CN110724142B - Amide or sulfonamide substituted hydrazine derivatives as JAK kinase inhibitors - Google Patents

Amide or sulfonamide substituted hydrazine derivatives as JAK kinase inhibitors Download PDF

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CN110724142B
CN110724142B CN201911036824.3A CN201911036824A CN110724142B CN 110724142 B CN110724142 B CN 110724142B CN 201911036824 A CN201911036824 A CN 201911036824A CN 110724142 B CN110724142 B CN 110724142B
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pyrrolo
pyridin
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CN110724142A (en
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沈旺
刘鹏飞
白如珺
刘宇飞
柯平波
龚燕川
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Qiyuan Biology Hangzhou Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Abstract

The invention provides an amide or sulfonamide substituted hydrazine derivative, which is characterized in that: the compound is shown as the following structural formula, and stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof:

Description

Amide or sulfonamide substituted hydrazine derivatives as JAK kinase inhibitors
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a JAK enzyme inhibitor, and a preparation method and application thereof.
Background
Protein kinases (Protein kinases) are a class of enzymes that catalyze Protein phosphorylation reactions and are key factors in the regulation of cellular signals including cell proliferation and cell differentiation, including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair and regeneration, and the like.
Signaling by many cytokines such as the Interferon (IFN) family, the glycoprotein 130(gpl30) family, the γ -C family (common gamma chain, CD132 family), and the single chain family involves the Janus kinase family (JAK), and Signal Transducers and Activators of Transcription (STATs) downstream of the JAK kinases. Currently, there are four known mammalian JAK family members: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3(Janus kinase-3) and TYK2 (also known as protein-tyrosine kinase 2).
Blocking signal transduction at the JAK kinase level offers promise for the development of therapies for inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer. Inhibition of JAK kinases is also helpful in the treatment of skin immune diseases such as psoriasis and skin sensitization. Tovatinib (Toxictinib) and Baricitinib (Baricitinib) are already on the market for the treatment of rheumatoid arthritis; and ruxolitinib (ruxolitinib), for the treatment of myelofibrosis and acute graft versus host disease.
However, some of the JAK enzyme inhibitors currently available also have some significant toxic side effects. Immune-related side effects that JAK inhibitors can cause: infections, including pneumonia, viral infections (e.g., herpes zoster infection), bacterial infections, actinomycete infections (mycobacterial infections), fungal infections, decreased immunity (e.g., NK cell depletion), and anemia. But also have some non-immunological side effects such as pulmonary embolism (which may be fatal).
Therefore, the external JAK preparation reduces the systemic exposure of the drug, can be used for treating local inflammation or local immune diseases, can achieve good treatment effect, and simultaneously avoids the toxicity caused by systemic exposure.
Ophthalmic diseases such as allergic conjunctivitis, dry eye, secondary xerosis (Sjogren's disease), uveitis, inflammation after ocular surgery, ocular corneal graft rejection, chronic graft-versus-host disease of the ocular region, and the like are all immune and inflammation related diseases. The JAK kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is closely related to the pathogenesis of inflammatory and autoimmune diseases. Therefore, the JAK inhibitor is developed to be applied in ophthalmology, and has a good effect on treating ophthalmic diseases. Ophthalmic drugs are generally used in the form of eye drops, and therefore, it is necessary to develop a JAK kinase inhibitor having good water solubility and high activity.
Disclosure of Invention
The invention aims to provide a novel inhibitor which has high activity on JAK1 kinase inhibition and good water solubility and can be developed into an eye drop preparation.
The invention provides an amide or sulfonamide substituted hydrazine derivative, which is characterized in that: the compound is shown as the following structural formula, and stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof:
Figure BDA0002251731350000011
wherein the above ring A is C 4-9 Heterocyclic group, C 6-12 Fused heterobicyclic radicals or C 6-12 Spiro heterobicyclic ring with 1-3 heteroatoms selected from N, O, S;
r is as defined above 1 Is one or more of hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted C optionally substituted on the ring A 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 A heteroalkyl group;
r is as defined above 2 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 A heteroalkyl group;
n is selected from 0, any natural number;
r is as defined above 3 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 4-6 A heterocycloalkyl group;
r is as defined above 4 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Heteroalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or notSubstituted C 4-10 Heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-10 Heteroaryl, substituted or unsubstituted amino, amino;
y is selected from C, S (═ O).
Further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized in that: when n is not 0;
-(CH 2 ) n at least one of the hydrogen atoms bonded to the carbon atoms in (a) is substituted by alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl.
Further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized in that: r is as defined above 3 And R 4 And form a 5-to 10-membered heterocyclic ring with the atoms to which they are attached.
Further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized by:
Figure BDA0002251731350000021
wherein m is 0, a natural number.
Any one or more carbon atoms of the above ring B are replaced by carbon, nitrogen, oxygen or sulfur.
Further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized in that: and a substituted or unsubstituted aliphatic ring, a substituted or unsubstituted aliphatic heterocyclic ring, a substituted or unsubstituted aromatic ring and a substituted or unsubstituted aromatic heterocyclic ring are connected to any or any number of carbon bonds on the ring B in parallel.
Further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized by: the compound is shown as the following structural formulas, and stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof:
Figure BDA0002251731350000022
wherein the above ring A is C 4-9 Heterocyclic group, C 6-12 Fused heterobicyclic radicals or C 6-12 Spiro heterobicyclic ring with 1-3 heteroatoms selected from N, O, S;
r is as defined above 1 Is one or more of hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted C optionally substituted on the ring A 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 A heteroalkyl group;
r is as defined above 2 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 A heteroalkyl group;
n is selected from 0, any natural number;
r is as defined above 3 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Heteroalkyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted C 4-6 A heterocycloalkyl group;
Prot 1 and Prot 2 Are the same or different amine protecting groups.
In addition, the invention also provides an amide or sulfonamide substituted hydrazine derivative, which is characterized in that: the compound is shown as the following structural formula, and stereoisomers, geometric isomers, tautomers, racemates, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof:
Figure BDA0002251731350000031
wherein the above ring A is C 4-9 Heterocyclic group, C 6-12 Fused heterobicyclic radicals or C 6-12 Spiro heterobicyclic ring with 1-3 heteroatoms selected from N, O, S;
r is as defined above 1 Is one or more of the same or different hydrogen or hydroxy optionally substituted on the ring ARadical, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 A heteroalkyl group;
r is as defined above 2 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 A heteroalkyl group;
n is selected from 0, any natural number;
r is as defined above 4 Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Heteroalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 4-10 Heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 5-10 Heteroaryl, substituted or unsubstituted amino, amino;
y is selected from C, S (═ O).
Further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized in that: is a compound represented by the following structural formula:
Figure BDA0002251731350000032
the ring A is C containing two nitrogen atoms 5-9 Heterocyclic group, C 6-12 Fused heterobicyclic radicals or C 6-12 Spiro heterobicyclic rings.
In the present invention, ring A may have a structure represented by the following structure or a structure similar thereto:
Figure BDA0002251731350000033
substituted alkyl in the present invention means that one or more of the hydrogen atoms of the alkyl carbon chain are substituted by other groups, which may be hydroxy, cycloalkyl (in analogy to the above-mentioned groups)
Figure BDA0002251731350000034
Spiro, fused ring, etc., any hydrogen atom on the cycloalkyl ring may be substituted with a group such as halogen, cyano, alkyl, hydroxyl, carboxyl, etc. (one or more carbons on the carbocyclic ring may be substituted with C (═ O)), heterocycloalkyl (i.e., at least one carbon atom on the alkyl ring is substituted with oxygen, sulfur, or nitrogen in addition to the above-mentioned cycloalkyl), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonyl (-SO), etc 2 R a ，R a Alkyl, aryl, etc.), alkynyl (-C.ident.CH, -C.ident.CR) b ，R b Is alkyl, aryl, etc.), an amide group (-C (O) NR) x R y ，R x R y Alkyl, aryl, etc.), ester (-C (O) O-R) z ，R z Alkyl, aryl, etc.), aryl, heteroaryl, etc., or one or more carbons of the carbon chain substituted with C (═ O);
substituted or unsubstituted heteroalkyl in the present invention refers to: refers to the substituted or unsubstituted alkyl, one or more carbon atoms of the carbon chain of which are replaced by oxygen, sulfur, nitrogen.
Substituted cycloalkyl in the present invention refers to a cyclic ring wherein one or more of the hydrogen atoms are replaced by another group, which may be alkyl, substituted alkyl (as above), halo (F, Cl, Br, I), carboxy, cyano (-CN), sulfonyl (-SO) 2 R a ，R a Alkyl, aryl, etc.), alkynyl (-C.ident.CH, -C.ident.CR) b ，R b Is alkyl, aryl, etc.), an amide group (-C (O) NR) x R y ，R x R y Hydrogen, alkyl, aryl, etc.), ester (-C (O) O-R z ，R z Alkyl, aryl, etc.), aryl, heteroaryl, etc., or one or more carbons of the carbon chain may be substituted with C (═ O).
Substituted or unsubstituted heterocycloalkyl in the present invention means: refers to the substituted or unsubstituted cycloalkyl, one or more carbon atoms of the ring of which are replaced by oxygen, sulfur, nitrogen.
Substituted alkoxy in the context of the present invention means alkoxy(s) ((R))
Figure BDA0002251731350000041
n is selected from 0 or any natural number, m is a natural number including 0) one or more of the hydrogen atoms on the carbon chain are substituted with other groups, which may be cycloalkyl (in a manner similar to that of the cycloalkyl group)
Figure BDA0002251731350000042
Etc., any hydrogen atom on the cycloalkyl ring may also be substituted with a halogen, cyano, alkyl, hydroxyl, carboxyl, etc., heterocycloalkyl (i.e., where at least one carbon atom on the alkyl ring is replaced with oxygen, sulfur, nitrogen, etc., in addition to the cycloalkyl described above), halogen (F, Cl, Br, I), carboxyl, cyano (-CN), sulfonyl (-SO), etc 2 R a ，R a Alkyl, aryl, etc.), alkynyl (-C.ident.CH, -C.ident.CR) b ，R b Alkyl, aryl, etc.), amide (-C (O) NR) x R y ，R x R y Hydrogen, alkyl, aryl, etc.), ester group (-C (O) O-R z ，R z Alkyl, aryl, etc.), aryl, heteroaryl, etc., or one or more carbons of the carbon chain is substituted with C (═ O).
Substituted amine groups in the present invention refer to: amino (-NH) 2 ) One or more of the hydrogen atoms thereon are substituted with other groups, and the other groups referred to herein may be substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted amide groups, substituted or unsubstituted ester groups, substituted or unsubstituted aryl groups, and the like.
Substituted aryl in the present invention means that one or more hydrogen atoms on the aryl ring are substituted by other groups, which may be alkyl, cycloalkyl, amido, ester, hydroxyl, cyano, halogen, etc.
Substituted heteroaryl in the present invention refers to: it means that one or more carbon atoms on the ring are replaced by oxygen, sulfur and nitrogen on the basis of the substituted aromatic group.
Most preferred compounds are those represented by the following structure:
Figure BDA0002251731350000051
Figure BDA0002251731350000061
Figure BDA0002251731350000071
further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized in that: the specific preparation method is as follows: s1, nitrosating a compound shown as a formula IV-1 to obtain a nitroso product IV-2;
s2, reducing the nitroso product IV-2 to generate a compound shown as a formula IV-3;
s3, heating the compound IV-3 and a compound shown as a formula IV-4 to react under an alkaline condition to obtain a compound IV-5;
s4, hydrogenating and reducing the nitro group in the compound IV-5 into amino to obtain a compound IV-6;
s5, carrying out a ring closing reaction on the compound IV-6 to obtain a compound IV-7;
s6, carrying out deprotection on the compound IV-7 to obtain an intermediate product IV-8;
s7, obtaining the intermediate products IV-8 and R 4 COCl or R 4 SO 2 Cl reacts to obtain an intermediate product IV-9;
s8, removing protecting groups of the intermediate product IV-9 by alkali liquor to generate a target product;
wherein the structures of the compounds IV-1 to IV-9 are shown as follows:
Figure BDA0002251731350000081
wherein Prot is an amino protecting group.
The specific preparation equation is as follows:
Figure BDA0002251731350000091
further, the present invention provides an amide or sulfonamide substituted hydrazine derivative characterized in that: is used as a JAK enzyme inhibitor.
Detailed Description
Example 1
Figure BDA0002251731350000092
(R) -N- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methanesulfonamide
The specific embodiment is as follows:
Figure BDA0002251731350000101
step A:
4-Boc-aminopiperidine (5.38g, 26.9mmol) was dissolved in 30mL of acetic acid and 10mL of water, and an aqueous solution (20mL) containing sodium nitrite (3.72g, 53.8mmol) was slowly added dropwise at 0 ℃ and then warmed to room temperature under nitrogen and stirred for 18 hours. After the reaction was completed, it was quenched with water at 0 ℃ and extracted three times with ethyl acetate (240mL), filtered, spun-dried, and purified to give the product 1-nitroso-4-Boc-aminopiperidine (5.47g, 89% yield). LCMS ESI (+) m/z: 230.1(M +1).
And B, step B:
the compound 1-nitroso-4-Boc-aminopiperidine (5.47g, 25mmol) and zinc powder (16.2g, 250mmol) were suspended in acetic acid (10mL) and methanol (30mL) and stirred at room temperature for 2 hours under a nitrogen blanket. After the reaction was completed, it was filtered and spin-dried to obtain crude 1-amino-4-Boc-aminopiperidine (5.12g, yield 100%). LCMS ESI (+) m/z: 216.1(M +1).
Step C:
the compounds 1-amino-4-Boc-aminopiperidine (4.28g,21.3mmol), 4-chloro-5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridine (8.78g, 25mmol) and N, N-diisopropylethylamine (32.3g, 250mmol) were dissolved in 120mL of isopropanol and stirred at 100 ℃ for 20 hours. After the reaction was completed, spin-drying and purification were carried out to obtain the product tert-butyl (1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) carbamate (12.6g, yield 95%). LCMS ESI (+) m/z: 531.1(M +1).
Step D:
compound (tert-butyl 1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) carbamate (12.6g, 23.8mmol), iron powder (6.67g, 119mmol) and ammonium chloride (2.55g,47.6mmol) were suspended in 120mL of ethanol and 20mL of water, and stirred at 75 ℃ under nitrogen. After the reaction was completed, the product was obtained by filtration, spin-drying and purification (tert-butyl 1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) carbamate (7g, yield 59%). LCMS ESI (+) m/z: 501.1.
step E:
triethyloxytetrafluoroboron (1.14g, 6mmol) and R-lactamide (534mg, 6mmol) were dissolved in 20mL tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of compound (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) carbamate (1.0g, 2mmol) was dissolved. The reaction was stirred for 1 hour while the temperature was raised to 75 ℃. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and the mixture was extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered with suction, concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound (R) -tert-butyl (1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) carbamate (1.1g, yield 99%). LCMS ESI (+) m/z: 555.1.
step F:
dissolving a compound ((R) -tert-butyl (1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) carbamate (1.1g, 1.98mmol) in 20mL of anhydrous dichloromethane, adding 4-dimethylaminopyridine (25mg, 0.2mmol), triethylamine (606mg, 5.96mmol) and acetic anhydride (265mg, 2.6mmol) in this order at 0 ℃, stirring at room temperature for 16 hours under nitrogen protection, extracting with dichloromethane (100mL) twice after the reaction is finished, drying, spin-drying, and purifying to obtain a product (R) -1- (1- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -6-p-toluenesulfonyl-1, ethyl 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (900mg, 76% yield). LCMS ESI (+) m/z: 597.1(M +1).
