The reaction system was stirred at 60℃for 16 hours under nitrogen.
LCMS monitoring showed the disappearance of starting material followed by extraction with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give 2-chloro-4- (3-methyl-3- ((trimethylsilyl) oxy) butyl-1-butyn-1-yl) pyrimidine (1.0 g).
MS(ESI)M/Z:269.1[M+H] + .
And (B) step (B): 2-chloro-4- (3-methyl-3- ((trimethylsilyl) oxy) butyl-1-butyn-1-yl) pyrimidine (500.0 mg,1.8 mmol) was dissolved in N, N' -dimethylformamide (10 mL) at room temperature, cesium carbonate (1.8 g,5.6 mmol) was added, and the reaction system was stirred at 80℃for 1 hour.
LCMS monitoring showed the disappearance of starting material followed by extraction with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give ethyl 1- (4- (3-methyl-3- ((trimethylsilyl) oxy) butyl-1-butyn-1-yl) pyrimidin-2-yl) piperidine-4-carboxylate (500.0 mg).
MS(ESI)M/Z:390.2[M+H] + .
Step C: 1- (4- (3-methyl-3- ((trimethylsilyl) oxy) butyl-1-butyn-1-yl) pyrimidin-2-yl) piperidine-4-carboxylic acid ethyl ester (200.0 mg,0.5 mmol) and potassium hydroxide (86.4 mg,1.5 mmol) were dissolved in a mixed solvent (THF/MeOH/H) at room temperature 2 O=2:2:1, 10 mL). The reaction was stirred at room temperature for 1 hour.
After LCMS monitoring showed the disappearance of starting material, the reaction was adjusted to ph=5 with dilute hydrochloric acid and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (2X 50 mL). The organic phases were combined to give the crude 1- (4- (3-hydroxy-3-methyl-1-butyn-1-yl) pyrimidin-2-yl) piperidine-4-carboxylic acid (100.0 mg).
MS(ESI)M/Z:290.2[M+H] + .
Step D: 1- (4- (3-hydroxy-3-methyl-1-butyn-1-yl) pyrimidin-2-yl) piperidine-4-carboxylic acid (100.0 mg,0.3 mmol) and 5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazole (69.2 mg,0.4 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and triethylamine (139.9 mg,1.4 mmol) and 1-propylphosphoric anhydride (549.8 mg,1.7 mmol) were added thereto. The reaction was stirred at room temperature for 1 hour.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated directly under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give compound 2. Further purification (purification conditions as follows: xbridge 5u C18. Times.19 mm; mobile phase: water (containing 0.1% FA) and acetonitrile; flow rate: 20mL/min; product) afforded 9.91mg of compound 2-P1 (retention time: 0.946 min) and 9.81mg of compound 2-P2 (retention time: 1.575 min) were collected.
Compound 2-P1:
MS(ESI)M/Z:454.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.23(d,J＝4.8Hz,1H),6.97(s,1H),6.70-4.65(m,3H),6.51(d,J＝4.8Hz,1H),5.34-5.30(dd,J＝12.0,5.2Hz,1H),4.80-4.77(m,2H),3.47-3.34(m,2H),3.04-2.94(m,2H),2.80-2.73(m,1H),2.14(s,1H),2.01-1.84(m,2H),1.78-1.66(m,2H),1.61(s,6H).
compound 2-P2:
MS(ESI)M/Z:454.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.23(d,J＝4.4Hz,1H),6.97(s,1H),6.67-6.65(m,3H),6.51(d,J＝4.4Hz,1H),5.32(dd,J＝11.6,4.4Hz,1H),4.80-4.77(m,2H),3.46-3.34(m,2H),3.04-2.95(m,2H),2.79-2.74(m,1H),2.16(s,1H),1.98-1.84(m,2H),1.75-1.70(m,2H),1.61(s,6H).
example 3:
5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- ((3-hydroxyoxyalkyl-3-yl) ethynyl) pyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 10.98mg of compound 3 was obtained.
MS(ESI)M/Z:468.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.38-8.37(m,1H),7.25(s,1H),7.11(t,J＝9.2Hz,1H),6.84-6.82(m,2H),6.71-6.70(m,1H),5.35–5.31(m,1H),4.76-4.75(m,2H),4.63-4.57(m,4H),3.51-3.34(m,2H),3.03-2.95(m,2H),2.76-2.71(m,1H),1.91-1.75(m,2H),1.50-1.38(m,2H).
Example 4:
(5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3-morpholin-1-propyn-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone
With reference to the synthesis of example 2, 70mg of compound 4 were obtained.
MS(ESI)M/Z:495.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.34(d,J＝4.8Hz,1H),7.25(s,1H),7.18–7.05(m,1H),6.84(d,J＝6.4Hz,2H),6.67(d,J＝4.8Hz,1H),5.34(dd,J＝12.0,4.8Hz,1H),4.62(d,J＝13.0Hz,2H),3.66–3.58(m,4H),3.57–3.55(m,2H),3.51-3.45(m,2H),3.43–3.34(m,4H),3.04–2.92(m,2H),2.79–2.69(m,1H),1.93–1.72(m,2H),1.52–1.37(m,2H).
Example 5:
(3- (3, 5-difluorophenyl) isoxazolidin-2-yl) (1- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 7.4mg of compound 5 was obtained.
