CN117157297A - PRMT5 inhibitors - Google Patents

PRMT5 inhibitors Download PDF

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Publication number
CN117157297A
CN117157297A CN202280027588.2A CN202280027588A CN117157297A CN 117157297 A CN117157297 A CN 117157297A CN 202280027588 A CN202280027588 A CN 202280027588A CN 117157297 A CN117157297 A CN 117157297A
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mmol
reaction
pyrrolo
cyclopenta
amino
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付家胜
覃华
朱伟波
石谷沁
孙大庆
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

A PRMT5 kinase inhibitor, pharmaceutical compositions containing the compounds and methods of using the compounds in the treatment of cell proliferative disorders, such as cancer.

Description

PRMT5 inhibitors
The present application claims priority from the administration of China, 20 th 7 th 2021, china patent application with application number 202110816281.8 entitled "PRMT5 inhibitor", 7 th 2022, china patent application with application number 202210795578.5 entitled "PRMT5 inhibitor", the entire contents of which are incorporated herein by reference.
Technical Field
The application belongs to the field of pharmaceutical chemistry, and in particular relates to a quinoline-substituted PRMT5 inhibitor, a pharmaceutical composition containing the compound and a method for treating cell proliferation diseases such as cancers by using the compound.
Background
Protein arginine methyltransferases (protein arginine methyltransferase, PRMTs) play an important role in protein methylation, such as being involved in variable cleavage, post-transcriptional regulation, processing of RNA, cell proliferation, cell differentiation, apoptosis, and tumor formation, among others. Currently, 11 members of this family (PRMTs 1-11) have been identified, and PRMTs can be classified into 3 classes depending on the way they catalyze arginine methylation: form I includes PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8, catalyzed forms of monomethyl (MMA) and asymmetric dimethyl (acma); type II is symmetrical dimethyl (sDMA), including PRMT5 and PRMT9; type III is PRMT7.
PRMT5 was first isolated in a protein complex that interacted with Janus tyrosine kinase 2 (Jak 2), and is therefore also known as Jak binding protein 1 (JBP 1). PRMT5, an epigenetic enzyme, symmetrically methylates arginine residues of histone or non-histone substrates, affects multiple target genes and multiple signaling pathways, and thus performs multiple biological functions. Studies show that PRMT5 is also an oncogene, is highly expressed in various tumors, and the expression level is closely related to the occurrence, development and prognosis of the tumors.
The metabolic pathway in which CYP450 enzymes participate is a very important metabolic pathway in the clearance of compounds in vivo, inhibition of the activity of this family of enzymes can bring about changes in clearance and pharmacokinetics in the drug, drug-drug interactions (DDI) mediated by CYP450 enzymes is an important factor in drug efficacy and drug safety considerations (J Pharmacol Exp Ther.2006 Jan [ J ].2006,316 (1): 336-48). CYP3A4 is a major metabolizing enzyme of the CYP450 family, and inhibition of DDI by CYP3A4 can lead to serious safety problems (The AAPS Journal volume 24,Article number:12 (2022)). CYP3A4 is the P450 isozymes with the most abundant content in the liver and intestinal walls, and can participate in the metabolism of about 50% of clinical drugs, and drugs (drug) for inhibiting or inducing CYP3A4 can influence the pharmacokinetics of other drugs used in combination when used in combination clinically, so that the exposure of the drugs in plasma is influenced to cause pharmacokinetic DDI. Inhibitory (including reversible, mechanistic inactivation) drug interactions have increased efficacy, but drugs with a narrower therapeutic window are prone to cause clinical adverse reactions, which can be life threatening in severe cases. And the pharmacokinetics DDI caused by induction causes less medication safety problem, but can reduce the curative effect of the medicine. Therefore, predicting DDI likely to be caused by a new drug is important in evaluating candidate drug properties in the development of new drugs (Zhang Qing et al: quantitative prediction of in vivo drug-drug interactions based on in vitro CYP3A4 inhibition and induction data: pharmaceutical journal Acta Pharmaceutica Sinica [ J ] 2010,45 (8): 952-959).
Inhibition of P450 enzymes by drugs is generally classified into reversible inhibition (including competitive inhibition, non-competitive inhibition, and anti-competitive inhibition) and irreversible inhibition. The reversible inhibitor forms a complex with the enzyme (or enzyme-substrate complex) by non-covalent bond, prevents the normal enzymatic reaction between the enzyme and the substrate, and can continue to perform normal enzymatic reaction with the substrate without being affected by the enzyme activity after the inhibitor is removed. In irreversible inhibition, the inhibitory effect of the inhibitor on the enzyme does not disappear immediately after removal of the inhibitor, but exhibits a time-dependent characteristic. This phenomenon is commonly referred to as time-dependent suppression (TDI).
Drugs have a variety of mechanisms for the production of TDI by P450 enzymes, of which the mechanistic inhibition (mechanism based inhibition, MBI) is the most important mechanism of TDI, i.e. the inhibitor can be converted via CYP mediation to electrophilic reactive metabolites (reactive metabolite) which can interact with the enzyme (mainly in a covalently bound form) resulting in a change in the enzyme structure to inactivate it. The production of MBI requires a process of metabolism of the P450 enzyme, so that inhibition of the P450 enzyme by the inhibitor requires a certain time, and synthesis of a new P450 enzyme in vivo requires a certain time (generally 4-7 d), so that inhibition may occur for a certain period of time even if the inhibitor is removed. Compared with reversible inhibition, TDI brings more serious medication safety problems, because many medicines needing combined medication need to be taken for a long time, which tends to cause the inhibited CYP subtype to be inhibited for a long time, and even if medicines producing TDI are stopped, the inhibition effect can still last for a period of time; meanwhile, since the MBI-producing inhibitor is also a substrate of the P450 enzyme, after the enzyme activity is inhibited, the metabolism of the enzyme is also blocked, so that the exposure in the body is increased unevenly; furthermore, covalent modification of the P450 enzyme by reactive metabolites may lead to hapten production, may cause autoimmune reactions, and have serious consequences (Xie Shanshan et al. Time-dependent inhibition studies of cytochrome P450 enzymes and their role in the development of new drugs [ J ]. J. Chinese New drug & clinical J. Chin J New Drugs Clin Rem,2013,32 (6): 419-424).
At present, the PRMT5 inhibitor enters clinical medicines including GSK-3326595, JNJ-64619178, PF-06939999 and the like, and more safe PRMT5 kinase inhibitors still need to be developed.
Disclosure of Invention
The present invention provides a compound represented by the formula (I') or a pharmaceutically acceptable salt thereof,
wherein R is 1 Selected from H or NR 1a R 1b ；
R 1a And R is 1b Each independently selected from H or C 1-4 An alkyl group; the C is 1-4 Alkyl groups optionally being substituted by one or more R 1c Substituted by a group, said R 1c The radical being C 3-6 Cycloalkyl;
y is selected from N or CR 2 ；
R 2 Selected from H, halogen-substituted C 1-4 Alkyl, CN or-SO 2 -C 1-4 An alkyl group;
L 1 selected from chemical bond, -CH 2 -、-X-CH 2 、-(CH 2 ) n -CH＝CH-、-CH＝CH-(CH 2 ) n -、C 3-6 Cycloalkyl or 5-6 membered heteroaryl;
x is selected from O, S, NH or CH 2 ；
Ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl or 5-10 membered heterocyclyl;
R 3 selected from hydroxy or C 1-4 An alkyl group;
m is selected from 0, 1, 2 or 3;
n is selected from 0 or 1;
ring B is selected from
R 4 Selected from NR 4a R 4b Or C 1-4 An alkyl group;
R 4a and R is 4b Each independently selected from H or C 1-4 An alkyl group;
represents a single bond or a double bond;
when (when)R is a single bond 5 And R is 6 Each independently selected from H, deuterium, halogen or C 1-4 An alkyl group; r is R 7 And R is 8 Each independently is H;
when (when)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 And together with the C atom to which it is attached form phenyl or C 5-6 Cycloalkyl groups.
In some embodiments of the present invention, there is provided a compound of formula (I ') or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I') or a pharmaceutically acceptable salt thereof is a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Wherein R is 1 Selected from H or NR 1a R 1b ；
R 1a And R is 1b Each independently selected from H or C 1-4 An alkyl group; the C is 1-4 Alkyl groups optionally being substituted by one or more R 1c Substituted by radicals R 1c The radical being C 3-6 Cycloalkyl;
R 2 selected from H, halogen-substituted C 1-4 Alkyl, CN or-SO 2 -C 1-4 An alkyl group;
R 3 selected from hydroxy or C 1-4 An alkyl group;
R 4 selected from the group consisting of hydroxyl groups,NR 4a R 4b Or C 1-4 Alkyl, preferably R 4 Selected from NR 4a R 4b Or C 1-4 An alkyl group;
R 4a and R is 4b Each independently selected from H or C 1-4 An alkyl group;
L 1 selected from chemical bond, -CH 2 -、-X-CH 2 、-(CH 2 ) n -CH＝CH-、-CH＝CH-(CH 2 ) n -、C 3-6 Cycloalkyl or 5-6 membered heteroaryl;
x is selected from O, S, NH or CH 2 ；
Ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl or 5-10 membered heterocyclyl;
m is selected from 0, 1, 2 or 3;
n is selected from 0 or 1;
represents a single bond or a double bond;
when (when)R is a single bond 5 And R is 6 Each independently selected from H, deuterium, halogen or C 1-4 An alkyl group; r is R 7 And R is 8 Each independently is H;
when (when)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 And together with the C atom to which it is attached form phenyl or C 5-6 Cycloalkyl groups.
In some embodiments of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein R is 1 Selected from H or NR 1a R 1b ；
R 1a And R is 1b Each independently selected from H or C 1-4 An alkyl group; the C is 1-4 Alkyl groups optionally being substituted by one or more R 1c Substituted by radicals R 1c The radical being C 3-6 Cycloalkyl;
R 2 selected from H or halogen;
R 3 Selected from hydroxy or C 1-4 An alkyl group;
R 4 selected from the group consisting of hydroxyl groups,NR 4a R 4b Or C 1-4 Alkyl, preferably R 4 Selected from NR 4a R 4b Or C 1-4 An alkyl group;
R 4a and R is 4b Each independently selected from H or C 1-4 An alkyl group;
L 1 selected from chemical bond, -CH 2 -、-X-CH 2 、-(CH 2 ) n -CH＝CH-、C 3-6 Cycloalkyl or 5-6 membered heteroaryl;
x is selected from O, S, NH or CH 2 ；
Ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl or 5-10 membered heterocyclyl;
m is selected from 0, 1, 2 or 3;
n is selected from 0 or 1;
represents a single bond or a double bond;
when (when)R is a single bond 5 And R is 6 Each independently selected from H, deuterium, or halogen; r is R 7 And R is 8 Each independently is H;
when (when)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 And together with the C atom to which it is attached form phenyl or C 5-6 Cycloalkyl groups.
In some aspects of the invention, the R 1 Selected from H, amino or
In some aspects of the invention, the R 2 Selected from H, F, cl or Br.
In some aspects of the invention, the R 2 Selected from halogen-substituted C 1-4 Alkyl, CN or-SO 2 -C 1-4 An alkyl group.
In some aspects of the invention, the R 2 Selected from CF 3 CN or-SO 2 -CH 3 。
In one aspect of the inventionIn some embodiments, the L 1 Selected from chemical bond, -CH 2 -、-O-CH 2 -、-NH-CH 2 -、-CH 2 -CH 2 -、-CH＝CH-、-CH 2 -CH＝CH-、
In some aspects of the invention, the L 1 Selected from-ch=ch-CH 2 -。
In some embodiments of the invention, the ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl or a 5-10 membered heterocyclyl containing 1 or more heteroatoms selected from N or O.
In certain embodiments of the invention, ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, 5-10 membered mono-heterocycle, 5-10 membered spiro-heterocycle, 5-10 membered bridged-heterocycle or 5-10 membered fused-heterocycle.
In certain embodiments of the invention, ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered mono-heterocycle, 9-10 membered spiro-heterocycle, 7-10 membered bridged-heterocycle or 8-10 membered fused-heterocycle.
In some embodiments of the invention, the ring A is selected from
In some aspects of the invention, the R 3 Selected from hydroxyl or methyl; m is selected from 0, 1, 2 or 3.
In some aspects of the invention, the building blocksSelected from the group consisting of
In some aspects of the invention, the building blocksSelected from the group consisting of
In some aspects of the invention, the R 4 Selected from amino, methyl or-NHCH 3 。
In some aspects of the invention, theRepresents a single bond or a double bond;
when (when)R is a single bond 5 And R is 6 Each independently selected from H, deuterium, F, or methyl; r is R 7 And R is 8 Each independently is H;
when (when)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 And the C atom to which it is attached form a phenyl or cyclopentyl group.
In some aspects of the invention, the building blocksSelected from the group consisting of
In some aspects of the invention, the building blocksSelected from the group consisting of
In some aspects of the invention, the building blocks Is that
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (II):
wherein,
R 9 selected from H or C 1-4 An alkyl group; preferably, R 9 Selected from H or methyl;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、L 1 and m is as defined for formula (I') or formula (I).
In certain embodiments of the invention, a compound of formula (II), or a pharmaceutically acceptable salt thereof, R 9 Selected from H or C 1-4 An alkyl group; preferably, R 9 Selected from H or methyl; m is selected from 1 or 2; r is R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And L 1 As defined in formula (I') or formula (I).
In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
wherein R is 1 、R 2 、R 4 、R 5 、R 6 、R 7 、R 8 And R is 9 As defined by formula (II).
In some embodiments of the invention, the above compound, isomer or pharmaceutically acceptable salt thereof is selected from the group consisting of:
wherein R is 1 、R 2 、R 4 And R is 9 As defined by formula (II).
The present invention also provides the following compounds, isomers or pharmaceutically acceptable salts thereof, selected from:
the invention also relates to pharmaceutical compositions comprising the compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
The invention also relates to application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating cancers.
The invention also relates to the use of said compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of cancer.
The invention also relates to a method of treating cancer comprising administering to a subject in need thereof an effective dose of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The compound has good inhibition effect on PRMT5 methylase and human pancreatic cancer cell line MIA PaCa-2, has the potential advantage of higher cardiac safety, has small inhibition effect on CYP3A4 enzyme, has lower possibility of drug interaction (DDI), has lower risk of time-dependent inhibition (TDI), and has good pharmacokinetic property. Compared with the prior art, the compound has higher safety.
Interpretation of the terms
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 a relatively acidic functional group, reaction with an alkali metal, alkaline earth metal hydroxide or organic amine gives a base addition salt, including cations based on alkali metal and alkaline earth metal. 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 present invention exist as isomers, such as cis-trans isomers, enantiomers, diastereomers, as well as 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 a wedge-shaped dotted bondRepresenting the absolute configuration of a stereogenic center.
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.
Chiral carbon atoms are marked in the present invention. For exampleThe carbon atom on the cyclopentyl group being chiral and comprisingCompounds of two structures.
The isomers separated by chiral chromatography in the present invention are represented by P1 and P2, for example, examples 6-P1 and examples 6-P2 represent two isomers of the compound of example 6 obtained by chiral resolution.
The invention also includes isotopically-labeled compoundsIsotopes including 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. Preferably, the isotope is selected from the group consisting of: 2 H、 3 H、 11 c and C 18 F. More preferably, the radioisotope is 2 H. Specifically, deuterated compounds are intended to be included within the scope of the present invention.
When the number of one linking group is 0, such as- (CH) 2 ) n -ch=ch-, n=0 means that the linking group is a bond, i.e. -ch=ch-.
Where the bond of a substituent may be cross-linked to a ring, the substituent may be bonded to any atom on the ring. For example, structural unitsRepresents a substituent R 3 Substitution may occur at any position on ring a.
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 adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifying agents, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening agents, 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 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" means that the compound of the invention, or a pharmaceutically acceptable salt thereof, is a sufficient amount of the compound 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 "optionally substituted" means that the species and number of substituents may be any on the basis of being chemically realizable, unless otherwise indicated, e.g., the term "optionally substituted with one or more R 1c Substituted "means that one or more R's may be substituted 1c Substituted or not by R 1c And (3) substitution. When any variable (e.g. R 1c ) In the process of compoundingThe definition of a composition or structure of an agent is independent in each case when it occurs more than once. For example, if a group is substituted with 0-2R 1c Substituted, the radicals may optionally be substituted by up to two R 1c Substituted, and R in each case b There are independent options.
Unless otherwise specified, "ring" refers to saturated, partially saturated or unsaturated monocyclic and polycyclic rings.
Unless otherwise specified, the term "heterocyclyl" refers to a substituted or unsubstituted saturated or unsaturated non-aromatic ring and contains 1 to 3 heteroatoms selected from N, O or S. "heterocyclyl" as used herein refers to a non-aromatic cyclic group derived from the removal of one hydrogen atom, containing at least one heteroatom as a ring atom; including saturated or partially saturated monocyclic heterocyclyl and polycyclic heterocyclyl; the heterocyclic group is independent of the attachment position (i.e., may be bound through a carbon atom or heteroatom). The polycyclic heterocyclic group includes a condensed heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group.
The "fused heterocyclic group" refers to a cyclic structure formed by two or more rings sharing two adjacent ring atoms, and at least one ring is a heterocycle; the fused heterocyclic group includes a cyclic structure in which a mono-heterocyclic group is fused with a mono-heterocyclic group or a cycloalkyl group or an aryl group or a heteroaryl group, and also includes a cyclic structure in which a heteroaryl group is fused with a cycloalkyl group or a mono-heterocyclic group.
The term "spiroheterocyclic group" means a cyclic structure in which two or more rings share one ring atom with each other, and at least one ring is a heterocyclic ring.
The term "bridged heterocyclic group" means a cyclic structure in which two or more rings share non-adjacent ring atoms, and at least one ring is a heterocyclic ring.
The heterocyclic group is preferably 5-10 membered single heterocyclic group, 5-10 membered condensed heterocyclic group, 5-10 membered spiro heterocyclic group or 5-10 membered bridged heterocyclic group; further, the heterocyclic group is preferably a 5-6 membered mono-heterocyclic group, 8-10 membered condensed heterocyclic group, 8-10 membered spiro heterocyclic group or 7-9 membered bridged heterocyclic group.
Examples of "5-to 10-membered heterocyclic groups" include, but are not limited to, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1, 3-dioxolane, 1, 4-dioxane, Etc.
In the present invention, when both ends of the heterocyclic group are substituted, they are heterocyclylene groups, e.g., structural unitsWhen ring A is selected from 5-10 membered heterocyclyl, it is intended to represent that ring A is a 5-10 membered heterocyclylene, including without limitation
Unless otherwise specified, the term "aryl" refers to an unsaturated, typically aromatic, hydrocarbon group that may be a single ring or multiple rings fused together. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.
Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon, preferably containing carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. Preferably a 5-12 membered heteroaryl, more preferably a 5-6 membered heteroaryl; examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyrimidinyl, pyridinyl,
In the present invention, heteroaryl is heteroarylene when both ends of the heteroaryl group are substituted, e.g., L in a compound of formula (I') or formula (I) 1 Selected from 5-6 membered heteroaryl groups, which in fact represent L 1 Is a 5-6 membered heteroarylene group, including but not limited to
Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group. Cycloalkyl is preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl, more preferably C 5-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or
In the present invention, cycloalkyl groups are cycloalkylene groups when both ends are substituted, e.g. building blocksWherein ring A is selected from C 5-6 In the case of cycloalkyl, it is meant that ring A is C 5-6 Cycloalkylene radicals including, but not limited to
Unless otherwise specified, "cycloalkenyl" refers to a monocyclic ring containing a double bondOr a polycyclic hydrocarbon group. The cycloalkenyl group is preferably C 3-6 Cycloalkenyl group, more preferably C 5-6 Examples of cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, or 1, 4-cyclohexadiene.
In the present invention, cycloalkenyl groups are taken when both ends of the cycloalkenyl group are substituted, e.g., structural unitsRing A is selected from C 5-6 In the case of cycloalkenyl, it is actually meant that ring A is C 5-6 Cycloalkenylene radicals including, but not limited to
Ring B in the present invention is selected fromIn the case of (1)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 Together with the C atom to which it is attached form phenyl or C 5-6 Cycloalkyl group, corresponding to itRefers to
The term "alkyl" is used to denote a straight or branched saturated hydrocarbon group unless otherwise specified. Preferably C 1-6 More preferably C 1-4 Alkyl, alkyl of (2)Examples of (a) include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, n-hexyl, and the like.
The term "halogen" means a fluorine, chlorine, bromine or iodine atom unless otherwise specified.
It is specifically stated that combinations of all substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
In the examples of the present invention, the title compound is named after the compound structure is converted by Chemdraw. If the compound name is inconsistent with the compound structure, the compound name can be determined in an auxiliary way by combining the related information and the reaction route; cannot be confirmed by other methods, and the structural formula of the given compound is subject to. The preparation method of some compounds in the present invention refers to the preparation method of the aforementioned analogous compounds. It will be appreciated by those skilled in the art that the ratio of the reactants, the reaction solvent, the reaction temperature, etc. may be appropriately adjusted depending on the reactants when using or referring to the preparation method to which they are applied.
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.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention.
Summary of the laboratory instruments:
the structures of the compounds of the invention are obtained by Nuclear Magnetic Resonance (NMR) or/and liquidMass spectrometry (LC-MS), or ultra-high performance liquid chromatography (UPLC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker Neo 400M or Bruker Assend 400 nuclear magnetic instruments with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Heavy water (D) 2 O), internal standard is Tetramethylsilane (TMS).
Agilent 1260-6125B single quadrupole mass spectrometer for LC-MS measurement was used for column Welch Biomate column (C18, 2.7 μm, 4.6X150 mm) or waters H-Class SQD2, for column Welch Ultimate column (XB-C18, 1.8 μm, 2.1X150 mm) and electrospray ionization was used as the mass spectrometer ion source.
Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was performed using a Waters UPLC H-class SQD mass spectrometer (electrospray ionization as the ion source).
HPLC determinations used Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
The preparative HPLC used was Waters 2555-2489 (10 μm, ODS 250 cm. Times.5 cm) or GILSON Trilution LC, a Welch XB-C18 column (5 μm, 21.2X 150 mm).
Chiral HPLC assay using waters acquity UPC2; the columns were Daicel chiralpak AD-H (5 μm, 4.6X1250 mm), daicel chiralpak OD-H (5 μm, 4.6X1250 mm), daicel chiralpak IG-3 (3 μm, 4.6X150 mm), chiral Technologies Europe AD-3 (3 μm, 3.0X150 mm) and Trefoil TM Technology Trefoil TM AMY1 (2.5 μm, 3.0X150 mm).
Supercritical Fluid Chromatography (SFC) using waters SFC 80Q column Daicel Chiralcel OD/OJ/OZ (20X 250mm,10 μm) or Daicel Chiralpak IC/IG/IH/AD/AS (20X 250mm,10 μm).
The thin layer chromatography silica gel plate uses smoke table Jiang You silica gel to develop GF254 silica gel plate of the limited company or GF254 silica gel plate of the new material of the limited company on the opal market, the specification adopted by TLC is 0.15 mm-0.20 mm, the preparation is 20 multiplied by 20cm, and column chromatography is generally used for forming 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present application are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the application were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent, and the reaction temperature being in degrees celsius or in degrees celsius, without specific description.
The trifluoroacetate salt of the compound is obtained in part of the preparation examples of the present application, and it will be understood by those skilled in the art that the preparation of the compound by the trifluoroacetate salt, or the preparation of the trifluoroacetate salt by the compound is a relatively conventional means, and the structure of the trifluoroacetate salt of the compound disclosed in the present application or the preparation thereof can be regarded as equivalent to the structure of the free compound and the preparation thereof.
Abbreviations used in the examples of the present application and their corresponding chemical names are as follows:
an intermediate: int-1
3-bromo-7-iodoquinolin-2-amine
The reaction route is as follows:
the operation steps are as follows:
step A7-nitroquinoline (25 g,143 mmol) and acetic acid solution (50 mL) were added to the reaction flask. The displacement reaction system was a nitrogen system, which was then cooled to 0 ℃. N-bromosuccinimide (50.6 g,284 mmol) was added dropwise to the reaction system, and the reaction system was stirred at 100℃for 2 hours.
After TLC monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate (500 mL. Times.3), and the organic phases were combined, washed with saturated brine (300 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-bromo-7-nitroquinoline (24.5 g).
MS(ESI)M/Z:253.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ9.18(d,J＝2.0Hz,1H),8.97(s,1H),8.79(t,J＝11.4Hz,1H),8.41(dd,J＝9.0,2.0Hz,1H),8.23(d,J＝9.0Hz,1H).
Step B3-bromo-7-nitroquinoline (24.5 g,97 mmol) and ammonium chloride (20.0 g, 514 mmol) were added to a reaction flask, dissolved in a mixed solvent (ethanol/water=1.5/1, volume ratio, 250 mL), zinc powder (65.4 g,1000 mmol) was slowly added at room temperature, and the system was replaced with nitrogen atmosphere. After the completion of the dropwise addition, the reaction system was stirred at 80℃for 2 hours.
After TLC monitoring showed the disappearance of starting material, water was slowly added to the reaction solution for quenching. Dichloromethane (50 mL) and methanol (5 mL) were then added, stirred for 30 minutes, and the reaction solution was filtered. The filtrate was concentrated to give an oily crude product, which was purified by silica gel column chromatography to give 3-bromoquinolin-7-amine (6.2 g).
MS(ESI)M/Z:223.0[M+H] + .
Step C: sulfuric acid (108 mL) was added to the reaction flask, followed by a slow addition of a solution of 3-bromoquinolin-7-amine (6.2 g,27.8 mmol) at 0deg.C (86 mL). After stirring at 0deg.C for 10 min, a solution of sodium nitrite (3.8 g,55.1 mmol) was slowly added dropwise (6 mL). Subsequently stirring was continued for 30 minutes, and a solution of sodium iodide (12.5 g,83.4 mmol) was slowly added to the reaction system at 0 ℃. The reaction solution was stirred at 60℃for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, ethyl acetate (50 mL) was added to the reaction, stirred for 10 minutes, then filtered, the filter cake was repeatedly washed with a mixed solution of dichloromethane and methanol, the filtrates were combined, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-7-iodoquinoline (4 g, yield 25.6%).
