CN111620873B - Pyrrolo [2,3-d ] pyrimidine derivatives containing piperidine and preparation and application thereof - Google Patents

Pyrrolo [2,3-d ] pyrimidine derivatives containing piperidine and preparation and application thereof Download PDF

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CN111620873B
CN111620873B CN201910149538.1A CN201910149538A CN111620873B CN 111620873 B CN111620873 B CN 111620873B CN 201910149538 A CN201910149538 A CN 201910149538A CN 111620873 B CN111620873 B CN 111620873B
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pyrrolo
piperidin
pyrazol
pyrimidin
pyrimidines
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CN111620873A (en
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姜楠
翟鑫
臧凌鹤
宫平
蒋枫
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Shenyang Pharmaceutical University
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to pyrrolo [2,3-d ] containing piperidine, represented by general formula I or general formula II]Pyrimidine derivatives and methods of use and preparation. The invention also relates to a compound with a strong JAK kinase inhibition effect, and also relates to an application of the compound in preparing medicines for treating and/or preventing diseases caused by abnormal expression of JAK, in particular to an application in preparing medicines for treating inflammation/autoimmune diseases, fibrosis and cancers.

Description

Pyrrolo [2,3-d ] pyrimidine derivatives containing piperidine and preparation and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to pyrrolo [2,3-d ] pyrimidine derivatives containing piperidine, a preparation method thereof and a pharmaceutical composition containing the compounds. The invention also relates to a strong JAK kinase inhibition effect of the compound, and also relates to an application of the compound in preparing a medicine for treating diseases caused by abnormal expression of JAK, in particular to an application in preparing a medicine for treating inflammation/autoimmune diseases, fibrosis and cancer.
Background
Janus kinases (JAKs) belong to the family of intracellular non-receptor tyrosine protein kinases, four members have been discovered: JAK1, JAK2, JAK3 and TYK 2. Of these, JAK3 is present only in the bone marrow and lymphatic system, while others are widely distributed in various tissues and cells in the body. The transcription factors stat (signal transducer and activator of transcription), called "signal transducer and transcriptional activator", play a critical role in signal transduction and transcriptional activation.
The interaction of JAK kinase and STAT forms a JAK/STAT signal channel of an intracellular signal transduction channel closely related to cytokines. The pathway runs through the entire growth cycle of cells and key biological processes such as immune regulation. The JAK inhibitor is widely used for screening following disease treatment medicines in clinical aspects, such as blood system disease treatment medicines, tumor treatment medicines, RA and psoriasis treatment medicines and the like. Researches find that various inflammatory and autoimmune diseases are accompanied with the participation of JAK-dependent cytokines, small molecular JAK inhibitors which are on the market or applied to clinic at present mainly comprise pyrrolopyrimidine and pyrrolopyridine compounds, and the development of novel high-selectivity JAK inhibitors has urgent market demands and good application prospects.
The invention designs and synthesizes a series of pyrrolo [2,3-d ] pyrimidine derivatives containing piperidine. In vitro activity screening shows that the compounds have outstanding JAK kinase inhibition activity.
Disclosure of Invention
The invention provides a pyrrolo [2,3-d ] pyrimidine derivative containing piperidine shown in general formulas I and II, an optical isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, further provides application of a compound shown in general formulas I or II or a pharmaceutically acceptable salt thereof in preparation of a medicament for treatment, and further provides a preparation method of the compound shown in general formulas I or II.
Detailed Description
A compound shown in a general formula I or II, an optical isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
Figure GDA0003371613130000011
wherein:
l is SO2、CH2C ═ O or C ═ O;
R1is (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl radicals5-7 membered heterocyclic group, C6-C10Aryl, 5-to 10-membered heteroaryl, - (CH)2)n-NR3R4Wherein said heterocyclyl and heteroaryl groups may contain 1-4 heteroatoms selected from N, O and S, and said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be substituted with 1-3R, which may be the same or different5Optionally substituted;
R2is hydrogen, C1-C4Alkyl, halo C1-C4An alkyl group;
n is an integer between 0 and 3;
R3and R4The same or different, are respectively and independently selected from hydrogen and C1-C10Alkyl radical, C3-C7Cycloalkyl or C6-C10Aryl, said alkyl, cycloalkyl or aryl being substituted by 1 to 3R which may be the same or different5Optionally substituted;
or R3And R4Together with the nitrogen atom to which it is attached form a 5-7 membered heterocyclic group, except for R3And R4The nitrogen atom to which it is attached may contain 0 to 4 heteroatoms selected from N, O and S, and the heterocyclic group may be substituted by 1 to 3 identical or different R5Optionally substituted;
R5is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Alkoxy, hydroxy, hydroxymethyl, hydroxyethyl, cyano, nitro or carboxy;
the invention preferably selects the compound shown in the general formula I or II and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein:
R1is (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, phenyl, - (CH)2)n-NR3R4Wherein said phenyl group may be substituted by 1 to 3R which may be the same or different5Optionally substituted;
R2is hydrogen or methyl;
n is 0 or 1;
R3and R4The same or different, each independentlyIs selected from hydrogen and C1-C4Alkyl or phenyl, which phenyl may be substituted by 1 to 2 identical or different R5Optionally substituted;
or R3And R4Together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, except for R3And R4The nitrogen atom to which it is attached may contain 0 to 2 hetero atoms selected from N, O and S, and the heterocyclic group may be substituted by 1 to 2 identical or different R5Optionally substituted;
the invention preferably selects the compound shown in the general formula I or II and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein:
R1is methyl, ethyl, cyclopropyl, phenyl, - (CH)2)n-NR3R4Wherein said phenyl group may be substituted by 1-2R which may be the same or different5Optionally substituted;
R3and R4Identical or different, are each independently selected from hydrogen, methyl, ethyl or phenyl, which phenyl may be substituted by 1 to 2 identical or different R5Optionally substituted;
or R3And R4Together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, except for R3And R4The nitrogen atom to which it is attached may contain 0 to 1 hetero atom selected from N or O, and the heterocyclic group may be substituted with 1R5Optionally substituted;
preferably, R3And R4Together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl wherein the 4-position of the piperidinyl or piperazinyl may be interrupted by 1R5And (4) substitution.
The compounds of the present invention and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof are preferably the following compounds, but these compounds are not meant to limit the present invention in any way:
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (morpholin-1-yl) -1-one
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (diethylamino) ethan-1-one
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4-methylpiperidin-1-yl) ethan-1-one
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one
1- (2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) piperidine-4-carboxylic acid
1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4- (2-hydroxyethyl) piperidin-1-yl) ethan-1-one
4- (1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (ethylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (cyclopropylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (benzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (2-methylbenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (4-methylbenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (4-cyanophenylsulphonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (4-methoxybenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (2-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (3-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (4-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (4-chlorobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (3-bromobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (4-bromobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (4-fluorophenylsulphonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
4- (1- (1- (3, 5-difluorobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine.
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperidin-1-yl) ethan-1-one
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-morpholin-1-one
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (diethylamino) ethan-1-one
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one
2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1- (4-methylpiperidin-1-yl) ethan-1-one
2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -N- (2-methoxyphenyl) acetamide
2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -N- (2-methoxyphenyl) acetamide
2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1-morpholin-1-one
4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N- (2, 5-dimethylphenyl) piperidine-1-carboxamide
2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -N- (2-chlorophenyl) acetamide
4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N- (2-chlorophenyl) piperidine-1-carboxamide
N- (1- (methylsulfonyl) piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- (1- ((4-bromophenyl) sulfonyl) piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-morpholin-1-one
1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one
2- (diethylamino) -1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) ethan-1-one
1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one
2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1-morpholin-1-one
2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1- (4-methylpiperazin-1-yl) ethan-1-one
N- (2-methoxyphenyl) -2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) acetamide
N- (2, 5-dimethylphenyl) -2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) acetamide
N- (2-chlorophenyl) -2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) acetamide
N- (2, 5-dimethylphenyl) -4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxamide
N- (2-chlorophenyl) -4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxamide
N-methyl-N- (1- (methylsulfonyl) piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
N- (1- ((4-bromophenyl) sulfonyl) piperidin-4-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine.
Furthermore, the piperidine-containing pyrrolo [2,3-d ] pyrimidine derivatives of the general formula I and the general formula II of the present invention may form pharmaceutically acceptable salts with acids according to methods common in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are the piperidine-containing pyrrolo [2,3-d ] pyrimidine derivatives of formula I and formula II, which may themselves be less active or even inactive, but which upon administration are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
We have found that the compounds of the present invention have activity in inhibiting JAK kinases in vitro and thus, may be used as medicaments for the treatment and/or prevention of various inflammatory or autoimmune diseases including RA, fibrosis and cancer.