MS(ESI)M/Z:457.2[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ8.33(d,J＝4.8Hz,1H),7.14(t,J＝9.2Hz,1H),6.99(d,J＝6.4Hz,2H),6.62(d,J＝4.8Hz,1H),5.69(brs,1H),5.37-5.33(m,1H),4.62–4.58(m,2H),4.30-4.26(m,1H),3.94-3.88(m,1H),3.06-3.00(m,2H),2.93-2.88(m,2H),2.22-2.18(m,1H),1.95–1.91(m,1H),1.75–1.71(m,1H),1.51-1.46(m,8H).
Example 6:
5- (3, 5-difluorophenyl) -4, 5-dihydropyrazol-1-yl 1- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) -5-methylpyrimidin-2-yl) piperidin-4-yl methanone
Referring to the synthesis of example 2, 11.3mg of compound 6 was obtained.
MS(ESI)M/Z:468.3[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),7.24(s,1H),7.11(t,J＝9.2Hz,1H),6.83(d,J＝8.0Hz,2H),5.66(brs,1H),5.35–5.31(m,1H),4.60–5.52(m,2H),3.52–3.48(m,2H),2.96–2.90(m,2H),2.77-2.71(m,1H),2.12(s,3H),1.89–1.85(m,1H),1.75–1.71(m,1H),1.48(s,6H),1.46–1.38(m,2H).
Example 7:
(1- (4- (cyclopropynyl) -5-methylpyridin-2-yl) piperidin-4-yl) (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) methanone
Referring to the synthesis of example 2, 10.31mg of compound 7 was obtained.
MS(ESI)M/Z:450.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.24(s,1H),7.00(s,1H),6.72-6.65(m,3H),5.33–5.29(m,1H),4.69-4.55(m,2H),3.49-3.41(m,2H),3.31-3.25(m,2H),2.81-2.77(m,1H),2.19(s,3H),2.07-1.96(m,2H),1.85-1.76(m,2H),1.62-1.55(m,1H),1.10-1.00(m,4H).
Example 8:
(3- (3, 5-difluorophenyl) isoxazolidin-2-yl) (1- (4- (3-hydroxy-3-methylbutan-1-yn-1-yl) -5-methylpyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 3.2mg of compound 8 was obtained.
MS(ESI)M/Z:471.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.27(s,1H),7.19–7.09(m,1H),7.05–6.94(m,2H),5.70(brs,1H),5.42–5.27(m,1H),4.62–4.47(m,2H),4.32–4.22(m,1H),3.96–3.82(m,1H),3.10–2.81(m,4H),2.24–2.15(m,1H),2.12(s,3H),1.94–1.86(m,1H),1.76–1.65(m,1H),1.53–1.35(m,8H).
Example 9:
(5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3-methoxy-3-methylbut-1-yn-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 24.65mg of compound 9 was obtained.
MS(ESI)M/Z:468.2[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ8.35(d,J＝4.8Hz,1H),7.26(s,1H),7.12(t,J＝9.2Hz,1H),6.84(d,J＝6.4Hz,2H),6.68(d,J＝4.8Hz,1H),5.37-5.33(m,1H),4.65–4.61(m,2H),3.39–3.35(m,2H),3.31(s,3H),3.02-2.94(m,2H),2.78-2.72(m,1H),1.93–1.89(m,1H),1.80–1.76(m,1H),1.48(s,6H),1.46–1.42(m,2H).
Example 10:
(5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) -1,3, 5-triazin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 18.69mg of compound 10 was obtained.
MS(ESI)M/Z:455.2[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ8.51(s,1H),7.26(s,1H),7.14-7.09(m,1H),6.84(d,J＝6.4Hz,2H),5.36-5.32(m,1H),4.68-4.50(m,2H),3.45–3.38(m,2H),3.12-3.04(m,2H),2.78-2.72(m,1H),1.97-1.93(m,1H),1.84-1.81(m,1H),1.53-1.46(m,2H),1.46(s,6H).
Example 11:
5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) -5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) methanone
5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (2- (3-hydroxy-3-methylbut-1-yn-1-yl) -5- (trifluoromethyl) pyrimidin-4-yl) piperidin-4-yl) methanone
The reaction route is as follows:
/>
the operation steps are as follows:
step A: 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (500 mg,2.3 mmol), 2-methylbut-3-yn-2-ol (233.0 mg,2.8 mmol), triethylamine (1.2 g,11.5 mol), cuprous iodide (171.0 mg,0.9 mmol) and ditolylphosphoropalladium dichloride (351.0 mg,0.5 mmol) were dissolved in tetrahydrofuran (10 mL) at room temperature. The reaction system was stirred under nitrogen at 25℃for 4 hours.
LCMS monitoring showed the disappearance of starting material followed by extraction with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography on silica gel to give a mixture of 4- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -2-methyl-3-yn-2-ol and 4- (4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) -2-methylbutan-3-yn-2-ol and a mixture of 4- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -2-methylbutan-3-yn-2-ol.
MS(ESI)M/Z:265.1[M+H] + .
And (B) step (B): a mixture of 4- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -2-methyl-3-yn-2-ol and 4- (4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) -2-methyl-3-yn-2-ol (140.0 mg,0.5 mmol) was dissolved in acetonitrile (10 mL) at room temperature and the reaction was stirred at 80℃for 16H.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated directly under reduced pressure. The residue was purified by preparative high performance liquid chromatography. The purification conditions were as follows, column: xbridge 5u C18 150x 19mm; mobile phase: water (containing 0.1% tfa) and acetonitrile; the flow rate is 50mL/min; 23.95mg of compound 11-P1 (retention time: 2.318 min) and 16.37mg of compound 11-P2 (retention time: 2.105 min) were obtained as products.