MS(ESI)M/Z:333.8[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ9.16(dd,J＝5.3,2.3Hz,1H),8.96(t,J＝3.6Hz,1H),8.82(dd,J＝7.8,2.2Hz,1H),8.40(dd,J＝9.0,2.3Hz,1H),8.23(d,J＝9.0Hz,1H).
Step D: 3-bromo-7-iodoquinoline (500 mg,1.5 mmol) was dissolved in dichloromethane (10 mL) at room temperature. M-chloroperbenzoic acid (1.03 g,6 mmol) was slowly added at 0deg.C, and the reaction stirred at room temperature for 12 hours.
LCMS monitored the reaction, quenched by addition of water (30 mL) to the reaction solution at 0 ℃, then slowly adjusted to pH 7 by addition of saturated aqueous ammonium chloride, and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL) and then dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-7-iodoquinoline 1-oxide (160 mg).
MS(ESI)M/Z:349.8[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.96(d,J＝2.3Hz,1H),8.73(t,J＝13.1Hz,1H),8.44(d,J＝14.5Hz,1H),7.97(dd,J＝8.6,1.5Hz,1H),7.77(d,J＝8.6Hz,1H).
Step E: 3-bromo-7-iodoquinoline 1-oxide (160 mg,0.45 mmol) was dissolved in chloroform (10 mL) at room temperature. Phosphorus oxychloride (10 mL) was then slowly added at 0 c and the reaction was evacuated and replaced with nitrogen multiple times. The reaction solution was stirred for 12 hours at 70℃in an oil bath.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. Dichloromethane (20 mL) was added and then pH was adjusted to 7 with saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate (10 ml×3 times), the organic phases were combined, washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-2-chloro-7-iodoquinoline (90 mg).
MS(ESI)M/Z:367.8[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.96(s,1H),8.44(d,J＝18.2Hz,1H),8.03(t,J＝18.1Hz,1H),7.79(t,J＝10.1Hz,1H).
Step F: 3-bromo-2-chloro-7-iodoquinoline (90 mg,0.24 mmol) was dissolved in the mixed solution (ethanol/ammonia=1/1, volume ratio, 8 mL) at room temperature. The reaction solution was then stirred at 100℃for 20 hours under microwaves.
After LCMS monitoring showed the disappearance of starting material, concentrated under reduced pressure, the mixture was extracted with dichloromethane (5 ml×3 times) and the organic phases were combined, washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-7-iodoquinolin-2-amine (76 mg).
MS(ESI)M/Z:348.8[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.39(d,J＝10.2Hz,1H),7.86(s,1H),7.48(dt,J＝19.4,5.0Hz,2H),6.84(brs,2H).
Example 1
(1R, 2S,3R, 5S) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (2- (2-aminoquinolin-7-yl) ethyl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
Step A: 6-hydrazinopyrimidin-4-ol (2.0 g,15.9 mmol) and cyclopentanone (1.3 g,15.5 mmol) were dissolved in ethanol (15 mL). The reaction system was heated to 80 ℃ and stirred for 3 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was depressurized and the resulting solid was dissolved in diphenyl ether (20 mL). The reaction system was heated to 250 ℃ and stirred for 8 hours. After the reaction solution was cooled to room temperature, methyl t-butyl ether (20 mL) was added to the reaction solution, a large amount of solid was produced in the reaction solution, the solid was filtered and washed with methyl t-butyl ether (10 mL), and the cake was suspended by distillation under reduced pressure to give a crude 5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-ol (2.7 g).
MS(ESI)M/Z:176.2[M+H] + .
And (B) step (B): 5,6,7, 8-Tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-ol (2.7 g,15.4 mmol) was dissolved in phosphorus oxychloride (20 mL). The reaction system was heated to 100℃and stirred for 3 hours. LCMS monitoring showed that most of the phosphorus oxychloride was removed under reduced pressure distillation after the starting material had disappeared. The reaction solution was diluted with ethyl acetate (50 mL) and slowly dropped into an aqueous solution of sodium hydroxide (1N, 50 mL), the organic phase was extracted, washed with saturated brine (300 mL. Times.3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 4-chloro-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (370 mg).
1 H NMR(400MHz,DMSO-d 6 )δ12.35(s,1H),8.44(s,1H),2.94-2.84(m,4H),2.49-2.42(m,2H).
Step C: 4-chloro-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (243.0 mg,1.3 mmol) was dissolved in tetrahydrofuran (4 mL) at room temperature. Subsequently, potassium t-butoxide (141.3 mg,1.3 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropylethylamine (2 mL) was added and sonicated for 5 minutes, the filter cake was collected, and concentrated under reduced pressure to give the compound 4-chloro-6, 7-dihydro-5H-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine-8-carboxylic acid potassium (291.1 mg, yield 96.9%).
Step D: in a single vial, a solution of trifluoromethanesulfonic anhydride (1.16 g,4.11 mmol) in dichloromethane (20 mL) was added dropwise to the reaction mixture under ice-bath (3 aS,4S,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (500 mg,2.74mmol, reference J.org. chem.2004,69,3993-3996 method, the entire contents of which were incorporated herein by reference) and pyridine (649 mg,8.22 mmol) in dichloromethane (10 mL). The reaction solution was stirred at this temperature for half an hour.
After TLC monitoring showed the disappearance of starting material, ice water was added to the reaction solution for quenching. The reaction solution was extracted with dichloromethane (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 aR,4S,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl trifluoromethanesulfonate (685 mg).
1 H NMR(400MHz,CDCl 3 )δ5.83-5.69(m,1H),5.19-5.06(m,2H),5.05-4.96(m,1H),4.63(dd,J＝5.5Hz,1H),4.51(dd,J＝5.9,1.8Hz,1H),2.94-2.81(m,1H),2.45-2.31(m,1H),2.13-2.02(m,1H),1.53(s,3H),1.34(s,3H).
Step E: potassium 4-chloro-6, 7-dihydro-5H-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine-8-carboxylate (291.1 mg,1.26 mmol) was dissolved in N, N-dimethylformamide (4 mL) at 0deg.C, and then (3 aR,4S,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl trifluoromethane sulfonate (331.8 mg,1.05 mmol) was dissolved in N, N-dimethylformamide (0.5 mL) was slowly added to the reaction solution. The reaction was stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (30 mL), extract the mixture with ethyl acetate (15 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (50 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 4-chloro-8- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (300 mg).
MS(ESI)M/Z:360.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.52(s,1H),5.96(m,1H),5.25-5.06(m,2H),5.06-4.98(m,1H),4.92(dd,J＝7.3,5.4Hz,1H),4.56(t,J＝7.0Hz,1H),3.20-3.06(m,1H),3.06-2.95(m,1H),2.95-2.86(m,2H),2.79-2.68(m,1H),2.46-2.51(m,2H)2.38-2.24(m,2H),1.49(s,3H),1.22(s,3H).
Step F: 4-chloro-8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (180 mg,0.50 mmol), 7-bromoquinolin-2-amine (133.5 mg,0.60 mmol) and tetraethylammonium chloride (91.1 mg,0.55 mmol) were dissolved in N, N-dimethylformamide (5 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (22.4 mg,0.1 mmol) and N, N-diisopropylethylamine (322.5 mg,2.5 mmol) were added under nitrogen. The reaction solution was stirred at 80℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (20 mL), extract the mixture with ethyl acetate (20 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (15 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (140 mg).
MS(ESI)M/Z:502.0[M+H] + .
Step G: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (45 mg,0.09 mmol) was dissolved in aqueous ammonia/isopropanol (2 mL/0.8 mL) and the reaction system was capped at 120℃and stirred for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 8- ((3 as,4r,6 ar) -6- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (21.0 mg).
MS(ESI)M/Z:483.2[M+H] + .
Step H: 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrol [2,3-d ] pyrimidin-4-amine (15 mg,0.03 mmol) and palladium on charcoal (5 mg) were dissolved in methanol (4 mL), the reaction system was replaced with nitrogen gas for air and then with hydrogen gas for two times, and the reaction was stirred at room temperature under hydrogen for 3 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was filtered to remove palladium on charcoal and the solution was condensed to give the crude compound 8- ((3 as,4r,6s,6 ar) -6- (2- (2-aminoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (10.0 mg, yield 68.7%).
MS(ESI)M/Z:485.2[M+H] + .
Step I: 8- ((3 aS,4R,6S,6 aR) -6- (2- (2-aminoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (10 mg,0.02 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 s) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (2- (2-aminoquinolin-7-yl) ethyl) cyclopentane-1, 2-diol (2.0 mg).
MS(ESI)M/Z:445.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.95(s,1H),7.82(d,J＝8.8Hz,1H),7.53(d,J＝8.1Hz,1H),7.27(s,1H),7.03(d,J＝8.1Hz,1H),6.68(d,J＝8.8Hz,1H),6.43(s,2H),6.32(s,2H),4.79-4.66(m,2H),4.62(d,J＝4.7Hz,1H),4.25(dd,J＝13.7,6.3Hz,1H),3.77-3.68(m,1H),2.85(d,J＝5.2Hz,4H),2.77-2.62(m,2H),2.41-2.33(m,2H),2.19-2.06(m,1H),1.99-1.79(m,2H),1.72-1.51(m,2H).
Example 2
(1R, 2S,3R, 5R) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8- (5H) -yl) -5- ((E) -2- (2-aminoquinolin-7-yl) vinyl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (14 mg,0.03 mmol) was dissolved in methanol (1.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1.5 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- ((E) -2- (2-aminoquinolin-7-yl) vinyl) cyclopentane-1, 2-diol (4.0 mg).
MS(ESI)M/Z:443.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.98(s,1H),7.82(d,J＝8.8Hz,1H),7.56(d,J＝8.3Hz,1H),7.44-7.26(m,2H),6.68(d,J＝8.8Hz,1H),6.59-6.53(m,2H),6.46(s,2H),6.38(s,2H),4.86(t,J＝5.4Hz,2H),4.83-4.73(m,1H),4.29(dd,J＝12.5,6.2Hz,1H),3.93(q,J＝6.0Hz,1H),2.96-2.80(m,4H),2.77-2.64(m,1H),2.43-2.35(m,2H),2.25-2.11(m,1H),2.05-1.82(m,1H).
Example 3
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 4-chloro-8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (400 mg,1.11 mmol) was dissolved in aqueous ammonia/isopropanol (7 mL/5 mL) at room temperature, and the reaction was capped and heated to 120℃and stirred for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give compound 8- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (170.0 mg, yield 45.0%).
MS(ESI)M/Z:341.0[M+H] + .
And (B) step (B): 8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (30 mg,0.09 mmol), 3-bromo-7-iodoquinolin-2-amine (37.1 mg,0.11 mmol), and tetraethylammonium chloride (16.0 mg,0.10 mmol) were dissolved in N, N-dimethylformamide (3 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (3.9 mg,0.02 mmol) and N, N-diisopropylethylamine (56.8 mg,0.44 mmol) were added under nitrogen. The reaction solution was stirred at 70℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (20 mL), extract the mixture with ethyl acetate (20 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (15 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 8- ((3 as,4r,6 ar) -6- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (26 mg).
MS(ESI)M/Z:560.8[M+H] + .
Step C: 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (40 mg,0.07 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol (10.0 mg).
MS(ESI)M/Z:520.8[M+H] + .
1 H NMR(400MHz,MeOD)δ8.24(s,1H),8.01(s,1H),7.56(d,J＝8.4Hz,1H),7.48(s,1H),7.44(d,J＝8.5Hz,1H),6.76-6.51(m,2H),4.94-4.89(m,1H),4.49(t,J＝6.4Hz,1H),4.12(t,J＝6.4Hz,1H),3.03-2.82(m,5H),2.64-2.46(m,2H),2.39-2.28(m,1H),2.05(dd,J＝23.3,10.9Hz,1H).
Example 4
(1S, 2R,3R, 5R) -3- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -5- (4- (methylamino) -6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 4-chloro-8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (200 mg,0.56 mmol) was dissolved in methyl ammonia/isopropyl alcohol (1 mL/5 mL) at room temperature, and the reaction system was capped and heated to 120℃and stirred for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 8- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -N-methyl-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (140.0 mg).
MS(ESI)M/Z:355.0[M+H] + .
And (B) step (B): 8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -N-methyl-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (100 mg,0.28 mmol), 7-bromoquinolin-2-amine (75.2 mg,0.34 mmol) and tetraethylammonium chloride (51.0 mg,0.31 mmol) were dissolved in N, N-dimethylformamide (5 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (12.6 mg,0.056 mmol) and N, N-diisopropylethylamine (180.6 mg,1.4 mmol) were added under nitrogen. The reaction solution was stirred at 100℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (50 mL), extract the mixture with ethyl acetate (50 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (50 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 8- ((3 as,4r,6 ar) -6- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -N-methyl-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (80 mg).
MS(ESI)M/Z:497.0[M+H] + .
Step C: 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -N-methyl-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (40 mg,0.07 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3r,5 r) -3- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -5- (4- (methylamino) -6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol (35.0 mg).
MS(ESI)M/Z:457.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.28(s,1H),7.11(t,J＝9.0Hz,1H),6.85-6.75(m,1H),6.68(s,1H),6.66-6.54(m,1H),5.98(dd,J＝8.8,4.1Hz,1H),5.88-1.87(m,1H),5.82-5.69(m,1H),4.18-4.10(m,1H),3.70(t,J＝6.5Hz,1H),3.34(t,J＝6.4Hz,1H),2.23(s,3H),2.20-2.01(m,5H),1.79-1.67(m,2H),1.59-1.50(m,1H),1.29-1.21(m,1H).
Example 5
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A adding Compound 8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] to the reaction flask][1,3]Dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5]Pyrrolo [2,3-d]A solution of pyrimidin-4-amine (80 mg,0.235 mmol) in tetrahydrofuran (3 mL) was then replaced with nitrogen. A solution of 9-BBN (2.35 mmol) in tetrahydrofuran (0.5M, 4.7 mL) was slowly added dropwise at room temperature, and after completion of the addition, the reaction solution was heated to 65℃and stirred at this temperature for 1 hour. The reaction system was cooled to room temperature by removing an oil bath, and then an aqueous solution (1 mL) of potassium phosphate (249.1 mg,1.175 mmol) was added to the reaction mixture. After the reaction solution was stirred at room temperature for 30 minutes, 3-bromo-7-iodoquinolin-2-amine (79 mg,0.225 mmol) and PdCl were added 2 (dppf) (18 mg,0.024 mmol) in tetrahydrofuran (1 mL). The resulting reaction mixture was heated to 65℃and stirred overnight.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give 8- ((3 as,4r,6s,6 ar) -6- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (60 mg).
MS(ESI)M/Z:562.8[M+H] + ,564.8[M+H+2] + .
And (B) step (B): the compound 8- ((3 aS,4R,6S,6 aR) -6- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (60 mg,0.106 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was dissolved in methanol (2 mL) and then 7M methanolic ammonia was added to adjust the pH to approximately 8-9. The resulting solution was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3s,5 r) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol (5.5 mg).
MS(ESI)M/Z:523.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.26(s,1H),7.97(s,1H),7.56(d,J＝8.2Hz,1H),7.41(s,1H),7.20(dd,J＝8.3,1.5Hz,1H),4.82-4.77(m,1H),4.44(dd,J＝7.9,6.2Hz,1H),3.94-3.86(m,1H),3.01-2.74(m,6H),2.56-2.46(m,2H),2.36-2.25(m,1H),2.12-1.96(m,2H),1.88-1.69(m,2H).
Example 6
(1S, 2R,3R, 5R) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- ((1R) -2- (2-aminoquinolin-7-yl) cyclopropyl) cyclopentane-1, 2-diol and isomers thereof
The reaction route is as follows:
the operation steps are as follows:
step A: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (250.0 mg,0.50 mmol), di-tert-butyl dicarbonate (326.8 mg,1.5 mmol) and 4-dimethylaminopyridine (12.2 mg,0.1 mmol) were dissolved in tetrahydrofuran (12 mL) at room temperature. Subsequently, triethylamine (202.4 mg,2.0 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. To the crude product was added water (100 mL) and quenched, the mixture was extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give di-tert-butyl (7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-yl) carbamate (250 mg, yield 71.2%).
MS(ESI)M/Z:724.3[M+Na] + .
And (B) step (B): an aqueous solution of potassium hydroxide (1.7 g,25mL of water) was slowly added to diethyl ether (60 mL) at-10deg.C, and the reaction solution of 1-methyl-1-nitrosourea (3.0 g,29.1 mmol) was further added and stirring was continued at-10deg.C for 1 hour. The reaction solution was cooled to-78℃and the aqueous phase was frozen to pour out an organic phase, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered to give an ether solution (50 mL) of diazomethane prepared now.
Di-tert-butyl (7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-yl) carbamate (150 mg,0.21 mmol) and palladium acetate (43.2 mg,0.19 mmol) were dissolved in tetrahydrofuran (6 mL), the reaction system was replaced with nitrogen and cooled to-78℃and an ethereal solution of diazomethane (50 mL) prepared now was slowly added to the reaction solution. The reaction was slowly returned to room temperature and stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give di-tert-butyl (7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinolin-2-yl) carbamate (102 mg).
MS(ESI)M/Z:616.3[M+H-Boc] + .
Step C: di-tert-butyl (7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinolin-2-yl) carbamate (150.0 mg,0.21 mmol) was dissolved in aqueous ammonia/isopropanol (10 mL/3 mL) and the reaction was capped at 120℃and stirred for 24 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction solution was concentrated by distillation under reduced pressure to give the crude product 8- ((3 as,4R,6 ar) -6- ((1R) -2- (2-aminoquinolin-7-yl) cyclopropyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (90 mg).
MS(ESI)M/Z:497.2[M+H] + .
Step D: 8- ((3 aS,4R,6 aR) -6- ((1R) -2- (2-aminoquinolin-7-yl) cyclopropyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (90 mg,0.19 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. Purifying the mixed solution by preparative high performance liquid chromatography. Purification conditions were as follows, and column welch XBC18, 21.2X105 mm,5 μm (particle size) was prepared; mobile phase: water (containing 10 mmoles/liter of ammonium bicarbonate) and acetonitrile; flow rate: 20 ml/min; gradient: acetonitrile increased from 40vol% to 60vol% over 10 minutes; detection wavelength: 214nm. The product was collected and lyophilized under reduced pressure. Two isomers of (1S, 2R,3R, 5R) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- ((1R) -2- (2-aminoquinolin-7-yl) cyclopropyl) cyclopentane-1, 2-diol (example 6-P1:15.0mg, example 6-P2:13.0 mg) were obtained.
Example 6-P1:
HPLC: retention time 6.254 minutes. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:457.2[M+H] + .
1 H NMR(400MHz,MeOD)δ7.91(s,1H),7.84(d,J＝8.8Hz,1H),7.50(d,J＝8.3Hz,1H),7.23(s,1H),7.00(dd,J＝8.3,1.6Hz,1H),6.71(d,J＝8.8Hz,1H),4.93-4.85(m,1H),4.56(dd,J＝8.4,5.7Hz,1H),4.08(dd,J＝5.6,4.2Hz,1H),2.95-2.70(m,4H),2.52-2.27(m,3H),2.02-1.83(m,2H),1.80-1.65(m,1H),1.51-1.29(m,1H),1.18-1.02(m,2H).
Example 6-P2:
HPLC: retention time 6.533 min. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
Example 7
(1R, 2S,3R, 5R) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (((2-aminoquinolin-7-yl) oxy) methyl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A in a single vial, (3 aR,6 aR) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxan-4-one (830 mg,5.39 mmol), benzophenone (196 mg,1.08 mmol) and methanol (350 mL) were added. Then, nitrogen was continuously bubbled for 1 hour, and the resultant reaction solution was stirred for 1 hour under irradiation of a high-pressure mercury lamp (darkroom operation).
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 ar,6r,6 ar) -6- (hydroxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-one (630 mg).
1 H NMR(400MHz,DMSO-d 6 )δ4.92(t,J＝4.6Hz,1H),4.63(d,J＝5.4Hz,1H),4.18(d,J＝5.4Hz,1H),3.64-3.52(m,1H),3.46-3.38(m,1H),2.63-2.52(m,2H),2.41-2.34(m,1H),1.31(s,3H),1.26(s,3H).
Step B in a single vial, (3 aR,6R,6 aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-one (450 mg,2.42 mmol), t-butyldiphenylchlorosilane (666 mg,2.42 mmol) and anhydrous dichloromethane (20 mL) were added. The reaction flask was cooled to zero℃in an ice bath and imidazole (399 mg,4.84 mmol) was added in portions. The reaction mixture was warmed to room temperature and stirred for 3 hours.
After TLC monitoring showed the disappearance of starting material, ice water was added to the reaction solution for quenching. The reaction solution was extracted with dichloromethane (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 ar,6r,6 ar) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-one (550 mg).
1 H NMR(400MHz,DMSO-d 6 )δ7.63-7.55(m,4H),7.52-7.42(m,6H),4.73-4.60(m,1H),4.21(d,J＝5.4Hz,1H),3.78(dd,J＝10.1,2.9Hz,1H),3.59(dd,J＝10.1,3.6Hz,1H),2.80-2.61(m,1H),2.54-2.52(m,1H),2.49-2.45(m,1H),1.33(s,3H),1.27(s,3H),0.95(s,9H).
Step C A three-necked flask was charged with a solution of (3 aR,6R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-one (640 mg,1.5 mmol) in tetrahydrofuran (15 mL) and the system was replaced with nitrogen. The reaction flask was cooled to 0℃in an ice bath, and then a solution of lithium aluminum hydride (3.0 mmol) in tetrahydrofuran (2.5M, 1.2 mL) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 1 hour.
After TLC monitoring showed the disappearance of starting material, sodium sulfate decahydrate was slowly added to the reaction solution to quench until no bubbles emerged. Tetrahydrofuran was then added and stirred for 30 minutes, and the reaction solution was filtered. The filtrate was concentrated to give an oily crude product, which was purified by silica gel column chromatography to give (3 aS,4S,6R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (490 mg).
Step D A solution of trifluoromethanesulfonic anhydride (481 mg,1.73 mmol) in dichloromethane (15 mL) was added dropwise to the reaction mixture (5 mL) of a mixture of (3 aS,4S,6R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ D ] [1,3] dioxan-4-ol (490 mg,1.15 mmol) and pyridine (272 mg,3.45 mmol) in dichloromethane under ice-bath. The reaction solution was stirred at this temperature for half an hour.
After TLC monitoring showed the disappearance of starting material, ice water was added to the reaction solution for quenching. The reaction solution was extracted with dichloromethane (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 aR,4S,6R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl trifluoromethanesulfonate (640 mg).
Step E to a solution of 4-chloro-6, 7-dihydro-5H-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine-8-potassium salt (266 mg,1.15 mmol) in N, N-dimethylformamide (8 mL) was added dropwise a solution of (3 aR,4S,6R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl trifluoromethyl sulfonate (640 mg,1.15 mmol) in N, N-dimethylformamide (2 mL) under ice-bath. After the completion of the dropwise addition, the reaction solution was stirred at room temperature overnight.
TLC detection showed the formation of new spots, and the reaction was poured into ice water. The reaction solution was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by column chromatography on silica gel to give 8- ((3 as,4r,6 ar) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -4-chloro-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (492 mg).
MS(ESI)M/Z:602.2[M+H] + .
Step F-A three-necked flask was charged with a solution of 8- ((3 aS,4R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -4-chloro-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (492 mg,0.82 mmol) in tetrahydrofuran (10 mL), the system was replaced with a nitrogen atmosphere, and a solution of tetrabutylammonium fluoride (2.0 mmol) in tetrahydrofuran (1.0M, 2.0 mL) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give ((3 ar,4r,6 as) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) methanol (220 mg).
MS(ESI)M/Z:364.0[M+H] + .
Step G ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) methanol (170 mg,0.47 mmol) and 2-chloroquinolin-7-ol (126 mg,0.71 mmol) were dissolved in toluene (2 mL) at room temperature. 2- (tributylphosphoranylidene) acetonitrile (457 mg,1.88 mmol) was dissolved in toluene (0.5 mL). Subsequently, a toluene solution of 2- (tributylphosphoranylidene) acetonitrile was slowly added to the reaction system at room temperature. The reaction solution was stirred under an oil bath for 4 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (20 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-chloro-8- ((3 as,4r,6 ar) -6- (((2-chloroquinolin-7-yl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (190 mg).
MS(ESI)M/Z:525.0[M+H] + .
Step H4-chloro-8- ((3 aS,4R,6 aR) -6- (((2-chloroquinolin-7-yl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (190 mg,0.36 mmol) was dissolved in ammonia/isopropanol (5 mL/1.5 mL) at room temperature and the reaction was capped and heated to 120℃and stirred for 24 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction solution was concentrated by distillation under reduced pressure and the resulting residue was purified by column chromatography on silica gel to give 8- ((3 aS,4R,6 aR) -6- (((2-aminoquinolin-7-yl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (190 mg).
MS(ESI)M/Z:487.0[M+H] + .
Step I8- ((3 aS,4R,6 aR) -6- (((2-aminoquinolin-7-yl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (58 mg,0.12 mmol) was dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to approximately 8-9. The mixture was extracted with dichloromethane (5 ml×3 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (((2-aminoquinolin-7-yl) oxy) methyl) cyclopentane-1, 2-diol (12.8 mg).