The active compound or the pharmaceutically acceptable salt and the solvate thereof can be used alone as the only anti-rheumatoid arthritis drug or can be combined with the anti-inflammatory drugs (such as tofacitinib, rocitinib and the like) on the market. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes outline and describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the means described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or being commercially available. All final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.
Figure GDA0003371613130000041
Route 1
Figure GDA0003371613130000042
Route 2
The derivatives of formula I according to the invention can be prepared from intermediates M by the methods of schemes 1 and 21Or M2And corresponding arylamine, aliphatic amine or sulfonyl chloride in corresponding solvent through nucleophilic substitution or sulfonylation reaction and then removing protecting group. Wherein R in the compound1、R3、R4As defined in the claims.
Figure GDA0003371613130000051
Route 3
Figure GDA0003371613130000052
Route 4
Intermediate M1The intermediate I can be used as a raw material according to the scheme 3 and is obtained by protecting group application, Suzuki coupling and Boc protection removal.
Intermediate M2The intermediate I is used as a raw material according to a route 3, and is obtained by protecting group application, Suzuki coupling, Boc protection removal and acylation.
The intermediate VII can be obtained from the intermediate IV through sulfonylation, nucleophilic substitution and boration according to the scheme 4.
Figure GDA0003371613130000053
Route 5
Figure GDA0003371613130000061
Route 6
Figure GDA0003371613130000062
Route 7
Figure GDA0003371613130000063
Route 8
Figure GDA0003371613130000064
The derivatives of formula II according to the present invention may be prepared from intermediate M according to the methods of scheme 5, scheme 6, scheme 7, scheme 83、M4、M5、M6And corresponding arylamine, aliphatic amine and sulfonyl chloride are prepared in corresponding solvents through nucleophilic substitution. Wherein R in the compound1、R3、R4As defined in the claims.
Figure GDA0003371613130000065
Route 9
Figure GDA0003371613130000071
Route 10
Intermediate M3、M4According to the scheme 9, the intermediate II is used as a raw material and is subjected to N alkylation, Boc removal protection and acylation to obtain the intermediate.
Intermediate M5、M6According to the route 10, the intermediate II is used as a raw material and is subjected to N alkylation, Boc removal protection and acylation to obtain the intermediate.
The specific implementation mode is as follows:
the examples are intended to illustrate, but not to limit, the scope of the invention. The NMR of the compound was measured by Bruker ARX-400 and the mass spectrum by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
Figure GDA0003371613130000072
TABLE 1
Figure GDA0003371613130000073
Figure GDA0003371613130000081
Figure GDA0003371613130000091
Figure GDA0003371613130000101
Figure GDA0003371613130000111
Figure GDA0003371613130000112
TABLE 2
Figure GDA0003371613130000113
Figure GDA0003371613130000121
Figure GDA0003371613130000131
Figure GDA0003371613130000141
Figure GDA0003371613130000151
Figure GDA0003371613130000161
Example 1: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one
Step A: (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) methylpivalate (II)
15.4g (100.28mmol) of 4-chloropyrrolopyrimidine and 100mL of tetrahydrofuran were put into a 500mL three-necked flask, 8g (200.56mmol) of 60% NaH was added in portions under ice-bath conditions, stirred for 30min, and 30.08g (200.56mmol) of chloromethyl pivalate was added and reacted at room temperature for 1.5 h. After the reaction, 100mL of saturated ammonium chloride solution was added for quenching, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (50 mL. times.2), the organic layers were combined, washed with saturated brine, dried and evaporated to dryness to obtain 27.48g (102.92mmol) of a pale yellow solid with a yield of 85%.
And B: N-Boc-4-methanesulfonyloxypiperidine (V)
20.0g (100mmol) of N-Boc-4-hydroxypiperidine, 14.1g (100mmol) of triethylamine and 200mL of dichloromethane were introduced into a 500mL eggplant-shaped flask, and 11.4g (140mmol) of methanesulfonyl chloride was slowly added dropwise under ice-bath conditions, and the mixture was reacted at room temperature for 1 hour. After the reaction, the reaction solution was poured into 150mL of water, stirred for 10min, and allowed to stand for layering, and the organic layer was separated. The organic phase was washed with saturated brine, dried and evaporated to dryness to give 27.3g (97.8mmol) of a white solid with a yield of 97.8%.
And C: 4- (4-iodo-1H-pyrazol-1-yl) -1-piperidinecarboxylic acid 1, 1-dimethylethyl ester (VI)
7g (36.1mmol) of 4-iodopyrazole, 15.3g (46.93mmol) of cesium carbonate and 10mL of azomethylpyrrolidone are introduced into a 50mL three-necked flask and 10mL of a solution of intermediate V in azomethylpyrrolidone (15.3g, 46.93mmol) are added dropwise under nitrogen. Reacting at 80 ℃ for 8 h. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was poured into a mixed solution of 10mL of methyl t-butyl ether and 10mL of water, stirred for 10min, the organic layer was separated, added to 30mL of n-heptane, stirred for 6h, and after a large amount of white solid was precipitated, filtered by suction, and dried to obtain 7.88g (20.9mmol) of white solid with a yield of 57.9%.
Step D: 4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (VII)
25g (36.1mmol) of intermediate VI and 200mL of anhydrous tetrahydrofuran are added into a 50mL three-necked bottle, the temperature is reduced to-10 ℃, 60mL (2mol/L,54.15mmol) of isopropyl magnesium chloride solution is slowly dropped under the protection of nitrogen, the internal temperature does not exceed 0 ℃, and the temperature is raised to 20 ℃ for reaction for 2 h. 13.8g of methoxy pinacol ester was then dissolved in 10mL of redistilled tetrahydrofuran and slowly added dropwise to the above reaction system. After dropping, the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the reaction solution was quenched by pouring into 200mL of saturated ammonium chloride solution, stirred for 20min, extracted with ethyl acetate (200 mL. times.2), and the organic layers were combined. The organic layer was washed with saturated brine, dried and evaporated to dryness to give a pale yellow oily liquid, which was purified by column chromatography to give 15.38g (40.78mmol) of a white solid with a yield of 61.5%.
Step E: (4- (1- (1- (tert-Butyloxycarbonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalic acid methyl ester (III)
9.3g (34.83mmol) of intermediate II, 11.93g (31.67mmol) of intermediate VII, 0.67g (0.95mmol) of bistriphenylphosphine palladium dichloride, 200mL of dioxane and 9.3g (95.01mmol) of cesium carbonate solution are introduced into a 500mL eggplant-shaped flask and the temperature is raised to 80 ℃ for 2h of reflux reaction. After the reaction was completed, the reaction solution was poured into 200mL of water, stirred for 20min, extracted with dichloromethane (200 mL. times.2), and the organic layers were combined. Drying, evaporating to dryness to obtain dark red oily liquid, and purifying by column chromatography to obtain crimson solid 10.47g (21.72mmol), with yield of 62.4%.
Step F: (4- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) neopentanoic acid methyl ester (M)1)
10.47g (21.72mmol) of intermediate III, 40mL of HCl/MeOH solution, were added to a 100mL eggplant-shaped flask and reacted at 30 ℃ for 8h to precipitate a large amount of white solid. After the reaction, 7.07g (18.46mmol) of white solid was obtained by suction filtration, and the yield was 85.2%.
Step G: (4- (1- (1- (2-chloroacetyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) neopentanoic acid methyl ester (M)2)
0.2g (0.58mmol) of intermediate M1Dissolving in 10ml chloroform, adding 0.07g (0.69mmol) chloroacetyl chloride in ice bath, removing ice bath after dropwise addition, reacting at room temperature for 30min, and precipitating milky white solid. After the reaction, 0.19g (0.41mmol) of a white solid was obtained by suction filtration, and the yield was 70.1%.
Step H (4- (1- (1- (2- (piperidin-1-yl) acetyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidine-7-)) pivalic acid methyl ester (C)2)
0.11g (0.24mmol) of intermediate M2Dissolving in 10mL DMA, adding 0.08g (0.96mmol) piperidine, reacting at 110 deg.C for 3h, extracting with dichloromethane (20mL × 2), combining organic layers, drying, and steamingDry to give 0.10g of a light brown solid in 83% yield.
Step I: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one (example 1)
0.10g (0.19mmol) of intermediate C2Dissolving in 10mL of methanol, adding 3mL of 1mol/L sodium hydroxide solution, stirring at room temperature for reaction for 2h, after the reaction is finished, quenching the sodium hydroxide by using 1mol/L hydrochloric acid, adjusting the pH to 10, extracting by using dichloromethane (20mL x 2), combining organic layers, drying, and separating and purifying by using a silica gel preparation thin layer to obtain 0.032g of white solid with the yield of 43.2%. m.p. 203.1-206.7 ℃; MS (ESI) M/z 393[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.66(s,2H),8.31(s,1H),7.61–7.54(m,1H),7.03–6.98(m,1H),4.63–4.53(m,1H),4.48(d,J＝13.3Hz,1H),4.25(d,J＝13.3Hz,1H),3.24(d,J＝13.2Hz,1H),3.17(t,J＝11.9Hz,1H),3.02(d,J＝13.1Hz,1H),2.76(t,J＝11.7Hz,1H),2.36(s,4H),2.11(t,J＝13.2Hz,2H),2.04–1.80(m,2H),1.58–1.46(m,4H),1.38(d,J＝4.2Hz,2H).