Step G:
ethyl compound (R) -1- (1- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (900mg, 1.53mmol) was dissolved in 20mL of dichloromethane, trifluoroacetic acid (3mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, crude (R) -1- (1- (4-aminopiperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethyl ester (700mg, yield 100%) was obtained by spin-drying. LCMS ESI (+) m/z: 497.1(M +1).
Step H:
compound (R) -1- (1- (4-aminopiperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethyl ester (120mg, 0.24mmol) and triethylamine (242mg, 2.4mmol) were dissolved in 10mL of dichloromethane, methanesulfonyl chloride (120mg, 1.08mmol) was added while cooling on ice, and the mixture was stirred at room temperature for 18 hours under nitrogen. After the reaction was completed, it was quenched with water, extracted three times with ethyl acetate (240mL), dried, spin-dried, and purified to give the product ethyl (R) -1- (1- (4- (methylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (60mg, yield 43%). LCMS ESI (+) m/z: 575.1(M +1).
Step I:
the compound (R) -1- (1- (4- (methylsulfonamido) piperidine-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (60mg, 0.1mmol) was dissolved in 10mL of methanol, and hydrogen was addedAqueous sodium oxide (2N, 2mL) was stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product (R) -N- (1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methanesulfonamide (20mg, 49% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.91(s,1H),8.54(s,1H),7.54-7.49(m,1H),7.25(brs,1H),6.81(d,J＝3.5Hz,1H),5.30(brs,1H),5.15(q,J＝6.6Hz,1H),3.70-3.50(m,2H),3.20-3.00(m,2H),3.04(s,3H),2.12-1.69(m,3H),2.13-1.85(m,2H),1.58(d,J＝6.6Hz,3H).LCMS ESI(+)m/z：379.1(M+1).
Example 2
Figure BDA0002251731350000111
(R) -N- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) ethylsulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000121
step A:
compound (R) -1- (1- (4-aminopiperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethyl ester (120mg, 0.24mmol) and triethylamine (242mg, 2.4mmol) were dissolved in 10mL of dichloromethane, and ethylsulfonyl chloride (62mg, 0.48mmol) was added under ice bath and stirred at room temperature for 18 hours under nitrogen. After the reaction was completed, it was quenched with water, extracted three times with ethyl acetate (24mL), dried, spun-dried, and purified to give the product, ethyl (R) -1- (1- (4- (ethylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-) acetate (60mg, yield 42%). LCMS ESI (+) m/z: 589.1(M +1).
And B:
the compound (R) -1- (1- (4- (ethylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazoleAzolo [4,5-d]Pyrrolo [2,3-b]Pyridine-2-) acetic acid ethyl ester (60mg, 0.1mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N, 2mL) was added and the mixture was stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (50mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product (R) -N- (1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) piperidin-4-yl) ethylsulfonamide (16mg, 42% yield). 1 H NMR(400MHz,MeOD-d 4 )δ8.75(s,1H),7.74(d,J＝3.6Hz,1H),7.06(d,J＝3.6Hz,1H),5.48-5.40(m,1H),4.10-3.60(m,3H),3.40-3.32(m,2H),3.17(q,J＝7.3Hz,2H),2.32-1.88(m,4H),1.73(d,J＝6.7Hz,3H),1.38(t,J＝7.3Hz,3H).LCMSESI(+)m/z：393.1(M+1).
Example 3
Figure BDA0002251731350000122
(R) -N- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) propylsulfonamide
The specific embodiment is as follows:
Figure BDA0002251731350000123
step A:
compound (R) -1- (1- (4-aminopiperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethyl ester (100mg, 0.2mmol) and triethylamine (202mg, 2.0mmol) were dissolved in 10mL of dichloromethane, propylsulfonyl chloride (37mg, 0.26mmol) was added under ice bath, and stirred at room temperature for 18 hours under nitrogen. After the reaction was completed, it was quenched with water, extracted three times with ethyl acetate (24mL), dried, spun-dried, and purified to give the product, ethyl (R) -1- (1- (4- (propylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-) acetate (80mg, yield 66%). LCMS ESI (+) m/z: 603.1(M +1).
And B:
a compound (R)-1- (1- (4- (propylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridine-2-) acetic acid ethyl ester (80mg, 0.13mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N, 2mL) was added and the mixture was stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (50mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product (R) -N- (1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) ethylsulfonamide (20mg, 38% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.91(s,1H),8.54(s,1H),7.50(d,J＝3.4Hz,1H),6.79(d,J＝3.4Hz,1H),5.15(q,J＝6.6Hz,1H),3.80-3.45(m,3H),3.21-3.00(m,4H),2.12-1.95(m,2H),1.90-1.68(m,4H),1.56(d,J＝6.6Hz,3H),1.02(t,J＝7.4Hz,3H).LCMS ESI(+)m/z：407.1(M+1).
Example 4
Figure BDA0002251731350000131
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000132
step A:
the compound 1-Boc-4-aminomethylpiperidine (1.00g, 4.67mmol) was dissolved in 50mL of dichloromethane and triethylamine (2.36g, 23.3mmol), 4-dimethylaminopyridine (570mg, 4.67mmol) and CbzCl (2.39g, 14.0mmol) were added dropwise under nitrogen protection in an ice bath. Stirred at room temperature for 16 hours. Concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound 1-Boc-4- (((benzyloxycarbonyl) amino) methyl) piperidine (1.32g, yield 81%). 1 H NMR(400MHz,CDCl 3 )δ7.42-7.28(m,5H),4.82(s,1H),4.11(d,J＝11.9Hz,2H),3.09(t,J＝6.0Hz,2H),2.67(t,J＝12.3Hz,2H),1.72-1.60(m,3H),1.45(s,9H),1.19-1.03(m,2H).
And B:
the compound 1-Boc-4- (((benzyloxycarbonyl) amino) methyl) piperidine (400mg, 1.15mmol) was dissolved in 8mL tetrahydrofuran and HMPA (2mL) and a 2N solution of NaHDMS in tetrahydrofuran (2.30mL, 4.60mmol) was added dropwise at-70 ℃ under nitrogen. Stirring at-70 ℃ for 10 minutes. CbzCl (1.57g, 9.18mmol) was added dropwise at-70 ℃. Stirring at-70 ℃ for 2 hours. Saturated ammonium chloride (15mL) was added, the mixture was warmed to room temperature, and stirred for 30 minutes. 50mL of ethyl acetate was extracted 3 times, and the organic phases were combined, washed with 10mL of water, washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound 1-Boc-4- (((bis-benzyloxycarbonyl) amino) methyl) piperidine (515mg, yield 93%). 1 H NMR(400MHz,CDCl 3 )δ7.43-7.28(m,12H),5.24(s,4H),4.03(d,J＝12.9Hz,2H),3.62(d,J＝7.1Hz,2H),2.57(td,J＝13.2,2.4Hz,2H),1.82-1.70(m,1H),1.53(d,J＝12.7Hz,2H),1.44(s,9H),1.17-1.02(m,2H).
And C:
the compound 1-Boc-4- (((bis-benzyloxycarbonyl) amino) methyl) piperidine (515mg, 1.1mmol) was dissolved in 12mL of dichloromethane and 4N dioxane hydrochloride solution (4mL) was added dropwise under ice bath and nitrogen protection. The mixture was warmed to room temperature under nitrogen and stirred for 3 hours. The reaction solution was concentrated under reduced pressure. To obtain a crude product, namely 4- (((bis-benzyloxycarbonyl) amino) methyl) piperidine hydrochloride. LCMS ESI (+) m/z: 383.1(M +1).
Step D:
the crude 4- (((bis-benzyloxycarbonyl) amino) methyl) piperidine hydrochloride compound obtained in the above step was dissolved in 15mL of dichloromethane, and sodium nitrite (294mg, 4.3mmol) and methylbenzenesulfonic acid monohydrate (609mg, 3.2mmol) were added at room temperature. After stirring at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure, and silica gel column chromatography was performed to give the compound 1-nitroso-4- (((bis-benzyloxycarbonyl) amino) methyl) piperidine (355mg, yield 81%). 1 H NMR(400MHz,CDCl 3 )δ7.35(s,10H),5.24(s,4H),4.93(d,J＝13.8Hz,1H),4.69(d,J＝13.3Hz,1H),3.67(d,J＝7.1Hz,2H),3.59-3.50(m,1H),2.53-2.39(m,1H),2.07-1.95(m,1H),1.84(d,J＝13.5Hz,1H),1.65(d,J＝13.4Hz,1H),1.41-1.27(m,1H),1.12-0.96(m,1H).LCMS ESI(+)m/z：435.1(M+23).
And E, step E:
compound 1-nitroso-4- (((bis-benzyloxycarbonyl) amino) methyl) piperidine (355mg, 0.86mmol) was dissolved in 6mL of methanol, and zinc powder (1.13g, 17.3mmol) was added successively at room temperature, and acetic acid (1.1mL) was added dropwise. Stirred for 10 minutes at 30 ℃. The reaction solution was filtered with suction, washed with 10mL of methanol, and the filtrate was concentrated to give an oil which was used directly in the next reaction. LCMS ESI (+) m/z: 398.2(M +1).
Step F:
the oil obtained in the previous step was dissolved in 15mL of isopropanol, DIEA (553mg, 4.3mmol) and 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (250mg, 0.7mmol) were added in this order, and the mixture was heated to 85 ℃ under nitrogen and stirred for 16 hours. The reaction solution was concentrated, and silica gel column chromatography was performed to give the compound N- ((1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methyl) (bis-benzyloxycarbonyl) amine (328mg, yield 64%). LCMS ESI (+) m/z: 712.2.
step G:
the compound N- ((1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methyl) (bis-benzyloxycarbonyl) amine (328mg, 0.3mmol) was added to 6mL of ethanol, and iron powder (336mg, 6.0mmol) and saturated ammonium chloride (0.3mL) were successively added at room temperature, followed by stirring at 75 ℃ for reaction for 15 minutes. The hot diatomaceous earth is filtered off with suction, washed with 15mL of methanol and the filtrate is concentrated. Column chromatography on silica gel afforded the compound N- ((1- ((5-amino-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methyl) (bis-benzyloxycarbonyl) amine (184mg, 59% yield). LCMS ESI (+) m/z: 683.2(M +1).
Step H:
r-lactamide (47mg, 0.54mmol) and triethyloxonium tetrafluoroborate (92mg, 0.54mmol) were added to 4.5mL of dry tetrahydrofuran under nitrogen and stirred for 2 hours at 30 ℃. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 2mL of dry ethanol, and the compound N- ((1- ((5-amino-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methyl) (bis-benzyloxycarbonyl) amine (184mg, 0.27mmol) was added under nitrogen and the reaction was stirred at 75 ℃ for 1 hour. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate solution (5mL) and ethyl acetate (25mL) were added and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted 3 times with 15mL of ethyl acetate. The organic phases were combined, washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound ethyl (R) -1- (1- (4- ((dibenzyloxycarbonyl) amino) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (160mg, yield 80%). LCMS ESI (+) m/z: 737.2(M +1).
Step I:
the compound (R) -1- (1- (4- ((dibenzyloxycarbonyl) amino) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethanol (160mg, 0.22mmol) was dissolved in 10mL of dichloromethane, and triethylamine (110mg, 1.1mmol), 4-dimethylaminopyridine (8mg, 0.07mmol) and acetic anhydride (55mg, 0.54mmol) were added in this order under nitrogen protection in ice bath. Stirred at room temperature under nitrogen for 16 hours. Concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound ethyl (R) -1- (1- (4- ((dibenzyloxycarbonyl) amino) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (106mg, yield 63%). LCMS ESI (+) m/z: 780.3(M +1).
Step J:
the compound ethyl (R) -1- (1- (4- ((dibenzyloxycarbonyl) amino) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (106mg, 0.14mmol) was dissolved in 10mL of methanol, and 10% palladium on carbon (53mg) was added under nitrogen. Displacing the hydrogen. Stirred at room temperature for 3 hours. Suction filtration and washing with 10mL of methanol. The filtrate was concentrated under reduced pressure to give a crude product, ethyl (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate, which was used directly in the next reaction (69mg, 100% yield). LCMS ESI (+) m/z: 511.2(M +1).
Step K:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (69mg, 0.14mmol) was dissolved in 6mL of dichloromethane, and triethylamine (55mg, 0.55mmol) and methanesulfonyl chloride (47mg, 0.41mmol) were added dropwise under ice bath and nitrogen protection. Stirred at room temperature for 3 hours. 10mL of water was added and stirred for 15 minutes. The organic phase is separated and the aqueous phase is extracted 3 times with 10mL of dichloromethane. The organic phases were combined, washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by TLC to give ethyl (R) -1- (1- (4- (methylsulfonylamino) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (50mg, yield 60%). LCMS ESI (+) m/z: 589.2(M +23).
Step L:
the compound (R) -1- (1- (4- (methylsulfonylamino) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (50mg, 0.09mmol) was dissolved in 3mL of methanol, and 1N sodium hydroxide solution (0.9mL,0.9mmol) was added. Stirred at room temperature for 16 hours. The reaction mixture was diluted with 50mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was distilled off under reduced pressure. TLC preparation of the residue to obtain compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide (22mg, 66% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.51(t,J＝3.0Hz,1H),7.11(t,J＝6.1Hz,1H),6.68-6.61(m,1H),5.26(d,J＝6.2Hz,1H),5.19-5.12(m,1H),3.62-3.49(m,2H),3.22-3.17(m,1H),3.14-3.09(m,1H),2.98-2.95(m,2H),2.94(s,3H),1.98-1.90(m,2H),1.85-1.76(m,1H),1.58-1.44(m,5H).LCMS ESI(+)m/z：393.0(M+1).
Example 5
Figure BDA0002251731350000161
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) ethylsulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000162
step A:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (69mg, 0.14mmol) was dissolved in 6mL of dichloromethane, and triethylamine (55mg, 0.55mmol) and ethylsulfonyl chloride (54mg, 0.41mmol) were added dropwise under ice bath and nitrogen protection. Stirred at room temperature for 3 hours. 10mL of water was added and stirred for 15 minutes. The organic phase is separated and the aqueous phase is extracted 3 times with 10mL of dichloromethane. The combined organic phases were washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and TLC was performed to obtain ethyl (R) -1- (1- (4- (ethylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (38mg, yield 24%). LCMS ESI (+) m/z: 603.2(M +23).
And B:
ethyl compound (R) -1- (1- (4- (ethylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (38mg, 0.06mmol) was dissolved in 3mL of methanol, and 1N sodium hydroxide solution (0.6mL,0.6mmol) was added. Stirred at room temperature for 16 hours. The reaction mixture was diluted with 50mL of dichloromethane, dried over anhydrous sodium sulfate, filtered under suction, and the solvent was distilled off under reduced pressure. The residue was prepared by TLC to give compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) ethylsulfonamide (13mg, 51% yield).