MS(ESI)M/Z:447.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.95(s,1H),7.78(d,J＝8.8Hz,1H),7.52(d,J＝8.8Hz,1H),6.90(d,J＝2.4Hz,1H),6.81(dd,J＝8.8,2.4Hz,1H),6.58(d,J＝8.8Hz,1H),6.43(s,2H),6.31(s,2H),4.96-4.84(m,1H),4.80(dd,J＝9.9,5.5Hz,2H),4.35(dt,J＝8.8,6.2Hz,1H),4.19-4.05(m,2H),3.94(dd,J＝8.8,4.4Hz,1H),2.98-2.80(m,4H),2.44-2.34(m,3H),2.19(dt,J＝12.6,8.4Hz,1H),1.85-1.75(m,1H).
Example 8
(1R, 2S,3R, 5R) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (((2- ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl) cyclopentane-1, 2-diol
Preparation method referring to example 7, the target product (1 r,2s,3r,5 r) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (((2- ((cyclopropylmethyl) amino) quinolin-7-yl) oxy) methyl) cyclopentane-1, 2-diol is finally obtained.
MS(ESI)M/Z:501.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.95(s,1H),7.72(d,J＝8.8Hz,1H),7.49(d,J＝8.6Hz,1H),7.02(t,J＝5.4Hz,1H),6.96(d,J＝2.4Hz,1H),6.77(dd,J＝8.7,2.4Hz,1H),6.61(d,J＝8.8Hz,1H),6.43(s,2H),4.90(dd,J＝19.6,8.8Hz,1H),4.79(dd,J＝10.2,5.6Hz,2H),4.35(dt,J＝8.8,6.2Hz,1H),4.13(p,J＝9.8Hz,2H),3.94(dd,J＝8.6,4.6Hz,1H),3.28-3.22(m,2H),2.97-2.81(m,4H),2.45-2.35(m,3H),2.18(dt,J＝13.0,8.6Hz,1H),1.79(dd,J＝21.0,11.0Hz,1H),1.18-1.02(m,1H),0.50-0.43(m,2H),0.29-0.21(m,2H).
Example 9
(1S, 2R,3R, 5R) -3- ((1R) -2- (2-amino-3-bromoquinolin-7-yl) cyclopropyl) -5- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentyl-1, 2-diol and isomers thereof
The reaction route is as follows:
the operation steps are as follows:
step A: 4-chloro-8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (137.2mg,0.38 mmol), 3-bromo-7-iodoquinolin-2-amine (140.0 mg,0.40 mmol) and tetraethylammonium chloride (69.2 mg,0.42 mmol) were dissolved in N, N-dimethylformamide (6 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (17.1 mg,0.07 mmol) and N, N-diisopropylethylamine (245.1 mg,1.9 mmol) were added under nitrogen. The reaction solution was stirred at 70℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (100 mL), extract the mixture with ethyl acetate (100 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (150 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 3-bromo-7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) vinyl) quinolin-2-amine (125 mg).
MS(ESI)M/Z:580.0[M+H] + .
And (B) step (B): 3-bromo-7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) vinyl) quinolin-2-amine (145.0 mg,0.25 mmol), di-tert-butyl dicarbonate (191.3 mg,0.88 mmol) and 4-dimethylaminopyridine (6.1 mg,0.05 mmol) are dissolved in tetrahydrofuran (7 mL) at room temperature. Subsequently, triethylamine (126.5 mg,1.25 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. To the crude product was added water (50 mL) and the mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound di-tert-butyl (3-bromo-7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-yl) carbamate (190 mg).
MS(ESI)M/Z:802.2[M+Na] + .
Step C: an aqueous solution (25 mL) of potassium hydroxide (1.7 g) was slowly added to diethyl ether (60 mL) at-10deg.C, and the reaction solution of 1-methyl-1-nitrosourea (3.0 g,29.1 mmol) was added and stirring continued at-10deg.C for 1 hour. The reaction solution was cooled to-78℃and the aqueous phase was frozen to pour out an organic phase, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered to give an ether solution (50 mL) of diazomethane prepared now.
Di-tert-butyl (3-bromo-7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-yl) carbamate (160 mg,0.21 mmol) and palladium acetate (41.4 mg,0.18 mmol) were dissolved in tetrahydrofuran (4 mL), the reaction system was purged with nitrogen and cooled to-78deg.C, and the freshly prepared diethyl ether solution of diazomethane (50 mL) was slowly added to the reaction solution. The reaction was slowly returned to room temperature and stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound di-tert-butyl (3-bromo-7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinolin-2-yl) carbamate (85 mg).
MS(ESI)M/Z:816.3[M+Na] + .
Step D: di-tert-butyl (3-bromo-7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-chloro-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinolin-2-yl) carbamate (75.0 mg,0.09 mmol) was dissolved in the mixed solution (ammonia/isopropanol=7/3, volume ratio, 10 mL) at room temperature, the reaction system was capped and heated to 120℃and stirred for 24 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction solution was concentrated by reduced pressure distillation to give the crude compound 8- ((3 as,4R,6 ar) -6- ((1R) -2- (2-amino-3-bromoquinolin-7-yl) cyclopropyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (45 mg).
MS(ESI)M/Z:575.2[M+H] + .
Step E: 8- ((3 aS,4R,6 aR) -6- ((1R) -2- (2-amino-3-bromoquinolin-7-yl) cyclopropyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (45 mg,0.08 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. Purifying the mixed solution by preparative high performance liquid chromatography. Purification conditions were as follows, and column welch XBC18, 21.2X105 mm,5 μm (particle size) was prepared; mobile phase: water (containing 10 mmoles/liter of ammonium bicarbonate) and acetonitrile; flow rate: 20 ml/min; gradient: acetonitrile increased from 40vol% to 60vol% over 10 minutes; detection wavelength: 214nm. The product was collected and lyophilized under reduced pressure. Two isomers of (8- ((3 aS,4R,6 aR) -6- ((1R) -2- (2-amino-3-bromoquinolin-7-yl) cyclopropyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (example 9-P1:7.1mg, example 9-P2:5.5 mg) were obtained.
Example 9-P1
HPLC: retention time 7.144 min. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:535.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.22(s,1H),7.91(s,1H),7.51(d,J＝8.3Hz,1H),7.27(s,1H),7.05(dd,J＝8.4,1.5Hz,1H),4.82-4.74(m,1H),4.58(dd,J＝8.3,5.7Hz,1H),4.17-3.95(m,1H),2.88(t,J＝6.4Hz,4H),2.53-2.27(m,3H),2.02-1.84(m,2H),1.79-1.65(m,1H),1.52-1.37(m,1H),1.20-0.99(m,2H).
Example 9-P2
HPLC: retention time 7.376 min. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:535.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.24(s,1H),7.98(s,1H),7.53(d,J＝8.3Hz,1H),7.28(s,1H),7.08(dd,J＝8.3,1.6Hz,1H),4.83-4.79(m,1H),4.51(dd,J＝8.2,6.0Hz,1H),4.07-3.96(m,1H),3.03-2.83(m,4H),2.59-2.46(m,2H),2.33(m,1H),2.13-2.02(m,1H),2.02- 1.83(m,1H),1.79-1.67(m,1H),1.40-1.29(m,1H),1.13-1.06(m,1H),1.06-0.95(m,1H).
Example 10
(1R, 2S,3R, 5R) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- ((E) -2- (3-bromo-2- ((cyclopropylmethyl) amino) quinolin-7-yl) vinyl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 3-bromo-2-chloro-7-iodoquinoline (150 mg,0.43 mmol) and cyclopropylmethylamine (2 mL) were dissolved in ethanol (2 mL) at room temperature, and the reaction system was heated to 120℃under sealed tube conditions and stirred for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-bromo-N- (cyclopropylmethyl) -7-iodoquinolin-2-amine (70.0 mg).
MS(ESI)M/Z:402.8[M+H] + .
And (B) step (B): 8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (20.0 mg,0.059 mmol), 3-bromo-N- (cyclopropylmethyl) -7-iodoquinolin-2-amine (24.7 mg,0.062 mmol) and tetraethylammonium chloride (10.7 mg, 0.065 mmol) were dissolved in N, N-dimethylformamide (1.5 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (2.6 mg,0.012 mmol) and N, N-diisopropylethylamine (38.1 mg,0.29 mmol) were added under nitrogen. The reaction solution was stirred at 70℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (20 mL), extract the mixture with ethyl acetate (20 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (20 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 8- ((3 as,4r,6 ar) -6- ((E) -2- (3-bromo-2- ((cyclopropylmethyl) amino) quinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (25.0 mg).
MS(ESI)M/Z:308.2[2M+2H] 2+ .
Step C: 8- ((3 aS,4R,6 aR) -6- ((E) -2- (3-bromo-2- ((cyclopropylmethyl) amino) quinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (25 mg,0.04 mmol) was dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (2 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- ((E) -2- (3-bromo-2- ((cyclopropylmethyl) amino) quinolin-7-yl) vinyl) cyclopentane-1, 2-diol (6.0 mg).
MS(ESI)M/Z:575.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.98(s,1H),7.60(d,J＝8.4Hz,1H),7.52(s,1H),7.39(d,J＝8.3Hz,1H),6.69(t,J＝5.5Hz,1H),6.60(d,J＝5.5Hz,2H),6.46(s,2H),4.87(t,J＝6.1Hz,2H),4.84-4.74(m,1H),4.29(dd,J＝12.4,6.2Hz,1H),3.94(dd,J＝6.1Hz,1H),3.37-3.35(m,2H),2.95-2.79(m,4H),2.72(d,J＝6.4Hz,1H),2.44-2.36(m,2H),2.24-2.11(m,1H),1.91(dd,J＝23.1,10.7Hz,1H),1.30-1.14(m,1H),0.48-0.39(m,2H),0.35-0.22(m,2H).
Example 11
(1R, 2S,3R, 5R) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (((2-aminoquinolin-7-yl) amino) methyl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 8- ((3 aS,4R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -4-chloro-5, 6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidine (405.0 mg,0.67 mmol) was dissolved in ammonia/isopropanol (8 mL/3 mL) at room temperature, and the reaction system was capped and heated to 120℃and stirred for 40 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 8- ((3 as,4r,6 ar) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (200.0 mg).
MS(ESI)M/Z:583.5[M+H] + .
And (B) step (B): 8- ((3 aS,4R,6 aR) -6- (((tert-butyldiphenylsilyl) oxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (170.0 mg,0.29 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature. Tetrabutylammonium fluoride (1.0M, 0.58 mL) was slowly added dropwise to the reaction system, and the reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (30 mL), extract the mixture with ethyl acetate (30 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (15 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography to give ((3 ar,4r,6 as) -6- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) methanol (73 mg).
MS(ESI)M/Z:345.3[M+H] + .
Step C: ((3 aR,4R,6 aS) -6- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) methanol (88 mg,0.26 mmol) was dissolved in pyridine (4 mL) at 0℃and trimethylchlorosilane (86.1 mg,0.79 mmol) was slowly dropped into the reaction system under nitrogen protection, and the reaction solution was stirred at 0℃for 3 hours. Benzoyl chloride (43.8 mg,0.31 mmol) was then slowly added dropwise to the reaction system, and the reaction mixture was slowly returned to room temperature, and stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction mixture was quenched by addition of ammonia (4 mL), stirred at room temperature for 1 hour, the mixture was extracted with dichloromethane (50 mL. Times.2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N- (8- ((3 aS,4R,6 aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-yl) benzamide (70 mg).
MS(ESI)M/Z:449.3[M+H] + .
Step D: n- (8- ((3 aS,4R,6 aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-yl) benzamide (50 mg,0.11 mmol) was dissolved in dichloromethane (3 mL) at room temperature, and a dess-Martin oxidizing agent (56.8 mg,0.13 mmol) was slowly added dropwise to the reaction system under nitrogen protection, and the reaction solution was stirred at room temperature for 2 hours.
After TLC monitoring showed the disappearance of starting material, the reaction was filtered to remove most of the solids and the filtrate was concentrated to give the crude product N- (8- ((3 aS,4R,6S,6 aR) -6-formyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-yl) benzamide (70.0 mg) directly used in the next step.
Step E: n- (8- ((3 aS,4R,6S,6 aR) -6-formyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-yl) benzamide (49.9 mg,0.11 mmol), 2-chloroquinolin-7-amine (29.9 mg,0.17 mmol), acetic acid (33.6 mg,0.56 mmol) and potassium acetate (32.9 mg,0.34 mmol) were dissolved in methanol (3 mL) at room temperature. The reaction solution was stirred at room temperature under nitrogen for 2 hours. Sodium cyanoborohydride (21.1 mg,0.33 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. To the residue was added ethyl acetate (25 mL), followed by washing with saturated sodium bicarbonate (20 mL. Times.2), followed by drying over anhydrous sodium sulfate, filtration, and finally concentration under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give N- (8- ((3 aS,4R,6 aR) -6- ((2-chloroquinolin-7-yl) amino) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-yl) benzamide (45 mg).
MS(ESI)M/Z:609.4[M+H] + .
Step F: n- (8- ((3 aS,4R,6 aR) -6- ((2-chloroquinolin-7-yl) amino) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-yl) benzamide (33.3 mg,0.067 mmol) was dissolved in ammonia/ethanol (20 mL/4 mL) at room temperature and the reaction was heated to 200℃in a closed jar with stirring for 40 hours.
After LCMS monitoring showed 60% disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The residue obtained was not purified and was used directly in the next step.
MS(ESI)M/Z:486.2[M+H] + .
Step G: at room temperature, N 7 - ((3 aR,4R,6 aS) -6- (4-amino-6, 7-dihydro-cyclopenta [4, 5) ]Pyrrolo [2,3-d]Pyrimidin-8 (5H) -yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ]][1,3]Dioxa-4-yl) methyl-quinoline-2, 7-diamine (35 mg,0.07 mmol) was dissolved in methanol (0.5 mL). Subsequently, 4M hydrochloric acid-methanol solution (2 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- (4-amino-6, 7-dihydro-cyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-8 (5H) -yl) -5- (((2-aminoquinolin-7-yl) amino) methyl) cyclopentane-1, 2-diol (1.0 mg).
MS(ESI)M/Z:446.2[M+H] + .
1 H NMR(400MHz,MeOD)δ7.98(s,1H),7.78(d,J＝8.9Hz,1H),7.35(d,J＝9.0Hz,1H),7.07(dd,J＝9.0,2.6Hz,1H),6.78(d,J＝2.6Hz,1H),6.74(d,J＝8.9Hz,1H),4.93-4.86(m,1H),4.60-4.46(m,1H),4.05(dd,J＝5.9,4.3Hz,1H),3.43-3.35(m,1H),3.28-3.21(m,1H),2.97-2.86(m,4H),2.55-2.45(m,2H),2.44-2.36(m,1H),2.36-2.26(m,1H),1.96-1.81(m,1H).
Example 12
(1R, 2S,3R, 5R) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((E) -2- (2-aminoquinolin-7-yl) vinyl) cyclopentane-1, 2-diol trifluoroacetate
The reaction route is as follows:
the operation steps are as follows:
step A: 4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-D ] pyrimidine (775 mg,5.0 mmol) was dissolved in tetrahydrofuran (40 mL) at room temperature. Potassium tert-butoxide (559 mg,5.0 mmol) was added in portions to the reaction system at room temperature. The reaction solution was stirred at room temperature for 2 hours.
After the disappearance of the starting material, the reaction solution was a white turbid liquid. The reaction solution was concentrated, dried by spin, N-diisopropylethylamine (20 mL) was added, and sonicated for 10 minutes. The reaction mixture was filtered, and the cake was 4-chloro-5, 6-dihydropyrrolo [2,3-d ] pyrimidine-7-potassium salt (wet weight: 1.1 g).
1 H NMR(400MHz,DMSO-d 6 )δ7.38(s,1H),3.48(t,J＝8.6Hz,2H),2.66(t,J＝8.4Hz,2H).
And (B) step (B): potassium 4-chloro-5, 6-dihydropyrrolo [2,3-d ] pyrimidine-7-carboxylate (562 mg,2.9 mmol) and dissolved in N, N-dimethylformamide (12 mL) at room temperature. (3 aR,4S,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl trifluoromethanesulfonate (910 mg,2.9 mmol) is dissolved in N, N-dimethylformamide (6 mL). Subsequently, the above solution was slowly added to the reaction system under an ice bath. The reaction was stirred overnight at 25 ℃ in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-chloro-7- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (520 mg).
MS(ESI)M/Z:322.0[M+H] + .
Step C: 4-chloro-7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (150 mg,0.5 mmol), 7-bromoquinolin-2-amine (125 mg,0.6 mmol) and tetraethylammonium chloride (85.1 mg,0.5 mmol) are dissolved in N, N-dimethylformamide (6 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (21 mg,0.1 mmol), N, N-diisopropylethylamine (0.4 mL,2.42 mmol) was added under nitrogen. The reaction solution was stirred at 100℃in an oil bath for 12 hours.
After TLC monitoring showed the disappearance of starting material, the reaction mixture was quenched by addition of water (20 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) vinyl) quinolin-2-amine (115 mg).
1 H NMR(400MHz,DMSO-d 6 )δ8.14(s,1H),7.84(d,J＝8.8Hz,1H),7.57(d,J＝8.2Hz,1H),7.37(s,1H),7.35-7.30(m,1H),6.70(d,J＝8.8Hz,1H),6.59(d,J＝15.8Hz,1H),6.54-6.40(m,3H),4.80(dd,J＝7.4,5.6Hz,1H),4.51-4.46(m,2H),3.86-3.68(m,2H),3.05(t,J＝9.2Hz,2H),2.78(dd,J＝16.2,7.8Hz,1H),2.08(d,J＝7.6Hz,2H),1.48(s,3H),1.25(s,3H).
Step D7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-D ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ D ] [1,3] dioxa-4-yl) vinyl) quinolin-2-amine (237 mg,0.5 mmol) and tert-butyl carbamate (240 mg,2.1 mmol) are dissolved in N, N-dimethylformamide (5 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Tri (dibenzylideneacetone) dipalladium (47 mg,0.05 mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (25 mg,0.05 mmol), cesium carbonate (333 mg,1.0 mmol) were added under nitrogen. The reaction solution was stirred for 3 hours at 100℃under microwaves.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (60 mg).
MS(ESI)M/Z:445.2[M+H] + .
Step E: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (60 mg,0.1 mmol) was dissolved in methanol (2 mL) at room temperature. Subsequently, 4mol/L hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1mol/L sodium hydroxide solution was added to the reaction solution to adjust the pH to approximately 8-9. The mixture was extracted with dichloromethane (5 ml×3 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((E) -2- (2-aminoquinolin-7-yl) vinyl) cyclopentane-1, 2-diol trifluoroacetate (12.6 mg).
MS(ESI)M/Z:405.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.30(d,J＝9.2Hz,1H),8.20(s,1H),7.85(d,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,1H),7.54(s,1H),7.17(brs,2H),6.98(d,J＝9.2Hz,1H),6.64-6.55(m,2H),5.10-4.75(m,2H),4.45-4.35(m,1H),4.05-3.94(m,1H),3.86-3.70(m,3H),2.93-2.82(m,2H),2.71-2.65(m,1H),2.03-1.96(m,1H),1.63-1.54(m,1H).
Example 13
(1R, 2S,3R, 5S) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- (2- (2-aminoquinolin-7-yl) ethyl) cyclopentane-1, 2-diol and isomers thereof
The reaction route is as follows:
the operation steps are as follows:
compound 13-2 was prepared by the method of reference compound 1-6.
Step A: to a solution of 4-chloropyrrolo [2,3-d ] pyrimidine-7-amide potassium (416 mg,2.16 mmol) in N, N-dimethylformamide (2 mL) was added dropwise (3 aR,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl trifluoromethane sulfonate (685 mg,2.16mmol, preparation method reference compound 1-6) in N, N-dimethylformamide (2 mL) under ice-bath. After the completion of the dropwise addition, the reaction solution was stirred at room temperature overnight.
TLC detection showed the formation of new spots and the reaction was poured into ice water. The reaction solution was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 4-chloro-7- ((3 as,6r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine (390 mg).
MS(ESI)M/Z:320.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.64(s,1H),7.30(d,J＝3.6Hz,1H),6.63(d,J＝3.6Hz,1H),6.03-5.89(m,1H),5.23-5.12(m,2H),5.06-4.97(m,2H),4.62(t,J＝6.7Hz,1H),2.83(dd,J＝12.6,6.4Hz,1H),2.53-2.30(m,2H),1.59(s,3H),1.32(s,3H).
And (B) step (B): 4-chloro-7- ((3 aS,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine (330 mg,1.03 mmol), 7-bromoquinolin-2-amine (250 mg,1.13 mmol) and tetraethylammonium chloride (188 mg,1.13 mmol) were dissolved in N, N-dimethylformamide (2 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (46 mg,0.206 mmol) and N, N-diisopropylethylamine (661mg, 5.16 mmol) were added under nitrogen. The reaction solution was stirred at 100℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (130 mg).
MS(ESI)M/Z:462.2[M+H] + .
Step C: to a 10mL tube seal was added 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (130 mg,0.28 mmol), concentrated aqueous ammonia (4 mL), and isopropanol (2 mL). The reaction solution was sealed, then heated to 110 ℃ and stirred at this temperature overnight.
TLC monitoring showed the disappearance of starting material and concentration under reduced pressure gave the crude product. The crude product was purified by silica gel chromatography to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (120 mg).
1 H NMR(400MHz,MeOD)δ8.14(d,J＝9.2Hz,1H),8.11(s,1H),7.73(d,J＝8.3Hz,1H),7.58-7.48(m,2H),7.32(d,J＝3.6Hz,1H),6.91(d,J＝9.1Hz,1H),6.76-6.54(m,3H),5.13-5.01(m,2H),4.75(t,J＝6.9Hz,1H),3.09-2.94(m,1H),2.56-2.35(m,2H),1.57(s,3H),1.31(s,3H).
Step D. In an autoclave, the compound 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-7H-pyrrolo [2,3-D ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ D ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (35 mg,0.079 mmol), 10wt% palladium on carbon (10 mg) and ethanol (20 mL) were added. The reaction system was replaced with a hydrogen atmosphere, heated to 35℃at 15 atm, and after 24 hours of reaction, the reaction was monitored to find that there were 20% (mole fraction) of the product and 80% (mole fraction) of the starting material. Stirring was then continued for two days at this pressure temperature.
LCMS monitoring showed complete consumption of starting material. The reaction solution was filtered, and the cake was washed 3 times with ethanol. The combined filtrates were concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography to give 7- (2- ((3 aR,4S,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) ethyl) quinolin-2-amine (9 mg).
MS(ESI)M/Z:447.2[M+H] + .
1 H NMR(400MHz,MeOD)δ8.08(s,1H),7.31(d,J＝3.5Hz,1H),7.20(d,J＝7.7Hz,1H),7.08(d,J＝7.7Hz,1H),6.97(s,1H),6.65(d,J＝3.5Hz,1H),5.34(t,J＝4.8Hz,1H),4.96(d,J＝2.9Hz,1H),4.51(t,J＝5.9Hz,1H),2.99-2.91(m,4H),2.72(t,J＝7.7Hz,2H),2.40-2.32(m,1H),2.06-2.00(m,2H),1.94-1.87(m,1H),1.84-1.76(m,1H),1.51(s,3H), 1.33(s,3H).
Step E Compound 7- (2- ((3 aR,4S,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) ethyl) quinolin-2-amine (9 mg,0.02 mmol) is dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was dissolved in 1mL of methanol and then 7M methanolic ammonia was added to adjust the pH to approximately 8-9. The obtained solution is purified by preparative high performance liquid chromatography. Purification conditions were as follows, and column welch XBC18, 21.2X105 mm,5 μm (particle size) was prepared; mobile phase: water (containing 10 mmoles/liter of ammonium bicarbonate) and acetonitrile; flow rate: 20 mL/min; gradient: acetonitrile increased from 40vol% to 60vol% over 10 minutes; detection wavelength: 214nm. The product was collected and lyophilized under reduced pressure. Two isomers of (1R, 2S, 5S) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- (2- (2-aminoquinolin-7-yl) ethyl) cyclopentane-1, 2-diol were obtained (example 13-P1,1.3mg, yield 15.8%; example 13-P2,1 mg).
Example 13-P1:
HPLC retention time 5.327 min. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:407.2[M+H] + .
1 H NMR(400MHz,MeOD)δ8.06(s,1H),7.22(d,J＝3.6Hz,1H),7.04(d,J＝7.5Hz,1H),6.87(d,J＝7.6Hz,1H),6.83(s,1H),6.60(d,J＝3.6Hz,1H),4.89(d,J＝8.0Hz,1H),4.31(dd,J＝7.8,6.2Hz,1H),3.90-3.83(m,1H),2.84-2.77(m,2H),2.74-2.51(m,4H),2.45-2.34(m,1H),2.06-1.93(m,2H),1.78-1.67(m,1H),1.66-1.56(m,1H).
Example 13-P2:
HPLC retention time 5.691 min. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:407.2[M+H] + .
1 H NMR(400MHz,MeOD)δ8.06(s,1H),7.22(d,J＝3.6Hz,1H),7.08(d,J＝7.7Hz,1H),6.86(dd,J＝7.6,1.5Hz,1H),6.74(s,1H),6.60(d,J＝3.6Hz,1H),4.90-4.88(m,1H),4.32(dd,J＝7.8,6.2Hz,1H),3.91-3.83(m,1H),2.94-2.87(m,2H),2.75-2.58(m,2H),2.54(dd,J＝8.4,6.7Hz,2H),2.43-2.34(m,1H),2.06-1.92(m,2H),1.77-1.68(m,1H),1.65-1.57(m,1H).
Example 14
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 4-chloro-7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (630 mg,1.96 mmol), tert-butyl carbamate (1.15 g,9.82 mmol) was dissolved in N, N-dimethylformamide (10 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Tri (dibenzylideneacetone) dipalladium (180 mg,0.2 mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (93.6 mg,0.2 mmol) and cesium carbonate (1.3 g,3.93 mmol) were added under nitrogen. The reaction solution was stirred for 3 hours at 100℃under microwaves.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 7- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -6, 7-dihydro-5H-pyrrolidin [2,3-d ] pyrimidin-4-amine (260 mg).