Compound 11-P1:
MS(ESI)M/Z:522.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.62(s,1H),7.26(s,1H),7.15-7.09(m,1H),6.85-6.83(m,2H),5.37–5.31(m,1H),4.66-4.64(m,3H),3.45-3.38(m,2H),3.16-3.08(m,2H),2.78-2.72(m,1H),1.96-1.81(m,2H),1.52-1.43(m,8H).
compound 11-P2:
MS(ESI)M/Z:522.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.61(s,1H),7.25-7.24(m,1H),7.14-7.10(m,1H),6.85-6.83(m,2H),5.52(brs,1H),5.36-5.32(m,1H),4.13-4.08(m,2H),3.52-3.38(m,2H),3.23-3.15(m,2H),2.78-2.71(m,1H),1.98-1.81(m,2H),1.66-1.51(m,2H),1.45(s,6H).
example 12:
(5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3-hydroxy-3-methylbut-1-yn-1-yl) -5, 7-dihydrofuran [3,4-d ] pyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 8.90mg of compound 12 was obtained.
MS(ESI)M/Z:496.3[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.24-7.23(m,1H),7.14-7.09(m,1H),6.85-6.82(m,2H),5.36–5.32(m,1H),4.92(s,2H),4.79(s,2H),4.62-4.59(m,3H),3.52-3.44(m,1H),3.40-3.34(m,1H),3.03-2.96(m,2H),2.77-2.71(m,1H),1.90-1.75(m,2H),1.51-1.39(m,8H).
Example 13:
(R) - (1- (4- (cyclopropylethynyl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) methanone
(S) - (1- (4- (cyclopropylethynyl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) methanone
Referring to the synthesis of example 2, 9.62mg of Compound 13-P1 (retention time: 1.862 min) and 10.61mg of Compound 13-P2 (retention time: 2.348 min) were obtained.
Resolution conditions: daicel CHIRALCEL OJ, chromatographic column; mobile phase: CO 2 /MeOH[0.2％NH 3 (7M Solution inMeOH)]=75/25; flow rate: 80g/min; detection wavelength: 214nm.
Compound 13-P1:
MS(ESI)M/Z:454.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.12(d,J＝0.8Hz,1H),6.98(s,1H),6.69-6.65(m,3H),5.34-5.30(m,1H),4.70-4.67(m,2H),3.42-3.30(m,2H),3.03-2.94(m,2H),2.80-2.74(m,1H),1.98–1.94(m,1H),1.87–1.83(m,1H),1.75-1.66(m,2H),1.56-1.50(m,1H),0.97-0.95(m,4H).
compound 13-P2:
MS(ESI)M/Z:454.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝1.2Hz,1H),6.98(s,1H),6.69-6.65(m,3H),5.34–5.30(m,1H),4.72-4.68(m,2H),3.43-3.33(m,2H),3.10-3.03(m,2H),2.81-2.74(m,1H),2.00-1.97(m,1H),1.90-1.87(m,1H),1.78-1.77(m,2H),1.57-1.53(m,1H),1.00-0.98(m,4H)
example 14:
(R) -1- (4- (cyclopropylethynyl) pyrimidin-2-yl) piperidin-4-yl) 5- (3, 5-difluorophenyl) -4, 5-dihydropyrazol-1-one
(S) -1- (4- (cyclopropylethynyl) pyrimidin-2-yl) piperidin-4-yl) 5- (3, 5-difluorophenyl) -4, 5-dihydropyrazol-1-one
The reaction route is as follows:
the operation steps are as follows:
Step A: 2, 4-dichloropyrimidine (500.0 mg,3.4 mmol) was dissolved in tetrahydrofuran (6 mL), ethynyl cyclopropane (332.8 mg,5.0 mmol), bis (triphenylphosphine) palladium (II) chloride (471.1 mg,0.7 mmol), cuprous iodide (255.7 mg,1.3 mmol) and triethylamine (2037.7 mg,20.1 mmol) were added and replaced three times with nitrogen. The mixture was stirred under nitrogen at 50 degrees celsius for 16 hours.
After LCMS monitoring showed the disappearance of starting material, the mixture was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) and dried to give 2-chloro-4- (2-cyclopropylethynyl) pyrimidine (380.0 mg).
MS(ESI)M/Z:179.1[M+H] + .
And (B) step (B): purification was dried to give 2-chloro-4- (2-cyclopropylethynyl) pyrimidine (120.0 mg,0.7 mmol) dissolved in tetrahydrofuran: to a mixture of N, N-dimethylformamide=10:1 (22 mL) was added 4- [5- (3, 5-difluorophenyl) -4, 5-dihydropyrazol-1-yl ] carbonyl } piperidine (236.5 mg,0.8 mmol) and potassium carbonate (278.6 mg,2.0 mmol) and stirred at 25 degrees celsius for 32 hours.
LCMS monitoring showed the disappearance of starting material and direct concentration of the resulting residue was purified by preparative hplc. The purification conditions were as follows, column: xtime 10u C18X 30mm; mobile phase: water (containing 0.1% fa) and acetonitrile; the product was collected to give compound 14. Resolving the pure product under the following conditions: daicel CHIRALCEL OJ,250mm×30mm I.D.,10 μm; mobile phase: carbon dioxide/methanol [0.2% NH 3 (7M methanol solution)]=70/30; 13.17mg of compound 14-P1 (retention time: 1.539 min) and 19.56mg of compound 14-P2 (retention time: 1.914 min) were obtained.