1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.51(t,J＝3.0Hz,1H),7.14(t,J＝6.0Hz,1H),6.63(dd,J＝3.2,1.8Hz,1H),5.25(d,J＝6.2Hz,1H),5.19-5.11(m,1H),3.60-3.48(m,2H),3.22-3.17(m,1H),3.14-3.09(m,1H),3.04(q,J＝7.3Hz,2H),2.94(t,J＝6.3Hz,2H),1.97-1.89(m,2H),1.85-1.74(m,1H),1.56(d,J＝6.6Hz,3H),1.53-1.45(m,2H),1.23(t,J＝7.6Hz,3H).LCMS ESI(+)m/z：407.1(M+1).
Example 6
Figure BDA0002251731350000163
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) propylsulfonamide
The specific embodiment is as follows:
Figure BDA0002251731350000171
step A:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (97mg, 0.19mmol) was dissolved in 6mL of dichloromethane, and triethylamine (76mg, 0.76mmol) and propylsulfonyl chloride (35mg, 0.25mmol) were added dropwise under ice bath and nitrogen protection. Stir in ice bath for 1 hour. 10mL of water was added and stirred for 10 minutes. The organic phase is separated and the aqueous phase is extracted 3 times with 10mL of dichloromethane. The organic phases were combined, washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by TLC to give ethyl (R) -1- (1- (4- (propylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (72mg, 22% yield). LCMS ESI (+) m/z: 617.2(M +1).
And B:
the compound (R) -1- (1- (4- (propylsulfonamido) piperidine-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (82mg, 0.13mmol) was dissolved in 3mL of methanol, and 1N sodium hydroxide solution (1.3mL, 1.3mmol) was added. Stirred at room temperature for 16 hours. The reaction mixture was diluted with 50mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was distilled off under reduced pressure. The residue was prepared by TLC to give the compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) propylsulfonamide (15mg, 27% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.51(t,J＝3.0Hz,1H),7.13(t,J＝6.0Hz,1H),6.63(dd,J＝3.3,1.8Hz,1H),5.26(d,J＝6.2Hz,1H),5.19-5.12(m,1H),3.63-3.48(m,2H),3.22-3.16(m,1H),3.14-3.09(m,1H),3.05-2.99(m,2H),2.97-2.91(m,2H),1.98-1.90(m,2H),1.79-1.65(m,3H),1.55(s,3H),1.53-1.41(m,2H),1.01(t,J＝6.4Hz,3H).LCMS ESI(+)m/z：421.1(M+1).
Example 7
Figure BDA0002251731350000172
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) cyclopropylsulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000181
step A:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (97mg, 0.19mmol) was dissolved in 6mL of dichloromethane and pyridine (100mg, 1.3mmol) and cyclopropylsulfonyl chloride (40mg, 0.28mmol) were added dropwise under ice bath and nitrogen blanket. Stirred at room temperature for 8 hours. 10mL of water was added and stirred for 10 minutes. The organic phase is separated and the aqueous phase is extracted 3 times with 10mL of dichloromethane. The organic phases were combined, washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by TLC to give ethyl (R) -1- (1- (4- (cyclopropylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (32mg, 27% yield). LCMS ESI (+) m/z: 615.2(M +1).
And B:
the compound (R) -1- (1- (4- (cyclopropylsulfonamido) piperidine-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (32mg, 0.05mmol) was dissolved in 3mL of methanol, and 1N sodium hydroxide solution (1mL,1mmol) was added. Stirred at room temperature for 16 hours. The reaction mixture was diluted with 50mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was distilled off under reduced pressure. TLC preparation of the residue gave compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) cyclopropylsulfonamide (12mg, 55% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.51(t,J＝3.0Hz,1H),7.17(t,J＝6.0Hz,1H),6.63(dd,J＝3.2,1.8Hz,1H),5.30-5.20(m,1H),5.19-5.12(m,1H),3.61-3.49(m,2H),3.22-3.17(m,1H),3.15-3.09(m,1H),3.04-2.95(m,2H),2.65-2.57(m,1H),1.98-1.92(m,2H),1.85-1.77(m,1H),1.56(d,J＝6.6Hz,3H),1.54-1.43(m,2H),0.99-0.92(m,4H).LCMS ESI(+)m/z：419.1(M+1).
Example 8
Figure BDA0002251731350000182
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) 2-methoxyethylsulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000183
step A:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.2mmol) was dissolved in 6mL of dichloromethane, and triethylamine (60mg, 0.6mmol) and 2-methoxyethane-1-sulfonyl chloride (83mg, 0.29mmol) were added dropwise under ice bath and nitrogen protection. Stirred at room temperature for 2 hours. Concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound ethyl (R) -1- (1- (4- (((2-methoxyethyl) sulfonamido) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, yield 81%). LCMS ESI (+) m/z: 633.2(M +1).
And B:
the compound (R) -1- (1- (4- (((2-methoxyethyl) sulfonamido) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (100mg, 0.09mmol) was dissolved in 3mL of methanol, and 2N sodium hydroxide solution (0.5mL,1mmol) was added. Stirred at room temperature for 16 hours. Made neutral with 1N HCl (1 mL). The solvent was distilled off under reduced pressure. The residue was prepared by TLC to give the compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) 2-methoxyEthyl sulfonamide (30mg, 43% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.51(t,J＝3.2Hz,1H),7.17(t,J＝6.1Hz,1H),6.63(dd,J＝3.2,1.8Hz,1H),5.26(d,J＝6.1Hz,1H),5.20-5.11(m,1H),3.68(t,J＝6.2Hz,2H),3.55(dd,J＝23.7,11.4Hz,2H),3.39-3.34(m,2H),3.29(s,3H),3.23-3.07(m,3H),2.95(t,J＝6.3Hz,2H),2.00-1.87(m,2H),1.79(s,1H),1.56(d,J＝6.6Hz,3H),1.53-1.39(m,2H).LCMSESI(+)m/z：437.1(M+1).
Example 9
Figure BDA0002251731350000191
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) trifluoromethylsulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000192
step A:
compound (R) -ethyl 1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.2mmol) was dissolved in 6mL of dichloromethane, and triethylamine (60mg, 0.6mmol) and trifluoromethanesulfonic anhydride (85mg, 0.3mmol) were added dropwise in an ice bath under nitrogen. Stirred at room temperature for 3 hours. Concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound ethyl (R) -1- (6-p-toluenesulfonyl-1- (4- (((trifluoromethyl) sulfonamido) methyl) piperidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (60mg, yield 48%). LCMS ESI (+) m/z: 643.2(M +1).
And B:
the compound (R) -1- (6-p-toluenesulfonyl-1- (4- (((trifluoromethyl) sulfonamido) methyl) piperidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (60mg, 0.09mmol) was dissolved in 3mL of methanol, and 1N sodium hydroxide solution (1mL,1mmol) was added. Stirred at room temperature for 16 hours. Using 50mL twoThe reaction solution is diluted by chloromethane, dried by anhydrous sodium sulfate, filtered by suction, and the solvent is removed by evaporation under reduced pressure. TLC preparation of the residue to obtain compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) trifluoromethanesulfonamide (10mg, 25% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),9.48(t,J＝5.1Hz,1H),8.55(s,1H),7.52(t,J＝3.0Hz,1H),6.63(dd,J＝3.3,1.8Hz,1H),5.38-5.22(m,1H),5.18-5.11(m,1H),3.65-3.50(m,4H),3.22-3.08(m,4H),1.97-1.83(m,3H),1.56(d,J＝6.6Hz,3H),1.54-1.44(m,2H).LCMS ESI(+)m/z：447.1(M+1).
Example 10
Figure BDA0002251731350000201
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) cyanomethylsulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000202
step A:
compound (R) -ethyl 1- (1- (4- (aminomethyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (120mg, 0.24mmol) was dissolved in 6mL of dichloromethane, and triethylamine (71mg, 0.71mmol) and cyanomethanesulfonyl chloride (49mg, 0.35mmol) were added dropwise under ice bath and nitrogen protection. Stir for 2 hours in an ice bath. Concentrated under reduced pressure, and subjected to silica gel column chromatography to give ethyl (R) -1- (1- (4- (((cyanomethyl) sulfonamido) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (116mg, yield 80%). LCMS ESI (+) m/z: 614.1(M +1).
And B, step B:
the compound (R) -1- (1- (4- (((cyanomethyl) sulfonamido) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (116mg, 0.19mmol) was dissolved in 3mL of methanol, and 2N sodium hydroxide solution (0.5mL,1mmol) was added. Stirred at room temperature for 16 hours. Made neutral with 1N HCl (1 mL). The solvent was distilled off under reduced pressure. The residue was prepared by TLC and liquid phase to give the compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) cyanomethylsulfonamide (25mg, 32% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),8.16(s,1H),7.51(s,1H),6.65(d,J＝3.2Hz,1H),5.26(d,J＝6.1Hz,1H),5.23-5.09(m,1H),4.79(s,2H),3.62-3.48(m,2H),3.22-3.10(m,2H),3.06(d,J＝6.5Hz,2H),1.98-1.80(m,3H),1.63-1.45(m,5H).LCMS ESI(+)m/z：418.1(M+1).
Example 11
Figure BDA0002251731350000211
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) levocamphorsulfonamide
The specific embodiment is as follows:
Figure BDA0002251731350000212
step A:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.2mmol) was dissolved in 6mL of dichloromethane, and triethylamine (47mg, 0.6mmol) and levocamphorsulfonyl chloride (75mg, 0.3mmol) were added dropwise under ice bath and nitrogen protection. Stir for 2 hours in an ice bath. Concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether to ethyl acetate in a ratio of 1 to 1) to give ethyl (R) -1- (1- (4- ((levocamphorsulfonylamino) methyl) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (109mg, yield 77%). LCMS ESI (+) m/z: 725.3(M +1).
And B, step B:
mixing compound (R) -1- (1- (4- ((levo-camphorsulfonylamino) methyl) piperidine-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (109mg, 0.15mmol) was dissolved in 3mL of methanol, and 2N sodium hydroxide solution (0.5mL,1mmol) was added. Stirred at room temperature for 16 hours. Made neutral with 1N HCl (1 mL). The solvent was distilled off under reduced pressure. TLC preparation of the residue gave compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) levocamphorsulfonamide (30mg, 38% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),8.56(s,1H),7.51(t,J＝3.0Hz,1H),7.15(t,J＝6.1Hz,1H),6.64(dd,J＝3.3,1.8Hz,1H),5.41-5.20(m,1H),5.16(q,J＝6.6Hz,1H),3.62-3.49(m,2H),3.22-3.11(m,3H),3.05-2.98(m,2H),2.40-2.32(m,2H),2.09-2.06(m,1H),2.01-1.76(m,6H),1.63-1.37(m,8H),1.05(s,3H),0.83(s,3H).LCMS ESI(+)m/z：529.2(M+1).
Example 12
Figure BDA0002251731350000213
(R) -2- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide
The specific reaction equation is as follows:
Figure BDA0002251731350000221
step A:
the compound tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (2.50g, 11.7mmol) was dissolved in 40mL ethyl acetate and potassium carbonate (1.77g, 12.8mmol) and 3-chloropropyl-1-sulfonyl chloride (2.27g, 12.8mmol) were added under protection of nitrogen in an ice bath. Stirred at room temperature for 48 hours. Concentrated under reduced pressure, and subjected to column chromatography on a silica gel column to give the compound tert-butyl 4- (((3-chloropropyl) sulfonamido) methyl) piperidine-1-carboxylate (2.58g, yield 62%). 1 H NMR(400MHz,CDCl 3 )δ4.30-4.21(m,1H),4.20-4.08(m,2H),3.73-3.65(m,2H),3.25-3.14(m,2H),3.08-2.99(m,2H),2.75-2.63(m,2H),2.33-2.22(m,2H),1.79-1.68(m,2H),1.46(s,10H),1.20-1.07(m,2H).LCMS ESI(+)m/z：377.1(M+23).
And B:
the compound tert-butyl 4- (((3-chloropropyl) sulfonamido) methyl) piperidine-1-carboxylate (2.38g, 6.7mmol) was added to 50mL of toluene and DBU (2.55g, 16.8mmol) was added under nitrogen. Stirred at 110 ℃ for 16 hours. Concentrated under reduced pressure, and subjected to column chromatography on a silica gel column to give tert-butyl 4- ((1, 1-dioxoisothiazolidin-2-yl) methyl) piperidine-1-carboxylate (2.10g, yield 98%). 1 H NMR(400MHz,CDCl 3 )δ4.22-4.04(m,2H),3.26(t,J＝6.7Hz,2H),3.21-3.10(m,2H),2.96-2.84(m,2H),2.80-2.61(m,2H),2.44-2.28(m,2H),1.81-1.71(m,3H),1.45(s,9H),1.20-1.05(m,2H).LCMS ESI(+)m/z：341.1(M+23).
And C:
tert-butyl 4- ((1, 1-dioxoisothiazolidin-2-yl) methyl) piperidine-1-carboxylate (2.18g, 6.85mmol) was dissolved in 50mL of dichloromethane and trifluoroacetic acid (35mL) was added dropwise under ice bath and nitrogen blanket. The temperature was raised to room temperature under nitrogen and stirred for 16 hours. After the reaction is finished, the reaction liquid is dried in a spinning mode, and the saturated sodium bicarbonate solution is washed and concentrated to obtain the 2- (piperidine-4-methyl) isothiazolidine 1, 1-dioxide which is directly used for the next reaction. LCMS ESI (+) m/z: 219.1(M +1).
Step D:
the crude compound 2- (piperidin-4-ylmethyl) isothiazolidine 1, 1-dioxide was dissolved in 80mL of dichloromethane, and sodium nitrite (2.16g, 31.4mmol) was added at room temperature. The reaction mixture was stirred at 30 ℃ for 3 hours, and the reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography to give 2- ((1-nitrosopiperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (1.84g, yield 100%). 1 H NMR(400MHz,DMSO-d 6 )δ4.83-4.72(m,1H),4.68-4.55(m,1H),4.03(q,J＝7.1Hz,1H),3.74(td,J＝12.6,2.9Hz,1H),3.20(dt,J＝11.6,7.3Hz,4H),2.81(d,J＝7.0Hz,2H),2.68(td,J＝12.8,3.6Hz,1H),2.28-2.17(m,2H),1.98-1.90(m,2H),1.83-1.71(m,1H),1.35-1.20(m,1H),1.17(t,J＝7.1Hz,1H),1.02-0.87(m,1H).LCMS ESI(+)m/z：248.1(M+1).
Step E:
compound 2- ((1-nitrosopiperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (1.00g, 4.0mmol) was dissolved in 40mL of methanol, and zinc powder (5.29g, 80.9mmol) was added successively at room temperature, and acetic acid (5mL) was added dropwise. Stirred for 5 minutes at 30 ℃. The reaction solution was filtered with suction, washed with 5mL of methanol, and the filtrate was concentrated to give 2- ((1-aminopiperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide as an oily substance to be used directly in the next reaction. LCMS ESI (+) m/z: 234.1(M +1).