MS(ESI)M/Z:303.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.82(s,1H),6.00(s,2H),5.87(ddd,J＝17.4,10.4,7.2Hz,1H),5.15-4.96(m,2H),4.70(dd,J＝7.4,5.4Hz,1H),4.32-4.24(m,2H),3.59-3.44(m, 2H),2.73-2.67(m,2H),2.55-2.52(m,1H),1.98-1.84(m,2H),1.43(s,3H),1.21(s,3H).
And (B) step (B): 7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -6, 7-dihydro-5H-pyrrolidin [2,3-d ] pyrimidin-4-amine (57 mg,0.19 mmol), 3-bromo-7-iodoquinolin-2-amine (79 mg,0.23 mmol) and tetraethylammonium chloride (34.6 mg,0.21 mmol) were dissolved in N, N-dimethylformamide (2 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (4.3 mg,0.02 mmol) and N, N-diisopropylethylamine (0.01 mL,0.06 mmol) were added under nitrogen. The reaction solution was stirred for 12 hours at 65℃in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) vinyl) -3-bromoquinolin-2-amine (20 mg).
MS(ESI)M/Z:523.2[M+H] + ,525.2[M+2+H] + .
Step C: the compound 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) vinyl) -3-bromoquinolin-2-amine (20 mg,0.04 mmol) was dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to approximately 8-9. The mixture was extracted with dichloromethane (5 ml×3 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (5.2 mg).
MS(ESI)M/Z:483.0[M+H] + ,485.2[M+2+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.81(s,1H),7.59(d,J＝8.98Hz,1H),7.40(d,J＝6.4Hz,2H),6.61(s,2H),6.61-6.44(m,2H),5.94(s,2H),4.82(d,J＝5.2Hz,1H),4.68(d,J＝5.6Hz,1H),4.22(dd,J＝16.0,8.0Hz,1H),3.97(dd,J＝11.8,5.98Hz,1H),3.72(q,J＝5.6Hz,1H),3.52(t,J＝8.8Hz,2H),2.75-2.71(m,2H),2.61-2.59(m,1H),1.97-1.91(m,1H),1.56-1.48(m,1H).
Example 15
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (50 mg,0.164 mmol) and tetrahydrofuran (1 mL) were added to a three-necked flask. The displacement reaction system was a nitrogen system, and then a tetrahydrofuran solution (0.5M, 3.2 mL) of 9-BBN (1.64 mmol) was dropwise added to the reaction system, and after the completion of the dropwise addition, the reaction solution was heated to 60℃and reacted for 1 hour. The reaction was also cooled to room temperature, and a solution of potassium phosphate (174 mg,0.82 mmol) in water (2 mL) was added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for another 30 minutes, and then 3-bromo-7-iodoquinolin-2-amine (60 mg,0.17 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (10 mg,0.014 mmol) were added to the reaction system. The reaction system was replaced again with a nitrogen system, then heated to 60℃and stirred overnight. After TLC monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting mixture was purified by silica gel chromatography to give 7- (2- ((3 aR,4S,6R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) ethyl) -3-bromoquinolin-2-amine (55 mg, yield 63.9%).
MS(ESI)M/Z:525.8[M+H] + .
Step B7- (2- ((3 aR,4S,6R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) ethyl) -3-bromoquinolin-2-amine (55 mg,0.104 mmol) is dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure, then diluted with methanol and pH adjusted to about 8-9 by simultaneous addition of 7M methanolic ammonia solution. The mixture was concentrated under pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3s,5 r) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (18 mg, yield 36.0%).
MS(ESI)M/Z:484.8[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.79(s,1H),7.57(d,J＝8.2Hz,1H),7.30(s,1H),7.10(d,J＝8.2Hz,1H),6.56(s,2H),5.92(s,2H),4.77(d,J＝5.6Hz,1H),4.40(d,J＝4.7Hz,1H),4.20-4.07(m,1H),3.93-3.82(m,1H),3.60-3.41(m,3H),2.79-2.68(m,4H),1.97-1.80(m,2H),1.80-1.63(m,1H),1.63-1.45(m,1H),1.31-1.11(m,1H).
Example 16
(1R, 2S,3R, 5R) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((1R) -2- (2-aminoquinolin-7-yl) cyclopropyl) cyclopentane-1, 2-diol and isomers thereof
The reaction route is as follows:
the operation steps are as follows:
step A: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (300 mg,0.65 mmol), di-tert-butyl dicarbonate (0.6 mL,2.6 mmol) and 4-dimethylaminopyridine (16 mg,0.13 mmol) are dissolved in tetrahydrofuran (10 mL) at room temperature. Subsequently, triethylamine (0.36 ml,2.6 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. To the crude product was added water (50 mL) and the mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give di-tert-butyl (7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-yl) carbamate (190 mg).
MS(ESI)M/Z:664.2[M+H] + .
And (B) step (B): an aqueous solution of potassium hydroxide (1.92 g,30mL of water) was slowly added to diethyl ether (70 mL) at-10deg.C, and the reaction solution of 1-methyl-1-nitrosourea (3.5 g,33.9 mmol) was further added and stirring was continued at-10deg.C for 1 hour. The reaction solution was cooled to-78℃and the aqueous phase was frozen to pour out an organic phase, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered to give an ether solution (50 mL) of diazomethane prepared now.
Di-tert-butyl (7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-yl) carbamate (150 mg,0.23 mmol) and palladium acetate (50.8 mg,0.23 mmol) were dissolved in tetrahydrofuran (4 mL), the reaction system was replaced with nitrogen and cooled to-78℃and the freshly prepared diethyl ether solution of diazomethane (70 mL) was slowly added to the reaction solution. The reaction was slowly returned to room temperature and stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give di-tert-butyl 7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinoline-2-carbamate (85 mg).
Step C: di-tert-butyl (7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinoline-2-carbamate (160 mg,0.24 mmol), tert-butyl carbamate (139 mg,1.18 mmol) was dissolved in N, N-dimethylformamide (2 mL) the reaction was evacuated for a plurality of times under nitrogen atmosphere, tris (dibenzylideneacetone) dipalladium (21.5 mg,0.024 mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (11.2 mg,0.024 mmol) and cesium carbonate (153 mg,0.47 mmol) reaction solution was stirred under microwaves at 100℃for 3 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give di-tert-butyl (7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinoline-2-carbamate (62 mg).
MS(ESI)M/Z:659.2[M+H] + .
Step D: the compound di-tert-butyl (7- ((2R) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) cyclopropyl) quinoline-2-carbamate (62 mg,0.094 mmol) was dissolved in methanol (1 mL) at room temperature.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to approximately 8-9. The mixture was extracted with dichloromethane (5 ml×3 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, and column welch XBC18, 21.2X105 mm,5 μm (particle size) was prepared; mobile phase: water (containing 10 mmoles/liter of ammonium bicarbonate) and acetonitrile; flow rate 20 ml/min; gradient: acetonitrile increased from 40vol% to 60vol% over 10 minutes; detection wavelength: 214nm. The product was collected to give two isomers of (1R, 2S,3R, 5R) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((1R) -2- (2-aminoquinolin-7-yl) cyclopropyl) cyclopentane-1, 2-diol (example 16-P1:9.6mg, example 16-P2:3.2 mg).
Example 16-P1
HPLC: retention time 5.495 min. The conditions are as follows, column XBIridge BEH C18.5 μm,4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:419.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.81-7.74(m,2H),7.46(d,J＝8.2Hz,1H),7.11(s,1H),6.86(dd,J＝8.2,1.6Hz,1H),6.63(d,J＝8.8Hz,1H),6.32(s,2H),5.90(s,2H),4.83(s,1H),4.47(d,J＝4.7Hz,1H),4.13(dd,J＝18.0,8.0Hz,1H),3.96(t,J＝6.8Hz,1H),3.70(dd,J＝10.0,4.9Hz,1H),3.57-3.39(m,2H),2.70(dd,J＝17.7,6.3Hz,2H),1.96-1.80(m,2H),1.58-1.45(m,1H),1.36-1.22(m,1H),1.19-1.08(m,1H),1.02-0.91(m,2H).
Example 16-P2
HPLC retention time 3.380 min. The conditions were as follows, column ACQUITY UPLC BEH C, 1.7 μm, 2.1X106 mm; column temperature is 30 ℃; mobile phase water (0.05 vol% tfa) and acetonitrile (0.05 vol% tfa); a flow rate of 0.3 ml/min; gradient: 5vol% acetonitrile (0.05 vol% TFA) for 0.5 min, acetonitrile (0.05 vol% TFA) increased to 95vol% over 9 min, and a 95vol% gradient was maintained for 3 min.
MS(ESI)M/Z:419.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.79(t,J＝4.4Hz,2H),7.47(d,J＝8.2Hz,1H),7.12(s,1H),6.86(d,J＝8.2Hz,1H),6.64(d,J＝8.8Hz,1H),6.30(s,2H),5.92(s,2H),4.80(d,J＝5.6Hz,1H),4.47(d,J＝4.6Hz,1H),4.15(dd,J＝18.0,8.0Hz,1H),3.93(dd,J＝13.2,5.6Hz,1H),3.66(dd,J＝9.8,4.8Hz,1H),3.56-3.41(m,2H),2.76-2.70(m,2H),1.94-1.82(m,2H),1.59-1.45(m,1H),1.40-1.28(m,1H),1.17-1.07(m,1H),0.97-0.84(m,2H).
Example 17
(1R, 2S,3R, 5R) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((E) -2- (3-bromo-2- ((cyclopropylmethyl) amino) quinolin-7-yl) vinyl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (50.0 mg,0.17 mmol), 3-bromo-N- (cyclopropylmethyl) -7-iodoquinolin-2-amine (69.6 mg,0.17 mmol) and tetraethylammonium chloride (30.4 mg,0.18 mmol) were dissolved in N, N-dimethylformamide (3 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (7.5 mg,0.03 mmol) and N, N-diisopropylethylamine (107.7 mg,0.83 mmol) were added under nitrogen. The reaction solution was stirred at 70℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (30 mL), extract the mixture with ethyl acetate (30 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (30 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) -3-bromo-N- (cyclopropylmethyl) quinolin-2-amine (30.0 mg).
MS(ESI)M/Z:577.0[M+H] + .
And (B) step (B): 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) -3-bromo-N- (cyclopropylmethyl) quinolin-2-amine (30 mg,0.05 mmol) is dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (2 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((E) -2- (3-bromo-2- ((cyclopropylmethyl) amino) quinolin-7-yl) vinyl) cyclopentane-1, 2-diol (6.0 mg).
MS(ESI)M/Z:537.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.31(s,1H),7.80(d,J＝8.4Hz,1H),7.58(d,J＝8.4Hz,1H),7.49(s,1H),7.35(dd,J＝8.4,1.5Hz,1H),6.68(t,J＝5.6Hz,1H),6.57-6.44(m,2H),5.94(s,2H),4.81(d,J＝5.3Hz,1H),4.68(d,J＝5.6Hz,1H),4.23(dd,J＝16.3,8.1Hz,1H),4.03-3.92(m,1H),3.78-3.68(m,1H),3.52(t,J＝9.0Hz,2H),3.37-3.33(m,2H),3.30-3.29(m,1H),2.76-2.69(m,2H),2.01-1.86(m,1H),1.53(dd,J＝22.9,9.9Hz,1H),1.24-1.21(m,1H),0.48-0.38(m,2H),0.33-0.25(m,2H).
Example 18
(1S, 2R,3R, 5R) -3- ((1R) -2- (2-amino-3-bromoquinolin-7-yl) cyclopropyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol and isomers thereof
The reaction route is as follows:
the operation steps are as follows:
step A: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) -3-bromoquinolin-2-amine (160.0 mg,0.31 mmol), di-tert-butyl dicarbonate (434.9 mg,1.99 mmol) and 4-dimethylaminopyridine (7.6 mg,0.06 mmol) are dissolved in tetrahydrofuran (8 mL) at room temperature. Subsequently, triethylamine (250.9 mg,2.5 mmol) was added to the above solution. The reaction solution was stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. To the crude product was added water (50 mL) and the mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give di-tert-butyl (7- ((3 aS,4R,6 aR) -6- ((E) -2- (2- (di-tert-butoxycarbonyl) amino) -3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) iminodicarbonate (160 mg).
MS(ESI)M/Z:923.5[M+H] + .
And (B) step (B): an aqueous solution of potassium hydroxide (1.7 g,25mL of water) was slowly added to diethyl ether (60 mL) at-10deg.C, and the reaction solution of 1-methyl-1-nitrosourea (3.0 g,29.1 mmol) was further added and stirring was continued at-10deg.C for 1 hour. The reaction solution was cooled to-78℃and the aqueous phase was frozen to pour out an organic phase, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered to give an ether solution (50 mL) of diazomethane prepared now.
Di-tert-butyl (7- ((3 aS,4R,6 aR) -6- ((E) -2- (2- (di-tert-butoxycarbonyl) amino) -3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) iminodicarbonate (150 mg,0.16 mmol) and palladium acetate (32.8 mg,0.15 mmol) were dissolved in tetrahydrofuran (4 mL), the reaction system was replaced with nitrogen and cooled to-78℃and an ethereal solution of diazomethane (50 mL) prepared now was slowly added to the reaction solution. The reaction was slowly returned to room temperature and stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give di-tert-butyl (7- ((3 aS,4R,6 aR) -6- ((1R) -2- (2- (di-tert-butoxycarbonyl) amino) -3-bromoquinolin-7-yl) cyclopropyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) iminodicarbonate (90 mg).
MS(ESI)M/Z:937.6[M+H] + .
Step C: di-tert-butyl (7- ((3 as,4R,6 ar) -6- ((1R) -2- (2- (di-tert-butoxycarbonyl) amino) -3-bromoquinolin-7-yl) cyclopropyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-yl) iminodicarbonate (70 mg,0.07 mmol) is dissolved in dichloromethane (2 mL) at room temperature. Subsequently, trifluoroacetic acid (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. Purifying the mixed solution by preparative high performance liquid chromatography. Purification conditions were as follows, and column welch XBC18, 21.2X105 mm,5 μm (particle size) was prepared; mobile phase: water (containing 10 mmoles/liter of ammonium bicarbonate) and acetonitrile; flow rate 20 ml/min; gradient: acetonitrile increased from 40vol% to 60vol% over 10 minutes; detection wavelength: 214nm. The product was collected to give two isomers of (1S, 2R,3R, 5R) -3- ((1R) -2- (2-amino-3-bromoquinolin-7-yl) cyclopropyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (example 18-P1:10.2mg, example 18-P2:4.9 mg).
Example 18-P1:
HPLC retention time 6.532 min. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:497.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.22(s,1H),7.81(s,1H),7.50(d,J＝8.3Hz,1H),7.23(s,1H),7.02(dd,J＝8.4,1.7Hz,1H),4.45-4.15(m,1H),4.12(dd,J＝8.5,5.9Hz,1H),3.91(dd,J＝5.8,4.0Hz,1H),3.77-3.60(m,1H),3.59-3.49(m,1H),2.80(t,J＝8.9Hz,2H),2.28-2.02(m,1H),1.96-1.83(m,1H),1.73-1.56(m,1H),1.56-1.41(m,1H),1.24-1.15(m,1H),1.12-1.00(m,2H).
Example 18-P2:
HPLC retention time 6.676 min. The conditions are as follows, column XBIridge BEH C18.5 μm 4.6 mm. Times.150 mm; column temperature is 30 ℃; mobile phase water (10 mM NH) 4 HCO 3 ) And acetonitrile; a flow rate of 1 ml/min; gradient: 5vol% acetonitrile for 0.5 min, acetonitrile was raised to 95vol% in 9 min, and a 95vol% gradient was maintained for 2 min.
MS(ESI)M/Z:497.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.24(s,1H),7.85(s,1H),7.53(d,J＝8.4Hz,1H),7.27(s,1H),7.07(dd,J＝8.4,1.6Hz,1H),4.48-4.18(m,1H),4.16-4.01(m,1H),3.89(dd,J＝5.8,4.0Hz,1H),3.83-3.66(m,1H),3.67-3.57(m,1H),2.99-2.65(m,2H),2.17-2.09(m,1H),2.09-2.00(m,1H),1.70-1.60(m,1H),1.57-1.47(m,1H),1.26-1.16(m,1H),1.11-1.03(m,1H),1.03-0.94(m,1H).
Example 19
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-methylcyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A to a three-necked flask, cuprous iodide (5.92 g,31.08 mmol) and anhydrous tetrahydrofuran (100 mL) were added. The displacement reaction system was a nitrogen system, which was then cooled to 0 ℃. To the reaction system was dropwise added a tetrahydrofuran solution (1.6M, 37.3 mL) of methyllithium (59.7 mmol), and stirring was continued at this temperature for 10 minutes after completion of the addition, and then the reaction system was cooled to-78 ℃. A tetrahydrofuran solution of (3 aR,6 aR) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxan-4-one (4 g,25.9 mmol) was added dropwise to the reaction system. After the completion of the dropwise addition, the reaction system was stirred at-78℃for 1 hour.
After TLC monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 aR,6S,6 aR) -2, 6-trimethyldihydro-4H-cyclopenta [ d ] [1,3] dioxan-4 (5H) -one (3.27 g).
1 H NMR(400MHz,DMSO-d 6 )δ4.47(d,J＝5.3Hz,1H),4.35(d,J＝5.3Hz,1H),2.66(dd,J＝18.3,8.3Hz,1H),2.38(dd,J＝11.1,4.1Hz,1H),1.98-1.87(m,1H),1.31(s,3H),1.27(s,3H),0.99(d,J＝7.5Hz,3H).
Step B A solution of (3 aR,6S,6 aR) -2, 6-trimethyldihydro-4H-cyclopenta [ d ] [1,3] dioxan-4 (5H) -one (500 mg,2.94 mmol) and triethylchlorosilane (1 mL,5.88 mmol) in tetrahydrofuran (8 mL) was added and the system was replaced with nitrogen atmosphere. The reaction flask was cooled to-78 ℃ in an ice bath, and then a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1 m,4.41ml,4.41 mmol) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 20 minutes.
After TLC monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give triethyl3 aR,6S,6 aR) -2, 6-trimethyl-6, 6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) oxy-silane (660 mg).
1 H NMR(400MHz,DMSO-d 6 )δ4.77(dd,J＝6.1,1.5Hz,1H),4.67(d,J＝2.2Hz,1H),4.16(d,J＝6.1Hz,1H),2.53-2.52(m,1H),1.32(s,3H),1.24(s,3H),1.03-0.90(m,12H),0.67(q,6H).
Step C in a single vial, triethyl3 aR,6S,6 aR) -2, 6-trimethyl-6, 6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) oxy-silane (660 mg,2.32 mmol), palladium acetate (155 mg,0.696 mmol) and dimethyl sulfoxide (10 mL) were added and the system was replaced with an oxygen atmosphere. The reaction solution was heated to 65℃and reacted at this temperature overnight.
After TLC monitoring showed the disappearance of starting material, the reaction was poured into ice water. The reaction solution was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, the organic phase was successively washed with water (30 mL. Times.3) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 ar,6 ar) -2, 6-trimethyl-4H-cyclopenta [ d ] [1,3] dioxan-4 (6 aH) -one (268 mg).
1 H NMR(400MHz,DMSO-d 6 )δ5.98(d,J＝1.4Hz,1H),5.07(d,J＝5.5Hz,1H),4.46(d,J＝5.5Hz,1H),2.13(s,3H),1.33(s,3H),1.28(s,3H).
Step D lithium chloride (20 mg, 0.470 mmol), cuprous iodide (45 mg,0.238 mmol) and tetrahydrofuran (4 mL) were added to a three-necked flask, and the system was replaced with nitrogen atmosphere. The reaction solution was cooled to 0℃and stirred at this temperature for 10 minutes, and then a solution of trimethylchlorosilane (308.5 mg,2.85 mmol) and (3 aR,6 aR) -2, 6-trimethyl-4H-cyclopenta [ d ] [1,3] dioxan-4 (6 aH) -one (400 mg,2.38 mmol) in tetrahydrofuran (2 mL) was dropwise added thereto. After the completion of the dropwise addition, the reaction solution was stirred at 0℃for 20 minutes. Then a solution of vinylmagnesium bromide (3.8 mmol) in tetrahydrofuran (1M, 3.8 mL) was added dropwise. The resulting reaction solution was stirred at 0℃for 30 minutes.
After TLC monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 ar,6r,6 ar) -2, 6-trimethyl-6-vinyldihydro-4H-cyclopenta [ d ] [1,3] dioxan-4 (5H) -one (300 mg).
1 H NMR(400MHz,DMSO-d 6 )δ5.85(dd,J＝17.6,10.9Hz,1H),5.05(dd,J＝14.3,12.5Hz,2H),4.52(d,J＝5.0Hz,1H),4.24(d,J＝5.0Hz,1H),2.53-2.48(m,1H),2.30(d,J＝17.7Hz,1H),1.35(s,3H),1.30(s,3H),1.21(s,3H).
Step E A three-necked flask was charged with a solution of (3 aR,6R,6 aR) -2, 6-trimethyl-6-vinyldihydro-4H-cyclopenta [ d ] [1,3] dioxan-4 (5H) -one (700 mg,3.57 mmol) in tetrahydrofuran (10 mL) and the system was then purged under nitrogen. The reaction flask was cooled to 0deg.C in an ice bath, and then a solution of lithium aluminum hydride (7.14 mmol) in tetrahydrofuran (1M, 7.14 mL) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 1 hour.
After TLC monitoring showed the disappearance of starting material, sodium sulfate decahydrate was slowly added to the reaction solution to quench until no bubbles emerged. Tetrahydrofuran was then added and stirred for 30 minutes, and the reaction solution was filtered. The filtrate was concentrated to give an oily crude product, which was purified by silica gel column chromatography to give (3 as,4s,6r,6 ar) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (400 mg).
1 H NMR(400MHz,CDCl 3 )δ5.70(dd,J＝17.6,11.0Hz,1H),5.08-4.95(m,2H),4.46(t,J＝5.7Hz,1H),4.33(dd,J＝5.4,0.8Hz,1H),4.09-3.94(m,1H),2.02-1.90(m,1H),1.59-1.52(m,1H),1.51(s,3H),1.36(s,3H),1.12(s,3H).
Step F: 4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (275 mg,1.77 mmol) and (3 aS,4S,6R,6 aR) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (440 mg,2.22 mmol) were dissolved in toluene (5 mL) at room temperature, and the reaction was replaced with a nitrogen atmosphere. A solution of 2- (tributylphosphoranylidene) acetonitrile (853 mg,3.54 mmol) in toluene (2 mL) was then slowly added to the reaction system. The reaction solution was heated to 110℃and stirred at this temperature for 5 hours.
After TLC monitoring showed the disappearance of starting material, the reaction mixture was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-chloro-7- ((3 as,4r,6 ar) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (160 mg).
MS(ESI)M/Z:336.0[M+H] + .
Step G A solution of 4-chloro-7- ((3 aS,4R,6 aR) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (130 mg,0.39 mmol) in ethanol (3 mL) was added to the autoclave at room temperature. Subsequently, ammonia (30 mL) was slowly added to the reaction system at room temperature. The reaction was stirred at 135℃for 2 days in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((3 as,4r,6 ar) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (45 mg).
MS(ESI)M/Z:317.3[M+H] + .
Step H: 7- ((3 aS,4R,6 aR) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (80 mg,0.25 mmol), 3-bromo-7-iodoquinolin-2-amine (88 mg,0.25 mmol) and tetraethylammonium chloride (45.6 mg,0.28 mmol) were dissolved in N, N-dimethylformamide (1 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (11.2 mg,0.05 mmol) and N, N-diisopropylethylamine (0.09 mL,0.5 mmol) were added under nitrogen. The reaction solution was stirred for 12 hours at 70℃in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 4-trimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) -3-bromoquinolin-2-amine (28 mg).
MS(ESI)M/Z:537.4[M+H] + .
Step I: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 4-trimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) -3-bromoquinolin-2-amine (28 mg,0.05 mmol) was dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (2 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to approximately 8-9. The mixture was extracted with dichloromethane (5 ml×3 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. Purification conditions were as follows, and column welch XBC18, 21.2X105 mm,5 μm (particle size) was prepared; mobile phase: water (containing 10 mmoles/liter of ammonium bicarbonate) and acetonitrile; flow rate: 20 ml/min; gradient: acetonitrile increased from 40vol% to 60vol% over 10 minutes; detection wavelength: 214nm. The product was collected to give (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-methylcyclopentane-1, 2-diol (4.7 mg).
MS(ESI)M/Z:497.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.81(s,1H),7.59(d,J＝9.0Hz,1H),7.41(d,J＝7.6Hz,2H),6.60(s,2H),6.53(d,J＝4.8Hz,2H),5.93(s,2H),4.85(d,J＝5.6Hz,1H),4.63(d,J＝5.6Hz,1H),4.34(t,J＝8.4Hz,1H),4.13(dd,J＝12.6,5.8Hz,1H),3.70(t,J＝5.6Hz,1H),3.52(t,J＝8.8Hz,2H),3.29-2.69(m,2H),1.81(dd,J＝13.2,9.4Hz,1H),1.70(dd,J＝13.2,9.4Hz,1H),1.17(s,3H).
Example 20
(1S, 2R,3S, 5R) -3- ((E) -3- (2-amino-3-bromoquinolin-7-yl) allyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
Reaction route
The operation steps are as follows:
step A: in a three-necked flask, cuprous bromide dimethyl sulfide complex (411 mg,2 mmol) and tetrahydrofuran (80 mL) were added. The displacement reaction system was nitrogen and then cooled to-78 ℃. A tetrahydrofuran solution (1M, 25 mL) of vinylmagnesium bromide (25 mmol) was dropwise added to the reaction system, stirring was continued at this temperature for 20 minutes after completion of the addition, and then a tetrahydrofuran solution of (3 aR,6 aR) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxan-4-one (3.08 g,20 mmol), trimethylchlorosilane (4.34 mL,40 mmol) and hexamethylphosphoric triamide (9.2 g,51.4 mmol) was dropwise added to the reaction system. After the completion of the dropwise addition, the reaction system was stirred at-78℃for 3 hours, and then stirred at 0℃for 1 hour.