Example 2: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (morpholin-1-yl) -1-one
Reacting the intermediate C2Example 2 was prepared according to the procedure for example 1 in 51.4% yield. m.p. 217.2-238.2 deg.C; MS (ESI) M/z 396[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.66(d,J＝2.0Hz,2H),8.30(s,1H),7.57(s,1H),7.00(s,1H),4.58(t,J＝11.4Hz,1H),4.48(d,J＝12.7Hz,1H),4.21(d,J＝12.6Hz,1H),3.59(s,4H),3.29(d,J＝13.5Hz,1H),3.26–3.05(m,2H),2.77(t,J＝12.1Hz,1H),2.43(s,4H),2.10(d,J＝14.6Hz,2H),2.05–1.80(m,2H).
Example 3: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (diethylamino) ethan-1-one
Reacting the intermediate C2Example 3 was prepared according to the procedure for example 1, yield 57.3%. m.p. 193.7-196.1 ℃; MS (ESI) M/z 382[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ8.78–8.63(m,2H),8.34(d,J＝9.5Hz,1H),7.58(t,J＝3.6Hz,1H),7.12–6.95(m,1H),4.62(d,J＝30.0Hz,1H),4.52–4.37(m,1H),4.25(dd,J＝26.0,14.1Hz,1H),3.51(s,1H),3.18(d,J＝13.5Hz,1H),2.88(t,J＝11.9Hz,1H),2.76(s,1H),2.17(d,J＝37.0Hz,2H),2.06–1.92(m,2H),1.23(s,6H),1.12–0.78(m,4H)。
Example 4: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4-methylpiperidin-1-yl) ethan-1-one
Reacting the intermediate C2Example 4 was prepared according to the procedure for example 1 in 49.7% yield. 241.9-247.2 ℃ in m.p.; MS (ESI) M/z 408[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.67(d,J＝4.3Hz,1H),8.31(d,J＝4.9Hz,1H),7.62(d,J＝3.6Hz,1H),7.03(t,J＝3.1Hz,1H),4.64–4.53(m,1H),4.48(d,J＝13.0Hz,1H),4.19(dd,J＝18.7,8.9Hz,1H),3.17(t,J＝11.8Hz,2H),2.84(s,1H),2.82–2.72(m,1H),2.22–1.95(m,5H),1.94–1.79(m,1H),1.60(s,2H),1.34(d,J＝8.4Hz,1H),1.27–1.07(m,4H),0.86(dd,J＝16.4,6.7Hz,3H)。
Example 5: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Reacting the intermediate C2Example 5 was prepared according to the procedure for example 1 in 55.8% yield. m.p. 203.7-204.9 ℃; MS (ESI) M/z 409[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.68(d,J＝3.7Hz,2H),8.33(d,J＝5.1Hz,1H),7.58(d,J＝3.3Hz,1H),7.01(d,J＝3.5Hz,1H),4.58(td,J＝11.3,5.6Hz,1H),4.49(d,J＝13.1Hz,1H),4.23(d,J＝13.3Hz,1H),3.50(t,J＝6.2Hz,3H),3.36–3.25(m,1H),3.18(dd,J＝13.5,10.4Hz,1H),3.08(t,J＝8.2Hz,1H),2.78(t,J＝11.9Hz,1H),2.44(s,4H),2.38(t,J＝6.3Hz,4H),2.12(t,J＝12.1Hz,2H),2.07–1.97(m,1H),1.89(qd,J＝12.1,4.0Hz,1H).
Example 6: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one
Reacting the intermediate C2Example 6 was prepared according to the procedure for example 1 in 58.3% yield. 198.3-200.6 ℃ in m.p.; MS (ESI) M/z 380[ M + H]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.64(s,2H),8.28(s,1H),7.55(d,J＝2.0Hz,1H),6.98(d,J＝3.3Hz,1H),4.63–4.51(m,1H),4.52–4.39(m,1H),4.17(d,J＝12.8Hz,1H),3.27(d,J＝13.4Hz,4H),3.16(t,J＝12.1Hz,1H),2.75(t,J＝11.8Hz,1H),2.07(s,2H),2.03–1.91(m,1H),1.87(dt,J＝11.9,8.2Hz,1H),1.69(s,4H),1.21(s,2H)。
Example 7: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one
Reacting the intermediate C2Example 7 was prepared according to the procedure for example 1 in 47.2% yield. m.p. 210.6-213.1 deg.C; MS (ESI) M/z 354[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.69(s,2H),8.33(s,1H),7.59(dd,J＝3.3,2.4Hz,1H),7.03(dd,J＝3.5,1.5Hz,1H),4.59(dd,J＝9.8,5.7Hz,1H),4.51(d,J＝13.1Hz,1H),4.22(d,J＝13.1Hz,1H),3.42(s,4H),3.22(d,J＝13.2Hz,2H),3.14(t,J＝12.6Hz,2H),2.24(s,6H),2.08–1.83(m,2H)。
Example 8: 1- (2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) piperidine-4-carboxylic acid
Reacting the intermediate C2Example 8 was prepared according to the procedure for example 1 in 39.4% yield. 257.4-261.1 ℃ in m.p.; MS (ESI) M/z 438[ M + H]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.63(d,J＝3.6Hz,2H),8.26(s,1H),7.53(d,J＝3.5Hz,1H),6.96(d,J＝3.6Hz,1H),4.64–4.51(m,2H),4.45(d,J＝12.7Hz,1H),4.12(s,2H),3.81(d,J＝13.3Hz,1H),3.13(t,J＝12.0Hz,1H),2.80(t,J＝12.1Hz,1H),2.07(d,J＝10.5Hz,2H),1.93(ddd,J＝30.8,19.9,9.6Hz,3H),1.19(s,4H)。
Example 9: 1- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4- (2-hydroxyethyl) piperidin-1-yl) ethan-1-one
Reacting the intermediate C2Example 9 was prepared according to the procedure for example 1 in 48.6% yield.
m.p.:241.8-242.5℃；MS(ESI)m/z:438[M+H]+；1H NMR(400MHz,DMSO-d6)(400MHz,DMSO)δ12.10(s,1H),8.66(d,J＝2.9Hz,2H),8.31(s,1H),7.57(s,1H),7.00(d,J＝2.1Hz,1H),4.58(t,J＝11.3Hz,1H),4.48(d,J＝12.7Hz,1H),4.23(d,J＝13.1Hz,1H),3.50–3.41(m,2H),3.27(d,J＝13.3Hz,1H),3.17(t,J＝12.1Hz,1H),3.07(d,J＝13.2Hz,1H),2.81(s,2H),2.75(d,J＝13.8Hz,1H),2.12(t,J＝20.2Hz,2H),2.00(d,J＝11.0Hz,2H),1.97–1.79(m,2H),1.57(d,J＝10.4Hz,2H),1.30(s,2H),1.15–1.01(m,2H).
Example 10: 4- (1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Step A: (4- (1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) neopentanoic acid methyl ester (C)1)
1.0g (3.7mmol) of intermediate M10.51g (4.4mmol) of methanesulfonyl chloride, 1.12g (11.1mmol) of triethylamine and 10mL of N, N-dimethylacetamide were put into a 25mL eggplant type flask and reacted at 60 ℃ for 4 hours. After the reaction, the reaction solution was cooled to room temperature, poured into 50mL of ice water, to precipitate a white flocculent solid, filtered, washed with water, and dried to obtain 0.83g (1.86mmol) of a white solid with a yield of 68.3%.
And B: 4- (1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine (example 10)
0.5g (1.01mmol) of intermediate C10.42g (3.03mmol) of potassium carbonate and 10mL of N, N-dimethylacetamide were added to a 25mL eggplant-shaped flask and reacted at 80 ℃ for 4 hours. After the reaction is finished, the reaction solution is cooled to room temperature, the reaction solution is poured into 50mL of ice water, white flocculent solid is separated out, and is filtered, washed and dried, and is separated and purified by a silica gel preparation thin layer to obtain 0.32g (0.84mmol) of white solid with the yield of 82.1%. m.p. 222.2-225.3 deg.C; MS (ESI) M/z 361.4[ M + H ]]+；1HNMR(400MHz,DMSO-d6)δ12.07(s,1H),8.68(s,1H),8.66(s,1H),8.31(s,1H),7.59-7.54(m,1H),7.01(dd,J＝3.5,1.6Hz,1H),4.47(td,J＝11.1,5.5Hz,1H),3.75(d,J＝12.6Hz,2H),,3.05(dd,J＝11.9,10.0Hz,2H),2.23-2.02(m,4H),1.25(t,J＝7.3Hz,3H).