Step F:
2- ((1-Aminopiperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (853mg, 3.66mmol) was dissolved in 15mL of isopropanol, DIPEA (3.96mL, 22.7mmol) and the compound 4-chloro-5-nitro-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] were added in that order]Pyridine (1.00g, 2.44mmol) was heated to 85 ℃ under nitrogen and the reaction stirred for 16 hours. Concentrating the reaction solution, and performing silica gel column chromatography to obtain compound 2- ((1- ((5-nitro-1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-4-yl) amino) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (690mg, 44% yield). 1 H NMR(400MHz,CDCl 3 )δ9.25(s,1H),9.07(s,1H),8.06(d,J＝8.4Hz,2H),7.53(d,J＝4.5Hz,1H),7.39(d,J＝4.0Hz,1H),7.30(d,J＝8.2Hz,2H),3.33-3.20(m,4H),3.20-3.14(m,2H),2.98(d,J＝7.2Hz,2H),2.52(t,J＝10.7Hz,2H),2.45-2.34(m,5H),1.99-1.90(m,2H),1.73-1.60(m,1H),1.54-1.41(m,2H).LCMS ESI(+)m/z：549.1(M+1).
Step G:
compound 2- ((1- ((5-nitro-1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-4-yl) amino) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (690mg, 1.26mmol) was added to 30mL of ethanol, and iron powder (1.40g, 25.2mmol) and a saturated ammonium chloride solution (3mL) were sequentially added at room temperature, followed by stirring at 75 ℃ for reaction for 10 minutes. The hot diatomaceous earth is filtered off with suction, washed with 40mL of methanol and the filtrate is concentrated. The residue was separated into 10mL of water and 30mL of ethyl acetate. The organic phase was separated and the aqueous phase was extracted 4 times with 20mL ethyl acetate. The combined organic phases were washed with 10mL of saturated brine and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, and performing silica gel column chromatography to obtain compound 2- ((1- ((5-amino-1-tosyl-1H-pyrrolo [2, 3-b)]Pyridin-4-yl) amino) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (456mg, 70% yield). 1 H NMR(400MHz,CDCl 3 )δ8.06-7.96(m,2H),7.80(s,1H),7.43(d,J＝4.0Hz,1H),7.23(d,J＝8.1Hz,3H),6.95(d,J＝4.1Hz,1H),5.38(s,1H),3.27(t,J＝6.7Hz,2H),3.23-3.11(m,4H),2.95(d,J＝7.3Hz,2H),2.41-2.30(m,7H),1.87(d,J＝13.4Hz,2H),1.50-1.36(m,2H),1.26(t,J＝7.1Hz,1H).LCMS ESI(+)m/z：519.1(M+1).
Step H:
r-lactamide (103mg, 1.16mmol) and triethyloxonium tetrafluoroborate were added (220mg, 1.16mmol) to 5mL of anhydrous tetrahydrofuran under nitrogen and stirred at 30 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 2.5mL of dry ethanol, and the compound 2- ((1- ((5-amino-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (200mg, 0.39mmol) was added under nitrogen and the reaction was stirred at 75 ℃ for 1 hour. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate solution (10mL) and ethyl acetate (15mL) were added and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted 3 times with 15mL of ethyl acetate. The organic phases were combined, washed with 10mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound (R) -2- ((1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (180mg, 82% yield). LCMS ESI (+) m/z: 573.2(M +1).
Step I:
mixing compound (R) -2- ((1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazole [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (180mg, 0.31mmol) was dissolved in 4.5mL of methanol, and 2N sodium hydroxide solution (1.5mL,3.0mmol) was added. Stirred at 35 ℃ for 4 hours. The reaction mixture was diluted with 12mL of water, and methanol was distilled off under reduced pressure. The residue was extracted 4 times with 30mL ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate, filtered with suction and the solvent is distilled off under reduced pressure. Subjecting the residue to high performance liquid chromatography to obtain compound (R) -2- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) isothiazolidine 1, 1-dioxide (40mg, 30% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.91(s,1H),8.55(s,1H),7.50(t,J＝3.0Hz,1H),6.70(dd,J＝3.3,1.9Hz,1H),5.26(d,J＝6.2Hz,1H),5.21-5.13(m,1H),3.64-3.48(m,2H),3.31-3.28(m,2H),3.24-3.08(m,4H),2.92-2.83(m,2H),2.30-2.22(m,2H),1.99-1.89(m,3H),1.56(d,J＝6.6Hz,3H),1.53-1.41(m,2H).LCMS ESI(+)m/z：419.1(M+1).
Example 13
Figure BDA0002251731350000241
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) cyclohexyl sulfonamide
The specific embodiment is as follows:
Figure BDA0002251731350000242
step A:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.19mmol) was dissolved in 1mL of pyridine, and cyclohexylsulfonyl chloride (54mg, 0.29mmol) was added dropwise under ice bath and nitrogen protection. Stirred at room temperature for 4 hours. Concentrated under reduced pressure, and subjected to silica gel column chromatography (petroleum ether to ethyl acetate in a ratio of 1 to 3) to give the compound ethyl (R) -1- (1- (4- (cyclohexylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (38mg, yield 38%). LCMS ESI (+) m/z: 675.2(M +1+18).
And B:
the compound (R) -1- (1- (4- (cyclohexylsulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (49mg, 0.075mmol) was dissolved in 3mL of methanol and 1N sodium hydroxide solution (1mL,1mmol) was added. Stirred at room temperature for 16 hours. The reaction mixture was diluted with 50mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was distilled off under reduced pressure. TLC preparation of the residue to obtain compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) cyclohexylsulfonic acidAmide (18mg, 51% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.56-7.48(m,1H),6.62(dd,J＝3.2,1.8Hz,1H),5.82(t,J＝6.0Hz,1H),5.25(d,J＝6.2Hz,1H),5.15(p,J＝6.5Hz,1H),3.60-3.47(m,2H),3.22-3.00(m,4H),2.84(s,1H),2.04-1.79(m,8H),1.79-1.69(m,2H),1.69-1.58(m,3H),1.58-1.42(m,5H).LCMS ESI(+)m/z：479.2(M+1+18).
Example 14
Figure BDA0002251731350000243
(R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) benzenesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000251
step A:
ethyl compound (R) -1- (1- (4- (aminomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.19mmol) was dissolved in 6mL of dichloromethane, and triethylamine (76mg, 0.76mmol) and phenylsulfonyl chloride (62mg, 0.35mmol) were added dropwise under ice bath and nitrogen protection. Stir at room temperature for 8 hours. Stirred at room temperature for 1 hour. 10mL of water was added and stirred for 10 minutes. The organic phase is separated and the aqueous phase is extracted 3 times with 10mL of dichloromethane. The organic phases were combined, washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by TLC to give ethyl (R) -1- (1- (4- (benzenesulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (78mg, 22% yield). LCMS ESI (+) m/z: 651.2(M +1).
And B:
the compound (R) -1- (1- (4- (benzenesulfonylamino) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (78mg, 0.12mmol) was dissolved in 3mL of methanol, and 1N sodium hydroxide solution (1 m)L,1 mmol). Stirred at room temperature for 16 hours. The reaction mixture was diluted with 50mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was distilled off under reduced pressure. TLC preparation of the residue to obtain compound (R) -N- ((1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) benzenesulfonamide (27mg, 49% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H),8.54(s,1H),7.88–7.84(m,2H),7.81(s,1H),7.70–7.61(m,3H),7.54(t,J＝3.0Hz,1H),6.48(d,J＝1.4Hz,1H),5.24(d,J＝6.2Hz,1H),5.17–5.08(m,1H),3.42(d,J＝12.7Hz,2H),3.13(d,J＝9.1Hz,1H),3.05(d,J＝8.9Hz,1H),2.79(t,J＝6.2Hz,2H),1.83(d,J＝11.2Hz,2H),1.53(d,J＝6.6Hz,3H),1.49–1.34(m,2H),1.23(s,1H).LCMS ESI(+)m/z：455.2(M+1).
Example 15
Figure BDA0002251731350000252
(R) -N- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) -N-methylmethanesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000261
step A:
ethyl compound (R) -1- (1- (4- (methylsulfonylamino) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (110mg, 0.19mmol) was dissolved in 3mLN, N-dimethylformamide and 60% NaH (9mg,0.4mmol) was added, followed by stirring at room temperature for 4 hours. Methyl iodide (32mg,0.22mmol) was added under nitrogen protection in an ice bath and stirred in the ice bath for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride (1mL), and water (10mL) and ethyl acetate (15mL) were added. The organic phase was separated and extracted three times with ethyl acetate (15 mL). The organic phases were combined, washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (ethyl acetate) to give ethyl (R) -1- (1- (4- (N-methylmethanesulfonamido) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (47mg, 42% yield). ESI (+) m/z: 603.2(M +1).
And B:
the compound (R) -1- (1- (4- (N-methylmethanesulfonamido) piperidine-1-yl) -6-paratoluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (47mg, 0.075mmol) was dissolved in 3mL of methanol and 2N sodium hydroxide solution (0.5mL,1mmol) was added. Stirred at 35 ℃ for 4 hours. Adjusted to neutral with 1N hydrochloric acid (1 mL). The solvent was distilled off under reduced pressure. TLC preparation of the residue gave compound (R) -N- (1- (2- (1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) -N-methylmethanesulfonamide (15mg, 47% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.91(s,1H),8.55(s,1H),7.56-7.46(m,1H),6.74(dd,J＝3.2,1.8Hz,1H),5.26(d,J＝6.2Hz,1H),5.19-5.13(m,1H),3.65-3.49(m,2H),3.21-3.16(m,1H),3.14-3.08(m,1H),3.04-2.97(m,2H),2.90(s,3H),2.85(s,3H),2.04-1.95(m,1H),1.95-1.85(m,2H),1.56(d,J＝6.6Hz,3H),1.53-1.39(m,2H).LCMS ESI(+)m/z：407.1(M+1).
Example 16
Figure BDA0002251731350000262
N- ((1- (imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000271
step A:
the compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (2.32g, 6.6mmol), N-diisopropylethylamine (3.41g, 26.4mmol) and 1-amino-4-hydroxymethylpiperidine (1.03g, 7.9mmol) were added to 60mL of isopropanol (suspension). The reaction was stirred at 95 ℃ for 16 hours. After completion of the reaction, it was cooled to room temperature, 100mL of water was added, extraction was performed with ethyl acetate (3 × 100mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to give a compound (1- ((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methanol (2.11g, yield 71%). LCMS ESI (+) m/z: 446.2(M +1).
And B:
compound (1- ((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methanol (2.11g,4.7mmol) was added to a mixed solution of 45mL ethanol and 15mL water, followed by the addition of ammonium chloride solid (0.75g, 14.1mmol) and iron powder (0.78g, 14.1mmol) in that order. The temperature was raised to 80 ℃ and stirred for 4 hours. After the reaction was completed, the reaction solution was filtered, and the residue was washed with an appropriate amount of ethyl acetate. The filtrate was concentrated under reduced pressure, and silica gel column chromatography was performed to give the compound (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methanol (1.47g, yield 75%). LCMS ESI (+) m/z: 416.2(M +1).
Step C:
compound (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b) under nitrogen]Pyridin-4-yl) amino) piperidin-4-yl) methanol (200mg, 0.48mmol), triethyl orthoformate (78mg, 0.53mmol) were added to 3mL of acetic acid. The reaction was stirred at room temperature for 2 hours. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (15mL) and stirred for 10 minutes. The mixture was extracted 3 times with ethyl acetate (15mL), and the organic phases were combined, washed with saturated brine (5mL), dried over anhydrous sodium sulfate, filtered under suction, and the solvent was evaporated under reduced pressure. Subjecting the residue to silica gel column chromatography to obtain compound (1- (6-p-toluenesulfonylimidazole [4,5-d ]]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) piperidin-4-yl) methanol (135mg, 66% yield). 1 H NMR(400MHz,CDCl 3 )δ8.87(s,1H),8.10(d,J＝8.4Hz,2H),7.77(d,J＝3.8Hz,1H),7.26-7.22(m,3H),6.94(s,1H),3.64(d,J＝6.1Hz,2H),3.44-3.34(m,2H),3.27-3.13(m,2H),2.34(d,J＝4.9Hz,4H),2.03-1.98(m,3H),1.69-1.59(m,3H),1.28-1.24(m,2H).LCMS ESI(+)m/z：426.2(M+1).
Step D:
to 6mL of toluene, under ice-bath cooling and nitrogen blanket, were added the compound (1- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methanol (135mg, 0.32mmol), DPPA (231mg, 0.95mmol) and DBU (242mg, 1.59 mmol). The temperature is raised to 100 ℃ and the mixture is stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the compound 1- (4- (azidomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine (69mg, yield 48%). LCMS ESI (+) m/z: 451.2(M +1).
Step E:
the compound 1- (4- (azidomethyl) piperidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine (69mg, 0.15mmol) was dissolved in 5mL of methanol, and 10% palladium on charcoal (35mg) was added under nitrogen protection. Displacing the hydrogen. Stirred at room temperature for 2 hours under a hydrogen atmosphere. It is filtered off with suction and washed with 10mL of methanol. The filtrate was concentrated under reduced pressure to give the crude compound ((1- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methylamine, which was used directly in the next reaction (52mg, yield 80%). LCMSEISI (+) M/z: 425.0(M +1).
Step F: (Compound 5) V1955-008
The compound ((1- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methylamine (52mg, 0.12mmol) was dissolved in 5mL of dichloromethane, triethylamine (37mg, 0.38mmol) and a solution of methanesulfonyl chloride (18mg, 0.16mmol) in dichloromethane (0.2mL) were added dropwise under ice bath and nitrogen blanket stirring for 1 hour under ice bath the reaction was subjected to direct silica gel column chromatography (ethyl acetate) to give the compound N- ((1- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide (50mg, yield 81%). LCMS ESI (+) m/z: 503.0(M +1).
Step G:
a compound N- ((1- (6-p-toluenesulfonylimidazole [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide (50mg, 0.1mmol) was dissolved in 3mL of methanol, and 2N sodium hydroxide solution (0.5mL,1.0mmol) was added. Stirred at room temperature for 5 hours. The reaction solution was neutralized with 1N hydrochloric acid. The solvent was distilled off under reduced pressure. TLC preparation of the residue to obtain compound N- ((1- (imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide (10mg, 29% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.82(s,1H),8.65-8.52(m,2H),7.46-7.40(m,1H),7.17-7.08(m,1H),6.73(dd,J＝3.1,1.9Hz,1H),3.31-3.27(m,4H),3.00-2.92(m,5H),1.99-1.90(m,2H),1.76-1.64(m,1H),1.59-1.47(m,2H).LCMS ESI(+)m/z：349.2(M+1).
Example 17
Figure BDA0002251731350000281
N- ((1- (imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000282
step A:
the compound (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) methanol (1.25g, 3mmol), triethyl orthoformate (1.4g, 12mmol) was added to 12mL of acetic acid. Stir at room temperature under nitrogen for 3 hours. The reaction solution was evaporated under reduced pressure to remove the solvent. The obtained residue was subjected to silica gel column chromatography to give the compound (1- (2-methyl-6-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methanol (0.9g, yield 68%). LCMS ESI (+) m/z: 440(M +1).