Compound 14-P1:
MS(ESI)M/Z:436.2[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ8.28(d,J＝4.8Hz,1H),7.24(s,1H),7.15-7.09(m,1H),6.86-6.81(m,2H),6.57(d,J＝4.8Hz,1H),5.36-5.32(m,1H),4.63–4.59(m,2H),3.52-3.44(m,1H),3.40–3.36(m,1H),3.00-2.91(m,2H),2.77-2.71(m,1H),1.90–1.86(m,1H),1.77–1.73(m,1H),1.63-1.56(m,1H),1.50-1.36(m,2H),0.97–0.92(m,2H),0.83–0.79(m,2H).
compound 14-P2:
MS(ESI)M/Z:436.2[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ8.28(d,J＝4.8Hz,1H),7.24(t,J＝1.2Hz,1H),7.15-7.09(m,1H),6.86-6.81(m,2H),6.57(d,J＝4.8Hz,1H),5.36-5.32(m,1H),4.62–4.58(m,2H),3.52-3.44(m,1H),3.40-3.36(m,1H),3.00-2.91(m,2H),2.77-2.71(m,1H),1.90–1.86(m,1H),1.77–1.73(m,1H),1.63-1.56(m,1H),1.50-1.36(m,2H),0.97-0.92(m,2H),0.83-0.79(m,2H).
example 15:
(S) -1- (4- (cyclopropynyl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (3- (3, 5-difluorophenyl) isoxazolidin-2-yl) methanone
The reaction route is as follows:
the operation steps are as follows:
step A: 3, 5-difluorobenzaldehyde (10 g,70.4 mmol), 3-triphenylpropyl-2-enal (6.0 g,73.9 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, and the mixture was stirred at 65℃for 16 hours.
LCMS monitoring showed the disappearance of starting material. The mixture was filtered, and the filtrate was directly concentrated and purified by a silica gel column to give a final product, namely 3- (3, 5-difluorophenyl) acrolein (8 g).
MS(ESI)M/Z:169.1[M+H] + .
And (B) step (B): 3- (3, 5-difluorophenyl) acrolein (6.0 g,35.7 mmol), (S) -2- (diphenyl ((trimethylsilyl) oxy) methyl) pyrrolidine (3.5 g,10.7 mmol) was dissolved in chloroform (100 mL) at room temperature. After stirring for three hours under ice bath, methanol (10 mL) was added and lithium borohydride (2.7 g,71.5 mmol) was slowly added and the reaction was stirred at room temperature for 16 hours.
LCMS monitoring showed the disappearance of starting material. The reaction solution was concentrated under reduced pressure, and the filtrate was purified by a reverse phase column to give tert-butyl (S) - (1- (3, 5-difluorophenyl) -3-hydroxypropyl) (hydroxy) carbamate (2.8 g) as a product.
MS(ESI)M/Z:326[M+Na] + .
Step C: tert-butyl (S) - (1- (3, 5-difluorophenyl) -3-hydroxypropyl) (hydroxy) carbamate (1.6 g,5.3 mmol) and triphenylphosphine (2.8 g,10.6 mmol) were dissolved in tetrahydrofuran (30 mL) at room temperature, stirred in an ice bath, and diethyl azodicarboxylate (1.8 g,10.6 mmol) was slowly added under nitrogen protection and the reaction stirred at room temperature for 1 hour.
LCMS monitoring showed the disappearance of starting material. The mixture was extracted with ethyl acetate (3X 50 mL), and the organic phases were combined, washed with saturated brine (2X 50 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified with a silica gel column to give the final product (S) -tert-butyl 3- (3, 5-difluorophenyl) isoxazolidine-2-carboxylate (0.7 g).
MS(ESI)M/Z:230.1[M+H-56] + .
Step D: (S) -3- (3, 5-difluorophenyl) isoxazolidine-2-carboxylic acid tert-butyl ester (700.0 mg,2.5 mmol) was dissolved in 1, 4-dioxane (20 mL) of hydrochloric acid at room temperature. The reaction was stirred at room temperature for 1 hour.
LCMS monitoring showed the disappearance of starting material. The reaction solution was concentrated to give a crude product (S) -3- (3, 5-difluorophenyl) isoxazolidine (500.0 mg).
MS(ESI)M/Z:186.1[M+H] + .
Step E: (S) -3- (3, 5-difluorophenyl) isoxazolidine (500.0 mg,2.7 mmol) and 1- (t-butoxycarbonyl) piperidine-4-carboxylic acid (680.0 mg,2.9 mmol) were dissolved in acetonitrile (20 mL) at room temperature, and N, N, N ', N' -tetramethyl chloroformamidine hexafluorophosphate (1.3 g,4.0 mmol) and N-methylimidazole (443.4 mg,5.4 mmol) were added thereto. The reaction was stirred at room temperature for 1 hour.
LCMS monitoring showed the disappearance of starting material. The mixture was extracted with ethyl acetate (3X 50 mL), and the organic phases were combined, washed with saturated brine (2X 50 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified with a silica gel column to give the final product (S) -tert-butyl 4- (3, 5-difluorophenyl) isoxazolidine-2-carbonyl) piperidine-1-carboxylate (850.0 mg).