Example 11: 4- (1- (1- (ethylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Prepared by the method of example 10Example 11, yield 66.2%. m.p. 242.6-245.3 ℃; MS (ESI) M/z 361.4[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.68(s,1H),8.66(s,1H),8.31(s,1H),7.59-7.54(m,1H),7.01(dd,J＝3.5,1.6Hz,1H),4.47(td,J＝11.1,5.5Hz,1H),3.75(d,J＝12.6Hz,2H),3.12(q,J＝7.4Hz,2H),3.05(dd,J＝11.9,10.0Hz,2H),2.23-2.02(m,4H),1.25(t,J＝7.3Hz,3H).
Example 12: 4- (1- (1- (cyclopropylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 12 was prepared according to the procedure for example 10 in 75.6% yield. 271.6-273.8 ℃ in m.p.; MS (ESI) M/z 372.2.4[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.68(s,1H),8.66(s,1H),8.31(s,1H),7.59-7.54(m,1H),7.01(dd,J＝3.5,1.6Hz,1H),4.47(td,J＝11.1,5.5Hz,1H),3.75(d,J＝12.6Hz,2H),,3.05(dd,J＝11.9,10.0Hz,2H),2.23-2.02(m,4H),1.25(t,J＝7.3Hz,2H).
Example 13: 4- (1- (1- (benzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 13 was prepared according to the procedure for example 10, in 70.2% yield. m.p. 301.7-304.6 ℃; MS (ESI) M/z 409.1[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.64(s,1H),7.81(d,J＝7.3Hz,2H),7.70(d,J＝7.7Hz,2H),7.12(d,J＝3.6Hz,1H),7.12(d,J＝3.6Hz,1H),5.59(s,2H),4.46-4.24(m,1H),3.79(d,J＝11.9Hz,2H),3.23(s,2H),2.13(dd,J＝16.4,5.9Hz,4H).
Example 14: 4- (1- (1- (2-methylbenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 14 was prepared according to the procedure for example 10 in 80.3% yield. m.p. 315.7-316.6 ℃; MS (ESI) M/z 423.1[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.65(s,1H),8.64(s,1H),8.29(s,1H),7.88-7.82(m,1H),7.61(dd,J＝7.5,1.1Hz,1H),7.59-7.54(m,1H),7.46(dd,J＝15.8,7.7Hz,2H),6.99(dd,J＝3.5,1.7Hz,1H),4.51-4.38(m,1H),3.75(d,J＝12.4Hz,2H),2.85(dt,J＝12.2,6.2Hz,2H),2.61(s,3H),2.16(d,J＝9.9Hz,2H),2.06(ddd,J＝24.3,12.1,4.1Hz,2H).
Example 15: 4- (1- (1- (4-methylbenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 15 was prepared according to the procedure for example 10, in 70.8% yield. m.p. 326.3-328.2 ℃; MS (ESI) M/z 421.2[ M-H ]]-；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.65(s,1H),8.59(s,1H),8.27(s,1H),7.68(d,J＝8.2Hz,2H),7.56(dd,J＝3.4,2.5Hz,1H),7.48(d,J＝8.0Hz,2H),6.98(dd,J＝3.5,1.7Hz,1H),4.33(tt,J＝9.8,4.7Hz,1H),3.75(d,J＝12.0Hz,2H),3.17(d,J＝5.2Hz,2H),2.43(s,3H),2.20-2.06(m,4H).
Example 16: 4- (1- (1- (4-cyanophenylsulphonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 16 was prepared according to the procedure for example 10, yield 69.3%. 246.9-248.4 ℃ in m.p.; MS (ESI) M/z 434.2[ M + H]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.65(s,1H),8.61(s,1H),8.27(s,1H),8.17(d,J＝8.3Hz,2H),7.99(d,J＝8.3Hz,2H),7.57-7.55(m,1H),6.99(d,J＝2.0Hz,1H),4.42-4.29(m,1H),3.81(d,J＝12.0Hz,2H),2.60(t,J＝11.9Hz,2H),2.20-2.08(m,4H).
Example 17: 4- (1- (1- (4-methoxybenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 17 was prepared according to the procedure for example 10 in 83.3% yield. 296.9-301.3 ℃ in m.p.; MS (ESI) M/z 437.2[ M-H ]]-；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.62(d,J＝21.2Hz,2H),8.27(s,1H),7.73(d,J＝7.1Hz,2H),7.56(s,1H),7.18(d,J＝7.0Hz,2H),6.98(s,1H),4.32(s,1H),3.87(s,3H),3.74(d,J＝9.0Hz,2H),2.45(s,2H),2.14(s,4H).
Example 18: 4- (1- (1- (2-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 18 was prepared according to the procedure for example 10, yield 68.6%. m.p.:326.8-300.3℃；MS(ESI)m/z:452.2[M-H]-；1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),8.67(d,J＝5.9Hz,2H),8.31(s,1H),8.09(dd,J＝7.6,1.4Hz,1H),8.04(dd,J＝7.8,1.3Hz,1H),7.96(dd,J＝7.5,1.4Hz,1H),7.93(dd,J＝3.5,1.6Hz,1H),7.90(dd,J＝7.5,1.3Hz,1H),4.58-4.41(m,1H),3.88(d,J＝12.6Hz,2H),3.01(t,J＝11.2Hz,2H),2.22(d,J＝10.1Hz,2H),2.11(qd,J＝12.2,4.0Hz,2H).
Example 19: 4- (1- (1- (3-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 19 was prepared according to the procedure for example 10, yield 73.2%. m.p. 306.8-309.5 ℃; MS (ESI) M/z 454.2[ M + H]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.65(s,1H),8.62(s,1H),8.58(dd,J＝8.2,1.4Hz,1H),8.44(t,J＝1.8Hz,1H),8.26(d,J＝9.6Hz,2H),7.99(t,J＝8.0Hz,1H),7.58-7.55(m,1H),6.99(dd,J＝3.5,1.6Hz,1H),4.33(dt,J＝10.5,5.5Hz,1H),3.85(d,J＝12.0Hz,2H),2.63(dt,J＝11.7,6.0Hz,2H),2.13(tt,J＝12.2,6.6Hz,4H).
Example 20: 4- (1- (1-4-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 20 was prepared according to the procedure for example 10, yield 79.2%. m.p. 225.1-226.9 deg.C; MS (ESI) M/z 454.2[ M + H]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.65(s,1H),8.60(s,1H),8.28(d,J＝6.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.73(d,J＝8.4Hz,2H),7.56(s,1H),6.99(s,1H),4.36(t,J＝10.6Hz,1H),3.77(d,J＝11.6Hz,2H),3.17(d,J＝5.2Hz,2H),2.11(dd,J＝13.2,9.8Hz,4H).
Example 21: 4- (1- (1- (4-chlorobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 21 was prepared according to the procedure for example 10, yield 73.7%. 242.2-246.5 ℃ in m.p.; MS (ESI) M/z 442.2[ M-H ]]-；1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.66(s,1H),8.61(s,1H),8.28(s,1H),7.84-7.80(m,2H),7.78-7.74(m,2H),7.57(dd,J＝3.4,2.5Hz,1H),6.99(dd,J＝3.5,1.7Hz,1H),4.46-4.29(m,1H),3.78(d,J＝12.0Hz,2H),2.60-2.51(m,2H),2.23-2.03(m,4H).
Example 22: 4- (1- (1- (3-bromobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 22 was prepared according to the procedure for example 10 in 80.2% yield. m.p. 212.4-215.5 ℃; MS (ESI) M/z 487.1[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.71(s,1H),8.68(s,1H),8.34(s,1H),7.98(d,J＝8.0Hz,1H),7.95(s,1H),7.83(d,J＝7.9Hz,1H),7.66(t,J＝7.9Hz,1H),7.64-7.57(m,1H),7.05(d,J＝1.9Hz,1H),4.49-4.31(m,1H),3.82(d,J＝11.8Hz,2H),2.57(dt,J＝19.7,10.0Hz,2H),2.13(ddd,J＝18.2,15.4,8.1Hz,4H).
Example 23: 4- (1- (1- (4-bromobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 23 was prepared according to the procedure for example 10 in 63.3% yield. 238.1-241.9 ℃ in m.p.; MS (ESI) M/z 487.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),8.65(s,1H),8.60(s,1H),8.28(d,J＝6.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.73(d,J＝8.4Hz,2H),7.56(s,1H),6.99(s,1H),4.36(t,J＝10.6Hz,1H),3.77(d,J＝11.6Hz,2H),3.17(d,J＝5.2Hz,2H),2.11(dd,J＝13.2,9.8Hz,4H).