After TLC monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate (500 mL. Times.3), and the organic phases were combined, washed with saturated brine (300 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (6S) -6-allyl-2, 2-dimethyldihydro-4H-cyclopenta [ d ] [1,3] dioxan-4 (5H) -one (800 mg).
1 H NMR(400MHz,CDCl 3 )δ5.78-5.74(m,1H),5.17-5.09(m,2H),4.97(d,J＝5.4Hz,1H),4.37(d,J＝5.4Hz,1H),3.28-3.02(m,1H),2.82-2.48(m,1H),2.46-2.32(m,2H),2.25-2.00(m,1H),1.44(s,3H),1.39(s,3H).
And (B) step (B): a solution of (6S) -6-allyl-2, 2-dimethyldihydro-4H-cyclopenta [ d ] [1,3] dioxan-4 (5H) -one (1 g,5.1 mmol) in tetrahydrofuran (30 mL) was added to a three-necked flask, and the system was then replaced with a nitrogen atmosphere. The reaction flask was cooled to 0deg.C in an ice bath, and then a solution of lithium aluminum hydride (10 mmol) in tetrahydrofuran (1M, 10 mL) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 1 hour.
TLC monitoring showed the disappearance of starting material and was quenched by slow addition of sodium sulfate decahydrate to the reaction. Tetrahydrofuran was then added and stirred for 30 minutes, and the reaction solution was filtered. The filtrate was concentrated to give an oily crude product, which was purified by silica gel column chromatography to give (4 s,6 s) -6-allyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (300 mg).
1 H NMR(400MHz,DMSO-d 6 )δ5.81-5.68(m,1H),5.06-4.96(m,2H),4.37-4.30(m,2H),4.19(d,J＝5.7Hz,1H),3.93(dd,J＝10.8,4.6Hz,1H),2.04-1.93(m,1H),1.93-1.81(m,2H),1.80-1.70(m,1H),1.51-1.42(m,1H),1.37(s,3H),1.23(s,3H).
Step C4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (104 mg,0.67 mmol) and (4S, 6S) -6-allyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (200 g,1.01 mmol) were dissolved in toluene (2 mL) at room temperature. 2- (tributylphosphoranylidene) acetonitrile (480 mg,2.0 mmol) was dissolved in toluene (0.5 mL). Subsequently, a 2- (tributylphosphoranylidene) acetonitrile solution was slowly added to the reaction system at room temperature. The reaction solution was stirred at 110℃in an oil bath for 12 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (20 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((3 as,4r,6s,6 ar) -6-allyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (164 mg).
MS(ESI)M/Z:336.0[M+H] + .
Step D A solution of 7- ((3 aS,4R,6S,6 aR) -6-allyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ D ] [1,3] dioxan-4-yl) -4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-D ] pyrimidine (244 mg,0.73 mmol) in ethanol (3 mL) was added to the autoclave at room temperature. Subsequently, ammonia (25 mL) was slowly added to the reaction system at room temperature. The reaction was stirred at 135℃for 2 days in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((3 as,4r,6s,6 ar) -6-allyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (90 mg).
MS(ESI)M/Z:317.2[M+H] + .
Step E7- ((3 aS,4R,6S,6 aR) -6-allyl-2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (70 mg,0.22 mmol), 3-bromo-7-iodoquinolin-2-amine (77 mg,0.22 mmol) and tetraethylammonium chloride (40 mg,0.24 mmol) are dissolved in N, N-dimethylformamide (1 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (5 mg,0.02 mmol) and N, N-diisopropylethylamine (0.08 mL, 0.284 mmol) were added under nitrogen. The reaction solution was stirred for 12 hours at 65℃in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -3- ((3 aR,4S,6R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) prop-1-en-1-yl) -3-bromoquinolin-2-amine (54 mg).
MS(ESI)M/Z:537.0[M+H] + .
Step F: 7- ((E) -3- ((3 aR,4S,6R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) prop-1-en-1-yl) -3-bromoquinolin-2-amine (62 mg,0.12 mmol) is dissolved in methanol (0.5 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (2 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction solution to adjust the pH to approximately 8-9. The mixture was extracted with dichloromethane (5 ml×3 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3s,5 r) -3- ((E) -3- (2-amino-3-bromoquinolin-7-yl) allyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (14.5 mg).
MS(ESI)M/Z:497.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.31(s,1H),7.78(s,1H),7.58(d,J＝8.8Hz,1H),7.41-7.35(m,2H),6.63-6.56(m,3H),6.47-6.42(m,1H),5.91(s,2H),4.81(d,J＝5.6Hz,1H),4.47(d,J＝4.8Hz,1H),4.16(dd,J＝17.8,7.8Hz,1H),3.91(dd,J＝13.6,5.8Hz,1H),3.59(dd,J＝9.9,4.8Hz,1H),3.54-3.41(m,2H),2.73-2.69(m,1H),2.44-2.38(m,2H),2.25-2.15(m,1H),1.97-1.83(m,2H),1.28-1.19(m,1H).
Example 21
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 4-chloro-7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (210 mg,0.65 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (95.1 mg,0.13 mmol) and potassium carbonate (179.6 mg,1.3 mmol) were dissolved in dioxane/water (5 mL/0.5 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. 2,4, 6-trimethyl-1,3,5,2,4,6-trioxaborol hexane (246.9 mg,1.96 mmol) was added under nitrogen atmosphere, and the reaction system was capped and heated to 110℃and stirred for 18 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -4-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (160.0 mg).
MS(ESI)M/Z:302[M+H] + .
And (B) step (B): 7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -4-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (40 mg,0.13 mmol) and 3-bromo-7-iodoquinolin-2-amine (42.1 mg,0.12 mmol) were dissolved in N, N-dimethylformamide (2 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (5.8 mg,0.026 mmol) and N, N-diisopropylethylamine (83.8 mg,0.65 mmol) were added under nitrogen. The reaction solution was stirred at 70℃for 18 hours in an oil bath.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (50 mL), extract the mixture with ethyl acetate (50 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (50 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 3-bromo-7- ((E) -2- ((3 aR,4R,6 aS) -2, 2-dimethyl-6- (4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) tetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (23 mg).
MS(ESI)M/Z:522[M+H] + .
Step C: 3-bromo-7- ((E) -2- ((3 aR,4R,6 aS) -2, 2-dimethyl-6- (4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) tetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinolin-2-amine (36.0 mg,0.07 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5-) 4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (11.7 mg).
MS(ESI)M/Z:482.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.25(s,1H),8.13(s,1H),7.56(d,J＝8.4Hz,1H),7.47(s,1H),7.42(dd,J＝8.4,1.6Hz,1H),6.62(d,J＝15.9Hz,1H),6.49(dd,J＝15.8,7.8Hz,1H),4.56-4.31(m,1H),4.29-4.14(m,1H),3.91(t,J＝6.0Hz,1H),3.77(t,J＝8.7Hz,2H),3.04(t,J＝8.6Hz,2H),2.88-2.71(m,1H),2.21(s,3H),2.19-2.07(m,1H),1.71(dt,J＝12.9,10.3Hz,1H).
Example 22
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3-methylcyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 7- ((3 aS,4R,6 aR) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] in a three-necked flask][1,3]Dioxazin-4-yl) 6, 7-dihydro-5H-pyrrolo [2,3-d]A solution of pyrimidin-4-amine (45 mg,0.14 mmol) in tetrahydrofuran (0.5 mL) was then replaced with nitrogen. A solution of 9-BBN (1.4 mmol) in tetrahydrofuran (0.5M, 2.8 mL) was slowly added dropwise at room temperature, and after completion of the addition, the reaction solution was heated to 60℃and stirred at this temperature for 1 hour. The reaction system was cooled to room temperature by removing from the oil bath, and then an aqueous solution (0.5 mL) of potassium phosphate (294 mg,1.4 mmol) was added to the reaction mixture. After the reaction solution was stirred at room temperature for 30 minutes, 3-bromo-7-iodoquinolin-2-amine (98 mg,0.28 mmol) and PdCl were added 2 (dppf) (10 mg,0.014 mmol) in tetrahydrofuran (1.2 mL). The resulting reaction mixture was heated to 60℃and stirred overnight.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography on silica gel to give 7- (2- ((3 aR,4S,6R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 4-trimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) ethyl) -3-bromoquinolin-2-amine (45 mg).
MS(ESI)M/Z:539.0[M+H] + .
And (B) step (B): 7- (2- ((3 aR,4S,6R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 4-trimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) ethyl) -3-bromoquinolin-2-amine (45 mg,0.083 mmol) is dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was dissolved in 3mL of methanol and then 7M methanolic ammonia solution was added to adjust the pH to approximately 8-9. The resulting solution was purified by preparative high performance liquid chromatography to give (1 s,2r,3s,5 r) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5,6H-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -3-methylcyclopentane-1, 2-diol (8.4 mg).
MS(ESI)M/Z:499.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.79(s,1H),7.57(d,J＝8.3Hz,1H),7.30(s,1H),7.10(dd,J＝8.2,1.6Hz,1H),6.55(s,2H),5.91(s,2H),4.81(d,J＝5.7Hz,1H),4.37(d,J＝5.1Hz,1H),4.25(dd,J＝7.8Hz,1H),4.08(dd,J＝7.5Hz,1H),3.58-3.53(m,1H),3.53-3.42(m,2H),2.73-2.69(m,2H),2.65-2.60(m,2H),1.69-1.56(m,2H),1.55-1.48(m,2H),1.04(s,3H).
Example 23
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -5- (4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
Preparation method referring to example 21, the target product (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -5- (4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol was finally obtained.
MS(ESI)M/Z:438.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.14(d,J＝2.2Hz,2H),7.60(d,J＝9.0Hz,1H),7.44-7.38(m,2H),6.70(s,2H),6.50-6.45(m,2H),4.82-4.71(m,2H),4.35(dd,J＝17.2,8.0Hz,1H),4.02(dd,J＝12.4,5.8Hz,1H),3.74(q,J＝5.6Hz,1H),3.65(dd,J＝13.8,8.8Hz,2H),2.96(t,J＝8.5Hz,2H),2.67-2.60(m,1H),2.13(s,3H),1.98(dt,J＝12.8,8.0Hz,1H),1.62-1.51(m,1H).
Example 24
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-9H-pyrimido [4,5-b ] indol-9-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A mixture of 4-chloro-9H-pyrimido [4,5-b ] indole (450 mg,2.2 mmol) and toluene (5 mL) of (3 aS,4S,6 aR) -2, 2-dimethyl-6-allyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (806 mg,4.4 mmol) was added to a 20mL lock tube at room temperature. The reaction mixture was replaced with a nitrogen system, and then a toluene (3 mL) solvent of 2- (tributylphosphoranylidene) acetonitrile (2.12 g,8.8 mmol) was slowly dropped into the reaction system at room temperature. The reaction solution was stirred at 100℃in an oil bath for 12 hours.
LCMS monitoring showed the disappearance of starting material and the reaction quenched with water. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-chloro-9- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -9H-pyrimido [4,5-b ] indole (360 mg).
MS(ESI)M/Z:370.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.87(s,1H),8.38(d,J＝7.8Hz,1H),7.97(d,J＝8.4Hz,1H),7.72(dd,J＝11.5,4.1Hz,1H),7.52(t,J＝7.6Hz,1H),6.02(td,J＝10.3,5.2Hz,1H),5.42(d,J＝4.9Hz,1H),5.30(dd,J＝7.3,5.1Hz,1H),5.15(dd,J＝31.7,13.8Hz,2H),4.76(t,J＝7.0Hz,1H),2.90-2.81(m,1H),2.74(d,J＝12.1Hz,1H),2.29(d,J＝6.1Hz,1H),1.53(s,3H),1.22(s,3H).
Step B A solution of 4-chloro-9- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -9H-pyrimido [4,5-B ] indole (360 mg,0.98 mmol) in isopropanol (3 mL) was added to a 20mL closed tube reactor at room temperature. Subsequently, ammonia (6 mL) was slowly added to the reaction system at room temperature. The tube was sealed and the reaction was stirred overnight at 120℃in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 9- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (300 mg).
MS(ESI)M/Z:351.2[M+H] + .
Step C: 9- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] in a three-necked flask ][1,3]Dioxan-4-yl) -9H-pyrimido [4,5-b]A solution of indol-4-amine (50 mg,0.14 mmol) in tetrahydrofuran (0.5 mL) is then replaced with nitrogen. A solution of 9-BBN (1.4 mmol) in tetrahydrofuran (0.5M, 2.8 mL) was slowly added dropwise at room temperature, and after completion of the addition, the reaction solution was heated to 60℃and stirred at this temperature for 1 hour. The reaction system was cooled to room temperature by removing from the oil bath, and then an aqueous solution (0.5 mL) of potassium phosphate (148 mg,0.7 mmol) was added to the reaction mixture. After the reaction solution was stirred at room temperature for 30 minutes, 3-bromo-7-iodoquinolin-2-amine (50 mg,0.14 mmol) and PdCl were added 2 (dppf) (10 mg,0.014 mmol) in tetrahydrofuran (1.2 mL). The resulting reaction mixture was heated to 60℃and stirred overnight.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give 9- ((3 as,4r,6s,6 ar) -6- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxy-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (70 mg, 60% purity).
MS(ESI)M/Z:573.0[M+H] + ，575.0[M+H+2] + .
Step D: 9- ((3 aS,4R,6S,6 aR) -6- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (70 mg,0.12 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was dissolved in 3mL of methanol and then 7M methanolic ammonia solution was added to adjust the pH to approximately 8-9. The resulting solution was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3s,5 r) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-9H-pyrimido [4,5-b ] indol-9-yl) cyclopentane-1, 2-diol (9.6 mg).
MS(ESI)M/Z:533.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.36-8.31(m,2H),8.28(s,1H),7.60(t,J＝8.1Hz,2H),7.40(t,J＝7.7Hz,1H),7.35(s,1H),7.25(t,J＝7.5Hz,1H),7.21-7.11(m,3H),6.57(s,2H),5.11-5.00(m,1H),4.73(dd,J＝10.9,4.5Hz,2H),4.63(d,J＝5.4Hz,1H),3.99-3.87(m,1H),2.85-2.71(m,2H),2.14-1.95(m,4H),1.86-1.73(m,1H).
Example 25
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-9H-pyrimido [4,5-b ] indol-9-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 9- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (50 mg,0.14 mmol), 3-bromo-7-iodoquinolin-2-amine (60.0 mg,0.17 mmol) and tetraethylammonium chloride (26.0 mg,0.16 mmol) are dissolved in N, N-dimethylformamide (3 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (6.4 mg,0.03 mmol) and N, N-diisopropylethylamine (0.124 mL,0.75 mmol) were added under nitrogen. The reaction solution was stirred at 70℃for 18 hours.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (20 mL), extract the mixture with ethyl acetate (20 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (15 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 9- ((3 as,4r,6 ar) -6- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (35 mg).
MS(ESI)M/Z:571.0[M+H] + .
And (B) step (B): 9- ((3 aS,4R,6 aR) -6- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (35 mg,0.06 mmol) is dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-9H-pyrimido [4,5-b ] indol-9-yl) cyclopentane-1, 2-diol (15.0 mg).
MS(ESI)M/Z:531.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.39-8.29(m,3H),7.67(d,J＝8.3Hz,1H),7.62(d,J＝8.5Hz,1H),7.51-7.39(m,3H),7.27(t,J＝7.6Hz,1H),7.21(s,2H),6.74-6.59(m,4H),5.24-5.07(m,1H),4.93-4.86(m,2H),4.78-4.64(m,1H),4.25-4.07(m,1H),2.90-2.76(m,1H),2.37-2.28(m,1H),2.23-2.13(m,1H).
Example 26
(1R, 2S,3R, 5S) -3- (4-amino-9H-pyrimido [4,5-b ] indol-9-yl) -5- (2- (2-aminoquinolin-7-yl) ethyl) cyclopentaane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 9- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (100 mg,0.28 mmol), 7-iodoquinolin-2-amine (91.8 mg,0.34 mmol) and tetraethylammonium chloride (51.8 mg,0.31 mmol) were dissolved in N, N-dimethylformamide (3 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (12.8 mg,0.057 mmol) and N, N-diisopropylethylamine (0.25 mL,1.512 mmol) were added under nitrogen. The reaction solution was stirred at 70℃for 18 hours.
After LCMS monitoring showed the disappearance of starting material, quench the reaction by adding water (20 mL), extract the mixture with ethyl acetate (20 mL x 3 times), combine the organic phases, wash the organic phases with saturated brine (15 mL), then dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 9- ((3 as,4r,6 ar) -6- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (130 mg).
MS(ESI)M/Z:493.2[M+H] + .
And (B) step (B): palladium on carbon (236.0 mg,2.2 mmol) was dissolved in ethanol (5 mL) at room temperature. The reaction system is vacuumized and replaced with hydrogen for many times. 9- ((3 aS,4R,6 aR) -6- ((E) -2- (2-aminoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (110 mg,0.22 mmol) was added under a hydrogen atmosphere. The reaction solution was stirred at room temperature for 18 hours.
After LCMS monitoring showed the disappearance of starting material, filtration and concentration, the mixture was extracted with ethyl acetate (20 ml×3 times) and the organic phases were combined, washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give the compound 9- ((3 as,4r,6s,6 ar) -6- (2- (2-aminoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (90 mg).
MS(ESI)M/Z:495.2[M+H] + .
Step C: 9- ((3 aS,4R,6S,6 aR) -6- (2- (2-aminoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxa-4-yl) -9H-pyrimido [4,5-b ] indol-4-amine (70 mg,0.14 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. Methanol (1 mL) was added to the residue, and an aqueous ammonia solution was added to the reaction mixture to adjust the pH to about 8-9. The mixture was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 s) -3- (4-amino-9H-pyrimido [4,5-b ] indol-9-yl) -5- (2- (2-aminoquinolin-7-yl) ethyl) cyclopentane-1, 2-diol (48.5 mg).
MS(ESI)M/Z:555.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.33(d,J＝7.7Hz,1H),8.29(s,1H),7.82(d,J＝8.8Hz,1H),7.62(d,J＝8.3Hz,1H),7.53(d,J＝8.1Hz,1H),7.44-7.37(m,1H),7.28(d,J＝6.6Hz,1H),7.25(d,J＝7.3Hz,1H),7.18(s,2H),7.06(dd,J＝8.1,1.5Hz,1H),6.68(d,J＝8.8Hz,1H),6.33(s,2H),5.13-5.01(m,1H),4.81-4.69(m,2H),4.67-4.57(m,1H),3.99-3.88(m,1H),2.87-2.64(m,2H),2.19-1.91(m,4H),1.89-1.72(m,1H).
Example 27
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-8H-pyrimidine [5,4-b ] [1,4] oxazin-8-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A acetonitrile (50 mL), 4-amino-6-chloropyrimidin-5-ol (433 mg,3 mmol) and cesium carbonate (1955 mg,6 mmol), 1, 2-dibromoethane (1127 mg,6 mmol) were added in a single vial at room temperature, and then heated to 65℃and stirred for 16 hours.
The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 4-chloro-7, 8-dihydro-6H-pyrimidine [5,4-b ] [1,4] oxazine (235 mg).
MS(ESI)M/Z:172.0[M+H] + .
Step B4-chloro-7, 8-dihydro-6H-pyrimidine [5,4-B ] [1,4] oxazine (205 mg,1.2 mmol) and (3 aS,4S,6R,6 aR) -2, 6-trimethyl-6-vinyltetrahydro-4H-cyclopentane [ d ] [1,3] dioxin-4-ol (442 mg,2.4 mmol) were dissolved in toluene (3 mL) in a closed tube. Cyanomethylene tri-n-butylphosphine (869 mg,3.6 mmol) was dissolved in toluene (1 mL), the above liquid was added dropwise under nitrogen atmosphere, and the reaction solution was stirred at 110℃for 18 hours.
The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 4-chloro-8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b ] [1,4] oxazine (295 mg).
MS(ESI)M/Z:338.2[M+H] + .
Step C4-chloro-8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b ] [1,4] oxazine (295 mg,0.872 mmol), tert-butyl carbamate (202.5 mg,1.74 mmol) was dissolved in anhydrous toluene (2 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Brettphos Pd G2 (73.6 mg,0.087 mmol) was added under nitrogen atmosphere cesium carbonate (566.8 mg,1.74 mmol). The reaction solution was stirred at 110℃for 18 hours.
The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxy-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b ] [1,4] oxazin-4-amine (105 mg).
MS(ESI)M/Z:319.2[M+H] + .
Step D, in a three-necked flask, anhydrous tetrahydrofuran (5 mL) was added under nitrogen protection, 8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentane [ D ]][1,3]Dioxol-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b][1,4]Oxazin-4-amine (115 mg,0.35 mmol) followed by 9-BBN (299 mg,2.45 mmol) was added dropwise. The reaction solution was heated to 55℃and stirred for 1 hour. The reaction solution was cooled to room temperature again, and potassium phosphate (520 mg,2.45mmol, dissolved in 1.5mL of water) was added thereto and stirred for 20 minutes. 3-bromo-7-iodoquinolin-2-amine (147 mg,0.42mmol in 2mL dry tetrahydrofuran) was added PdCl 2 (dppf) (55 mg,0.07 mmol). The reaction was heated to 55℃and stirred for 16 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The crude product obtained is purified by silica gel column chromatography to obtain 8- ((3 aS,4R,6S,6 aR) -6- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -2, 2-dimethyl tetrahydro-4H-cyclopentane [ d ]][1,3]Dioxy-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b][1,4]Oxazin-4-amine (105 mg).
MS(ESI)M/Z:541.1[M+H] + .
Step E, methanol (2 mL), 8- ((3 aS,4R,6S,6 aR) -6- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b ] [1,4] oxazin-4-amine (81 mg,0.15 mmol) was added to a single vial at room temperature, 4N methanolic hydrochloride solution (2 mL) was added dropwise, followed by stirring for 2 hours. After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The crude product obtained was purified by reverse phase chromatography to give (1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-8H-pyrimidine [5,4-b ] [1,4] oxazin-8-yl) cyclopentane-1, 2-diol (32 mg).
MS(ESI)M/Z:501.0[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.82(s,1H),7.54–7.42(m,2H),7.17(d,J＝8.3Hz,1H),5.34(s,2H),4.69(s,2H),4.45–4.33(m,1H),4.28–4.18(m,2H),3.92(t,J＝7.3Hz,1H),3.81–3.70(m,1H),3.58–3.42(m,2H),2.92-2.82(m,2H),2.15-1.93(m,3H),1.77-1.70(m,1H),1.40-1.36(m,1H).
Example 28
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydro-8H-pyrimidine [5,4-b ] [1,4] oxazin-8-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A Anhydrous DMF (2 mL), 8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b ] [1,4] oxazin-4-amine (63 mg,0.2 mmol), 3-bromo-7-iodoquinolin-2-amine (84 mg,0.24 mmol), palladium acetate (10 mg,0.04 mmol), TEAC (66 mg,0.4 mmol), DIPEA (51 mg, 0.390 mmol) was added to a single vial. The system was converted to nitrogen, heated to 70℃and stirred for 4 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The crude product was purified by column chromatography on silica gel to give 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-b ] [1,4] oxazin-4-amine (25 mg).
MS(ESI)M/Z:539.1[M+H] + .
Step B methanol (2 mL), 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxo-4-yl) -7, 8-dihydro-6H-pyrimidine [5,4-B ] [1,4] oxazin-4-amine (25 mg,0.05 mmol) was added to a single vial at room temperature, followed by dropwise addition of 4N methanolic hydrochloric acid (2 mL) and stirring for 2 hours. After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure. The crude product was dissolved in 3mL of methanol and then 7M methanolic ammonia solution was added to adjust the pH to approximately 8-9. The resulting solution was purified by reverse phase chromatography to give (1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydro-8H-pyrimidine [5,4-b ] [1,4] oxazin-8-yl) cyclopentane-1, 2-diol (6.5 mg).
MS(ESI)M/Z:499.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.25(s,1H),7.69(s,1H),7.56(d,J＝8.4Hz,1H),7.47(s,1H),7.42(dd,J＝8.4,1.5Hz,1H),6.63(d,J＝15.9Hz,1H),6.49(dd,J＝15.8,7.7Hz,1H),4.92-4.84(m,1H),4.20-4.19(m,2H),4.15(dd,J＝16.4,9.8Hz,1H),3.91(t,J＝6.4Hz,1H),3.63–3.52(m,2H),2.79-2.75(m,1H),2.10-2.02(m,1H),1.74-1.58(m,1H).
Example 29
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-8H-pyrimidine [5,4-b ] [1,4] oxazin-8-yl) -3-methylcyclopentane-1, 2-diol
Preparation method referring to example 27, the final product, (1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-8H-pyrimidine [5,4-b ] [1,4] oxazin-8-yl) -3-methylcyclopentane-1, 2-diol was obtained.
MS(ESI)M/Z:515.3[M+H] + .
1 H NMR(400MHz,MeOD)δ8.26(s,1H),7.67(s,1H),7.55(d,J＝8.2Hz,1H),7.38(s,1H),7.17(dd,J＝8.3,1.6Hz,1H),4.99-4.88(m,1H),4.26-4.22(m,1H),4.22-4.13(m,2H),3.75(d,J＝6.3Hz,1H),3.56–3.43(m,2H),2.85–2.72(m,2H),1.86–1.66(m,3H),1.66–1.56(m,1H),1.18(s,3H).