MS(ESI)M/Z:419.2[M+Na] + .
Step F: (S) -4- (3, 5-difluorophenyl) isoxazolidine-2-carbonyl) piperidine-1-carboxylic acid tert-butyl ester (850.0 mg,2.1 mmol) was dissolved in 1, 4-dioxane (20 mL) of hydrochloric acid at room temperature. The reaction was stirred at room temperature for 1 hour.
LCMS monitoring showed the disappearance of starting material. The reaction solution was concentrated to give a crude product (S) - (3, 5-difluorophenyl) isoxazolidin-2-yl) (piperidin-4-yl) methanone (800.0 mg).
MS(ESI)M/Z:297.1[M+H] + .
Step G: 2-chloro-4- (cyclopropynyl) -5-fluoropyrimidine (80.0 mg,0.4 mmol) and (S) - (3, 5-difluorophenyl) isoxazolidin-2-yl) (piperidin-4-yl) methanone (144.7 mg,0.5 mmol) were dissolved in 1, 4-dioxane (10 mL) and tris (dibenzylidene-BASE acetone) dipalladium (37.3 mg,0.05 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (47.1 mg,0.1 mmol) were added and the reaction stirred at 100℃for 6 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated directly under reduced pressure. The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, column Welch 10u C18 250x 21.2mm; mobile phase: water (containing 0.1% NH) 3 ) And acetonitrile to give 8.06mg of the final product (S) - (1- (4- (cyclopropynyl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (3- (3, 5-difluorophenyl) isoxazolidin-2-yl) methanone (compound 15).
MS(ESI)M/Z:457.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.43(d,J＝1.2Hz,1H),7.15-7.10(m,1H),7.00-6.96(m,2H),5.36-5.33(m,1H),4.51-4.47(m,2H),4.29-4.25(m,1H),3.93-3.87(m,1H),3.03-2.85(m,4H),2.20-2.15(m,1H),1.93-1.89(m,1H),1.72-1.65(m,2H),1.52-1.42(m,2H),1.02-0.97(m,2H),0.87-0.83(m,2H).
Example 16:
(S) - (1- (4- (cyclopropynyl) -5-methylpyridin-2-yl) piperidin-4-yl) (3- (3, 5-difluorophenyl) isoxazolidin-2-yl) methanone
Referring to the synthesis method of example 15, 4.25mg of the product (S) - (1- (4- (cyclopropynyl) -5-methylpyridin-2-yl) piperidin-4-yl) (3- (3, 5-difluorophenyl) isoxazolidin-2-yl) methanone (compound 16) was obtained.
MS(ESI)M/Z:453.1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),6.86–6.78(m,2H),6.75–6.67(m,1H),5.41-5.33(m,1H),4.77–4.69(m,2H),4.30-4.24(m,1H),3.94–3.86(m,1H),3.08-2.79(m,4H),2.13(s,3H),1.99–1.95(m,1H),1.81-1.67(m,4H),1.55-1.49(m,1H),0.97-0.87(m,4H).
Example 17:
(5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (5-fluoro-4- (3-methylbut-1-yn-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 19.84mg of the product (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (5-fluoro-4- (3-methylbut-1-yn-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone (compound 17) was obtained.
MS(ESI)M/Z:456.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.44(d,J＝1.2Hz,1H),7.25(s,1H),7.15-7.09(m,1H),6.87–6.81(m,2H),5.36-5.32(m,1H),4.55–4.49(m,2H),3.51-3.44(m,2H),3.02–2.88(m,3H),2.77-2.71(m,1H),1.92-1.86(m,1H),1.79–1.73(m,1H),1.53–1.38(m,2H),1.23(d,J＝6.8Hz,6H).
Example 18:
(S) - (3, 5-difluorophenyl) isoxazolidin-2-yl) (1- (5-fluoro-4- (3-methylbutan-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 15, 8.68mg of the product (S) - (3, 5-difluorophenyl) isoxazolidin-2-yl) (1- (5-fluoro-4- (3-methylbutan-1-yl) pyrimidin-2-yl) piperidin-4-yl) methanone (compound 18) was obtained.
MS(ESI)M/Z:459.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝1.2Hz,1H),6.85-6.80(m,2H),6.75-6.70(m,1H),5.40-5.35(m,1H),4.73-4.64(m,2H),4.30-4.25(m,1H),3.95-3.90(m,1H),2.98-2.95(m,3H),2.89-2.80(m,2H),2.38-2.26(m,1H),2.05-2.00(m,1H),1.79–1.71(m,3H),1.35-1.27(m,6H).
Example 19:
(5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3, 3-dimethylbut-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 2, 38.53mg of the final product (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) (1- (4- (3, 3-dimethylbut-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) methanone (compound 19) was obtained.
MS(ESI)M/Z:470.2[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.44(d,J＝1.2Hz,1H),7.24(s,1H),7.14-7.09(m,1H),6.86–6.81(m,2H),5.36-5.32(m,1H),4.55–4.49(m,2H),3.52-3.44(m,2H),3.01-2.92(m,2H),2.77-2.71(m,1H),1.89(d,J＝11.6Hz,1H),1.76(d,J＝11.6Hz,1H),1.53–1.39(m,2H),1.31(s,9H).
Example 20:
(3- (3, 5-difluorophenyl) isoxazolidin-2-yl) (1- (4- (3, 3-dimethylbut-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) methanone
Referring to the synthesis of example 15, 37.11mg of the product (3- (3, 5-difluorophenyl) isoxazolidin-2-yl) (1- (4- (3, 3-dimethylbut-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) methanone (compound 20) was obtained.