Example 24: 4- (1- (1- (4-fluorophenylsulphonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting the intermediate C1Example 24 was prepared according to the procedure for example 10, yield 76.1%. m.p. 312.2-314.5 ℃; MS (ESI) M/z 425.2[ M-H ]]-；1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.66(s,1H),8.61(s,1H),8.28(s,1H),7.84-7.80(m,2H),7.78-7.74(m,2H),7.57(dd,J＝3.4,2.5Hz,1H),6.99(dd,J＝3.5,1.7Hz,1H),4.46-4.29(m,1H),3.78(d,J＝12.0Hz,2H),2.60-2.51(m,2H),2.23-2.03(m,4H).
Example 25: 4- (1- (1- (3, 5-difluorobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine
The intermediate is reacted with a catalystC1Example 25 was prepared according to the procedure for example 10 in 63.3% yield. m.p. 351.6-354.7 ℃; MS (ESI) M/z 445.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),8.65(s,1H),8.62(s,1H),8.28(s,1H),7.74(t,J＝9.2Hz,1H),7.56(s,3H),6.99(d,J＝2.1Hz,1H),4.38(t,J＝10.7Hz,1H),3.82(d,J＝12.0Hz,2H),2.67(dd,J＝27.1,17.3Hz,2H),2.22-2.03(m,4H).
Example 26: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one step a: 4- ((7- ((pivaloyloxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (VIII)
13.5g (50.56mmol) of intermediate II, 15.1g (75.84mmol) of tert-butyl 4-aminopiperidine-1-carboxylate and 10.21g (101.12mmol) of triethylamine are introduced into 150mL of isopropanol and the reaction is heated to 80 ℃ and refluxed for 8 hours. After the reaction, the reaction solution was evaporated to dryness to obtain a pale yellow solid, which was then slurried with n-hexane (100mL) to obtain 14.1g (31.68mmol) of a white solid with a yield of 62.6%.
And B: (4- (piperidin-4-ylamino) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) methyl pivalate (M)3)
14.1g (31.68mmol) of intermediate VIII, 100mL of HCl/dioxane solution, are added to a 250mL eggplant-shaped flask and reacted at 30 ℃ for 2h to form a white emulsion. After the reaction was complete, 10.0g (27.10mmol) of white solid was evaporated to dryness, yield 85.2%.
And C: (4- ((1- (2-chloroacetyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d]Pyrimidin-7-yl) methyl pivalate (M)4)
10.0g (27.10mmol) of intermediate M3And 5.47g (54.20mmol) of triethylamine were dissolved in 100mL of tetrahydrofuran, 3.64g (32.52mmol) of chloroacetyl chloride was added while cooling on ice, and after the addition was completed, the ice bath was removed and the reaction was carried out at room temperature for 30 min. After the reaction, the reaction mixture was poured into 200mL of water, extracted with dichloromethane (50mL × 2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow liquid 7.72g (18.96mmol) with a yield of 70.1%.
Step D: (4- ((1- (2- (4-methylpiperidin-1-yl) acetyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d]Pyrimidines-7-yl) methyl pivalate (C)4)
0.4g (1.00mmol) of intermediate M40.27g (2.00mmol) of potassium carbonate and 0.12g (1.2mmol) of 4-methylpiperidine are dissolved in 20mL of acetonitrile and the reaction is stirred at room temperature for 3 h. After the reaction, the reaction mixture was poured into 50mL of water, extracted with dichloromethane (20mL × 2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid with a yield of 0.29g (0.63mmol) of 63.1%.
Step E: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperidin-1-yl) ethan-1-one (example 26)
0.29g (0.63mmol) of intermediate C4Dissolving in 10mL of methanol, adding 3mL of 1mol/L sodium hydroxide solution, stirring at room temperature for reaction for 2 hours, quenching the sodium hydroxide with 1mol/L hydrochloric acid after the reaction is finished, adjusting the pH to 10, extracting with dichloromethane (20mL of x 2), combining organic layers, drying, and separating and purifying by a silica gel preparation thin layer to obtain 0.085g (0.24mmol) of white solid with the yield of 37.9%. m.p. 201.7-205.2 ℃; MS (ESI) M/z 357.1[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.15(d,J＝25.9Hz,1H),7.29–7.05(m,1H),6.63(dd,J＝25.1,2.6Hz,1H),5.01(s,1H),4.50(d,J＝12.8Hz,1H),4.20(d,J＝12.9Hz,1H),3.25(d,J＝13.1Hz,1H),3.10(d,J＝12.3Hz,1H),2.99(d,J＝13.1Hz,1H),2.79(t,J＝11.2Hz,2H),2.67(t,J＝11.6Hz,1H),1.96(dd,J＝20.4,9.4Hz,2H),1.88–1.69(m,2H),1.69–1.50(m,4H),1.30(dd,J＝12.7,8.7Hz,1H),0.89(d,J＝6.4Hz,3H).
Example 27: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-morpholin-1-one
Reacting the intermediate C4Example 27 was prepared according to the procedure for example 26 in 38.7% yield. 226.7-228.2 ℃ in m.p.; MS (ESI) M/z 345.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.07(d,J＝10.6Hz,1H),7.20(d,J＝7.7Hz,1H),7.05(s,1H),6.56(s,1H),3.58(s,4H),3.27(d,J＝13.2Hz,2H),3.12(t,J＝11.9Hz,1H),3.02(d,J＝13.3Hz,1H),2.72(t,J＝12.0Hz,1H),2.39(s,4H),1.95(t,J＝10.9Hz,2H),1.50(dd,J＝20.8,11.5Hz,1H),1.32(dd,J＝20.2,11.7Hz,1H).
Example 28: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one
Reacting the intermediate C4Example 28 was prepared according to the procedure for example 26, yield 41.9%. 183.8-188.4 ℃ in m.p.; MS (ESI) M/z (%): 329.2[ M + H)]+；1H NMR(400MHz,DMSO-d6)δ11.62(d,J＝22.5Hz,1H),8.20–8.10(m,1H),7.18–7.07(m,1H),6.70–6.56(m,1H),5.03(d,J＝19.9Hz,1H),4.51(d,J＝13.8Hz,1H),4.06(d,J＝13.6Hz,1H),3.59(d,J＝14.0Hz,1H),3.48(d,J＝14.2Hz,1H),3.12(s,1H),2.94(d,J＝7.1Hz,1H),2.67(s,4H),1.89–1.79(m,1H),1.76(s,4H),1.69(d,J＝9.5Hz,2H),1.62(dd,J＝11.9,4.1Hz,1H).
Example 29: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (diethylamino) ethan-1-one
Reacting the intermediate C4Example 29 was prepared according to the procedure for example 26 in 43.7% yield. 227.4-229.1 ℃ in m.p.; MS (ESI) M/z 331.2[ M + H]+.
Example 30: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Reacting the intermediate C4Example 30 was prepared according to the procedure for example 26 with a yield of 32.6%. 237.5-239.1 ℃ in m.p.; MS (ESI) m/z 358.2; [ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.11(s,1H),7.16–7.09(m,1H),6.59(d,J＝1.6Hz,1H),5.03(d,J＝21.2Hz,1H),4.50(d,J＝12.8Hz,1H),4.17(d,J＝13.6Hz,1H),3.38(dd,J＝18.5,11.5Hz,2H),3.29(d,J＝13.2Hz,1H),3.01(d,J＝13.1Hz,1H),2.67(t,J＝11.6Hz,2H),2.38(d,J＝32.1Hz,8H),2.16(s,3H),1.83(dt,J＝11.9,8.5Hz,1H),1.68(d,J＝13.0Hz,2H),1.60(dd,J＝12.1,3.9Hz,1H).
Example 31: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one
Reacting the intermediate C4Example 31 was prepared according to the procedure for example 26, with a yield of 41.6%. 204.7-206.2 ℃ in m.p.; MS (ESI) M/z 343.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.12(s,1H),7.17–7.09(m,1H),6.63–6.54(m,1H),4.99(d,J＝17.9Hz,1H),4.50(d,J＝12.8Hz,1H),4.19(d,J＝13.0Hz,1H),3.33(s,1H),3.27(d,J＝11.7Hz,1H),3.01(d,J＝13.2Hz,1H),2.68(t,J＝11.6Hz,1H),2.39(s,4H),1.81(td,J＝12.4,4.1Hz,1H),1.67(t,J＝14.2Hz,2H),1.55–1.49(m,4H),1.39(d,J＝4.7Hz,2H),1.14–1.05(m,1H).