Example 30
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydro-cyclopentane [4,5] pyrrole [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopentan [4,5] pyrrole [2,3-d ] pyrimidin-4-amine (53 mg,0.156 mmol), 7-bromo-3-chloroquinolin-2-amine (40 mg,0.156mmol, prepared by the synthetic method referencing intermediate Int-1) and tetraethylammonium chloride (52.2 mg,0.315 mmol) were dissolved in N, N-dimethylformamide (1 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (7 mg,0.03 mmol) and N, N-diisopropylethylamine (40 mg,0.312 mmol) were added under nitrogen. The reaction solution was stirred at 100℃in an oil bath for 12 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 8- ((3 as,4r,6 ar) -6- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) -5,6,7, 8-tetrahydrocyclopenta [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (63 mg).
MS(ESI)M/Z:517.2[M+H] + .
And (B) step (B): 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxo-4-yl) -5,6,7, 8-tetrahydrocyclopentan [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (63 mg,0.122 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction to adjust the pH to approximately 8-9. The mixture was extracted with ethyl acetate (5 mL. Times.3), the organic phases were combined, the organic phases were washed with saturated brine (10 mL) and then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified to give the final product (1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydropyran [4,5] pyrrole [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol (33.9 mg).
MS(ESI)M/Z:477.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.15(s,1H),7.97(s,1H),7.61(d,J＝8.8Hz,1H),7.43(d,J＝7.6Hz,2H),6.69(s,2H),6.59(s,2H),6.45(s,2H),4.92–4.83(m,2H),4.81–4.75(m,1H),4.29(dd,J＝12.4,6.4Hz,1H),3.93(dd,J＝11.8,5.8Hz,1H),2.95–2.78(m,4H),2.75-2.70(m,1H),2.42-2.39(m,2H),2.23–2.15(m,1H),1.93–1.88(m,1H).
Example 31
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-fluoroquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydro-cyclopentane [4,5] pyrrole [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A7-bromo-3-fluoroquinoline (900 mg,4 mmol) was dissolved in dichloromethane (25 mL) at room temperature. M-chloroperbenzoic acid (2.75 g,16 mmol) was slowly added at 0deg.C, and the reaction stirred at room temperature for 12 hours.
After LCMS monitoring showed the disappearance of starting material, quench by adding water (50 mL) to the reaction at 0 ℃ followed by slow addition of saturated aqueous ammonium chloride to adjust pH to 7 and concentration under reduced pressure. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7-bromo-3-fluoroquinoline 1-oxide (850 mg).
MS(ESI)M/Z:242.2[M+H] + .
Step B7-bromo-3-fluoroquinoline 1-oxide (850 mg,3.54 mmol) was dissolved in chloroform (15 mL) at room temperature. Phosphorus oxychloride (15 mL) was then slowly added at 0 ℃ and the reaction was evacuated and replaced with nitrogen multiple times. The reaction was stirred for 3 hours at 70℃in an oil bath.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. Dichloromethane (30 mL) was added, then the pH was adjusted to 7 with saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7-bromo-2-chloro-3-fluoroquinoline (700 mg).
MS(ESI)M/Z:259.9[M+H] + .
Step C7-bromo-2-chloro-3-fluoroquinoline (745 mg,2.86 mmol) was dissolved in ethanol (10 mL) and aqueous ammonia (20 mL) at room temperature. The reaction solution was then placed in a stewing pot and stirred at 100℃for 20 hours.
After LCMS monitoring showed the disappearance of starting material, concentrated under reduced pressure, the mixture was extracted with dichloromethane (20 ml×3 times) and the organic phases were combined, washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7-bromo-3-chloroquinolin-2-amine (530 mg).
MS(ESI)M/Z:241.0[M+H] + .
Step D8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ D ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopentan [4,5] pyrrole [2,3-D ] pyrimidin-4-amine (125 mg,0.36 mmol), 7-bromo-2-chloro-3-fluoroquinoline (86 mg,0.36 mmol) and tetraethylammonium chloride (65 mg,0.39 mmol) are dissolved in N, N-dimethylformamide (2 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (16 mg,0.07 mmol) and N, N-diisopropylethylamine (0.13 mL,0.786 mmol) were added under nitrogen. The reaction solution was stirred at 100℃in an oil bath for 12 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (20 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 8- ((3 as,4r,6 ar) -6- ((E) -2- (2-amino-3-fluoroquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) -5,6,7, 8-tetrahydrocyclopentane [4,5] pyrrole [2,3-d ] pyrimidin-4-amine (87 mg).
MS(ESI)M/Z:501.2[M+H] + .
Step E: 8- ((3 aS,4R,6 aR) -6- ((E) -2- (2-amino-3-fluoroquinolin-7-yl) vinyl) -2, 2-dimethyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxo-4-yl) -5,6,7, 8-tetrahydrocyclopentan [4,5] pyrrolo [2,3-d ] pyrimidin-4-amine (87 mg,0.174 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was dissolved in 2mL of methanol and then 7M methanolic ammonia solution was added to adjust the pH to approximately 8-9. The resulting solution was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-fluoroquinolin-7-yl) vinyl) -5- (4-amino-6, 7-dihydro-cyclopentane [4,5] pyrrole [2,3-d ] pyrimidin-8 (5H) -yl) cyclopentane-1, 2-diol (23.7 mg).
MS(ESI)M/Z:461.2[M+H] + .
1 H NMR(400MHz,MeOD)δ7.98(s,1H),7.77(d,J＝11.8Hz,1H),7.60(d,J＝8.9Hz,1H)7.44–7.40(m,2H),6.74(s,2H),6.59-6.53(m,2H),6.46(s,2H),4.86(dd,J＝5.8,2.9Hz,2H),4.83–4.75(m,1H),4.29(dd,J＝12.5,6.2Hz,1H),3.93(dd,J＝6.0Hz,1H),2.96-2.80(m,4H),2.78-2.65(m,1H),2.45–2.35(m,2H),2.26-2.14(m,1H),1.97-1.85(m,1H).
Example 32
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-fluoroquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
Preparation method referring to example 31, the final product, (1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-fluoroquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol was obtained.
MS(ESI)M/Z:423.2[M+H] + .
1 H NMR(400MHz,MeOD)δ7.85(s,1H),7.65(d,J＝11.3Hz,1H),7.57(d,J＝8.4Hz,1H),7.49(s,1H),7.41(d,J＝8.3Hz,1H),6.63-6.57(m,1H),6.48-6.38(m,1H),4.33-4.25(m,1H),4.15–4.11(m,1H),3.90–3.86(m,1H),3.72–3.61(m,2H),2.89-2.81(m,2H),2.81-2.74(m,1H),2.16–2.08(m,1H),1.70-1.58(m,1H).
Example 33
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (60 mg,0.2 mmol), 7-bromo-3-chloroquinolin-2-amine (51 mg,0.2 mmol) and tetraethylammonium chloride (36.3 mg,0.22 mmol) are dissolved in N, N-dimethylformamide (1.5 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (9 mg,0.04 mmol) and N, N-diisopropylethylamine (51.6 mg,0.4 mmol) were added under nitrogen. The reaction solution was stirred at 100℃in an oil bath for 12 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) -3-chloroquinolin-2-amine (40 mg).
MS(ESI)M/Z:479.0[M+H] + .
And (B) step (B): 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) vinyl) -3-chloroquinolin-2-amine (40 mg,0.084 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction to adjust the pH to approximately 8-9. The mixture was extracted with ethyl acetate (5 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3-chloroquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (10.8 mg).
MS(ESI)M/Z:220.6[1/2M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.14(s,1H),7.81(s,1H),7.60(d,J＝8.6Hz,1H),7.40(s,2H),6.69(s,2H),6.58–6.42(m,2H),5.94(s,2H),4.83(d,J＝5.2Hz,1H),4.69(d,J＝5.4Hz,1H),4.26–4.15(m,1H),4.05-3.95(m,1H),3.78-3.68(m,1H),3.52(t,J＝8.6Hz,2H),2.79–2.68(m,2H),2.65-2.58(m,1H),1.98–1.90(m,1H),1.57–14.9(m,1H).
Example 34
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A solution of methyl 2- (4, 6-dichloropyrimidin-5-yl) acetate (2 g,9.1 mmol) in tetrahydrofuran (100 mL) was added to a three-necked flask. The displacement reaction system was nitrogen and then cooled to-78 ℃. A solution of lithium bistrimethylsilylaminide (18.2 mmol) in tetrahydrofuran (1M, 18.2 mL) was added dropwise to the reaction system, stirring was continued at this temperature for 1 hour after the addition was completed, then methyl iodide (2.58 g,18.2 mmol) was added dropwise to the reaction system, and after the addition was completed, the reaction system was raised to 0℃and stirring was continued for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of saturated aqueous ammonium chloride. The reaction solution was extracted with ethyl acetate (200 mL. Times.3), and the organic phases were combined, washed with saturated brine (200 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give methyl 2- (4, 6-dichloropyrimidin-5-yl) propionate (1.54 g).
MS(ESI)M/Z:234.9[M+H] + .
Step B A three-necked flask was charged with a solution of methyl 2- (4, 6-dichloropyrimidin-5-yl) propionate (1 g,4.27 mmol) in tetrahydrofuran (30 mL). The displacement reaction system is a nitrogen system and then cooled to-78 ℃. A solution of diisobutylaluminum hydride (12.8 mmol) in tetrahydrofuran (1.5M, 8.5 mL) was added dropwise thereto, and after completion of the addition, the reaction system was slowly warmed to room temperature and stirred continuously overnight.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of saturated aqueous ammonium chloride. The reaction solution was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 2- (4, 6-dichloropyrimidin-5-yl) propan-1-ol (450 mg).
MS(ESI)M/Z:207.2[M+H] + .
Step C2- (4, 6-dichloropyrimidin-5-yl) propan-1-ol (540 mg,2.62 mmol) and 4-dimethylaminopyridine (32 mg,0.262 mmol) were dissolved in dichloromethane (420 mL) in a three-necked flask. Methanesulfonyl chloride (750 mg,6.55 mmol) and triethylamine (1.19 g,11.8 mmol) were added at 0℃and the reaction was stirred at 0℃to room temperature for 3 hours.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was extracted with dichloromethane (30 ml×3 times), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give propyl 2- (4, 6-dichloropyrimidin-5-yl) methylsulfonate (700 mg).
MS(ESI)M/Z:285.0[M+H] + .
Step D propyl 2- (4, 6-dichloropyrimidin-5-yl) methylsulfonate (700 mg,2.46 mmol) and (4-methoxyphenyl) formamide (1.04 g,7.4 mmol) were dissolved in dichloromethane (30 mL) at room temperature, then triethylamine (749 mg,7.4 mmol) was added, the displacement reaction system was nitrogen system, and the reaction solution was stirred at 55℃overnight.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-chloro-7- (4-methoxybenzyl) -5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (710 mg).
MS(ESI)M/Z:290.1[M+H] + .
Step E4-chloro-7- (4-methoxybenzyl) -5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (710 mg,2.46 mmol) was dissolved in trifluoroacetic acid (3 mL) and trifluoromethanesulfonic acid (0.3 mL) at room temperature, and the reaction solution was stirred at 70℃for 3 hours.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was adjusted to ph=8-9 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-chloro-5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (280 mg).
MS(ESI)M/Z:170.0[M+H] + .
Step F4-chloro-5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (460 mg,2.72 mmol) and (3 aS,4S,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (763.5 mg,4.08mmol, reference J.org.chem.2004,69,3993-3996 methods, the entire contents of which are incorporated herein by reference) were dissolved in toluene (2 mL) in a lock tube. Cyanomethylene tri-n-butylphosphine (1.31 g,5.44 mmol) was dissolved in toluene (2 mL), the above liquid was added dropwise under nitrogen atmosphere, and the reaction solution was stirred at 110℃for 18 hours.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-chloro-7- ((3 as,4r,6 ar) -2, 2-dimethyl-6-ethenyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxy-4-yl) -5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (300 mg).
MS(ESI)M/Z:336.2[M+H] + .
Step G4-chloro-7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyl tetrahydro-4H-cyclopentane [ d ] [1,3] dioxy-4-yl) -5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (300 mg,0.895 mmol) was dissolved in a mixture of ethanol (20 mL) and aqueous ammonia (100 mL) at room temperature, and the reaction was stirred in a 160℃autoclave for 60 hours.
After LCMS monitoring showed mostly product, concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxy-4-yl) -5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (120 mg).
MS(ESI)M/Z:317.0[M+H] + .
Step H A solution of the compound 7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -5-methyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (38 mg,0.11 mmol) in tetrahydrofuran (4 mL) was added to a three-necked flask, and the system was replaced with a nitrogen atmosphere. To the reaction solution was slowly added dropwise a tetrahydrofuran solution (0.5M, 2.2 mL) of 9-BBN (1.1 mmol) at room temperature, and after completion of the addition, the reaction solution was heated to 55℃and stirred at this temperature for 1 hour. The reaction system was cooled to room temperature by removing an oil bath, and then an aqueous solution (1 mL) of potassium phosphate (233 mg,1.1 mmol) was added to the reaction mixture. After stirring the reaction solution at room temperature for 30 minutes, a solution of 3-bromo-7-iodoquinolin-2-amine (38.5 mg,0.11 mmol) and PdCl2 (dppf) (8 mg,0.01 mmol) in tetrahydrofuran (1 mL) was added. The resulting reaction mixture was heated to 55℃and stirred overnight.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give 7- (2- ((3 aR,4S,6R,6 aS) -6- (4-amino-5-methyl-5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -2, 2-dimethyltetrahydro-3 aH-cyclopentane [ d ] [1,3] dioxo-4-yl) ethyl) -3-bromoquinolin-2-amine (30 mg).
MS(ESI)M/Z:539.0[M+H] + .
Step I7- (2- ((3 aR,4S,6R,6 aS) -6- (4-amino-5-methyl-5H-pyrrolo [2,3-d ] pyrimidin-7 (6H) -yl) -2, 2-dimethyltetrahydro-3 aH-cyclopentan [ d ] [1,3] dioxo-4-yl) ethyl) -3-bromoquinolin-2-amine (30 mg,0.055 mmol) is dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was dissolved in 5mL of methanol and then 7M methanolic ammonia solution was added to adjust the pH to approximately 8-9. The resulting solution was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3s,5 r) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (15 mg).
MS(ESI)M/Z:499.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.79(d,J＝6.2Hz,1H),7.57(d,J＝8.3Hz,1H),7.30(d,J＝3.5Hz,1H),7.13–7.06(m,1H),6.56(s,2H),5.89(d,J＝22.1Hz,2H),4.86(d,J＝5.6Hz,1H),4.62(d,J＝5.8Hz,1H),4.40(dd,J＝6.6,4.8Hz,1H),4.18-4.10(m,1H),3.92-3.82(m,1H),3.56–3.49(m,1H),3.23–3.13(m,1H),3.08–2.98(m,1H),2.78–2.62(m,2H),1.95–1.80(m,2H),1.78–1.68(m,1H),1.62–1.50(m,1H),1.21–1.16(m,1H),1.15–1.08(m,3H).
Example 35
(1S, 2R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopent-3-ene-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A a solution of the compound 4-chloro-7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxy-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (75 mg,0.23 mmol) in tetrahydrofuran (1 mL) was added to a three-necked flask, and the system was replaced with a nitrogen atmosphere. A solution of 9-BBN (2.35 mmol) in tetrahydrofuran (0.5M, 4.7 mL) was slowly added dropwise at room temperature, and after completion of the addition, the reaction solution was heated to 55℃and stirred at this temperature for 1 hour. The reaction system was cooled to room temperature by removing from the oil bath, and then an aqueous solution (2 mL) of potassium phosphate (498 mg,2.35 mmol) was added to the reaction mixture. After stirring the reaction solution at room temperature for 30 minutes, a solution of 3-bromo-7-iodoquinolin-2-amine (80.5 mg,0.23 mmol) and PdCl2 (dppf) (14.6 mg,0.02 mmol) in tetrahydrofuran (2 mL) was added. The resulting reaction mixture was heated to 55℃and stirred overnight.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give 3-bromo-7- (2- ((3 as,6 ar) -4- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxo-6-yl) ethyl) quinolin-2-amine (120 mg).
MS(ESI)M/Z:542.0[M+H] + .
Step B3-bromo-7- (2- ((3 aS,6 aR) -4- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] azoidin-7-yl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxo-6-yl) ethyl) quinolin-2-amine (120 mg,0.22 mmol) was dissolved in ethanol (5 mL) and aqueous ammonia (30 mL) at room temperature. The reaction solution was stirred in a 140℃autoclave for 2 days.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7- ((3 as,6 ar) -2, 2-dimethyl-6-vinyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxy-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (30 mg).
MS(ESI)M/Z:523.3[M+H] + .
Step C: 7- ((3 aS,6 aR) -2, 2-dimethyl-6-vinyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (30 mg,0.057 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction to adjust the pH to approximately 8-9. The mixture was extracted with ethyl acetate (5 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2 r) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopent-3-ene-1, 2-diol (3.3 mg).
MS(ESI)M/Z:483.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ8.32(s,1H),7.79(s,1H),7.57(d,J＝8.2Hz,1H),7.31(s,1H),7.11(dd,J＝8.2,1.6Hz,1H),6.56(s,2H),5.93(s,2H),5.28(d,J＝1.4Hz,1H),4.82(s,1H),4.74(dd,J＝6.2,4.8Hz,2H),4.29(t,J＝5.8Hz,1H),3.88(dd,J＝10.6,5.8Hz,1H),3.22(dd,J＝16.8,9.0Hz,1H),2.98(dd,J＝18.8,9.2Hz,1H),2.93–2.80(m,2H),2.57(t,J＝9.0Hz,2H),2.48–2.38(m,2H).
Example 36
(1S, 2R, 3S) -3- (2- (2-amino-3-chloroquinolin-7-yl) ethyl) -5- (4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-ol
Preparation method referring to example 34, the target product (1S, 2R, 3S) -3- (2- (2-amino-3-chloroquinolin-7-yl) ethyl) -5- (4-methyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-ol was finally obtained.
MS(ESI)M/Z:440.4[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.27(s,1H),7.95(s,1H),7.54–7.47(m,2H),7.18(dd,J＝8.2,1.5Hz,1H),5.38(s,2H),4.12–4.04(m,1H),3.91–3.83(m,2H),3.78–3.70(m,1H),3.51(dd,J＝9.6Hz,1H),3.00(t,J＝7.6Hz,2H),2.85(t,J＝7.7Hz,2H),2.31–2.22(m,4H),2.11–1.94(m,4H),1.75–1.70(m,1H),1.46–1.35(m,1H).
Example 37
(1S, 2R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopent-3-ene-1, 2-diol
Preparation method referring to example 35, the target product (1S, 2R) -3- ((E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopent-3-ene-1, 2-diol was finally obtained.
MS(ESI)M/Z:481.0[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ8.27(s,1H),7.87(s,1H),7.62–7.54(m,2H),7.50(d,J＝8.4Hz,1H),7.11–6.97(m,2H),5.99(s,1H),5.09(d,J＝6.0Hz,1H),4.24–4.18(m,1H),3.71–3.67(m,1H),3.56–3.52(m,2H),2.89–2.85(m,2H).
Example 38
(1S, 2R) -3- (2- (2-amino-3-chloroquinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopent-3-ene-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A. In a three-necked flask, the compound 4-chloro-7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyl-3 a,6 a-dihydro-4H-cyclopentane [ d ]][1,3]Dioxol-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d]A solution of pyrimidine (110 mg,0.34 mmol) in tetrahydrofuran (1 mL) was then replaced with nitrogen. A solution of 9-BBN (3.44 mmol) in tetrahydrofuran (0.5M, 6.89 mL) was slowly added dropwise at room temperature, and after completion of the addition, the reaction solution was heated to 55℃and stirred at this temperature for 1 hour. The reaction system was cooled to room temperature by removing an oil bath, and then an aqueous solution (2 mL) of potassium phosphate (729 mg,3.44 mmol) was added to the reaction mixture. After the reaction solution was stirred at room temperature for 30 minutes, 7-bromo-3-chloroquinolin-2-amine (88 mg,0.34 mmol) and PdCl were added 2 (dppf) (21.9 mg,0.03 mmol) in tetrahydrofuran (2 mL). The resulting reaction mixture was heated to 55℃and stirred overnight.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography to give 3-chloro-7- (2- ((3 as,6 ar) -4- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopentane [ d ] [1,3] dioxo-6-yl) ethyl) quinolin-2-amine (100 mg).
MS(ESI)M/Z:498.0[M+H] + .
Step B3-chloro-7- (2- ((3 aS,6 aR) -4- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxo-6-yl) ethyl) quinolin-2-amine (60 mg,0.12 mmol) was dissolved in ethanol (5 mL) and aqueous ammonia (30 mL) at room temperature. The reaction solution was stirred in a 140℃autoclave for 2 days.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7- (2- ((3 as,6 ar) -4- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopentane [ d ] [1,3] dioxo-6-yl) ethyl) -3-chloroquinolin-2-amine (20 mg).
MS(ESI)M/Z:479.0[M+H] + .
Step C: 7- (2- ((3 aS,6 aR) -4- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxo-6-yl) ethyl) -3-chloroquinolin-2-amine (20 mg,0.042 mmol) was dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction to adjust the pH to approximately 8-9. The mixture was extracted with ethyl acetate (5 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2 r) -3- (2- (2-amino-3-chloroquinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopent-3-ene-1, 2-diol (2.7 mg).
MS(ESI)M/Z:439.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.07(s,1H),7.81(s,1H),7.57(d,J＝8.2Hz,1H),7.37(s,1H),7.23-7.15(m,1H),5.35(s,1H),4.58(s,1H),4.42(d,J＝5.8Hz,1H),4.04–3.96(m,1H),3.26–3.20(m,2H),3.02–2.95(m,2H),2.69–2.53(m,4H).
Example 39
(1R, 2S,3R, 5R) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((E) -2- (2-aminoquinazolin-7-yl) vinyl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine (100 mg,0.33 mmol), 7-bromoquinazolin-2-amine (81.2 mg,0.33 mmol) and tetraethylammonium chloride (60.15 mg,0.363 mmol) are dissolved in N, N-dimethylformamide (1.5 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (15 mg,0.066 mmol) and N, N-diisopropylethylamine (85 mg,0.66 mmol) were added under nitrogen. The reaction solution was stirred at 100℃in an oil bath for 12 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) quinazolin-2-amine (130 mg).
MS(ESI)M/Z:446.2[M+H] + .
And (B) step (B): 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) vinyl) quinazolin-2-amine (130 mg,0.29 mmol) was dissolved in methanol (2 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (2 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction to adjust the pH to approximately 8-9. The mixture was extracted with ethyl acetate (5 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -5- ((E) -2- (2-aminoquinazolin-7-yl) vinyl) cyclopentane-1, 2-diol (7.7 mg).
MS(ESI)M/Z:406.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ9.00(s,1H),7.80(s,1H),7.70(d,J＝8.0Hz,1H),7.39(d,J＝8.8Hz,1H),7.31(s,1H),6.76(s,2H),6.56(s,2H),5.94(s,2H),4.83(d,J＝5.2Hz,1H),4.69(d,J＝5.6Hz,1H),4.22(dd,J＝16.0,8.8Hz,1H),3.97(dd,J＝11.2,5.6Hz,1H),3.73(dd,J＝11.6,5.8Hz,1H),3.52(t,J＝8.8Hz,2H),2.78–2.68(m,2H),2.65–2.61(m,1H),1.98-1.95(m,1H),1.58-1.50(m,1H).
Example 40
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-fluoroquinolin-7-yl) ethyl) -5- (4-amino-9H-pyrimidine [4,5-b ] indol-9-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A prepared by the method of 4-chloro-9H-pyrimido [4,5-b ] indole (660 mg,3.24 mmol) and (3 aS,4S,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (780 mg,4.88mmol, reference J.Org.chem.2004,69,3993-3996, the entire contents of which are incorporated herein by reference) in a dry toluene (5 mL) in a capped tube. Cyanomethylene tri-n-butylphosphine (1.56 g,6.48 mmol) was dissolved in toluene (3 mL), the above liquid was added dropwise under nitrogen atmosphere, and the reaction solution was stirred at 110℃for 18 hours.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-chloro-9- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxy-4-yl) -9H-pyrimidine [4,5-b ] indole (379 mg).
MS(ESI)M/Z:370.0[M+H] + .
1 H NMR(400MHz,DMSO)δ8.87(s,1H),8.38(d,J＝8.0Hz,1H),7.97(d,J＝8.4Hz,1H),7.73(t,J＝7.8Hz,1H),7.51(t,J＝7.6Hz,1H),6.07-5.98(m,1H),5.45–5.38(m,1H),5.30(dd,J＝7.2,5.8Hz,1H),5.19(d,J＝17.2Hz,1H),5.11(d,J＝10.4Hz,1H),4.76(t,J＝7.0Hz,1H),2.88-2.76(m,1H),2.71(dd,J＝24.4,12.0Hz,1H),2.34–2.25(m,1H),1.53(s,3H),1.22(s,3H).
Step B in a tube sealer, 4-chloro-9- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -9H-pyrimidine [4,5-B ] indole (379 mg,1.02 mmol) was dissolved in a mixture of ethanol (4 mL) and aqueous ammonia (10 mL), and the reaction was stirred in a tube sealer at 120℃for 18 hours.
After LCMS monitoring showed mostly product, concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((3 as,4r,6 ar) -9- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxy-4-yl) -9H-pyrimidine [4,5-b ] indol-4-amine (179 mg).
MS(ESI)M/Z:351.2[M+H] + .