And B:
to 40mL of toluene at room temperature under a nitrogen blanket was added the compound (1- (2-methyl-6-tosylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methanol (0.9g, 2.05mmol), DBU (1.56g, 10.25mmol) and DPPA (1.49g, 6.15 mmol). The temperature is raised to 100 ℃ and the mixture is stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the compound 1- (4- (azidomethyl) piperidin-1-yl) -2-methyl-6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine (0.785g, yield 82%). LCMS ESI (+) m/z: 465(M +1).
And C:
the compound 1- (4- (azidomethyl) piperidin-1-yl) -2-methyl-6-tosyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine (785mg, 1.69mmol) is dissolved in 30mL of methanol and 10% palladium on carbon (78mg) is added under nitrogen. Displacing the hydrogen. Stir at room temperature overnight. Suction filtration and washing with 10mL of methanol. The filtrate was concentrated under reduced pressure to give the crude compound (1- (2-methyl-6-tosylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methylamine, which was used directly in the next reaction (785mg, yield 100%). LCMSISI (+) m/z: 439(M +1).
Step D:
the compound (1- (2-methyl-6-tosylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methylamine (120mg, 0.23mmol) was dissolved in 5mL of dichloromethane, and triethylamine (71mg, 0.71mmol) and methanesulfonyl chloride (54mg, 0.34mmol) were added dropwise under ice bath and nitrogen protection. Stir at zero for 1 hour. 10mL of water was added and stirred for 15 minutes. The organic phase is separated and the aqueous phase is extracted 3 times with 10mL of dichloromethane. The organic phases were combined, washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and prepared by TLC to give the compound (N- ((1- (2-methyl-6-tosylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide (90mg, yield 76%). LCMS ESI (+) M/z: 518(M +1).
Step E:
a compound (N- ((1- (2-methyl-6-tosylimidazole [4, 5-d))]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide (89mg, 0.17mmol) was dissolved in 4mL of methanol and 1N sodium hydroxide solution (0.5mL, N) was added. Stirred at 75 ℃ for 1 hour. Neutralized to neutrality with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. TLC preparation of the residue to obtain compound N- ((1- (2-methylimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) methyl) methanesulfonamide (35mg, 56% yield). 1 H NMR(400MHz,DMSO-d 6 ) 1 H NMR(400MHz,DMSO)δ11.86(s,1H),8.46(s,1H),7.49(t,J＝3.0Hz,1H),7.14(d,J＝5.9Hz,1H),6.61(s,1H),3.53(t,J＝10.4Hz,2H),3.32–3.27(m,3H),3.13(d,J＝10.3Hz,2H),2.95(d,J＝3.0Hz,2H),2.94(s,3H),1.94(d,J＝12.1Hz,2H),1.80(s,1H),1.47(d,J＝8.1Hz,2H).LCMS ESI(+)m/z：363(M+1).
Example 18
Figure BDA0002251731350000291
3-cyano-N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) benzenesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000301
step A:
tert-butylpyrrolidin-3-ylcarbamate (4.33g, 23.3mmol) was dissolved in 30mL of acetic acid and 10mL of water, and an aqueous solution (20mL) containing sodium nitrite (3.21g, 46.6mmol) was slowly added dropwise at 0 deg.C, followed by stirring at room temperature under nitrogen for 18 hours. After the reaction was completed, it was quenched with water at 0 ℃ and extracted with ethyl acetate (240mL) three times, filtered, spun-dried, and purified to give the product tert-butyl (1-nitrosopyrrolidin-3-yl) tert-butylcarbamate (4.58g, yield 93%). LCMS ESI (+) m/z: 216.1(M +1).
And B, step B:
compound (1-nitrosopyrrolidin-3-yl) tert-butyl carbamate (4.58g, 21.3mmol), zinc powder (13.8g, 213mmol) were suspended in acetic acid (5mL) and methanol (50mL), and stirred at room temperature for 2 hours under nitrogen. After the reaction was completed, it was filtered and spin-dried to obtain crude tert-butyl (1-aminopyrrolidin-3-yl) tert-butylcarbamate (4.28g, yield 100%). LCMS ESI (+) m/z: 202.1(M +1).
And C:
compound (1-Aminopyrrolidin-3-yl) tert-butyl carbamate (7.75g,22mmol) was dissolved in 100mL of isopropanol, followed by addition of tert-butyl (1-aminopyrrolidin-3-yl) carbamate (4.28g,21.3mmol) and N, N-diisopropylethylamine (11g, 85.3mmol), and stirring at 100 ℃ for 20 hours. After the reaction is finished, spin-drying and column chromatography purification are carried out to obtain a compound (1- ((5-nitro-1-tosyl-1-1H-pyrrole [2,3-b ] pyridine-4-yl) amino) pyridine-3-yl) tert-butyl carbamate (6.6g, yield 60%). LCMSISI (+) m/z: 517.1(M +1).
Step D:
compound 1- ((5-nitro-1-p-toluenesulfonyl-1-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyridin-3-yl) tert-butylcarbamate (1.5g, 2.9mmol), iron powder (977mg, 17.4mmol) and ammonium chloride (311mg, 5.8mmol) were suspended in 12mL of ethanol and 4mL of water, and stirred at 75 ℃ under nitrogen. After the reaction was completed, the product was filtered, spin-dried, and purified by column chromatography to give 1- ((5-amino-1-p-toluenesulfonyl-1-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyridin-3-yl) tert-butyl carbamate (770mg, yield 55%). LCMS ESI (+) m/z: 487.1(M +1).
Step E:
r-lactamide (285mg, 3.2mmol) and triethyloxonium tetrafluoroborate were added (608mg, 3.2mmol) to 15mL of anhydrous tetrahydrofuran under nitrogen and stirred at 30 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 10mL of anhydrous ethanol, and 1- ((5-amino-1-p-toluenesulfonyl-1-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyridin-3-yl) tert-butylcarbamate (770mg, 1.6mmol) was added under nitrogen, and the reaction was stirred at 75 ℃ for 1 hour. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate solution (10mL) and ethyl acetate (15mL) were added and stirred for 5 min. The organic phase was separated and the aqueous phase was extracted 3 times with 45mL ethyl acetate. The combined organic phases were washed with 20mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography to give compound (1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyridin-3-yl) tert-butylcarbamate (536mg, yield 62%). LCMS ESI (+) m/z: 573.2(M +1).
Step F:
compound (1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyridin-3-yl) tert-butylcarbamate (536mg, 0.94mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (10mL) was added at 0 ℃, and stirred at room temperature for 5 hours under nitrogen. After the reaction was completed, the reaction mixture was spin-dried, washed with a saturated aqueous sodium bicarbonate solution, dried, and concentrated to obtain the compound (1R) -1- (1- (3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethanol (400mg, yield 97%). LCMS ESI (+) m/z: 441.2(M +1).
G:
compound (1R) -1- (1- (3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethanol (400mg, 0.91mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added at 0 ℃ and stirred at 30 ℃ for 18 hours under nitrogen. After the reaction, 20mL of water was added, the pH was adjusted to 8-9, the mixture was extracted with dichloromethane (6X 50mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography to give the compound (1R) -1- (1- (3-aminopyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethanol (167mg, 64% yield). LCMS ESI (+) m/z: 287.2(M +1).
Step H:
mixing the compound (1R) -1- (1- (3-aminopyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) ethanol (100mg, 0.35mmol) was dissolved in 10mL of anhydrous dichloromethane and triethylamine (177mg, 1.75mmol) and 3-cyanobenzenesulfonyl chloride (53mg, 0.26mmol) were added at 0 deg.C and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product 3-cyano-N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) benzenesulfonamide (diastereomer, 54mg, 30% yield). 1 H NMR(400MHz,MeOH-d 4 )δ8.71(s,1H),8.28(s,1H),8.20(d,J＝8.4Hz,1H),8.02-7.96(m,1H),7.77(t,J＝7.9Hz,1H),7.69(dd,J＝14.5,3.2Hz,1H),6.97(dd,J＝6.6,3.2Hz,0.4H),6.72(d,J＝3.2Hz,0.6H),5.45-5.38(m,0.6H),5.36-5.28(m,0.4H),4.41-4.29(m,1.2H),4.16-4.06(m,0.8H),3.82-3.42(m,8H),2.70-2.55(m,1.2H),2.46-2.35(m,0.8H),2.16-2.06(m,0.8H),2.05-1.89(m,1.2H),1.71-1.67(m,6H).LCMS ESI(+)m/z：452.1(M+1).
Example 19
Figure BDA0002251731350000311
N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) methanesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000312
step A:
compound (1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyridin-3-yl) tert-butylcarbamate (216mg, 0.4mmol) was dissolved in 10mL of anhydrous dichloromethane, and 4-dimethylaminopyridine (5mg, 0.04mmol), triethylamine (122mg, 1.2mmol) and acetic anhydride (50mg, 0.48mmol) were added in this order at 0 ℃ and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was extracted twice with dichloromethane (100mL), dried, spun and purified to obtain ethyl (1R) -1- (1- (3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (226mg, yield 97%) as a compound. LCMS ESI (+) m/z: 583.1(M +1).
And B, step B:
ethyl compound (1R) -1- (1- (3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (226mg, 0.39mmol) was dissolved in 20mL of dichloromethane, trifluoroacetic acid (2mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, crude ethyl (1R) -1- (1- (3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate was obtained by spin-drying (190mg, yield 100%). LCMS ESI (+) m/z: 483.1(M +1).
And C:
ethyl (1R) -1- (1- (3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.21mmol) and N, N-diisopropylethylamine (135mg, 1.05mmol) were dissolved in 10mL of anhydrous dichloromethane, methanesulfonyl chloride (70mg, 0.27mmol) was added dropwise at 0 deg.C and stirred at room temperature under nitrogen for 18 h. After the reaction was completed, water was added to quench and extraction was performed with ethyl acetate (240mL) three times, followed by drying and spin-drying to obtain ethyl acetate (60mg, yield 49%) of the compound (1R) -1- (1- (3- (methylsulfonyl) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-) acetate. LCMS ESI (+) m/z: 561.1(M +1).
Step D:
mixing the compound (1R) -1- (1- (3- (methylsulfonyl) pyrrolidine-1-yl) -6-toluene sulfonyl-1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine-2-) acetic acid ethyl ester 60mg, 0.10mmol) was dissolved in 10mL of methanol, and an aqueous solution of sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, extracting the mixture by ethyl acetate (250mL) for five times, drying, spin-drying and purifying to obtain a compound N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) methanesulfonamide (diastereomer, 20mg, 54% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,2H),8.56(s,2H),7.52(s,2H),6.79(s,1H),6.54(s,1H),5.21(q,J＝6.4Hz,1H),5.12(q,J＝6.4Hz,1H),4.41-4.32(m,1H),4.20-4.10(m,1H),3.78-3.68(m,1H),3.67-3.57(m,1H),3.57-3.39(m,4H),3.30-3.20(m,2H),2.98(s,6H),2.71-2.59(m,1H),2.46-2.35(m,1H),2.20-2.10(m,1H),2.10-2.00(m,1H),1.62-1.52(m,6H).LCMS ESI(+)m/z：365.1(M+1).
Example 20
Figure BDA0002251731350000321
N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) ethanesulfonamide
The specific embodiment is as follows:
Figure BDA0002251731350000331
step A:
ethyl (1R) -1- (1- (3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.21mmol) and N, N-diisopropylethylamine (135mg, 1.05mmol) were dissolved in 10mL of anhydrous dichloromethane, ethylsulfonyl chloride (35mg, 0.27mmol) was added dropwise at 0 ℃ and stirred at room temperature under nitrogen for 18 hours. After the reaction was completed, water was added to quench and extraction was performed with ethyl acetate (240mL) three times, followed by drying and spin-drying to obtain ethyl acetate (80mg, yield 66%) of the compound (1R) -1- (1- (3- (ethylsulfonyl) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-) acetate. LCMS ESI (+) m/z: 576.1(M +1).
And B, step B:
mixing the compound (1R) -1- (1- (3- (ethylsulfonyl) pyrrolidine-1-yl) -6-toluene sulfonyl-1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine-2-) acetic acid ethyl ester 80mg, 0.14mmol) was dissolved in 10mL of methanol, and an aqueous solution of sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, extracting the mixture by ethyl acetate (250mL) for five times, drying, spin-drying and purifying to obtain a compound N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) methanesulfonamide (diastereomer, 20mg, 38% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,2H),8.55(s,2H),7.80(s,1H),7.67(s,1H),7.52(s,2H),6.80(s,1H),6.53(s,1H),5.38-5.26(m,2H),5.25-5.17(m,1H),5.16-5.07(m,1H),4.40-4.30(m,1H),4.16-4.06(m,1H),3.78-3.68(m,1H),3.67-3.57(m,1H),3.57-3.39(m,4H),3.30-3.20(m,2H),3.13-3.02(m,4H),2.71-2.59(m,1H),2.46-2.35(m,1H),2.22-2.12(m,1H),2.06-1.96(m,1H),1.63-1.50(m,6H),1.28-1.18(m,6H).LCMS ESI(+)m/z：379.1(M+1).
Example 21
Figure BDA0002251731350000332
N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) cyclopropanesulfonamide
The specific implementation mode is as follows:
Figure BDA0002251731350000333
step A:
ethyl (1R) -1- (1- (3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (100mg, 0.21mmol) and N, N-diisopropylethylamine (135mg, 1.05mmol) were dissolved in 10mL of anhydrous dichloromethane, cyclopropylsulfonyl chloride (38mg, 0.27mmol) was added dropwise at 0 ℃ and stirred at room temperature under nitrogen for 18 h. After the reaction was completed, water was added to quench and extraction was performed with ethyl acetate (240mL) three times, followed by drying and spin-drying to obtain ethyl acetate (60mg, yield 49%) of the compound (1R) -1- (1- (3- (ethylsulfonyl) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-) acetate. LCMS ESI (+) m/z: 576.1(M +1).
And B, step B:
mixing the compound (1R) -1- (1- (3- (ethylsulfonyl) pyrrolidine-1-yl) -6-toluene sulfonyl-1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine-2-) acetic acid ethyl ester 60mg, 0.1mmol) was dissolved in 10mL of methanol, and an aqueous solution of sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, 20mL of saturated ammonium chloride solution is added, ethyl acetate (150mL) is used for five times of extraction, drying, spin-drying and purification to obtain the compound N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) methanesulfonamide (diastereomer, 20mg, 50% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,2H),8.55(s,2H),7.51(s,2H),6.82(s,1H),6.54(s,1H),5.21(q,J＝6.4Hz,1H),5.12(q,J＝6.4Hz,1H),4.40-4.30(m,1H),4.20-4.10(m,1H),3.78-3.68(m,1H),3.67-3.57(m,1H),3.57-3.39(m,4H),3.30-3.20(m,2H),2.71-2.59(m,3H),2.46-2.35(m,1H),2.22-2.12(m,1H),2.06-1.96(m,1H),1.63-1.50(m,6H),1.02-0.86(m,8H).LCMSESI(+)m/z：391.1(M+1).