MS(ESI)M/Z:473.2[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ8.44(d,J＝1.2Hz,1H),7.15–7.11(m,1H),7.02–6.97(m,2H),5.37–5.33(m,1H),4.53–4.48(m,2H),4.30-4.25(m,1H),3.94-3.88(m,1H),3.10–2.82(m,4H),2.24-2.16(m,1H),1.96–1.90(m,1H),1.76–1.70(m,1H),1.53-1.47(m,2H),1.21(s,9H).
Example 21:
(1- (4- (but-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) methanone
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Referring to the synthesis of example 2, 3.96mg of the product (1- (4- (but-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) methanone (compound 21) was obtained.
MS(ESI)M/Z:442.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.14(d,J＝0.4Hz,1H),6.98(s,1H),6.71-6.66(m,3H),5.34-5.30(m,1H),4.70-4.67(m,2H),3.47-3.32(m,2H),3.02-2.93(m,2H),2.80-2.74(m,1H),2.52–2.48(m,2H),1.97-1.94(m,1H),1.86-1.83(m,1H),1.78-1.75(m,1H),1.72-1.69(m,1H),1.27(t,J＝7.6Hz,3H).
Example 22:
(S) - (1- (4- (but-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (3- (3, 5-difluorophenyl) isoxazolidin-2-yl) methanone
Referring to the synthesis method of example 15, 6.49mg of the product (S) - (1- (4- (but-1-yn-1-yl) -5-fluoropyrimidin-2-yl) piperidin-4-yl) (3- (3, 5-difluorophenyl) isoxazolidin-2-yl) methanone (compound 22) was obtained.
MS(ESI)M/Z:445.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.16–8.14(m,1H),6.84-6.79(m,2H),6.72-6.67(m,1H),5.39-5.35(m,1H),4.70-4.66(m,2H),4.30-4.25(m,1H),3.93-3.87(m,1H),3.04-3.00(m,3H),2.86-2.81(m,1H),2.53-2.49(m,2H),2.32-2.27(m,1H),2.01-1.98(m,1H),1.74-1.69(m,3H),1.28(t,J＝7.6Hz,3H).
Example 23:
(S) - (1- (4- (cyclopropylethynyl) pyrimidin-2-yl) -4-methylpiperidin-4-yl) (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) methanone/(R) - (1- (4- (cyclopropylethynyl) pyrimidin-2-yl) -4-methylpiperidin-4-yl) (5- (3, 5-difluorophenyl) -4, 5-dihydro-1H-pyrazol-1-yl) methanone
Referring to the synthetic method of example 2, high performance liquid phase resolution, resolution conditions: chromatographic column: daicelCHIRALCEL OJ,250mm×30mm I.D.,10 μm; mobile phase: carbon dioxide/methanol [0.2% NH 3 (7M methanol solution)]=65/35. 29.28mg of compound 23-P1 (retention time: 1.962 min) and 32.53mg of compound 23-P2 (retention time: 1.530 min) were obtained.
Compound 23-P1:
MS(ESI)M/Z:450.2[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ8.26(d,J＝4.8Hz,1H),7.25(s,1H),7.13-7.08(m,1H),6.84-6.82(m,2H),6.54(d,J＝4.8Hz,1H),5.41-5.37(m,1H),4.06–3.97(m,2H),3.43–3.40(m,1H),3.29–3.25(m,1H),2.68-2.62(m,1H),2.31–2.20(m,2H),1.61-1.54(m,1H),1.51–1.45(m,2H),1.35(s,3H),1.24–1.22(m,1H),0.97–0.92(m,2H),0.82–0.78(m,2H).
compound 23-P2:
MS(ESI)M/Z:450.2[M+H] + .
1 HNMR(400MHz,DMSO-d6)δ8.26(d,J＝4.8Hz,1H),7.25(s,1H),7.12-7.08(m,1H),6.86–6.81(m,2H),6.54(d,J＝4.8Hz,1H),5.41-5.37(m,1H),4.06-3.97(m,2H),3.43-3.38(m,1H),3.29–3.25(m,1H),2.69–2.62(m,1H),2.31-2.20(m,2H),1.63–1.56(m,1H),1.50–1.44(m,2H),1.35(s,3H),1.24–1.22(m,1H),0.96–0.92(m,2H),0.82–0.78(m,2H).
example 24:
(6, 7-dihydro-5H-imidazo [1,2-a ] [1,4] diaza-8 (9H) -yl) (1- (5-fluoropyrimidin-2-yl) piperidin-4-yl) methanone
The reaction route is as follows:
the operation steps are as follows:
Step A: 1H-imidazole-2-carbaldehyde (200 mg,2.08 mmol) was dissolved in acetonitrile (6 mL) at room temperature, tert-butyl (3-bromopropyl) carbamate (268 mg,2.29 mmol) and potassium carbonate (575 mg,4.16 mmol) were added, and the reaction system was stirred at 80℃for 16 hours. LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL. Times.2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product tert-butyl (3- (2-formyl-1H-imidazol-1-yl) propyl) carbamate (200 mg).
MS(ESI)M/Z:254.1[M+H] + .