Example 32: 2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1-morpholin-1-one
Step A: (4- (methyl (1- (2-morpholino-2-oxoethyl) piperidin-4-yl) amino) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) methyl pivalate (C)3)
0.33g (1.00mmol) of intermediate M30.16g (1.00mmol) of 2-chloro-1-morpholin-1-one and 0.28g (2.00mmol) of potassium carbonate are dissolved in 20mL of acetonitrile and the reaction is stirred for 1h with heating to 60 ℃. After the reaction, the reaction mixture was poured into 50mL of water, extracted with dichloromethane (20mL × 2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a pale yellow solid 0.42g (0.92mmol) with a yield of 92.1%.
And B: 2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1-morpholin-1-one (example 32)
0.42g (0.92mmol) of intermediate C3Dissolving in 10mL of methanol, adding 3mL of 1mol/L sodium hydroxide solution, stirring at room temperature for reaction for 2 hours, quenching the sodium hydroxide with 1mol/L hydrochloric acid after the reaction is finished, adjusting the pH to 10, extracting with dichloromethane (20mL of x 2), combining organic layers, drying, and separating and purifying by a silica gel preparation thin layer to obtain 0.065g (0.19mmol) of white solid with the yield of 20.7%. 239.8-240.6 ℃ in m.p.; MS (ESI) M/z 345.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.10(s,1H),7.20–7.10(m,1H),6.54(d,J＝1.8Hz,1H),4.72(s,1H),3.60(s,2H),3.56(dd,J＝9.3,4.9Hz,4H),3.45(d,J＝4.4Hz,2H),3.23(s,2H),3.07–3.00(m,2H),2.96(d,J＝10.8Hz,2H),1.83(dt,J＝11.9,8.9Hz,2H),1.63(d,J＝10.5Hz,2H)
Example 33: 2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1- (4-methylpiperazin-1-yl) ethan-1-one
Reacting the intermediate C3Example 33 was prepared according to the procedure for example 32, yield 39.2%. m.p. 228.1-230.2 ℃; MS (ESI) M/z 357.2[ M + H ]]+.
Example 34: 2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -N- (2-methoxyphenyl) acetamide
Reacting the intermediate C3Example 34 was prepared according to the procedure for example 32, yield 42.9%. m.p. 213.1-215.2 ℃; MS (ESI) M/z 381.2[ M + H ]]+.
Example 35: 2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -N- (2, 5-dimethylphenyl) acetamide
Reacting the intermediate C3Example 35 was prepared according to the procedure for example 32 in 29.3% yield. m.p. 231.2-233.3 ℃; MS (ESI) M/z 379.2[ M + H ]]+.
Example 36: 4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N- (2, 5-dimethylphenyl) piperidine-1-carboxamide
Reacting the intermediate C3Example 36 was prepared according to the procedure for example 32, yield 31.6%. m.p. 201.6-204.3 ℃; MS (ESI) M/z 365.2[ M + H]+.
Example 37: 2- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -N- (2-chlorophenyl) acetamide
Reacting the intermediate C3Example 37 was prepared according to the procedure for example 32 in 31.6% yield. 196.4-199.1 ℃ in m.p.; MS (ESI) M/z 385.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.02(s,1H),8.27(d,J＝7.9Hz,1H),8.12(s,1H),7.55(d,J＝7.9Hz,1H),7.37(t,J＝7.7Hz,1H),7.16(dd,J＝9.8,5.4Hz,2H),6.57(s,1H),4.80(s,1H),3.34(s,2H),3.03(d,J＝11.3Hz,2H),2.46(d,J＝11.3Hz,2H),1.97(dt,J＝12.2,8.8Hz,2H),1.71(d,J＝10.9Hz,2H).
Example 38: 4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -N- (2-chlorophenyl) piperidine-1-carboxamide
Reacting the intermediate C3Example 38 was prepared according to the procedure for example 32, yield 20.5%. 236.4-239.1 ℃ in m.p.; MS (ESI) M/z 381.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.28(s,1H),8.13(s,1H),7.51(d,J＝7.0Hz,1H),7.49–7.42(m,1H),7.29(t,J＝7.1Hz,1H),7.19–7.07(m,2H),6.60(d,J＝1.5Hz,1H),5.00(s,1H),4.25(d,J＝13.1Hz,2H),2.99(t,J＝12.0Hz,2H),1.88–1.63(m,4H).
Example 39: n- (1- (methylsulfonyl) piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Reacting the intermediate C3Example 39 was prepared according to the procedure for example 32 in 23.5% yield. 236.4-239.1 ℃ in m.p.; MS (ESI) M/z 295.2[ M + H]+；1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.10(s,1H),7.20–7.10(m,1H),6.54(d,J＝1.8Hz,1H),4.72(s,1H),3.60(s,2H),3.56(dd,J＝9.3,4.9Hz,4H),3.45(d,J＝4.4Hz,2H),3.23(s,2H),3.07–3.00(m,2H),2.96(d,J＝10.8Hz,2H),1.83(dt,J＝11.9,8.9Hz,2H),1.63(d,J＝10.5Hz,2H).
Example 40: n- (1- ((4-bromophenyl) sulfonyl) piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Reacting the intermediate C3Example 40 was prepared according to the procedure for example 32 in 27.4% yield. 236.4-239.1 ℃ in m.p.; MS (ESI) M/z 436.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.06(d,J＝9.1Hz,1H),7.90(d,J＝3.2Hz,1H),7.88(d,J＝3.0Hz,1H),7.73(s,1H),7.71(s,1H),7.16–7.08(m,1H),6.54(d,J＝1.6Hz,1H),4.67(d,J＝10.6Hz,1H),3.79(d,J＝11.8Hz,2H),2.46(d,J＝11.1Hz,2H),1.92–1.82(m,2H),1.72(d,J＝10.4Hz,2H).
Example 41: 1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Step A: 4- ((7- ((pivaloyloxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (M)5)
13.5g (50.56mmol) of intermediate II, 16.2g (75.84mmol) of tert-butyl 4- (methylamino) piperidine-1-carboxylate and 10.21g (101.12mmol) of triethylamine were placed in 150mL of N, N-dimethylformamide, and the reaction was refluxed at 110 ℃ for 8 hours. After the reaction, the reaction mixture was poured into 200mL of water, extracted with dichloromethane (50 mL. times.2), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give a brown oily liquid. The oily liquid was added to 100mL of dichloromethane, 100mL of 4M dioxane hydrochloride was added, and the reaction was stirred at room temperature to form a yellow emulsion, which was evaporated to dryness to give 67.2% yield of a pale yellow solid (11.72 g, 33.98 mmol).
And B: (4- ((1- (2-chloroacetyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d]Pyrimidin-7-yl) methyl pivalate (M)6)
9.35g (27.10mmol) of intermediate M5And 5.47g (54.20mmol) of triethylamine were dissolved in 100mL of tetrahydrofuran, 3.64g (32.52mmol) of chloroacetyl chloride was added while cooling on ice, and after the addition was completed, the ice bath was removed and the reaction was carried out at room temperature for 30 min. After the reaction, the reaction mixture was poured into 200mL of water, extracted with dichloromethane (50 mL. times.2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give 7.98g (18.96mmol) of pale yellow liquid with a yield of 70.1%.
And C: (4- ((1- (2- (4-methylpiperidin-1-yl) acetyl) piperidin-4-yl) amino) -7H-pyrrolo [2,3-d]Pyrimidin-7-yl) methyl pivalate (C)6)
0.42g (1.00mmol) of intermediate M60.27g (2.00mmol) of potassium carbonate and 0.12g (1.2mmol) of 4-methylpiperazine were dissolved in 20mL of acetonitrile, and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was poured into 50mL of water, extracted with dichloromethane (20 mL. times.2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow solid in a yield of 0.30g (0.63mmol) of 63.1%.
Step D: 1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one (example 41)
0.30g (0.63mmol) of intermediate C6Dissolving in 10mL of methanol, adding 3mL of 1mol/L sodium hydroxide solution, stirring at room temperature for reaction for 2 hours, quenching the sodium hydroxide with 1mol/L hydrochloric acid after the reaction is finished, adjusting the pH to 10, extracting with dichloromethane (20mL of x 2), combining organic layers, drying, and separating and purifying by a silica gel preparation thin layer to obtain 0.086g (0.24mmol) of white solid with the yield of 37.9%. m.p. 193.7-196.2 ℃; MS (ESI) M/z 371.1[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.15(d,J＝25.9Hz,1H),7.29–7.05(m,1H),6.63(dd,J＝25.1,2.6Hz,1H),5.01(s,1H),4.50(d,J＝12.8Hz,1H),4.20(d,J＝12.9Hz,1H),3.25(d,J＝13.1Hz,1H),3.14(s,3H),3.10(d,J＝12.3Hz,1H),2.99(d,J＝13.1Hz,1H),2.79(t,J＝11.2Hz,2H),2.67(t,J＝11.6Hz,1H),1.96(dd,J＝20.4,9.4Hz,2H),1.88–1.69(m,2H),1.69–1.50(m,4H),1.30(dd,J＝12.7,8.7Hz,1H),0.89(d,J＝6.4Hz,3H).