Step C, adding the compound 7- ((3 aS,4R,6 aR) -9- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyl tetrahydro-4H-cyclopentane [ d ] to a three-necked flask][1,3]Dioxy-4-yl) -9H-pyrimidine [4,5-b]A solution of indol-4-amine (60 mg,0.17 mmol) in tetrahydrofuran (1 mL) is then replaced with nitrogen. Tetrahydrofuran of 9-BBN (1.19 mmol) was slowly added dropwise to the reaction solution at room temperatureAfter the completion of the dropwise addition of the solution (0.5M, 2.39 mL), the reaction mixture was heated to 55℃and stirred at this temperature for 1 hour. The reaction system was cooled to room temperature by removing from the oil bath, and then an aqueous solution (2 mL) of potassium phosphate (252 mg,1.19 mmol) was added to the reaction mixture. After the reaction solution was stirred at room temperature for 30 minutes, 7-bromo-3-fluoroquinolin-2-amine (41 mg,0.17mmol, prepared by the method of synthesizing 7-bromo-3-chloroquinolin-2-amine of reference example 31) and PdCl were added 2 (dppf) (14.6 mg,0.02 mmol) in tetrahydrofuran (2 mL). The resulting reaction mixture was heated to 55℃and stirred overnight.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give a crude product which was purified to give 9- ((3 aS,4R,6S,6 aR) -6- (2- (2-amino-3-fluoroquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxy-4-yl) -9H-pyrimidine [4,5-b ] indol-4-amine (60 mg).
MS(ESI)M/Z:513.4[M+H] + .
Step D9- ((3 aS,4R,6S,6 aR) -6- (2- (2-amino-3-fluoroquinolin-7-yl) ethyl) -2, 2-dimethyltetrahydro-4H-cyclopentan [ D ] [1,3] dioxan-4-yl) -9H-pyrimidin [4,5-b ] indol-4-amine (60 mg,0.12 mmol) is dissolved in methanol (2 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (2 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction to adjust the pH to approximately 8-9. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3s,5 r) -3- (2- (2-amino-3-fluoroquinolin-7-yl) ethyl) -5- (4-amino-9H-pyrimidine [4,5-b ] indol-9-yl) cyclopentane-1, 2-diol (28 mg).
MS(ESI)M/Z:473.2[M+H] + .
1 H NMR(400MHz,MeOD)δ8.29(s,1H),8.13(d,J＝7.6Hz,1H),7.69–7.56(m,3H),7.49–7.41(m,2H),7.32(t,J＝7.2Hz,1H),7.22(d,J＝8.2Hz,1H),5.13(dd,J＝18.0,8.2Hz,1H),4.97(t,J＝6.8Hz,1H),4.12(t,J＝5.8Hz,1H),2.95–2.80(m,2H),2.32–2.07(m,4H),1.97–1.90(m,1H).
Example 41
(1S, 2R,3S, 5R) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5, 5-dimethyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A solution of (3 aR,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxin-4-one (550 mg,1.72 mmol) in N, N-dimethylformamide (10 mL) was added to a three-bottle, and the system was replaced with nitrogen atmosphere. The reaction flask was cooled to 0℃in an ice bath, and then potassium tert-butoxide powder (579 mg,5.16 mmol) was added in portions. After the addition was completed, the reaction system was stirred at 0℃for 1 hour. Methyl iodide (732 mg,5.16 mmol) was then added dropwise under nitrogen atmosphere, and the reaction system was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by slow addition of water (10 mL). Then extracted with ethyl acetate, (10 ml×3 times) and the organic phases combined, washed first with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-chloro-7- (2, 4-dimethoxybenzyl) -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one (560 mg).
MS(ESI)M/Z:348.2[M+H] + .
Step B A solution of 4-chloro-7- (2, 4-dimethoxybenzyl) -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one (460 mg,1.33 mmol) in tetrahydrofuran (10 mL) was added to a three-necked flask, and the system was replaced with nitrogen. The reaction flask was cooled to 0deg.C in an ice bath, and then a solution of lithium aluminum hydride (2.66 mmol) in tetrahydrofuran (1M, 2.66 mL) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 1 hour.
After TLC monitoring showed the disappearance of starting material, sodium sulfate decahydrate was slowly added to the reaction solution to quench until no bubbles emerged. Tetrahydrofuran was then added and stirred for 30 minutes, and the reaction solution was filtered. The filtrate was concentrated to give an oily crude product, which was purified by silica gel column chromatography to give 4-chloro-7- (2, 4-dimethoxybenzyl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-6-ol (370 mg).
MS(ESI)M/Z:350.2[M+H] + .
Step C A three-necked flask was charged with a solution of 4-chloro-7- (2, 4-dimethoxybenzyl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-6-ol (370 mg,1.06 mmol) in dichloromethane (20 mL) and the system was then replaced with nitrogen. The reaction flask was cooled to 0deg.C in an ice bath, followed by trifluoroacetic acid (2.3 mL) and triethylsilane (2.3 mL). After the addition was completed, the reaction system was stirred at room temperature for 1 hour.
LCMS monitoring showed the disappearance of starting material, followed by slow addition of saturated sodium bicarbonate solution to the reaction solution to adjust ph=9-10. Then extracted with dichloromethane (20 mL x 3 times) and the organic phases combined, washed first with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-chloro-7- (2, 4-dimethoxybenzyl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (330 mg).
MS(ESI)M/Z:334.2[M+H] + .
Step D4-chloro-7- (2, 4-dimethoxybenzyl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-D ] pyrimidine (330 mg,1.01 mmol) was dissolved in trifluoroacetic acid (15 mL) in a single-necked flask, and the reaction solution was stirred overnight at 70 ℃.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was adjusted to ph=8-9 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, the organic phases were washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-chloro-5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (180 mg).
MS(ESI)M/Z:184.2[M+H] + .
Step E4-chloro-5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (80 mg,0.44 mmol) and (3 aS,4S,6R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-ol (123.4 mg,0.66mmol, prepared by the method of reference J.org. chem.2004,69,3993-3996, the entire contents of which are incorporated herein by reference) were dissolved in dry toluene (1 mL) in a sealed tube. Cyanomethylene tri-n-butylphosphine (318 mg,1.32 mmol) was dissolved in toluene (0.5 mL), the above liquid was added dropwise under nitrogen atmosphere, and the reaction solution was stirred at 110℃for 18 hours.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 4-chloro-7- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxy-4-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (140 mg).
MS(ESI)M/Z:350.2[M+H] + .
Step F4-chloro-7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxan-4-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (140 mg,0.4 mmol) was dissolved in a mixture of ethanol (50 mL) and aqueous ammonia (150 mL) at room temperature, and the reaction mixture was stirred in a 160℃autoclave for 60 hours.
After LCMS monitoring showed mostly product, concentrate under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((3 as,4r,6 ar) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxy-4-yl) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidin-4-amine) (120 mg).
MS(ESI)M/Z:331.2[M+H + ].
Step G, taking a dry three-necked flask, replacing the system with nitrogen atmosphere, adding 7- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyl tetrahydro-4H-cyclopentane [ d ] [1,3] dioxy alcohol-4-group) -5, 5-dimethyl-6, 7-dihydro-5H-pyrrole [2,3-d ] pyrimidine-4-amine) (60 mg,0.182 mmol) tetrahydrofuran (2 mL), dropwise adding 9-BBN (1.274 mmol) tetrahydrofuran solution (0.5M, 2.55 mL) under ice bath, heating the reaction system at 55 ℃ for 1 hour under oil bath, and cooling the reaction solution to room temperature. Potassium phosphate (370 mg,1.274 mmol) was dissolved in tetrahydrofuran (1 mL). The solution was added dropwise to the reaction system, and after the addition was completed, the reaction system was stirred at room temperature for 20 minutes. 3-bromo-7-iodoquinolin-2-amine (63.25 mg,0.182 mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (13.3 mg,0.0182 mmol) were then added and the reaction stirred in an oil bath at 55deg.C overnight.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- (2- ((3 ar,4s,6r,6 as) -6- (4-amino-5, 5-dimethyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopentane [ d ] [1,3] dioxo-4-yl) ethyl) -3-bromoquinolin-2-amine (30 mg).
MS(ESI)M/Z:553.2[M+H] + .
Step H7- (2- ((3 aR,4S,6R,6 aS) -6- (4-amino-5, 5-dimethyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxo-4-yl) ethyl) -3-bromoquinolin-2-amine (30 mg,0.054 mmol) is dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (1 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, 1M sodium hydroxide solution was added to the reaction to adjust the pH to approximately 8-9. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product (1 s,2r,3s,5 r) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-5, 5-dimethyl-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (4.2 mg).
MS(ESI)M/Z:513.3[M+H] + .
1 H NMR(400MHz,MeOD)δ8.26(s,1H),7.83(s,1H),7.56(d,J＝8.2Hz,1H),7.40(s,1H),7.18(dd,J＝8.2,1.6Hz,1H),4.29–4.22(m,1H),4.00(dd,J＝8.2,6.2Hz,1H),3.71(dd,J＝6.0,4.2Hz,1H),3.54–3.33(m,2H),2.85–2.75(m,2H),2.12–2.05(m,1H),2.02–1.89(m,2H),1.73–1.70(m,1H),1.37(s,6H),1.34–1.25(m,1H).
Example 42
(1S, 2R, 3S) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-cyclopentane [4,5] pyrrole [2,3-d ] pyrimidine-8 (5H) -yl) -3-methylcyclopentane-1, 2-diol
Preparation method referring to example 5, the target product (1S, 2R, 3S) -3- (2- (2-amino-3-bromoquinolin-7-yl) ethyl) -5- (4-amino-6, 7-dihydro-cyclopentane [4,5] pyrrole [2,3-d ] pyrimidine-8 (5H) -yl) -3-methylcyclopentane-1, 2-diol was finally obtained.
MS(ESI)M/Z:537.6[M+H] + .
1 H NMR(400MHz,MeOD)δ8.26(s,1H),7.98(s,1H),7.56(d,J＝8.2Hz,1H),7.41(s,1H),7.19(dd,J＝8.2,1.6Hz,1H),4.99–4.92(m,1H),4.63–4.56(m,1H),3.90(d,J＝6.2Hz,1H),2.97–2.89(m,4H),2.89–2.71(m,2H),2.54–2.48(m,2H),2.08–1.83(m,4H),1.22(s,3H).
Example 43
(1R, 2S,3R, 5R) -3- ((E) -2- (2-amino-3- (trifluoromethyl) quinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A7-bromo-3- (trifluoromethyl) quinoline (950 mg,3.44 mmol) was dissolved in dichloromethane (25 mL) at room temperature. M-chloroperbenzoic acid (2.37 g,13.7 mmol) was slowly added at 0deg.C, and the reaction stirred at room temperature for 12 hours.
After LCMS monitoring showed the disappearance of starting material, quench by adding water (50 mL) to the reaction at 0 ℃ followed by slow addition of saturated aqueous ammonium chloride to adjust pH to 7 and concentration under reduced pressure. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7-bromo-3- (trifluoromethyl) quinoline 1-oxide (650 mg).
MS(ESI)M/Z:292.0[M+H] + .
Step B7-bromo-3- (trifluoromethyl) quinoline 1-oxide (650 mg,2.24 mmol) was dissolved in chloroform (15 mL) at room temperature. Phosphorus oxychloride (15 mL) was then slowly added at 0 ℃ and the reaction was evacuated and replaced with nitrogen multiple times. The reaction was stirred for 3 hours at 70℃in an oil bath.
LCMS monitoring showed the disappearance of starting material followed by concentration under reduced pressure. Dichloromethane (30 mL) was added, then the pH was adjusted to 7 with saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7-bromo-2-chloro-3- (trifluoromethyl) quinoline (560 mg).
MS(ESI)M/Z:310.0[M+H] + .
Step C7-bromo-2-chloro-3- (trifluoromethyl) quinoline (560 mg,1.8 mmol) was dissolved in ethanol (10 mL) and aqueous ammonia (20 mL) at room temperature. The reaction solution was then placed in a stewing pot and stirred at 100 ℃ for 20 hours.
After LCMS monitoring showed the disappearance of starting material, concentrated under reduced pressure, the mixture was extracted with dichloromethane (20 ml×3 times) and the organic phases were combined, washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7-bromo-3- (trifluoromethyl) quinolin-2-amine (400 mg).
MS(ESI)M/Z:291.4[M+H] + .
Step D8- ((3 aS,4R,6 aR) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopentan [ D ] [1,3] dioxan-4-yl) -5,6,7, 8-tetrahydrocyclopentan [4,5] pyrrole [2,3-D ] pyrimidin-4-amine (80 mg,0.26 mmol), 7-bromo-3- (trifluoromethyl) quinolin-2-amine (75 mg,0.26 mmol) and tetraethylammonium chloride (65 mg,0.39 mmol) are dissolved in N, N-dimethylformamide (2 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (6.7 mg,0.03 mmol) and N, N-diisopropylethylamine (0.09 mL,0.54 mmol) were added under nitrogen. The reaction solution was stirred at 100℃in an oil bath for 12 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (20 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 7- ((E) -2- ((3 aS,4R,6 aR) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxan-4-yl) vinyl) -3- (trifluoromethyl) quinolin-2-amine (80 mg).
MS(ESI)M/Z:512.6[M+H] + .
Step E: 7- ((E) -2- ((3 aS,4R,6 aR) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) vinyl) -3- (trifluoromethyl) quinolin-2-amine (80 mg,0.156 mmol) is dissolved in methanol (1 mL) at room temperature. Subsequently, 4M hydrochloric acid-methanol solution (3 mL) was added to the above solution. The reaction solution was stirred at room temperature for 2 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was dissolved in 2mL of methanol and then 7M methanolic ammonia solution was added to adjust the pH to approximately 8-9. The resulting solution was purified by preparative high performance liquid chromatography to give the final product (1 r,2s,3r,5 r) -3- ((E) -2- (2-amino-3- (trifluoromethyl) quinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (4 mg).
MS(ESI)M/Z:472.6[M+H] + .
1 H NMR(400MHz,MeOD)δ8.35(s,1H),7.76(s,1H),7.72(d,J＝8.3Hz,1H),7.52-7.46(m,2H),6.67–6.63(m,1H),6.57–6.51(m,1H),4.38-4.24(m,1H),4.16–4.12(m,1H),3.92–3.88(m,1H),3.76-3.61(m,2H),2.93-2.73(m,3H),2.21-2.07(m,1H),1.75-1.59(m,1H).
Example 44
(1R, 2S,3S, 5R) -3- (2- (2-amino-3- (trifluoromethyl) quinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
Preparation method referring to example 43, the target product (1 r,2s,3s,5 r) -3- (2- (2-amino-3- (trifluoromethyl) quinolin-7-yl) ethyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol is finally obtained.
MS(ESI)M/Z:474.6[M+H] + .
1 H NMR(400MHz,MeOD)δ8.36(s,1H),7.82(s,1H),7.72(d,J＝8.2Hz,1H),7.44(s,1H),7.24(d,J＝8.2Hz,1H),4.25-4.19(m,1H),4.10-3.99(m,1H),3.79-3.55(m,3H),2.96–2.75(m,4H),2.15-2.02(m,1H),2.02-1.87(m,2H),1.83–1.65(m,1H),1.42-1.26(m,1H).
Example 45
2-amino-7- ((E) -2- ((1R, 2R,3S, 4R) -4- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 3-dihydroxycyclopentyl) vinyl) quinoline-3-carbonitrile
The reaction route is as follows:
the operation steps are as follows:
step A: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxolan-4-yl) vinyl) -3-bromoquinolin-2-amine (prepared by the method for the synthesis of the product of step B, example 14, 100.0mg,0.19 mmol), cuprous cyanide (70 mg,0.77 mmol), tris (dibenzylideneacetone) dipalladium (20 mg,0.022 mmol) and 1,1' -bis (diphenylphosphino) ferrocene (43 mg,0.077 mmol) were added to 1, 4-dioxane (6 mL), the reaction solution was warmed to 100℃and stirred overnight by nitrogen substitution 3 times.
TLC monitoring showed the disappearance of starting material followed by cooling and direct concentration under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 2-amino-7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxolan-4-yl) vinyl) quinoline-3-carbonitrile (50 mg).
MS(ESI)M/Z:470.2[M+H] + .
And (B) step (B): 2-amino-7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxolan-4-yl) vinyl) quinoline-3-carbonitrile (50 mg,0.106 mmol) was dissolved in trifluoroacetic acid (2 mL) and water (1 mL) and stirred at room temperature for 2 hours.
LCMS monitored complete reaction of starting materials, diluted with acetonitrile, and purified directly to give 2-amino-7- ((E) -2- ((1 r,2r,3s,4 r) -4- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 3-dihydroxycyclopentyl) vinyl) quinoline-3-carbonitrile (4.06 mg).
MS(ESI)M/Z:430.1[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ8.77(s,1H),8.13(s,1H),7.83(d,J＝8.5Hz,1H),7.68–7.58(m,2H),6.69(d,J＝3.4Hz,2H),4.57–4.48(m,1H),4.20–4.16(m,1H),3.99–3.86(m,3H),3.02–2.98(m,2H),2.85–2.79(m,1H),2.24–2.09(m,1H).
Example 46
(1S, 2R,3R, 5R) -3- ((E) -2- (2-amino-3- (methylsulfonyl) quinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol
The reaction route is as follows:
the operation steps are as follows:
step A: 7- ((E) -2- ((3 aR,4R,6 aS) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxolan-4-yl) vinyl) -3-bromoquinolin-2-amine (prepared by the method for the synthesis of the product of step B, example 14), 150.0mg,0.29 mmol), sodium methane sulfinate (138 mg,1.35 mmol), proline (34 mg,0.3 mmol), cuprous iodide (36 mg,0.19 mmol) and cesium carbonate (66 mg,0.2 mmol) were added to dimethyl sulfoxide (5 mL), and the mixture was heated to 100℃under nitrogen and stirred for 2.5 hours.
TLC monitoring showed that the starting material had largely disappeared, cooled to room temperature, and water (20 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (30 mL. Times.2), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was used directly in the next step.
MS(ESI)M/Z:523.1[M+H] + .
And (B) step (B): the crude product of the above step was dissolved in methanol (5 mL), to which was added 4M aqueous hydrochloric acid (2 mL), and the reaction solution was stirred at room temperature for 2 hours.
TLC was used to monitor the completion of the reaction, saturated aqueous sodium hydrogencarbonate (20 mL) was added to the reaction system, the mixture was extracted with methylene chloride (30 mL. Times.3 times.), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Crude preparation purification gave (1 s,2r,3r,5 r) -3- ((E) -2- (2-amino-3- (methylsulfonyl) quinolin-7-yl) vinyl) -5- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) cyclopentane-1, 2-diol (14.71 mg).
MS(ESI)M/Z:483.1[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ9.00(s,1H),8.16(s,1H),8.00(d,J＝8.5Hz,1H),7.78-7.69(m,2H),6.84–6.68(m,2H),4.59–4.53(m,1H),4.24–4.20(m,1H),4.02–3.84(m,3H),3.34(s,3H),3.07–2.97(m,2H),2.88–2.84(m,1H),2.20–2.16(m,1H),1.80–1.76(m,1H).
Example 47
(1S, 4R,6R, 7R) -4- ((E) -2- (2-amino-3-bromoquinolin-7-yl) ethylene) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-oxabicyclo [2.2.1] cyclopentan-7-ol
The reaction route is as follows:
The operation steps are as follows:
step A, (3 aR,6 aR) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxin-4-one (924 mg,6.0 mmol) and benzophenone (218 mg,1.2 mmol) were dissolved in methanol (400 mL) at room temperature. The reaction system was protected by nitrogen substitution, and then the reaction flask was placed in a dark room and stirred for 2 hours under irradiation of a mercury lamp.
After TLC monitoring showed the disappearance of starting material, the reaction solution was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give (3 aR,6 aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxin-4-one (686 mg).
1 H NMR(400MHz,DMSO-d 6 )δ4.92(t,J＝4.6Hz,1H),4.63(d,J＝5.4Hz,1H),4.18(d,J＝5.4Hz,1H),3.64–3.52(m,1H),3.46–3.38(m,1H),2.63–2.52(m,2H),2.41–2.34(m,1H),1.31(s,3H),1.26(s,3H).
Step B (3 aR,6 aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydro-4H-cyclopentan [ d ] [1,3] dioxin-4-one (5.58 g,30 mmol) and imidazole (4.08 g,60 mmol) were dissolved in dichloromethane (60 mL) at room temperature. Then, the reaction solution was cooled to 0℃and a methylene chloride solution of t-butyldiphenylchlorosilane (12.37 g,450 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 16 hours.
After TLC monitoring showed the disappearance of starting material, the reaction mixture was quenched with water (300 mL), extracted with dichloromethane (60 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give (3 aR,6 aR) -6- (tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxin-4-one (10.96 g).
1 H NMR(400MHz,DMSO-d 6 )δ7.63–7.55(m,4H),7.52–7.42(m,6H),4.73–4.60(m,1H),4.21(d,J＝5.4Hz,1H),3.78(dd,J＝10.1,2.9Hz,1H),3.59(dd,J＝10.1,3.6Hz,1H),2.80–2.61(m,1H),2.54–2.52(m,1H),2.49–2.45(m,1H),1.33(s,3H),1.27(s,3H),0.95(s,9H).
Step C A three-necked flask was charged with a solution of (3 aR,6 aR) -6- (t-butyldiphenylsiloxy) methyl) -2, 2-dimethyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxin-4-one (10.6 g,25 mmol) and triethylchlorosilane (7.54 g,50 mmol) in tetrahydrofuran (50 mL), and the system was replaced with nitrogen. The reaction flask was cooled to-78 ℃ in an ice bath, and then a solution of lithium bis (trimethylsilyl) amide (50 mmol) in tetrahydrofuran (1 m,50 ml) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 40 minutes.
After TLC monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give tert-butyl (((3 aR,6 aR) -2, 2-dimethyl-6- (triethylsilyl) oxy) -3a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxin-4-yl) methoxy) diphenylsilane (6.25 g).
Step D in a single vial was added tert-butyl (((3 aR,6 aR) -2, 2-dimethyl-6- (triethylsilyl) oxy) -3a,6 a-dihydro-4H-cyclopenta [ D ] [1,3] dioxin-4-yl) methoxy) diphenylsilane (6.25 g,11.6 mmol), palladium acetate (779 mg,3.48 mmol) and dimethyl sulfoxide (100 mL), and the system was replaced with an oxygen atmosphere. The reaction solution was heated to 60℃and reacted at this temperature overnight.
After TLC monitoring showed the disappearance of starting material, the reaction was poured into ice water. The reaction solution was extracted with ethyl acetate (60 mL. Times.3), the organic phases were combined, the organic phase was successively washed with water (60 mL. Times.3) and saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 ar,6 ar) -6- (tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxin-4-one (3.45 g, yield 70.5%).
1 H NMR(400MHz,CDCl 3 )δ7.71–7.60(m,4H),7.48–7.33(m,6H),6.33(t,J＝1.9Hz,1H),4.98(d,J＝5.6Hz,1H),4.69(dd,J＝18.9,1.9Hz,1H),4.54–4.41(m,2H),1.34(d,J＝8.0Hz,6H),1.12–1.05(m,9H).
Step E lithium chloride (127 mg,3 mmol), cuprous iodide (284 mg,1.5 mmol) and tetrahydrofuran (100 mL) were added to a three-necked flask, and the system was replaced with nitrogen. The reaction solution was cooled to 0℃and stirred at this temperature for 10 minutes, and then a solution of trimethylchlorosilane (1.956 g,18 mmol) and (3 aR,6 aR) -6- (t-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-3 a,6 a-dihydro-4H-cyclopenta [ d ] [1,3] dioxin-4-one (6.34 g,15 mmol) in tetrahydrofuran (40 mL) was dropwise added thereto. After the completion of the dropwise addition, the reaction solution was stirred at 0℃for 20 minutes. A solution of vinylmagnesium bromide (24 mmol) in tetrahydrofuran (1M, 24 mL) was then added dropwise. The resulting reaction solution was stirred at 0℃for 30 minutes.
After TLC monitoring showed the disappearance of starting material, the reaction solution was quenched by addition of saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give (3 aR,6 aR) -6- (tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxin-4-one (4.15 g).
1 H NMR(400MHz,CDCl 3 )δ7.76–7.64(m,4H),7.47–7.33(m,6H),6.21–5.86(m,1H),5.29–5.19(m,1H),5.17–5.04(m,1H),4.94–4.70(m,1H),4.34–4.18(m,1H),3.96(d,J＝9.4Hz,1H),3.72(d,J＝9.4Hz,1H),2.46–2.27(m,2H),1.42–1.31(m,6H),1.13–1.03(m,9H).
Step F A three-necked flask was charged with a solution of (3 aR,6 aR) -6- (tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxin-4-one (4.15 g,9.2 mmol) in tetrahydrofuran (50 mL) and the system was replaced with nitrogen. The reaction flask was cooled to 0deg.C in an ice bath, and then a solution of lithium aluminum hydride (18.4 mmol) in tetrahydrofuran (1M, 18.4 mL) was added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 2 hours.
After TLC monitoring showed the disappearance of starting material, sodium sulfate decahydrate was slowly added to the reaction solution to quench until no bubbles emerged. Tetrahydrofuran was then added and stirred for 30 minutes, and the reaction solution was filtered. The filtrate was concentrated to give an oily crude product, which was purified by silica gel column chromatography to give (3 aS,4S,6 aR) -6- (tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxin-4-ol (2.95 g).
1 H NMR(400MHz,CDCl 3 )δ7.76–7.60(m,4H),7.46–7.30(m,6H),5.94(dd,J＝17.8,11.1Hz,1H),5.18(dd,J＝39.0,14.5Hz,2H),4.60(d,J＝5.4Hz,1H),4.46(t,J＝5.7Hz,1H),4.08–4.00(m,1H),3.82(d,J＝9.3Hz,1H),3.57(d,J＝9.3Hz,1H),1.98(dd,J＝12.2,6.4Hz,1H),1.43(s,3H),1.43–1.38(m,1H),1.36(s,3H),1.03(s,9H).
Step G: 4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (467 mg,3 mmol) and (3 aS,4S,6 aR) -6- (tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxin-4-ol (255 mg,2 mmol) were dissolved in toluene (20 mL) at room temperature, and the reaction system was replaced with a nitrogen atmosphere. A solution of 2- (tributylphosphoranylidene) acetonitrile (1.45 g,6 mmol) in toluene (2 mL) was then slowly added to the reaction system. The reaction solution was heated to 110℃and stirred at this temperature for 16 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel to give 7- (3 as,4r,6 ar) -6- ((tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) -4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (300 mg).