And (B) step (B): tert-butyl (3- (2-formyl-1H-imidazol-1-yl) propyl) carbamate (200 mg,0.78 mmol) was dissolved in dichloromethane (2 mL) at room temperature, and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give 1- (3-aminopropyl) -1H-imidazole-2-carbaldehyde. 1- (3-aminopropyl) -1H-imidazole-2-carbaldehyde (100 mg,0.65 mmol) was dissolved in dichloroethane (4 mL) at room temperature, and sodium borohydride acetate (208 mg,0.98 mmol) was added. The reaction was stirred at room temperature for 1 hour. Extracting the mixture with ethyl acetate (10 mL×3), dissolving the product in water phase, concentrating the water phase under reduced pressure, and filtering to obtain 6,7,8, 9-tetrahydro-5H-imidazole [1,2-a ] ][1,4]Dinitrogen(30mg)。
MS(ESI)M/Z:138.1[M+H] + .
Step C: 2-chloro-5-fluoropyrimidine (200 mg,1.51 mmol) was dissolved in acetonitrile (5 mL) at room temperature, piperidine-4-carboxylic acid ethyl ester (261 mg,1.66 mmol) and DIEA (585 mg,4.53 mmol) were added. The reaction system was stirred at 80℃for 16 hours. LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give ethyl 1- (5-fluoropyrimidin-2-yl) piperidine-4-carboxylate (380 mg).
MS(ESI)M/Z:254.1[M+H] + .
Step D: 1- (5-Fluoropyrimidin-2-yl) piperidine-4-carboxylic acid ethyl ester (380 mg,1.50 mmol) was dissolved in tetrahydrofuran (4 mL) and water (0.4 mL) at room temperature, and lithium hydroxide (108 mg,4.50 mmol) was added. The reaction was stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The mixture was made weakly acidic with 1N hydrochloric acid, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 1- (5-fluoropyrimidin-2-yl) piperidine-4-carboxylic acid (300 mg).
MS(ESI)M/Z:226.1[M+H] + .
Step E: 1- (5-Fluoropyrimidin-2-yl) piperidine-4-carboxylic acid (55 mg,0.24 mmol) was dissolved in acetonitrile (5 mL) at room temperature, 6,7,8, 9-tetrahydro-5H-imidazo [1,2-a ] was added ][1,4]Dinitrogen(30 mg,0.22 mmol), N, N, N ', N' -tetramethyl chloroformidine hexafluorophosphate (92 mg,0.32 mmol) and N-methylimidazole (45 mg,0.55 mmol). The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography. 11.6mg (6, 7-dihydro-5H-imidazo [1, 2-a) of product are obtained][1,4]Diaza-8 (9H) -yl) (1- (5-fluoropyrimidin-2-yl) piperidin-4-yl) methanone (compound 24).
MS(ESI)M/Z:345.2[M+H] + .
1 H NMR(400MHz,MeOD)δ8.24(s,2H),7.55–7.32(m,1H),7.12–6.92(m,1H),4.70–4.62(m,2H),4.45–4.39(m,1H),4.30–4.20(m,1H),4.07–3.98(m,1H),3.94-3.85(m,1H),3.05-2.94(m,2H),2.21-2.13(m,1H),1.94–1.86(m,1H),1.78–1.70(m,1H),1.65-1.49(m,3H),1.35-1.25(m,3H).
2. Biological in vitro enzyme activity experiment
The test adopts ADP-Glo kinase activity detection method to test the inhibition of the compound on the RIPK1 kinase activity and obtain the half inhibition concentration IC of the compound on the RIPK1 kinase activity 50 。
Experimental materials
White 384 well microplates, purchased from Greiner Bio-one.
RIPK1 Enzyme System (comprising Assay buffer, substrate protein MBP, ATP, DTT, mnCl 2) and ADP-Glo Kinase Assay, available from Promega corporation.
Microplate reader (SPARK) microplate reader, available from TECAN company.
2. Experimental method
1) Preparation of enzyme reaction Buffer: buffer mother liquor contained in Kit was diluted with ddH2O, and DTT and MnCl2 were added. An enzyme reaction Buffer containing 0.05mM DTT and 2mM MnCl2 was formed.
2) Dilution of RIPK1 enzyme: GST-hRIPK1 (1-375) enzyme was diluted in an enzyme reaction Buffer to form 5 ng/. Mu.L of enzyme;
3) Preparing a substrate/ATP mixed solution: ddH2O was diluted to form a mixture containing 25. Mu.M ATP and 0.25mg/ml MBP;
3) Preparing an enzyme reaction system: in 384 microwell plates, 5 μl of reaction system was used per well. The 5. Mu.L reaction system comprises 2. Mu.L of GST-hRIPK1 (1-375) enzyme, a mixture of substrate protein MBP and ATP (2. Mu.L), and the test compound (1. Mu.L, DMSO < 1%) diluted in a gradient.
5) After incubation of the reaction system for 1h at room temperature, 5. Mu.L of ADP-Glo was added to each well and incubation at room temperature was continued for 40min.
6) Finally, 10. Mu.L of the detection reagent of the kinase was added to each well, and incubated at room temperature for 10min.
7) ELISA apparatus (SPARK) ELISA apparatus was used to detect chemiluminescent signals from each well and data analysis was performed using GraphPad Prism software to obtain IC of the compound 50 。
The results of the inhibition of kinase activity are shown in Table 1.