Example 42: 1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-morpholin-1-one
Reacting the intermediate C6Example 42 was prepared according to the procedure for example 41, with a yield of 41.6%. m.p. 202.4-203.1 ℃; MS (ESI) M/z 359.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.07(d,J＝10.6Hz,1H),7.20(d,J＝7.7Hz,1H),7.05(s,1H),6.56(s,1H),3.58(s,4H),3.27(d,J＝13.2Hz,2H),3.14(s,3H),3.12(t,J＝11.9Hz,1H),3.02(d,J＝13.3Hz,1H),2.72(t,J＝12.0Hz,1H),2.39(s,4H),1.95(t,J＝10.9Hz,2H),1.50(dd,J＝20.8,11.5Hz,1H),1.32(dd,J＝20.2,11.7Hz,1H).
Example 43: 2- (diethylamino) -1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) ethan-1-one
Reacting the intermediate C6Example 43 was prepared according to the procedure for example 41, yield 43.1%. m.p. 205.3-207.0 ℃; MS (ESI) M/z 361.2[ M + H ]]+.
Example 44: 1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one
Reacting the intermediate C6Example 44 was prepared according to the procedure for example 41, yield 36.8%. 183.2-184.9 ℃ in m.p.; MS (ESI) M/z 343.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.62(d,J＝22.5Hz,1H),8.20–8.10(m,1H),7.18–7.07(m,1H),6.70–6.56(m,1H),5.03(d,J＝19.9Hz,1H),4.51(d,J＝13.8Hz,1H),4.06(d,J＝13.6Hz,1H),3.59(d,J＝14.0Hz,1H),3.48(d,J＝14.2Hz,1H),3.15(s,3H),3.12(s,1H),2.94(d,J＝7.1Hz,1H),2.67(s,4H),1.89–1.79(m,1H),1.76(s,4H),1.69(d,J＝9.5Hz,2H),1.62(dd,J＝11.9,4.1Hz,1H).
Example 45: 1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Reacting the intermediate C6Example 45 was prepared according to the procedure for example 41, yield 29.6%. 231.8-236.2 ℃ in m.p.; MS (ESI) M/z 372.2[ M + H]+；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.11(s,1H),7.16–7.09(m,1H),6.59(d,J＝1.6Hz,1H),5.03(d,J＝21.2Hz,1H),4.50(d,J＝12.8Hz,1H),4.17(d,J＝13.6Hz,1H),3.38(dd,J＝18.5,11.5Hz,2H),3.29(d,J＝13.2Hz,1H),3.14(s,3H),3.01(d,J＝13.1Hz,1H),2.67(t,J＝11.6Hz,2H),2.38(d,J＝32.1Hz,8H),2.16(s,3H),1.83(dt,J＝11.9,8.5Hz,1H),1.68(d,J＝13.0Hz,2H),1.60(dd,J＝12.1,3.9Hz,1H).
Example 46: 1- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (piperidin-1-yl) ethan-1-one
Reacting the intermediate C6Example 46 was prepared according to the procedure for example 41, yield 40.3%. 196.8-198.7 ℃ in m.p.; MS (ESI) M/z 357.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),8.12(s,1H),7.17–7.09(m,1H),6.63–6.54(m,1H),4.99(d,J＝17.9Hz,1H),4.50(d,J＝12.8Hz,1H),4.19(d,J＝13.0Hz,1H),3.33(s,1H),3.27(d,J＝11.7Hz,1H),3.14(s,3H),3.01(d,J＝13.2Hz,1H),2.68(t,J＝11.6Hz,1H),2.39(s,4H),1.81(td,J＝12.4,4.1Hz,1H),1.67(t,J＝14.2Hz,2H),1.55–1.49(m,4H),1.39(d,J＝4.7Hz,2H),1.14–1.05(m,1H).
Example 47: 2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1-morpholin-1-one
Step A: (4- (methyl (1- (2-morpholino-2-oxoethyl) piperidin-4-yl) amino) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) methyl pivalate (C)5)
0.35g (1.00mmol) of intermediate M50.16g (1.00mmol) of 2-chloro-1-morpholin-1-one and 0.28g (2.00mmol) of potassium carbonate are dissolved in 20mL of acetonitrile and the reaction is stirred for 1h with heating to 60 ℃. After the reaction, the reaction mixture was poured into 50mL of water, extracted with dichloromethane (20 mL. times.2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow solidYield of 0.43g (0.92mmol) was 92.1%.
And B: 2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1-morpholin-1-one (example 47)
0.48g (0.92mmol) of intermediate C5Dissolving in 10mL of methanol, adding 3mL of 1mol/L sodium hydroxide solution, stirring at room temperature for reaction for 2 hours, quenching the sodium hydroxide with 1mol/L hydrochloric acid after the reaction is finished, adjusting the pH to 10, extracting with dichloromethane (20mL of x 2), combining organic layers, drying, and separating and purifying by a silica gel preparation thin layer to obtain 0.068g (0.19mmol) of white solid with the yield of 20.7%. m.p. 200.4-201.1 deg.C; MS (ESI) M/z 359.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.10(s,1H),7.20–7.10(m,1H),6.54(d,J＝1.8Hz,1H),4.72(s,1H),3.60(s,2H),3.56(dd,J＝9.3,4.9Hz,4H),3.45(d,J＝4.4Hz,2H),3.23(s,2H),3.17(s,3H),3.07–3.00(m,2H),2.96(d,J＝10.8Hz,2H),1.83(dt,J＝11.9,8.9Hz,2H),1.63(d,J＝10.5Hz,2H)
Example 48: 2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -1- (4-methylpiperazin-1-yl) ethan-1-one
Reacting the intermediate C5Example 48 was prepared according to the procedure for example 47 in 23.7% yield. 231.6-234.1 ℃ in m.p.; MS (ESI) M/z 371.2[ M + H ]]+.
Example 49: n- (2-methoxyphenyl) -2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) acetamide
Reacting the intermediate C5Example 49 was prepared according to the procedure for example 47 in 22.4% yield. m.p. 249.1-251.0 deg.C; MS (ESI) M/z 395.2[ M + H]+.
Example 50: n- (2, 5-dimethylphenyl) -2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) acetamide
Reacting the intermediate C5Example 50 was prepared according to the procedure for example 47 in 29.0% yield. m.p. 241.8-244.0 ℃; MS (ESI) M/z 393.2[ M + H ]]+.
Example 51: n- (2-chlorophenyl) -2- (4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) acetamide
Reacting the intermediate C5Example 51 was prepared according to the procedure for example 47 in 21.6% yield. m.p. 253.8-259.3.1 ℃; MS (ESI) M/z 399.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.02(s,1H),8.27(d,J＝7.9Hz,1H),8.12(s,1H),7.55(d,J＝7.9Hz,1H),7.37(t,J＝7.7Hz,1H),7.16(dd,J＝9.8,5.4Hz,2H),6.57(s,1H),4.80(s,1H),3.34(s,2H),3.21(s,3H),3.03(d,J＝11.3Hz,2H),2.46(d,J＝11.3Hz,2H),1.97(dt,J＝12.2,8.8Hz,2H),1.71(d,J＝10.9Hz,2H).
Example 52: n- (2, 5-dimethylphenyl) -4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxamide
Reacting the intermediate C5Example 52 was prepared according to the procedure for example 47 in 20.3% yield. m.p. 215.7-216.9 ℃; MS (ESI) M/z 379.2[ M + H ]]+.
Example 53: n- (2-chlorophenyl) -4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxamide
Reacting the intermediate C5Example 53 was prepared according to the procedure for example 47 in 23.9% yield. 229.1-236.3 ℃ in m.p.; MS (ESI) M/z 385.2[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.28(s,1H),8.13(s,1H),7.51(d,J＝7.0Hz,1H),7.49–7.42(m,1H),7.29(t,J＝7.1Hz,1H),7.19–7.07(m,2H),6.60(d,J＝1.5Hz,1H),5.00(s,1H),4.25(d,J＝13.1Hz,2H),3.18(s,3H),2.99(t,J＝12.0Hz,2H),1.88–1.63(m,4H).
Example 54: N-methyl-N- (1- (methylsulfonyl) piperidin-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Reacting the intermediate C5Example 54 was prepared according to the procedure for example 47 in 31.6% yield. 197.3-201.6 ℃ in m.p.; MS (ESI) M/z 310.2[ M + H]+；1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.10(s,1H),7.20–7.10(m,1H),6.54(d,J＝1.8Hz,1H),4.72(s,1H),3.60(s,2H),3.56(dd,J＝9.3,4.9Hz,4H),3.45(d,J＝4.4Hz,2H),3.23(s,2H),3.17(s,3H),3.07–3.00(m,2H),2.96(d,J＝10.8Hz,2H),1.83(dt,J＝11.9,8.9Hz,2H),1.63(d,J＝10.5Hz,2H).