Example 22
Figure BDA0002251731350000341
3-cyano-N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) benzamide
The specific implementation mode is as follows:
Figure BDA0002251731350000342
step A:
mixing the compound (1R) -1- (1- (3-aminopyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) ethanol (180mg, 0.63mmol), HATU (359mg, 0.94mol), m-cyanobenzoic acid (139mg, 0.94mmol) were dissolved in 10mL N, N-dimethylformamide and N, N-diisopropylethylamine (244mg, 1.89mmol) was added at 0 ℃. Stirring was carried out at room temperature for 16 hours under nitrogen. After the reaction is finished, 20mL of saturated ammonium chloride solution is added, dichloromethane (150mL) is used for five times of extraction, drying, spin-drying and purification are carried out to obtain the compound 3-cyano-N- (1- (2- ((R) -1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) benzamide (diastereomer, 80mg, 30% yield). 1 H NMR(400MHz,DMSO-d 6 )δ12.02(s,1H),12.02(s,1H),9.07(s,1H),9.00(s,1H),8.59(s,2H),8.35(s,2H),8.20(d,J＝8.0Hz,2H),8.10(d,J＝8.0Hz,2H),7.76-7.72(m,2H),7.57(brs,1H),7.53(brs,1H),6.85(s,1H),6.62(s,1H),5.30-5.22(m,1H),5.22-5.14(m,1H),4.98-4.85(m,1H),4.78-4.65(m,1H),3.87-3.55(m,8H),3.00(s,1H),2.89(s,1H),2.73-2.63(m,1H),2.62-2.5(m,1H),2.42-2.30(m,1H),2.26-2.15(m,1H),1.59(d,J＝6.6Hz,3H),1.57(d,J＝6.6Hz,3H).LCMS ESI(+)m/z：416.1(M+1).
Example 23
Figure BDA0002251731350000351
3- (((1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) amino) methyl) benzonitrile
The specific implementation mode is as follows:
Figure BDA0002251731350000352
mixing the compound (1R) -1- (1- (3-aminopyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b ] s]Pyridin-2-yl) ethanol (100mg, 0.35mmol), 3-cyanobenzaldehyde (55mg, 0.42mol) were dissolved in 10mL of methanol, 0 ℃ C, 0.5mL of acetic acid was added, and the mixture was stirred at room temperature for 16 hours under nitrogen. Sodium borohydride (20mg, 0.53mmol) was added thereto, and the mixture was stirred at room temperature for 16 hours. After the reaction is finished, 20mL of saturated sodium bicarbonate solution is added, and then dichloromethane (150mL) is used for five times of extraction, drying, spin-drying and purification to obtain the compound 3- (((1- (2- ((R) -1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) amino) methyl) benzonitrile (diastereomer, 39mg, 27% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.91(s,1.25H),11.89(s,0.75H),8.55(s,2H),7.88(s,1.25H),7.84(s,0.75H),7.77-7.70(m,4H),7.57(t,J＝7.7Hz,2H),7.47(s,0.75H),7.43(s,1.25H),7.20(s,1.25H),6.46(s,0.75H),5.36-5.27(m,2H),5.24-5.07(m,2H),3.94-3.76(m,4H),3.75-3.35(m,8H),3.87-3.55(m,9H),3.28-3.18(m,1H),3.00-2.80(m,1H),2.30-2.18(m,1H),2.05-1.86(m,2H),1.60-1.52(m,6H).LCMS ESI(+)m/z：402.1(M+1).
Example 24
Figure BDA0002251731350000353
Tert-butyl ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate
The specific implementation mode is as follows:
Figure BDA0002251731350000361
step A:
(R) -3-t-Butoxycarbonylaminopyrrolidine (10g, 53.7mmol) was dissolved in a mixed solution of 60mL acetic acid and 20mL water, and an aqueous solution (40mL) containing sodium nitrite (7.41g, 107.4mmol) was slowly added dropwise at 0 deg.C, and the mixture was warmed to room temperature under nitrogen and stirred for 18 hours. After completion of the reaction, it was quenched with water at 0 ℃ and extracted with ethyl acetate (240mL) three times, filtered, spun-dried, and purified to give the compound tert-butyl (R) - (1-nitrosopyrrolidin-3-yl) carbamate (9.57g, yield 83%). LCMS ESI (+) m/z: 216.1(M +1).
And B:
compound (R) - (1-nitrosopyrrolidin-3-yl) carbamic acid tert-butyl ester (4.58g, 21.3mmol), zinc powder (13.8g, 213mmol) were suspended in acetic acid (5mL) and methanol (50mL), and stirred at room temperature for 2 hours under nitrogen. After the reaction was completed, filtration and spin-drying were carried out to obtain crude tert-butyl (R) - (1-aminopyrrolidin-3-yl) carbamate (4.28 g). LCMS ESI (+) m/z: 202.1(M +1).
And C:
tert-butyl (R) - (1-aminopyrrolidin-3-yl) carbamate from the above step was dissolved in 100mL of isopropanol, 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (7.85g, 22.4mmol) and N, N-diisopropylethylamine (27.5g, 213mmol) were added, and the mixture was heated to 100 ℃ and stirred for 20 hours. After the reaction was completed, spin-drying and purification were carried out to obtain the product tert-butyl (R) - (1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (7.3g, yield 66%). LCMS ESI (+) m/z: 517.1(M +1).
Step D:
compound (R) - (1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamic acid tert-butyl ester (7.2g, 14mmol), iron powder (4.6g, 83.7mmol) and ammonium chloride (1.49g, 27.9mmol) were suspended in 60mL ethanol and 15mL water and stirred at 75 ℃ under nitrogen. After the reaction was completed, the product (R) - (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamic acid tert-butyl ester was obtained by filtration, spin-drying and purification (4g, yield 59%). LCMS ESI (+) m/z: 487.1.
step E:
triethyloxy boron tetrafluoride (2.35g, 12.4mmol) and R-lactamide (1.1g, 12.4mmol) were dissolved in 30mL of tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil, which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of compound (R) - (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (2.0g,4.1 mmol) was dissolved. The reaction was stirred for 1 hour while the temperature was raised to 75 ℃. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and the mixture was extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure by suction filtration and subjected to silica gel column chromatography to give a compound of tert-butyl ((R) -1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (2g, yield 90%). LCMS ESI (+) m/z: 541.1.
step F:
the compound tert-butyl ((R) -1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (54mg, 0.1mmol) was dissolved in 10mL methanol, aqueous sodium hydroxide (2N,3mL) was added, and the mixture was stirred at room temperature for 16 hours under nitrogen. After the reaction, 20mL of saturated ammonium chloride solution was added, and the mixture was extracted five times with dichloromethane (150mL), dried, spun-dried, and purified to give a product, i.e., tert-butyl ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (20mg, 50% yield). 1 H NMR(400MHz,DMSO-d 6 )δ12.29(s，1H)，8.68(s,1H),7.65(s,1H),7.56-7.40(m,1H),6.63(s,1H),5.34-5.18(m,1H),4.32-4.1(m,1H),3.73-3.22(m,5H),2.66-2.28(m,1H),2.20-1.90(m,1H),1.59(t,J＝6.0Hz,3H),1.41(s,9H).LCMS ESI(+)m/z：387.1(M+1).
Example 25
Figure BDA0002251731350000371
1-tert-butyl-3- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000372
step A:
the compound tert-butyl ((R) -1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (2g, 3.7mmol) was dissolved in 20mL of anhydrous dichloromethane, and 4-dimethylaminopyridine (50mg, 0.4mmol), triethylamine (1.3g, 12.36mmol) and acetic anhydride (2.5g, 4.94mmol) were added successively at 0 ℃ and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, 20mL of a saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane (100mL) twice, drying, spin-drying, and purification to obtain ethyl (R) -1- (1- ((R) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate, which is a compound, 1.6g, yield 74%. LCMSISI (+) m/z: 583.1(M +1).
And B:
ethyl compound (R) -1- (1- ((R) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate (1.6g, 2.76mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (2mL) was added under ice bath, and stirred at room temperature under nitrogen for 16 hours. After the reaction was completed, the reaction mixture was spin-dried, washed with a saturated sodium bicarbonate solution, and concentrated to give crude ethyl (R) -1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (1.33g), LCMS ESI (+) M/z: 483.1(M +1).
And C:
dissolving the compound (R) -1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-tosyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetic acid ethyl ester (96mg, 0.2mmol) obtained in the previous step in 10mL of anhydrous tetrahydrofuran, dropwise adding tert-butyl isocyanate (40mg, 0.4mmol) under ice bath, stirring for 18 hours at room temperature under the protection of nitrogen, adding water for quenching after the reaction is finished, extracting with ethyl acetate (240mL) for three times, drying, spin-drying and purifying to obtain the product (R) -1- (1- ((R) -3- (3- (tert-butyl) ureido) pyrrolidin-1-yl) -6-tosyl-1, ethyl 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (60mg, 51% yield). LCMS ESI (+) m/z: 582.1(M +1).
Step D:
mixing compound (R) -1- (1- ((R) -3- (3- (tert-butyl) ureido) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (60mg, 0.1mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the compound 1-tert-butyl-3- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) urea (20mg, 52% yield). 1 H NMR(400MHz,DMSO-d 6 )δ12.46(s，1H),8.74(s,1H),7.72(t,J＝3.0Hz,1H),6.67(s,1H),6.33(s,1H),5.73(s,1H),5.35-5.25(m，1H),4.56(s,1H),3.73-3.17(m,4H),2.67-2.31(m,1H),2.03-1.75(m,1H),1.57(d,J＝6.5Hz,3H),1.21(s,9H).LCMS ESI(+)m/z：386.1(M+1).
Example 26
Figure BDA0002251731350000381
2, 2-difluoro-N- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) cyclopropylcarboxamide
The specific implementation mode is as follows:
Figure BDA0002251731350000382
step A:
ethyl (R) -1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (120mg, 0.25mmol), HATU (142mg, 0.37mol), 2, 2-difluorocyclopropane-1-carboxylic acid (36mg, 0.30mmol) are dissolved in 5mL N-dimethylformamide, N-diisopropylethylamine (161mg, 1.25mmol) is added at 0 ℃, under nitrogen protection, stirring is carried out for 16 hours at room temperature after the reaction is finished, water is added, extraction is carried out three times with ethyl acetate (240mL), drying and spin-drying to purify the product (1R) -1- (1- ((3R) -3- (2, 2-Difluorocyclopropane-1-carboxamido) pyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetic acid ethyl ester (80mg, 54% yield). LCMS ESI (+) m/z: 587.1(M +1).
And B:
mixing compound (1R) -1- (1- ((3R) -3- (2, 2-difluorocyclopropane-1-formamido) pyrrolidine-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (80mg, 0.14mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, dichloromethane (250mL) is used for five times of extraction, drying, spin-drying and purification to obtain the compound 2, 2-difluoro-N- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) cyclopropylcarboxamide (30mg, 56% yield). 1 H NMR(400MHz,DMSO-d 6 )δ12.34(s，1H),8.81(d,J＝7.2Hz,1H),8.70(s,1H),7.68(s,1H),6.68(s,1H),5.33-5.22(m,1H),4.73-4.41(m,1H),3.75-3.48(m,5H),2.67-2.53(m,2H),2.12-1.89(m,3H),1.60(d,J＝6.5Hz,3H).LCMS ESI(+)m/z：391.1(M+1).
Example 27
Figure BDA0002251731350000391
1- (2, 2-difluoroethyl) 3- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000392
step A:
ethyl (120mg, 0.25mmol) and triethylamine (253mg, 2.5mmol) of compound (R) -1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate were dissolved in 10mL of N, N-dimethylformamide, N' -carbonyldiimidazole (81mg, 0.5mmol) was added under ice bath, stirring was carried out at room temperature for 2 hours, 2-difluoroethylamine (31mg, 0.37mmol) was added to the reaction solution, stirring was carried out at room temperature under nitrogen atmosphere for 18 hours, after completion of the reaction, quenching was carried out with water, extraction was carried out three times with ethyl acetate (240mL), drying, rotary drying, and purification gave (R) -1- (1- ((R) -3- (3- (2, 2-Difluoroethyl) ureido) pyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetic acid ethyl ester (60mg, 51% yield). LCMS ESI (+) m/z: 590.1(M +1).
And B:
mixing compound (R) -1- (1- ((R) -3- (3- (2, 2-difluoroethyl) ureido) pyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ]]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (60mg, 0.1mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain a product 1- (2, 2-difluoroethyl) 3- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) urea (25mg, 64% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s，1H),8.56(s,1H),7.51(t,J＝3.0Hz,1H),6.76-6.51(m,2H),6.38-6.22(m,1H),5.98(t,J＝56.4Hz,1H),5.26-5.08(m,1H),4.68-4.28(m,1H),3.66-3.20(m,7H),2.66-2.30(m,1H),2.10-1.82(m,1H),1.54(d,J＝6.5Hz,3H).LCMS ESI(+)m/z：394.1(M+1).
Example 28
Figure BDA0002251731350000393
1- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000401
step A:
triphosgene (111mg, 0.37mmol) is dissolved in 10mL of anhydrous dichloromethane, pyridine (198mg, 2.5mmol) is added at 0 ℃,2,2, 2-trifluoroethylamine (111mg, 1.12mmol) is added, stirring is carried out at room temperature for 2 hours, then the compound (R) -ethyl 1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (120mg, 0.25mmol) is added, stirring is carried out at 60 ℃ for 1 hour under the protection of nitrogen, after the reaction is finished, water is added for quenching, ethyl acetate (250mL) is used for five times of extraction, drying, spin-drying and purification are carried out to obtain the product (R) -1- (6-p-toluenesulfonyl-1- ((R) -3- (3- (2,2, 2-trifluoroethyl) ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetic acid ethyl ester (61mg, 40% yield). LCMSEISI (+) m/z: 608.1(M +1).
And B:
the compound (1R) -1- (6-tosyl-1- (3- (3- (2,2, 2-trifluoroethyl) ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (61mg, 0.1mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product 1- ((R) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (20mg, 48% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),8.55(s,1H),7.50(s,1H),6.86-6.55(m,2H),6.52(s,1H),5.36-5.26(m,1H),5.26-5.08(m,1H),4.63-4.30(m,1H),3.90-3.10(m,6H),2.68-2.32(m,1H),2.09-1.89(m,1H),1.57(d,J＝6.5Hz,3H).LCMS ESI(+)m/z：412.1(M+1).
Example 29
Figure BDA0002251731350000402
1- ((R) -1- (2- ((S) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000403
step A:
triethyloxy boron tetrafluoride (633mg, 3.3mmol) and S-lactamide (297mg, 3.3mmol) were dissolved in 20mL of tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil, which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of compound (R) - (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (540mg, 1.1mmol) was dissolved. The reaction was stirred for 1 hour while the temperature was raised to 75 ℃. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and the mixture was extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure by suction filtration and subjected to silica gel column chromatography to give a compound of tert-butyl ((R) -1- (2- ((S) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (590mg, yield 98%). LCMS ESI (+) m/z: 541.1.
and B, step B:
the compound tert-butyl ((R) -1- (2- ((S) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (590mg, 1.1mmol) was dissolved in 15mL of anhydrous dichloromethane, 4-dimethylaminopyridine (13mg, 0.11mmol), triethylamine (330mg, 3.3mmol) and acetic anhydride (168mg, 1.65mmol) were added successively at 0 ℃ and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, 20mL of a saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane (100mL) twice, drying, spin-drying, and purification to obtain ethyl (S) -1- (1- ((R) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate, which is a compound, as a solid (530mg, 83% yield). LCMSISI (+) m/z: 583.1(M +1).