TABLE 1 enzymatic inhibition results
Note that: inhibition of RIPK1 Activity by Compounds of the invention IC 50 The data are shown in table 1. Wherein IC 50 Compounds of 50nM or less are identified by A, 50nM < IC 50 Compounds of between 100nM are identified by B, 100nM < IC 50 Compounds of less than or equal to 500nM are identified by C, IC 50 Compounds > 500nM are identified by D and NI indicates inactivity.
Conclusion: as can be seen from Table 1, the compounds of the present invention have excellent inhibitory effects on RIPK 1.
Compound pharmacokinetic testing
The pharmacokinetic profile of the compounds of the invention in mice was studied using CD-1 mice as test animals and LC-MS-MS to determine the drug concentration in plasma at various times after administration of the preferred compounds.
CD-1 mice: vetolihua laboratory animal technologies Co.Ltd
The administration mode is as follows: single intravenous administration and single gastric lavage
Dosage of administration: 50mg/kg (Single gastric lavage administration)
Administration preparation: 10% DMSO/60% PEG 400/30% Water
Sampling points: 5 minutes (suitable for intravenous administration only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours
Standard curve and quality control sample preparation: appropriate amounts of stock solution were diluted with 50% acetonitrile water to 10000ng/mL, 4000ng/mL, 2000ng/mL, 1000ng/mL, 200ng/mL, 40ng/mL, 20ng/mL and 10ng/mL standard curve working solutions, 8000ng/mL, 2000ng/mL and 20ng/mL quality control working solutions. mu.L of blank mouse plasma was taken and added to 2. Mu.L of standard curve and quality control working solution, followed by 200. Mu.L of acetonitrile: methanol (50:50, v:v), after vortexing, was centrifuged at 15000rpm at 4℃for 15 minutes, 100. Mu.L of the supernatant was taken and diluted with 100. Mu.L of deionized water for LC-MS-MS analysis. Pharmacokinetic parameters were calculated using WinNonlin.
The pharmacokinetic parameters of the compounds described in the present invention are shown in table 2.
Table 2: preferred pharmacokinetic parameters of the Compounds
Conclusion: the compounds of the examples of the present invention have significant pharmacokinetic advantages over the control compounds. Control compound structure:
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Claims (18)

1. a compound of formula (I') and pharmaceutically acceptable salts thereof:
wherein X is 1 、X 2 Each independently is CR d Or N;
R a 、R b each independently is hydrogen, C 1-4 Alkyl orAnd R is a And R is b Are not hydrogen at the same time;
R d is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogen atom,Or R is d And R is b Are linked to form a 5-6 membered heterocycloalkyl
Ring Q is a 5-6 membered heterocyclyl;
R a1 、R a2 、R a3 each independently is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl, halogen atom, hydroxy, 5-6 membered heterocycloalkyl; or R is a1 、R a2 、R a3 Any two groups and their carbon together form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; wherein the heteroatom in the 5-6 membered heterocycloalkyl is O or N, and the heteroatom in the 3-6 membered heterocycloalkyl is O;
R c is unsubstituted or substituted by 1-3R e Substituted 5-6 membered aryl;
R e is a halogen atom.
2. The compound according to claim 1, characterized in that R a Is that
3. The compound according to claim 1, characterized in that R b Is that
4. The compound of claim 1, characterized by the structureSelected from->
5. The compound according to claim 1, wherein ring Q is selected from the group consisting of
6. The compound according to claim 1, characterized in that R c Is that
7. The compound according to claim 1, characterized in that R d is-F, -CF 3 、-CH 3 。
8. The compound according to claim 1, characterized in that R e is-F.
9. The compound according to claim 1, characterized in that R a1 、R a2 、R a3 Each independently is hydroxy, methyl,Methoxy group.
10. The compound according to claim 1, characterized in that R a1 、R a2 、R a3 Any two groups and their carbon together form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, structural unitsSelected from the group consisting of
11. The compound and pharmaceutically acceptable salts thereof according to any one of claims 1 to 10, wherein the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
wherein X is 1 、X 2 、R a 、R b 、R c As defined above.
12. The compound and pharmaceutically acceptable salts thereof according to any one of claims 1 to 11, wherein the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
wherein X is 2 、R a 、R b 、R c As defined above.
13. The compound and pharmaceutically acceptable salts thereof according to any one of claims 1 to 12, wherein the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
wherein R is a 、R b 、R c As defined above.
14. The compound and pharmaceutically acceptable salts thereof according to any one of claims 1 to 13, wherein the compound and pharmaceutically acceptable salts thereof are selected from the structures shown below:
wherein R is a 、R b 、R c As defined above.
15. A compound and a pharmaceutically acceptable salt thereof,
16. a pharmaceutical composition comprising a compound according to any one of claims 1 to 15, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
17. Use of a compound according to any one of claims 1 to 15, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment of a related disorder mediated by the RIPK1 target.
18. The use of claim 17, wherein the RIPK1 target-mediated related disease comprises a cell inflammatory disease, a neurodegenerative disease, cancer.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018092089A1 (en) * 2016-11-18 2018-05-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2019130230A1 (en) * 2017-12-29 2019-07-04 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
CN110573504A (en) * 2017-02-27 2019-12-13 葛兰素史克知识产权开发有限公司 heterocyclic amides as kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018092089A1 (en) * 2016-11-18 2018-05-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
CN110573504A (en) * 2017-02-27 2019-12-13 葛兰素史克知识产权开发有限公司 heterocyclic amides as kinase inhibitors
WO2019130230A1 (en) * 2017-12-29 2019-07-04 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors

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