Example 55: n- (1- ((4-bromophenyl) sulfonyl) piperidin-4-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Reacting the intermediate C5Example 55 was prepared according to the procedure for example 47 in 36.1% yield. 204.7-210.2 ℃ in m.p.; MS (ESI) M/z 450.2[ M + H]+；1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.06(d,J＝9.1Hz,1H),7.90(d,J＝3.2Hz,1H),7.88(d,J＝3.0Hz,1H),7.73(s,1H),7.71(s,1H),7.16–7.08(m,1H),6.54(d,J＝1.6Hz,1H),4.67(d,J＝10.6Hz,1H),3.79(d,J＝11.8Hz,2H),3.14(s,3H),2.46(d,J＝11.1Hz,2H),1.92–1.82(m,2H),1.72(d,J＝10.4Hz,2H).
Activity study of the products of the invention
JAK1 and JAK2 enzyme activity assays
Pyrrolo [2,3-d ] pyrimidine derivatives of general formula I synthesized according to the present invention were tested for in vitro JAK1 and JAK2 kinase inhibition.
(1) Preparing a sample to be tested: diluting with 100% DMSO to 50 times of reaction final concentration, namely 50 μmol/L;
(2) diluting: 50 mu mol/L is used as the initial concentration, and then diluted by 4 times of concentration to obtain 10 concentration gradients;
(3) adding 100% DMSO into the positive control well and the negative control well respectively;
(4) diluting the prepared compounds with 10 concentrations by 10 times with 1 time of kinase buffer solution respectively; wherein the kinase buffer solution contains 50mmol/L of hydroxyethyl piperazine ethanethiosulfonic acid with pH of 7.5, 0.01% of dodecyl polyglycol ether, 10mmol/L of magnesium chloride, and 2mmol/L of dithiothreitol;
(5) preparing 2.5 times of enzyme solution: adding kinase into 1 time of kinase buffer solution to form 2.5 times of enzyme solution;
(6) preparing 2.5 times of substrate solution: adding FAM-labeled polypeptide and ATP into 1-time kinase buffer solution to form 2.5-time substrate solution;
(7) add enzyme solution to 384-well plates: 5 times of compound dissolved by 10 percent of mu LDMSO exists in the 384-hole reaction plate, then 10 mu L of 2.5 times enzyme solution is added, and the incubation is carried out for 10 minutes at room temperature;
(8) add substrate solution to 384-well plate: add 10. mu.L of 2.5 fold substrate solution to 384 well reaction plates;
(9) kinase reaction and termination: incubating for 1h at 28 ℃, and then adding 25 mu L of stop solution to stop the reaction; wherein the termination solution comprises hydroxyethyl piperazine ethanethiosulfonic acid with the concentration of 100mmol/L and the pH value of 7.5, 0.015 percent of dodecyl polyglycol ether, 0.2 percent of No. 3 surface reagent and 20mmol/L of ethylenediamine tetraacetic acid;
(10) reading conversion rate data on the Caliper reading data;
(11) and (3) calculating an inhibition rate: conversion data was copied from the Caliper and converted to inhibition data. Percent inhibition is (max-conversion)/(max-min) × 100.
Where max refers to the conversion of the DMSO control and min is the conversion of the no enzyme live control.
The results of the inhibition rate of JAK kinases by the compounds are shown in table 3.
TABLE 3
Figure GDA0003371613130000271
NO Release inhibition assay
The pyrrolo [2,3-d ] pyrimidine derivatives of the general formula I synthesized according to the invention were tested for the inhibition of NO release in RAW264.7 cells in vitro.
(1) Preparing a sample to be tested: diluting with 100% DMSO to 50 times of reaction final concentration, namely 50 μmol/L;
(2) diluting: taking 50 mu mol/L as an initial concentration, then diluting by 4 times of concentration, and diluting 3 concentration gradients which are respectively 2.5 mu mol/L,5 mu mol/L and 10 mu mol/L;
(3) log phase RAW264.7 cells (5 × 105 cells/mL) were pre-treated with different concentrations of the target compound for 2h, followed by incubation with 5 μ g/mL LPS for 18 h. And all control groups received no treatment.
(4) Nitrite accumulation in the supernatant was determined by Griess reagent. Briefly, equal volumes of cell-free medium (50 μ L) were reacted with Griess reagent I (50 μ L) and Griess reagent II (50 μ L) and the absorbance at 540nm was measured.
Examples NO inhibition ratio (100%) Examples NO inhibition ratio (100%)
Example 1 79.9 Example 14 15.3
Example 2 77.8 Example 15 47.1
Example 3 74.0 Example 16 74.9
Example 4 83.1 Example 17 69.7
Example 5 78.3 Example 18 76.5
Example 6 79.4 Example 19 65.5
Example 7 82.7 Example 20 89.0
Example 8 75.3 Example 21 85.5
Example 9 16.2 Example 22 89.9
Example 10 36.4 Example 23 73.6
Example 11 26.4 Example 24 90.1
Example 12 20.2 Example 25 71.9
Example 13 13.7 Baricitinib 77.5

Claims (8)

1. General formula (VII)
Figure DEST_PATH_IMAGE001
The compounds and the pharmaceutically acceptable salts thereof,
Figure 486340DEST_PATH_IMAGE002
wherein the content of the first and second substances,
l is SO2Or C = O;
R1is (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, phenyl, - (CH)2)n-NR3R4Wherein said phenyl group may be substituted by 1 to 3R which may be the same or different5Optionally substituted;
n is an integer between 0 and 3;
R3and R4Same or different, each independently selected from C1-C10Alkyl, said alkyl being substituted by 1 to 3R which may be the same or different5Optionally substituted;
or R3And R4Together with the nitrogen atom to which it is attached form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl wherein the 4-position of the piperidinyl or piperazinyl may be interrupted by 1R5Substitution;
R5is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Alkoxy, hydroxy, hydroxymethyl, hydroxyethyl, cyano, nitro or carboxy.
2. The general formula of claim 1
Figure 403175DEST_PATH_IMAGE001
The compounds and the pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1is (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, phenyl, - (CH)2)n-NR3R4Wherein said phenyl group may be substituted by 1 to 3R which may be the same or different5Optionally substituted;
n is 0 or 1;
R3and R4Same or different, each independently selected from C1-C4An alkyl group;
or R3And R4Together with the nitrogen atom to which it is attached form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl wherein the 4-position of the piperidinyl or piperazinyl may be interrupted by 1R5And (4) substitution.
3. The general formula of claim 1 or 2
Figure 101004DEST_PATH_IMAGE001
The compounds and the pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1is methyl, ethyl, cyclopropyl, phenyl, - (CH)2)n-NR3R4Wherein said phenyl group may be substituted by 1-2R which may be the same or different5Optionally substituted;
R3and R4The same or different, are each independently selected from methyl or ethyl;
or R3And R4Together with the nitrogen atom to which it is attached form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl wherein the 4-position of the piperidinyl or piperazinyl may be interrupted by 1R5And (4) substitution.
4. The following compounds and pharmaceutically acceptable salts thereof,
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (piperidin-1-yl)) Ethan-1-ones
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (morpholin-1-yl) -1-one
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (diethylamino) ethan-1-one
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4-methylpiperidin-1-yl) ethan-1-one
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (pyrrolidin-1-yl) ethan-1-one
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (dimethylamino) ethan-1-one
1-(2-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2-oxoethyl) piperidine-4-carboxylic acid
1-(4-(4-(7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl) piperidin-1-yl) -2- (4- (2-hydroxyethyl) piperidin-1-yl) ethan-1-one
4- (1- (1- (methylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (ethylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (cyclopropylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (phenylsulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (2-methylbenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (4-methylbenzenesulfonyl) piperidin-4-yl) -1H-pyridineOxazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (4-cyanophenylsulphonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (4-methoxybenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (2-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (3-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (4-nitrobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (4-chlorobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (3-bromobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (4-bromobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (4-fluorophenylsulphonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]Pyrimidines
4- (1- (1- (3, 5-difluorobenzenesulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d]A pyrimidine.
5. A pharmaceutical composition comprising a compound of any one of claims 1-4 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
6. The general formula of claim 1
Figure 741938DEST_PATH_IMAGE001
The preparation method of the compound and the pharmaceutically acceptable salt thereof is characterized in that,
Figure 491238DEST_PATH_IMAGE004
or
Figure 769904DEST_PATH_IMAGE006
Wherein R is1、R3、R4As claimed in claim 1.
7. Use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, in the preparation of a JAK kinase inhibitor.
8. Use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment of an inflammatory disease, an autoimmune disease, fibrosis or cancer.
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