And C:
ethyl compound (S) -1- (1- ((R) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate (530mg, 0.91mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (2mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, it was spin-dried, washed with saturated sodium bicarbonate solution, and concentrated to give crude (S) -ethyl 1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (439mg, yield 100%). LCMS ESI (+) M/z: 483.1(M +1).
Step D:
triphosgene (410mg, 1.37mmol) was dissolved in 10mL of anhydrous dichloromethane, pyridine (720mg, 9.1mmol) was added at 0 deg.C, 2, 2-trifluoroethylamine (500mg, 4.1mmol) was added, stirring was carried out at room temperature for 2 hours, then the compound (S) -ethyl 1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (439mg, 0.91mmol) was added, stirring was carried out at 60 deg.C for 1 hour under nitrogen protection, after completion of the reaction, quenching was performed with water, extraction was carried out five times with ethyl acetate (250mL), drying, spin-drying, and purification to give the product (S) -1- (6-p-toluenesulfonyl-1- ((R) -3- (3- (2,2, 2-trifluoroethyl) ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetic acid ethyl ester (160mg, 29% yield). LCMSEISI (+) m/z: 608.1(M +1).
Step E:
the compound (S) -1- (6-p-toluenesulfonyl-1- (R) -3- (3- (2,2, 2-trifluoroethyl) ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (160mg, 0.26mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product 1- ((R) -1- (2- ((S) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (60mg, 55% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s，1H),8.56(s,1H),7.50(t,J＝2.9Hz,1H),6.86-6.55(m,2H),6.53(s,1H),5.36-5.26(m,1H),5.26-5.08(m,1H),4.63-4.30(m,1H),3.90-3.06(m,6H),2.68-2.32(m,1H),2.09-1.89(m,1H),1.56(d,J＝6.5Hz,3H).LCMS ESI(+)m/z：412.1(M+1).
Example 30
Figure BDA0002251731350000421
1- ((S) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000422
step A:
(S) -3-tert-Butoxycarbonylaminopyrrolidine (4.66g, 25mmol) was dissolved in a mixed solution of 30mL acetic acid and 10mL water, and an aqueous solution (20mL) containing sodium nitrite (3.45g, 50mmol) was slowly added dropwise at 0 ℃ and stirred at room temperature under nitrogen for 18 hours. After completion of the reaction, it was quenched with water at 0 ℃ and extracted with ethyl acetate (240mL) three times, filtered, spun-dried, and purified to give the compound tert-butyl (S) - (1-nitrosopyrrolidin-3-yl) carbamate (4.6g, yield 85%). LCMS ESI (+) m/z: 216.1(M +1).
And B:
compound (S) - (1-nitrosopyrrolidin-3-yl) carbamic acid tert-butyl ester (4.6g, 21.4mmol), zinc powder (13.6g, 214mmol) were suspended in acetic acid (5mL) and methanol (50mL), and stirred at room temperature for 2 hours under nitrogen. After the reaction, filtration and spin-drying were carried out to give crude tert-butyl (S) - (1-aminopyrrolidin-3-yl) carbamate (4.3 g). LCMS ESI (+) m/z: 202.1(M +1).
Step C:
tert-butyl (S) - (1-aminopyrrolidin-3-yl) carbamate from the above step was dissolved in 100mL of isopropanol, 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (7.13g, 20.5mmol) and diisopropylethylamine (27.6g, 214mmol) were added, and the mixture was stirred at 100 ℃ for 20 hours. After the reaction was completed, spin-drying and purification were carried out to obtain the product tert-butyl (S) - (1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (7.0g, yield 63%). LCMS ESI (+) m/z: 517.1(M +1).
Step D:
compound (S) - (tert-butyl 1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (7.0g, 13.6mmol), iron powder (4.56g, 81.4mmol) and ammonium chloride (1.45g, 27.1mmol) were suspended in 60mL of ethanol and 15mL of water, and stirred at 75 ℃ under nitrogen. After the reaction was completed, the product was obtained by filtration, spin-drying and purification of tert-butyl (S) - (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (4.6g, yield 70%). LCMS ESI (+) m/z: 487.1.
step E:
triethyloxy boron tetrafluoride (2.70g,14.2mmol) and R-lactamide (1.26g,14.2mmol) were dissolved in 30mL of tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil, which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of compound (S) - (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (2.3g,4.7mmol) was dissolved. The reaction was stirred for 1 hour while the temperature was raised to 75 ℃. After the reaction was completed, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure by suction filtration and subjected to silica gel column chromatography to give a compound of tert-butyl ((S) -1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (2.2g, yield 86%). LCMS ESI (+) m/z: 541.1.
step F:
the compound tert-butyl ((S) -1- (2- ((R) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (2.2g, 4.1mmol) was dissolved in 15mL of anhydrous dichloromethane, 4-dimethylaminopyridine (50mg, 0.4mmol), triethylamine (1.23g, 12.2mmol) and acetic anhydride (496mg,4.9mmol) were added in that order at 0 ℃ and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, 20mL of a saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane (100mL) twice, drying, spin-drying, and purification to obtain ethyl (R) -1- (1- ((S) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate (1.7g, yield 72%) as a compound. LCMSISI (+) m/z: 583.1(M +1).
Step G:
ethyl compound (R) -1- (1- ((S) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate (500mg, 0.86mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (2mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, it was spin-dried, washed with a saturated sodium bicarbonate solution, and concentrated to give crude ethyl (R) -1- (1- ((S) -3-aminopyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (414mg, yield 100%). LCMS ESI (+) M/z: 483.1(M +1).
Step H:
triphosgene (410mg, 1.37mmol) was dissolved in 10mL of anhydrous dichloromethane, pyridine (720mg, 9.1mmol) was added at 0 deg.C, 2,2, 2-trifluoroethylamine (500mg, 4.1mmol) was added, stirring was carried out at room temperature for 2 hours, then the compound (R) -ethyl 1- (1- ((S) -3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (414mg, 0.86mmol) was added, stirring was carried out at 60 deg.C under nitrogen protection for 1 hour, after the reaction was completed, quenching was carried out with water, extraction was carried out five times with ethyl acetate (250mL), drying, spin-drying, and purification gave the product (R) -1- (6-p-toluenesulfonyl-1- ((S) -3- (3- (2,2, 2-trifluoroethyl) ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetic acid ethyl ester (180mg, 34% yield). LCMSISI (+) m/z: 608.1(M +1).
Step I:
the compound (R) -1- (6-p-toluenesulfonyl-1- (S) -3- (3- (2,2, 2-trifluoroethyl)) Ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (180mg, 0.30mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product 1- ((S) -1- (2- ((R) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (50mg, 41% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s，1H),8.56(s,1H),7.51(t,J＝2.8Hz,1H),6.90-6.58(m,2H),6.53(s,1H),5.36-5.26(m,1H),5.26-5.08(m,1H),4.63-4.30(m,1H),3.90-3.40(m,6H),2.68-2.32(m,1H),2.12-1.82(m,1H),1.56(d,J＝6.5Hz,3H).LCMS ESI(+)m/z：412.1(M+1).
Example 31
Figure BDA0002251731350000441
1- ((S) -1- (2- ((S) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000442
step A:
triethyloxytetrafluoroboron tetrafluoride (2.70g,14.2mmol) and S-lactamide (1.26g,14.2mmol) were dissolved in 20mL of tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil, which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of the compound (R) - (1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (2.3g,4.7mmol) was dissolved. The reaction was stirred for 1 hour while the temperature was raised to 75 ℃. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and the mixture was extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered with suction, concentrated under reduced pressure, and subjected to silica gel column chromatography to give a compound of tert-butyl ((S) -1- (2- ((S) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (1.69g, yield 66%). LCMS ESI (+) m/z: 541.1.
and B, step B:
the compound tert-butyl ((S) -1- (2- ((S) -1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (1.69g, 3.1mmol) was dissolved in 20mL of anhydrous dichloromethane, 4-dimethylaminopyridine (37mg, 0.3mmol), triethylamine (945mg, 9.4mmol) and acetic anhydride (382mg,3.7mmol) were added in this order at 0 ℃ and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, 20mL of a saturated sodium bicarbonate solution was added, followed by extraction with dichloromethane (100mL) twice, drying, spin-drying, and purification to obtain ethyl (S) -1- (1- ((R) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate (1.4g, yield 77%) as a compound. LCMSEISI (+) m/z: 583.1(M +1).
Step C:
ethyl compound (S) -1- (1- ((S) -3- ((tert-butoxycarbonyl) amino) pyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,1,3-b ] pyridin-2-yl) acetate (190mg, 0.33mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (2mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, it was spin-dried, washed with a saturated sodium bicarbonate solution, and concentrated to give crude ethyl (S) -1- (1- ((S) -3-aminopyrrolidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (157mg, yield 100%). LCMS ESI (+) M/z: 483.1(M +1).
Step D:
triphosgene (148mg, 0.5mmol) was dissolved in 10mL of anhydrous dichloromethane, pyridine (261mg, 3.3mmol) was added at 0 deg.C, 2, 2-trifluoroethylamine (180mg, 1.5mmol) was added, stirring was carried out at room temperature for 2 hours, then the compound (S) -ethyl 1- (1- ((R) -3-aminopyrrolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine-2-acetate (157mg, 0.33mmol) was added, stirring was carried out at 60 deg.C for 1 hour under nitrogen protection, after completion of the reaction, quenching was performed with water, extraction was carried out five times with ethyl acetate (250mL), drying, spin-drying, and purification gave the product (S) -1- (6-p-toluenesulfonyl-1- ((S) -3- (3- (2,2, 2-trifluoroethyl) ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetic acid ethyl ester (60mg, 30% yield). LCMSEISI (+) m/z: 608.1(M +1).
Step E:
the compound (S) -1- (6-p-toluenesulfonyl-1- (S) -3- (3- (2,2, 2-trifluoroethyl) ureido) pyrrolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (160mg, 0.1mmol) was dissolved in 10mL of methanol, and aqueous sodium hydroxide (2N, 2mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the product 1- ((S) -1- (2- ((S) -1-hydroxyethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (35mg, 86% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),8.56(s,1H),7.50(t,J＝2.9Hz,1H),6.86-6.55(m,2H),6.52(s,1H),5.36-5.26(m,1H),5.26-5.08(m,1H),4.63-4.30(m,1H),3.90-3.10(m,6H),2.68-2.32(m,1H),2.09-1.89(m,1H),1.56(d,J＝6.5Hz,3H).LCMS ESI(+)m/z：412.1(M+1).
Example 32
Figure BDA0002251731350000451
1- ((R) -1- (2- ((S) -1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000452
step A:
compound (R) - (tert-butyl 1- ((5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) pyrrolidin-3-yl) carbamate (2.0g,4.12mmol), triethyl orthoformate (2mL) and pyridine hydrochloride (48mg, 0.42mmol) were dissolved in 40mL toluene and stirred at 115 ℃ for 2 hours. After the reaction was completed, the reaction mixture was spin-dried and purified to obtain tert-butyl (R) - (1- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamate (1.5g, 73% yield). LCMSISI (+) m/z: 497.1.
and B:
compound (R) - (1- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (1.5g, 3mmol) was dissolved in 20mL dichloromethane, trifluoroacetic acid (2mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was complete, spin-dried, washed with saturated sodium bicarbonate solution, and concentrated to give crude (R) -1- (6-tosylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-amine (1.0g, 84% yield). LCMS ESI (+) m/z: 397.1(M +1).
And C:
triphosgene (135mg, 0.45mmol) was dissolved in anhydrous dichloromethane, pyridine (237mg, 3mmol) was added at 0 ℃,2,2, 2-trifluoroethylamine (135mg, 1.35mmol) was added, and stirring was carried out at room temperature for 2 hours, then compound (R) -1- (6-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-amine (120mg, 0.3mmol) was added, and stirring was carried out under nitrogen at 60 ℃ for 1 hour. After the reaction was completed, water was added to quench, and the reaction solution was extracted five times with ethyl acetate (250mL), dried, spun-dried, and purified to obtain the compound (R) -1- (1- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (60mg, yield 38%). LCMS ESI (+) m/z: 522.1(M +1).
Step D:
the compound (R) -1- (1- (6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (60mg, 0.12mmol) was dissolved in 10mL of methanol, and an aqueous solution of sodium hydroxide (2N,3mL) was added, followed by stirring at room temperature under nitrogen for 16 hours. After the reaction is finished, ethyl acetate (250mL) is used for extracting for five times, drying, spin-drying and purifying to obtain the compound 1- ((R) -1- (2- ((S) -1-hydroxy)Ethyl) imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) pyrrolidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (24mg, 57% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.88(s，1H),8.57(s,1H),8.48(s,1H),7.46(t,J＝2.8Hz,1H),6.77-6.74(m,2H),6.59(t,J＝6.5Hz,1H),4.50-4.38(m,1H),3.91-3.79(m,2H),3.66-3.58(m,1H),3.55-3.49(m,1H),3.45-3.37(m,1H),3.25-3.20(m,1H),2.48-2.44(m,1H),1.92-1.83(m,1H).LCMS ESI(+)m/z：368.1(M+1).
Example 33
Figure BDA0002251731350000461
(R) -1- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000462
step A:
compound (R) -1- (1- (4-aminopiperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethyl ester (449mg, 0.91mmol) was dissolved in anhydrous N, N-dimethylformamide (10mL), triethylamine (284mg, 2.81mmol) and N, N' -carbonyldiimidazole (220mg, 1.36mmol) were added at 0 ℃, stirring at room temperature for 2 hours, 2, 2-trifluoroethylamine (135mg, 1.36mmol) was added, and the mixture was warmed to room temperature and stirred for 18 hours. After the reaction was completed, water was added to quench, and the reaction solution was extracted three times with dichloromethane (240mL), dried, spin-dried, and purified to give the product ethyl (R) -1- (6-p-toluenesulfonyl-1- (4- (3- (2,2, 2-trifluoroethyl) ureido) piperidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (200mg, yield 35%). LCMSISI (+) m/z: 622.1(M +1).
And B:
the compound (R) -1- (6-p-toluenesulfonyl-1- (4- (3- (2,2, 2-trifluoroethyl) ureido) piperidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b ] s]Pyridine compound-2-yl) acetic acid ethyl ester (200mg, 0.32mmol) was dissolved in 15mL of methanol, and aqueous sodium hydroxide (2N, 4mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, dichloromethane (500mL) is used for extracting for ten times, drying, spin-drying and purifying to obtain the product (R) -1- (1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) -3- (2,2, 2-trifluoroethyl) urea (50mg, 36% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.52(t,J＝2.9Hz,1H),6.69(dd,J＝3.1,1.5Hz,1H),6.48(t,J＝6.3Hz,1H),6.32(d,J＝7.4Hz,1H),5.28(d,J＝6.3Hz,1H),5.16(t,J＝6.5Hz,1H),3.96-3.55(m,5H),3.21-3.05(m,2H),2.06-1.96(m,2H),1.76-1.66(m,2H),1.56(d,J＝6.6Hz,3H).LCMS ESI(+)m/z：426.1(M+1).