MS(ESI)M/Z:590.1[M+H] + .
Step H: 7- (3 aS,4R,6 aR) -6- ((tert-butyldiphenylsiloxy) methyl) -2, 2-dimethyl-6-vinyltetrahydro-4H-cyclopenta [ d ] [1,3] dioxo-4-yl) -4-chloro-6, 7-dihydro-5H-pyrrolo [2,3-d ] pyrimidine (560 mg,1 mmol) was dissolved in methanol (3 mL) at room temperature. To the reaction mixture was added 4N HCl in methanol (2.5 mL). The reaction solution was stirred at room temperature for 16 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column chromatography to give (1 s,2r,3r,5 r) -5- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3- (hydroxymethyl) -3-vinylcyclopentane-1, 2-diol (220 mg).
MS(ESI)M/Z:312.1[M+H] + .
Step I: (1S, 2R,3R, 5R) -5- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -3- (hydroxymethyl) -3-vinylcyclopentane-1, 2-diol (218 mg,0.7 mmol) was dissolved in toluene (2 mL) at room temperature, and the reaction system was replaced with a nitrogen atmosphere. A solution of 2- (tributylphosphoranylidene) acetonitrile (338 mg,1.4 mmol) in toluene (1 mL) was then slowly added to the reaction system. The reaction solution was heated to 110℃and stirred at this temperature for 16 hours.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (30 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (15 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to give (1 s,4r,6r,7 r) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -4-vinyl-2-oxa [2.2.1] heptane-7-ol (65 mg).
MS(ESI)M/Z:294.0[M+H] + .
Step J: (1S, 4R,6R, 7R) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -4-vinyl-2-oxa-cyclic [2.2.1] heptan-7-ol (65 mg,0.22 mmol), 3-bromo-7-iodoquinolin-2-amine (92 mg,0.264 mmol) and tetraethylammonium chloride (40 mg,0.24 mmol) were dissolved in N, N-dimethylformamide (2 mL) at room temperature. The reaction system is vacuumized and replaced with nitrogen for many times. Palladium acetate (10 mg,0.04 mmol), N, N-diisopropylethylamine (142 mg,1.1 mmol) was added under nitrogen. The reaction solution was stirred for 12 hours at 70℃in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was quenched by addition of water (10 mL) and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (1 s,4r,6r,7 r) -4- (E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-oxa [2.2.1] heptan-7-ol (45 mg).
MS(ESI)M/Z:514.1[M+H] + .
Step K A solution of 1S,4R,6R, 7R) -4- (E) -2- (2-amino-3-bromoquinolin-7-yl) vinyl) -6- (4-chloro-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-oxa [2.2.1] heptan-7-ol (45 mg,0.29 mmol) in ethanol (1 mL) was added to the lock at room temperature. Subsequently, ammonia (3 mL) was slowly added to the reaction system at room temperature. The reaction was stirred for 4 days at 135℃in an oil bath.
After LCMS monitoring showed the disappearance of starting material, the reaction was concentrated by distillation under reduced pressure. The resulting residue was purified to give the final product (1S, 4R,6R, 7R) -4- ((E) -2- (2-amino-3-bromoquinolin-7-yl) ethylene) -6- (4-amino-5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) -2-oxabicyclo [2.2.1] cyclopentan-7-ol (2.5 mg).
MS(ESI)M/Z:495.0[M+H] + .
1 H NMR(400MHz,MeOD)δ8.26(s,1H),7.88(d,J＝7.0Hz,1H),7.59(d,J＝8.4Hz,1H),7.51(s,1H),7.46(dd,J＝8.5,1.6Hz,1H),6.76(d,J＝16.2Hz,1H),6.63(d,J＝16.2Hz,1H),4.92-4.90(m,1H),4.68(d,J＝6.3Hz,1H)，4.15(dd,J＝9.9,3.9Hz,1H),3.84-3.69(m,2H),2.92-2.88(m,2H),2.12-1.98(m,2H),1.37-1.25(m,2H).
Biological test evaluation
Test example 1: evaluation of the inhibitory Activity of the Compounds of the invention against PRMT5 methylase
The test uses the TR-FRET (time resolved fluorescence resonance energy transfer) method to measure the inhibitory activity of the compound of the invention on the short peptide substrate of PRMT5 protein methylated H4 histone, and obtains the half Inhibition Concentration (IC) of the compound of the invention on the inhibition of PRMT5 methylation activity 50 )。
1. Experimental materials
PRMT5/MEP50 protein premix was purchased from BPS Bioscience, histone H4 peptide was purchased from GL Biochem, substrate SAM (S- (5' -adenosyl) -L-methionine chloride) was purchased from NEB (Noriovorax), TR-FRET reagent was purchased from Perkinelmer, and buffer components (Bicine (N, N-bis (2-hydroxyethyl) glycine), naCl, DTT (dithiothreitol), porcine skin gelatin (gelatin), tween-20 (Tween-20)) were purchased from Sigma.
2. Experimental method
1) Buffer composition was used at 1: the compound was serially diluted in a volume ratio of 3 to obtain 10 compound solutions at different concentration points, and the titration curve was used to determine the titer of each compound solution.
2) 100nL of compound solution was dispensed into each well of a white Greiner 384 well plate, and then 5. Mu.L of PRMT5/MEP50 protein premix and histone H4 peptide were added to 1:1, mixing the obtained mixed solution in a volume ratio, and incubating for 30 minutes at room temperature.
3) SAM was added separately to initiate each reaction, and the plates were sealed and placed in an incubator at 25℃and pre-incubated with the compounds for 90 minutes.
4) After the pre-incubation, 10. Mu.L of the detection solution for FRET was added to each well, and incubation was continued for 60 minutes, and the TR-FRET signal (excitation light 320nm or 340nm, emission light 665 nm) was detected on an Envision microplate reader (Perkinelmer).
5) Data analysis using GraphPad Prism 6 software, calculation of IC for compounds 50 。
The result of PRMT5 methylase inhibition by the compound of the present invention is shown in Table 1, and the activity data is divided into A, B, C, D four intervals, IC 50 Compounds of less than or equal to 10nM are identified by A, 10nM < IC 50 Compounds of less than or equal to 100nM are identified by B, 100nM < IC 50 Compounds of less than or equal to 500nM are identified by C, 500nM < IC 50 < 1000nM marked with D.
TABLE 1 inhibition of PRMT5 Methylase Activity by the Compounds of the invention
Conclusion: as can be seen from Table 1, the compounds of the present invention have a good inhibitory effect on PRMT5 methylase.
Test example 2: evaluation of proliferation inhibition by Compounds of the invention on human pancreatic cancer cell lines MIA PaCa-2
The experiment detects the proliferation inhibition effect of the compound of the invention on human pancreatic cancer cell line MIA PaCa-2 by measuring the intracellular ATP (adenosine triphosphate) content by adopting a chemiluminescence method, and obtains the half inhibition concentration IC of the compound of the invention on the proliferation inhibition of human pancreatic cancer cell line MIA PaCa-2 50 。
1. Experimental materials
DMEM medium, fetal Bovine Serum (FBS), 100 XStreptomyces lividans mixed solution (Pen/Strep), glutaMAX-I supply were purchased from GIBCO corporation. Cell Titer-Glo luminescence Cell viability assay reagents were purchased from Promega corporation. Human pancreatic cancer cell line MIA PaCa-2 was purchased from ATCC.
2. Experimental method
1) Human pancreatic cancer cell line MIA PaCa-2 was cultured in DMEM medium containing FBS with a mixture solution of Streptomyces lividans at 37℃with 5vol% CO 2 Culturing under conditions until log phase, counting with a cytometer, inoculating cells into 96-well culture plates at a density of 800 cells per well, 150 μl per well. Placed in an incubator (37 ℃,5vol% CO) 2 ) Incubate overnight.
2) Day 0: test compound (9 concentrations, 1:3 dilution) was added to the cells of the culture plate in a gradient of 750nL (final concentration of DMSO (dimethyl sulfoxide) 0.5 w/v) using a D300e (TECAN) ultramicro-applicator, and the culture plate was placed in a cell incubator and incubated for 6 days (37 ℃,5vol% co) 2 ). Blank control was added to 750nL of DMSO per well.
3) Day 6: mu.L of Cell Titer-Glo reagent was added to each well, and the mixture was shaken at 500rpm for 2 minutes, and incubated at room temperature for 10 minutes under dark conditions to stabilize the luminescence signal.
4) The luminescence signal was detected by an Envision enzyme-labeled instrument (PerkinElmer).
5) Data analysis using GraphPad Prism 6 software, calculation of IC for compounds 50 。
The proliferation inhibition effect results of the compound of the invention on human pancreatic cancer cell line MIA PaCa-2 are shown in Table 2, and the activity data is divided into A, B, C, D sections, and IC 50 Compounds of less than or equal to 10nM are identified by A, 10nM < IC 50 Compounds of less than or equal to 100nM are identified by B, 100nM < IC 50 Compounds of less than or equal to 500nM are identified by C, 500nM < IC 50 < 1000nM marked with D.
TABLE 2 inhibition of human pancreatic cancer cell line MIA PaCa-2
Conclusion: as can be seen from Table 2, the compounds of the present invention have a good inhibitory effect on human pancreatic cancer cell line MIA PaCa-2.
Test example 3: effect of the Compounds of the invention on hERG Potassium ion channel stably expressed in Chinese hamster ovary cells
Human ventricle rapid activation delay rectifier potassium current (I) Kr ) Is mediated mainly by cardiac hERG potassium ion channels. Pair I Kr Is the most common mechanism of action of ventricular muscle in prolonged duration due to non-heart-disease drugs. Prolongation of the action potential time course will lead to prolongation of QT interval on clinical electrocardiograms, which is associated with dangerous ventricular arrhythmias and torsades de pointes.
This test uses manual patch clamp to evaluate the effect of the compounds of the invention on the stable expression of hERG (human ether-a-go-go related gene) potassium channel (I Kr ) The concentration-response relationship of the current, and thus the determination of whether the compounds of the invention have inhibition of hERG potassium ion channel.
1. Experimental materials
Extracellular fluid (ECS): naCl,145mM; KCl,4mM; caCl (CaCl) 2 ，2mM；MgCl 2 1mM; HEPES (4-hydroxyethylpiperazine ethanesulfonic acid), 10mM; glucose, 10mM, was dissolved in pure water and the pH was adjusted to 7.3-7.4. Chinese hamster ovary cells (CHO-hERG) were derived from Sophion biosciences.
2. Experimental method
1) Diluting a part of the compound of the invention, a solvent control and a positive control (JNJ-64619178) mother liquor preparation with ECS mixed liquor to form working solutions with the concentration of 0.3 mu M, 1 mu M, 3 mu M, 10 mu M and 30 mu M; the ECS mixture is a mixture of ECS and DMSO, wherein the ECS ratio is 0.1% (v/v); the blank is DMSO. Two cells were assayed in duplicate for each concentration.
2) CHO-hERG cells in exponential growth phase were collected and resuspended in ECS for use.
3) hERG current was recorded under whole cell patch clamp technique, and recording temperature was room temperature. The patch clamp amplifier output signal is filtered by digital to analog conversion and 2.9KHz low pass. Data recording was collected using the PatchMaster Pro software.
4) The hERG current values were transcribed into Excel tables and IC of compounds to hERG was calculated 50 。
The inhibitory effects of the compounds of the invention and JNJ-64619178 on hERG potassium ion channel are shown in Table 3.
TABLE 3 inhibition of hERG current by compounds of the invention and JNJ-64619178
Remarks: JNJ-64619178 is compound 80 of WO2017032840A1, prepared by the method referred to the patent.
Results: as can be seen from Table 3, the half Inhibitory Concentrations (IC) of the compounds of example 22 and example 15 of the present invention on hERG 50 ) Values were 11.34. Mu.M and 14.81. Mu.M, respectively, superior to half Inhibition Concentrations (IC) of the control compound JNJ-64619178 50 ) A value of 9.17 μm indicates a potential advantage of higher cardiac safety.
Test example 4: inhibition effect of the compound of the invention on in vitro human liver microsome CYP450 enzyme is examined and evaluated for DDI risk
In this experimentEstablishing a model of inhibition of the human liver microsomal CYP450 subunit CYP3A4 by the compound, setting 7 concentrations of the test compound, and determining the half Inhibition Concentration (IC) of the compound of the invention on the CYP enzyme 50 ) To show the inhibition of CYP enzymes by the compounds of the invention, and further evaluate DDI risks of the compounds.
1. Test protocol
1.1 test drug:
some of the compounds of the invention.
1.2 test materials:
human liver microparticles were purchased from Corning at a concentration of 0.127mg/mL; potassium phosphate buffer, 100mM; magnesium chloride, 33mM; NADPH (reduced nicotinamide adenine dinucleotide phosphate), 10mM; stop solution, acetonitrile (containing internal standard 100ng/mL toluene sulfobutylurea).
1.3 positive control, test compound and substrate:
the positive control, test compounds and substrate are shown in table 4.
TABLE 4 Positive control, test Compounds and substrates
1.4 reaction System:
liver microsomal protein concentration, 0.127mg/mL; potassium phosphate buffer, 100mM; positive controls, substrates, test compounds and substrates are described in section 1.3; NADPH,10mM; magnesium chloride, 33mM.
1.5 reaction procedure:
adding a substrate, a positive control and a compound to be tested into a reaction system, pre-incubating for 10min at 37 ℃, then adding NADPH (reduced nicotinamide adenine dinucleotide phosphate) cofactor to start a reaction, incubating at 37 ℃, wherein 3A4 (meldonium) is incubated for 3min,3A4 (testosterone) is incubated for 10min, adding 400 mu M cold stop solution containing an internal standard at the end point of incubation, mixing to stop the reaction, centrifuging at 4000rpm for 20min, separating supernatant, and carrying out LC-MS/MS analysis after dilution.
By comparing pairs of test objectsHalf inhibition concentration of enzyme (I C) 50 ) The compounds of the present invention were evaluated for the risk of DDI (drug-drug interaction), i.e. drug interactions.
Test example 5: inhibition of the in vitro human liver microsome CYP450 enzyme by the compound of the invention is used for examining and evaluating the risk of TDI
The effect of compounds on CYP enzyme activity is related to the time of action, inhibition of enzyme activity by some compounds decreases with time, while some compounds exhibit time-dependent irreversible inhibition of enzyme activity, which affects the interactions between compounds, the in vivo metabolism of compounds, and safety. In this experiment, an inhibition model of the compound on human liver microsomal CYP450 subunit CYP3A4 was established, 7 concentrations were set for the test compound, and the time-dependent half-maximal Inhibitory Concentration (IC) of the compound of the invention on the CYP enzyme was determined 50 ) To assess whether the compounds of the invention have the risk of TDI (time-dependent inhibition, i.e. time-dependent inhibition).
1. Test protocol
1.1 test drug:
some of the compounds of the invention.
1.2 test materials:
human liver microparticles were purchased from Corning at a concentration of 20mg/mL; potassium phosphate buffer, 100mM; magnesium chloride, 300mM; NADP (nicotinamide adenine dinucleotide phosphate), 65mM; G6P (glucose 6-phosphate), 330mM; g6PDH (glucose 6-phosphate dehydrogenase), 250U/mL; stop solution, acetonitrile (containing internal standard 100ng/mL toluene sulfobutylurea).
1.3 positive control, test compound and substrate:
the positive control, test compounds and substrate are shown in table 5.
TABLE 5 Positive control, test Compounds and substrates
1.4 reaction System:
liver microsomal protein concentration, 0.1mg/mL; potassium phosphate buffer, 100mM; positive controls, substrates, test compounds and substrates are described in section 1.3; NADP,1mM; G6P,5.53mM; g6PDH,1.2U/mL; magnesium chloride, 3.3mM.
1.5 reaction procedure:
adding positive control and a compound to be tested into a reaction system, pre-incubating for 10min at 37 ℃, then adding NADPH (reduced nicotinamide adenine dinucleotide phosphate) cofactor to start reaction, incubating for 30min at 37 ℃, then adding substrate mixture to continue incubating for 10min at 37 ℃, adding 250 mu M cold stop solution mixture containing an internal standard at the end of incubation to stop reaction, centrifuging for 20min at 4000rpm, separating supernatant, and carrying out LC-MS/MS analysis after dilution.
By comparing the half-inhibition concentration (I.C) of the test substance on enzyme time dependence 50 ) The compounds of the invention were evaluated for the risk of TDI (time-dependent inhibition, i.e., immediate dependency inhibition).
2. Experimental results
TABLE 6 inhibitory Activity of the Compounds of the invention and JNJ-64619178 against CYP3A4 enzymes
Results: as can be seen from Table 6, the compounds of example 22 and example 15 of the present invention have an IC for CYP3A4 enzyme 50 Significantly higher than JNJ-64619178, indicating that the compounds of the invention have a lower risk of significant time-dependent inhibition (time-dependent inhibition, TDI).
Test example 6: in vivo pharmacokinetic assay of the compounds of the invention
After the compound is researched by intravenous injection, oral administration or intraperitoneal injection administration by taking beagle dogs as a tested animal, plasma samples are collected at specific time points, the concentration of the compound in the plasma is detected by LC-MS/MS, PK parameters are calculated, and the pharmacokinetic behavior of the compound in the plasma of dogs is reflected.
1. Test protocol
1.1 test drug:
some of the compounds of the invention.
1.2 test animals
Beagle, male, supplier Marshall.
1.3 administration of drugs
Example 15 compound dosing information: the IV (intravenous injection) experimental group and the PO (oral administration) experimental group are 3 dogs, the IV administration dosage is 1mg/kg, and the administration volume is 0.2mL/kg; PO was administered at a dose of 3mg/kg and a volume of 1mL/kg. The vehicle was 5vol% DMSO/10vol% Solutol (solubilizer)/85 vol% Saline (physiological saline).
Compound dosing information of example 22: beagle: the IV and PO experimental groups are 3 dogs, the IV administration dosage is 1mg/kg, and the administration volume is 0.2mL/kg; PO was administered at a dose of 3mg/kg and a volume of 1mL/kg. The dosing vehicle was 5vol% DMSO/10vol% Solutol/85vol% Saline.
1.4 experiment apparatus
The centrifuge was purchased from Eppendorf corporation and the pipettor was purchased from Eppendorf corporation.
1.5 sample collection
After canine dosing, 0.5mL each was collected intravenously at 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in EDTA-K2 tubes, centrifuged at 2000g for 10min at 4 ℃ to separate plasma, and stored at-80 ℃.
1.6 sample treatment
Canine plasma sample treatment:
1) mu.L of plasma sample was precipitated by adding 200. Mu.L of acetonitrile, vortexed and centrifuged for 15 minutes.
2) The supernatant after the treatment was taken and diluted with water, and the concentration of the test compound was analyzed by LC/MS.
2. Experimental results
Pharmacokinetic parameters were calculated using WinNonlin 6.1 and the pharmacokinetic parameters for intravenous, oral and intraperitoneal administration of canine drugs are shown in table 7. Wherein C is max Represents maximum blood concentration, CL represents clearance, vss represents steady-state distribution volume, T 1/2 Represents terminal elimination half-life, MRT Inf Mean residence time, AUC, area under the curve at time of administration, F, bioavailability.
Table 7 pharmacokinetic parameters of a portion of the compounds of the invention for intravenous, oral or intraperitoneal injection into beagle dogs
Note that: "/" indicates not measured
Results: as can be seen from table 7, the compounds of the present invention have good pharmacokinetic properties in beagle dogs.
Test example 7: in vivo pharmacodynamic study of the inventive Compounds on H520 xenograft tumor models
1. Experimental animals: BALB/c nude mice, females, 6-8 weeks old, weighing 18-22 g, were offered by Beijing Veantro laboratory animal Co.
2. Experimental method
And (3) establishing a model: will be 5X 10 6 Human lung squamous carcinoma cell NCI-H520 (ATCC, cat# HTB-182) TM ) Xenograft tumor models were established subcutaneously on the right side of BALB/c nude mice. On day 17 post inoculation, when the average tumor volume reached 134mm 3 At this time, tumor-bearing mice with appropriate tumor volumes were selected, randomized block grouping was performed according to tumor volumes, and treatment was then started. PK plasma was collected after the first and last dosing to assess the relationship between drug efficacy and exposure.
The animal experiment groups and dosing regimens are shown in table 8 below; where N represents the number of mice, PO represents oral administration, QD represents once a day, and 4W represents 4 weeks.
Table 8 animal experiment groups and dosing regimen
A solvent: 5vol% DMSO+10vol% Solutol+85vol% Saline.
Tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is: v=0.5a×b 2 A and b represent the major and minor diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated by tumor growth inhibition ratio TGI (%) or relative tumor proliferation ratio T/C (%).
Tumor growth inhibition ratio TGI (%) = [ (1- (average tumor volume of the administration group on a certain day-average tumor volume of the administration group administration))/(average tumor volume of the vehicle control group on a certain day-average tumor volume of the vehicle control group administration) ]100%.

Claims (23)

  1. A compound represented by the formula (I') or a pharmaceutically acceptable salt thereof,
    wherein R is 1 Selected from H or NR 1a R 1b ；
    R 1a And R is 1b Each independently selected from H or C 1-4 An alkyl group; the C is 1-4 Alkyl groups optionally being substituted by one or more R 1c Substituted by a group, said R 1c The radical being C 3-6 Cycloalkyl;
    y is selected from N or CR 2 ；
    R 2 Selected from H, halogen-substituted C 1-4 Alkyl, CN or-SO 2 -C 1-4 An alkyl group;
    L 1 selected from chemical bond, -CH 2 -、-X-CH 2 、-(CH 2 ) n -CH＝CH-、-CH＝CH-(CH 2 ) n -、C 3-6 Cycloalkyl or 5-6 membered heteroaryl;
    x is selected fromO, S, NH or CH 2 ；
    Ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl or 5-10 membered heterocyclyl;
    R 3 selected from hydroxy or C 1-4 An alkyl group;
    m is selected from 0, 1, 2 or 3;
    n is selected from 0 or 1;
    ring B is selected from
    R 4 Selected from NR 4a R 4b Or C 1-4 An alkyl group;
    R 4a and R is 4b Each independently selected from H or C 1-4 An alkyl group;
    represents a single bond or a double bond;
    when (when)R is a single bond 5 And R is 6 Each independently selected from H, deuterium, halogen or C 1-4 An alkyl group; r is R 7 And R is 8 Each independently is H;
    when (when)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 And together with the C atom to which it is attached form phenyl or C 5-6 Cycloalkyl groups.
  2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the formula (I),
    wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、L 1 And m is as defined for formula (I').
  3. The compound according to claim 1 or 2, wherein the compound is a compound represented by the formula (I),
    wherein R is 1 Selected from H or NR 1a R 1b ；
    R 1a And R is 1b Each independently selected from H or C 1-4 An alkyl group; the C is 1-4 Alkyl groups optionally being substituted by one or more R 1c Substituted by radicals, said R 1c The radical being C 3-6 Cycloalkyl;
    R 2 selected from H or halogen;
    R 3 selected from hydroxy or C 1-4 An alkyl group;
    R 4 selected from NR 4a R 4b Or C 1-4 An alkyl group;
    R 4a and R is 4b Each independently selected from H or C 1-4 Alkyl group；
    L 1 Selected from chemical bond, -CH 2 -、-X-CH 2 、-(CH 2 ) n -CH＝CH-、C 3-6 Cycloalkyl or 5-6 membered heteroaryl;
    x is selected from O, S, NH or CH 2 ；
    Ring A is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl or 5-10 membered heterocyclyl;
    m is selected from 0, 1, 2 or 3;
    n is selected from 0 or 1;
    represents a single bond or a double bond;
    when (when)R is a single bond 5 And R is 6 Each independently selected from H, deuterium, or halogen; r is R 7 And R is 8 Each independently is H;
    when (when)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 Together with the C atom to which it is attached form phenyl or C 5-6 A cycloalkyl group.
  4. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from H, amino or
  5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from H, F, cl, br, CF 3 CN or-SO 2 CH 3 。
  6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from chemical bond, -CH 2 -、-O-CH 2 、-NH-CH 2 、-CH 2 -CH 2 、-CH＝CH-、-CH 2 -CH＝CH-、-CH＝CH-CH 2 -、
  7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from C 5-6 Cycloalkyl, C 5-6 Cycloalkenyl or a 5-10 membered heterocyclyl containing 1 or more heteroatoms selected from N or O.
  8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from
  9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydroxyl or methyl; m is selected from 0, 1, 2 or 3.
  10. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from the group consisting of
  11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from the group consisting of
  12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from amino, methyl or-NHCH 3 。
  13. A compound according to any one of claims 1-12 or a pharmaceutically acceptable thereofA salt of the formulaRepresents a single bond or a double bond; when (when)R is a single bond 5 And R is 6 Each independently selected from H, deuterium, F, or methyl; r is R 7 And R is 8 Each independently is H; when (when)In the case of double bonds, R 5 And R is 8 Absent, R 6 And R is 7 And the C atom to which it is attached form a phenyl or cyclopentyl group.
  14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from the group consisting of
  15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein the structural unitIs that
  16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (II):
    wherein,
    R 9 selected from H or C 1-4 An alkyl group; preferably, R 9 Selected from H or methyl; m is selected from 1 or 2;
    R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and L 1 As defined in formula (I') or formula (I).
  17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, selected from:
    wherein R is 1 、R 2 、R 4 、R 5 、R 6 、R 7 、R 8 And R is 9 As defined by formula (II).
  18. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, selected from:
    wherein R is 1 、R 2 、R 4 And R is 9 As defined by formula (II).
  19. A compound, or a pharmaceutically acceptable salt thereof, selected from:
  20. a pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  21. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the manufacture of a medicament for the treatment of cancer.
  22. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, in the treatment of cancer.
  23. A method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20.
CN202280027588.2A 2021-07-20 2022-07-19 PRMT5 inhibitors Pending CN117157297A (en)

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