Example 34
Figure BDA0002251731350000471
(S) -1- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000472
step A:
triethyloxytetrafluoroboron (1.14g, 6mmol) and S-lactamide (534mg, 6mmol) were dissolved in 20mL tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil, which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of compound (1- ((5-amino-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) carbamate (1.0g, 2.0mmol) was dissolved. The reaction was stirred for 1 hour at 75 ℃. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and the mixture was extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. The filtrate was filtered with suction, concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound (S) -tert-butyl (1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) carbamate (1.01g, yield 91%). LCMS ESI (+) m/z: 555.1.
and B, step B:
dissolving a compound ((R) -tert-butyl (1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) piperidin-4-yl) carbamate (520mg,0.94mmol) in 20mL of anhydrous dichloromethane, adding 4-dimethylaminopyridine (11mg, 0.094mmol), triethylamine (285mg, 2.82mmol) and acetic anhydride (115mg, 1.13mmol) in this order at 0 ℃, stirring at room temperature for 16 hours under nitrogen protection, extracting with dichloromethane (100mL) twice after the reaction is finished, drying, spin-drying, and purifying to obtain a product (S) -1- (1- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -6-p-toluenesulfonyl-1, ethyl 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (800mg, 73% yield). LCMS ESI (+) m/z: 597.1(M +1).
And C:
ethyl compound (S) -1- (1- (4- ((tert-butoxycarbonyl) amino) piperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (800mg, 1.34mmol) was dissolved in 20mL of dichloromethane, trifluoroacetic acid (3mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, the solvent was spin-dried, washed with a saturated sodium bicarbonate solution, and concentrated to give crude (S) -1- (1- (4-aminopiperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethyl ester (665mg, yield 100%). LCMS ESI (+) m/z: 497.1(M +1).
Step D:
compound (S) -1- (1- (4-aminopiperidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) ethyl ester (665mg, 1.34mmol) was dissolved in anhydrous N, N-dimethylformamide (10mL), triethylamine (667mg, 6.7mmol) and N, N' -carbonyldiimidazole (434mg, 2.68mmol) were added at 0 ℃ and stirred at room temperature for 2 hours, 2,2, 2-trifluoroethylamine (159mg, 1.61mmol) was added and stirred at room temperature for 18 hours. After the reaction was completed, it was quenched with water, extracted three times with dichloromethane (240mL), dried, spin-dried, and purified to give the product ethyl (S) -1- (6-p-toluenesulfonyl-1- (4- (3- (2,2, 2-trifluoroethyl) ureido) piperidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (385mg, yield 46%). LCMSISI (+) m/z: 622.1(M +1).
Step E:
the compound (S) -1- (6-p-toluenesulfonyl-1- (4- (3- (2,2, 2-trifluoroethyl) ureido) piperidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (385mg, 0.62mmol) was dissolved in 15mL of methanol, and aqueous sodium hydroxide (2N, 4mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, dichloromethane (500mL) is used for extracting for ten times, drying, spin-drying and purifying to obtain the product (S) -1- (1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) piperidin-4-yl) -3- (2,2, 2-trifluoroethyl) urea (60mg, 22% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.55(s,1H),7.52(t,J＝2.9Hz,1H),6.69(dd,J＝3.1,1.5Hz,1H),6.49(t,J＝6.3Hz,1H),6.33(d,J＝7.4Hz,1H),5.28(d,J＝6.3Hz,1H),5.16(t,J＝6.5Hz,1H),3.96-3.55(m,5H),3.21-3.05(m,2H),2.06-1.96(m,2H),1.76-1.66(m,2H),1.56(d,J＝6.6Hz,3H).LCMS ESI(+)m/z：426.1(M+1).
Example 35
Figure BDA0002251731350000481
(R) -1- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) azetidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000491
step A:
the compound tert-butyl N-azetidin-3-ylcarbamate (3.3g, 19.2mmol) was dissolved in 30mL of acetic acid and 10mL of water, and an aqueous solution (20mL) containing sodium nitrite (2.65g, 38.4mmol) was slowly added dropwise at 0 deg.C, then warmed to room temperature under nitrogen and stirred for 18 hours. After the reaction was completed, it was quenched with water at 0 ℃ and extracted three times with ethyl acetate (240mL), filtered, spun-dried, and purified to give the product tert-butyl (1-nitrosoazetidin-3-yl) carbamate (3.5g, 90% yield). LCMS ESI (+) m/z: 202.1(M +1).
And B:
compound (1-nitrosoazetidin-3-yl) carbamic acid tert-butyl ester (3.5g, 17.4mmol), zinc powder (11.3g, 174mmol) were suspended in acetic acid (10mL) and methanol (30mL), and stirred at room temperature for 2 hours under nitrogen. After the reaction was completed, filtration and spin-drying were carried out to obtain crude tert-butyl (1-aminoazetidin-3-yl) carbamate (3.25g, yield 100%). LCMS ESI (+) m/z: 188.1(M +1).
And C:
the compound tert-butyl (1-aminoazetidin-3-yl) carbamate (3.25g, 17.4mmol), 4-chloro-5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridine (5.8g, 16.5mmol) and diisopropylethylamine (22.4g, 174mmol) were dissolved in 100mL of isopropanol and stirred at elevated temperature to 100 ℃ for 20 hours. After the reaction was completed, spin-dried and purified to obtain the product tert-butyl (1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) azetidin-3-yl) carbamate (1.56g, yield 19%). LCMS ESI (+) m/z: 503.1(M +1).
Step D:
compound (tert-butyl 1- ((5-nitro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) azetidin-3-yl) carbamate (1.56g, 3.1mmol), iron powder (1.39g, 24.9mmol) and ammonium chloride (332mg, 6.2mmol) were suspended in 30mL of ethanol and 10mL of water, and stirred at 75 ℃ under nitrogen. After the reaction was completed, the product was obtained (tert-butyl 1- ((5-amino-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) azetidin-3-yl) carbamate (930mg, yield 63%) by filtration, spin-drying and purification. LCMS ESI (+) m/z: 473.1.
step E:
triethyloxy boron tetrafluoride (562mg, 2.96mmol) and R-lactamide (263mg, 2.96mmol) were dissolved in 20mL of tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil, which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of compound (1- ((5-amino-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) carbamate (465mg,0.99mmol) was dissolved. The reaction was stirred for 1 hour while the temperature was raised to 75 ℃. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and the mixture was extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure concentration of the filtrate, silica gel column chromatography gave compound (R) - (1- (2- (1-hydroxyethyl) -6-tosylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) azetidin-3-yl) carbamic acid tert-butyl ester (510mg, 100% yield). LCMS ESI (+) m/z: 527.1.
step F:
compound (R) - (1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) azetidin-3-yl) carbamic acid tert-butyl ester (510mg, 0.98mmol) was dissolved in 20mL of anhydrous dichloromethane and 4-dimethylaminopyridine (12mg, 0.1mmol), triethylamine (990mg, 9.8mmol) and acetic anhydride (130mg, 1.27mmol) were added sequentially at 0 ℃ and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was extracted twice with dichloromethane (100mL), dried, spin-dried and purified to obtain the product ethyl (R) -1- (1- (3- ((tert-butoxycarbonyl) amino) azetidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (499mg, yield 90%). LCMS ESI (+) m/z: 569.1(M +1).
G:
ethyl compound (R) -1- (1- (3- ((tert-butoxycarbonyl) amino) azetidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (499mg, 0.88mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (3mL) was added under ice bath, and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, the solvent was spin-dried, washed with a saturated sodium bicarbonate solution, and concentrated to give crude ethyl (R) -1- (1- (3-aminoazetidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (419mg, yield 100%). LCMS ESI (+) m/z: 469.1(M +1).
Step H:
ethyl compound (R) -1- (1- (3-aminoazetidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (412mg, 0.88mmol) is dissolved in 10mL of anhydrous N, N-dimethylformamide, triethylamine (889mg, 8.8mmol) and N, N' -carbonyldiimidazole (214mg, 1.32mmol) are added at 0 deg.C, stirring is carried out at room temperature for 2 hours, additional 2,2, 2-trifluoroethylamine (113mg, 1.24mmol) is added, the mixture is warmed to room temperature and stirred for 18 hours. After the reaction was completed, it was quenched with water, extracted three times with dichloromethane (240mL), dried, spun-dried, and purified to give the product ethyl (R) -1- (6-tosyl-1- (3- (3- (2,2, 2-trifluoroethyl) ureido) azetidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (200mg, yield 38%). LCMS ESI (+) m/z: 594.1(M +1).
Step I:
the compound (R) -1- (6-tosyl-1- (3- (3- (2,2, 2-trifluoroethyl) ureido) azetidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-2-yl) acetic acid ethyl ester (200mg, 0.34mmol) was dissolved in 15mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, dichloromethane (500mL) is used for extracting for ten times, drying, spin-drying and purifying to obtain the product (R) -1- (1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) azetidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (30mg, 21%). 1 H NMR(400MHz,DMSO-d 6 )δ12.00(s,1H),8.56(s,1H),7.55(t,J＝2.9Hz,1H),7.26(d,J＝5.6Hz,1H),6.85(dd,J＝3.0,1.3Hz,1H),6.77(t,J＝6.4Hz,1H),5.31(d,J＝6.3Hz,1H),5.22-5.15(m,1H),4.58-4.48(m,1H),4.44-4.34(m,2H),4.15-4.02(m,2H),3.95-3.82(m,2H),1.54(d,J＝6.6Hz,3H).LCMS ESI(+)m/z：398.1(M+1).
Example 36
Figure BDA0002251731350000501
(S) -1- (1- (2- (1-hydroxyethyl) imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) azetidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea
The specific implementation mode is as follows:
Figure BDA0002251731350000511
step A:
triethyloxytetrafluoroboron tetrafluoride (562mg, 2.96mmol) and S-lactamide (263mg, 2.96mmol) were dissolved in 20mL of tetrahydrofuran and the reaction was stirred at room temperature for 2 hours. Concentration under reduced pressure gave a colorless oil, which was dissolved in 10mL of anhydrous ethanol and added to 10mL of ethanol in which tert-butyl ester of compound (1- ((5-amino-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) piperidin-4-yl) carbamate (465mg,0.99mmol) was dissolved. The reaction was stirred for 1 hour at 75 ℃. After completion of the reaction, the reaction mixture was quenched with aqueous sodium bicarbonate, 100mL of water was added, and the mixture was extracted three times with 180mL of ethyl acetate. The organic phases were combined, washed with 100mL of saturated brine and dried over anhydrous sodium sulfate. Suction filtration, concentration of the filtrate under reduced pressure, silica gel column chromatography gave the compound tert-butyl (S) - (1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) azetidin-3-yl) carbamate (515mg, yield 100%). LCMS ESI (+) m/z: 527.1.
and B:
compound (S) - (tert-butyl 1- (2- (1-hydroxyethyl) -6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) azetidin-3-yl) carbamate (515mg, 0.98mmol) was dissolved in 20mL of anhydrous dichloromethane, and 4-dimethylaminopyridine (12mg, 0.1mmol), triethylamine (990mg, 9.8mmol) and acetic anhydride (130mg, 1.27mmol) were added sequentially at 0 ℃ and stirred at room temperature for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was extracted twice with dichloromethane (100mL), dried, spin-dried, and purified to obtain the product ethyl (S) -1- (1- (3- ((tert-butoxycarbonyl) amino) azetidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (540mg, yield 97%). LCMS ESI (+) m/z: 569.1(M +1).
Step G:
ethyl (S) -1- (1- (3- ((tert-butoxycarbonyl) amino) azetidin-1-yl) -6-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (540mg, 0.95mmol) was dissolved in 10mL dichloromethane, trifluoroacetic acid (3mL) was added under ice bath, and stirred at room temperature under nitrogen blanket for 16 hours. After the reaction was completed, the solvent was spin-dried, washed with a saturated sodium bicarbonate solution, and concentrated to give crude ethyl (S) -1- (1- (3-aminoazetidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (445mg, yield 100%). LCMS ESI (+) m/z: 469.1(M +1).
Step H:
ethyl compound (S) -1- (1- (3-aminoazetidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (445mg, 0.95mmol) was dissolved in 10mL of anhydrous N, N-dimethylformamide, triethylamine (960mg, 9.5mmol) and N, N' -carbonyldiimidazole (231mg, 1.43mmol) were added at 0 ℃, stirring was carried out at room temperature for 2 hours, further 2,2, 2-trifluoroethylamine (122mg, 1.24mmol) was added, and the mixture was warmed to room temperature and stirred for 18 hours. After the reaction was completed, water was added to quench and the mixture was extracted three times with dichloromethane (240mL), dried, spun-dried and purified to give the product ethyl (R) -1- (6-tosyl-1- (3- (3- (2,2, 2-trifluoroethyl) ureido) azetidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-2-yl) acetate (150mg, yield 27%). LCMS ESI (+) m/z: 594.1(M +1).
Step I:
the compound (S) -1- (6-tosyl-1- (3- (3- (2,2, 2-trifluoroethyl) ureido) azetidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b ] s]Pyridin-2-yl) acetic acid ethyl ester (150mg, 0.25mmol) was dissolved in 15mL of methanol, and aqueous sodium hydroxide (2N,3mL) was added and stirred at room temperature for 16 hours under nitrogen. After the reaction is finished, dichloromethane (500mL) is used for extracting for ten times, drying, spin-drying and purifying to obtain the product (R) -1- (1- (2- (1-hydroxyethyl) imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) azetidin-3-yl) -3- (2,2, 2-trifluoroethyl) urea (30mg, 30%). 1 H NMR(400MHz,DMSO-d 6 )δ12.00(s,1H),8.56(s,1H),7.55(t,J＝2.9Hz,1H),7.26(d,J＝5.6Hz,1H),6.85(dd,J＝3.0,1.3Hz,1H),6.77(t,J＝6.4Hz,1H),5.31(d,J＝6.3Hz,1H),5.22-5.15(m,1H),4.58-4.48(m,1H),4.44-4.34(m,2H),4.15-4.02(m,2H),3.95-3.82(m,2H),1.54(d,J＝6.6Hz,3H).LCMS ESI(+)m/z：398.1(M+1).
Example 37
Figure BDA0002251731350000521
3- ((4-Ethyl-3- (imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) imidazolin-1-yl) sulfonyl) benzonitrile
The specific implementation mode is as follows:
Figure BDA0002251731350000522
step A:
the compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2,3-b]Pyridine (4.80g, 13.7mmol), tert-butoxycarbonylhydrazine (1.98g, 15.0mmol), N, N-dimethylaminopyridine (3.81mL, 27.3mmol) were added to 100mL of isopropanol. Stirring was carried out at 85 ℃ under nitrogen for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. Performing silica gel column chromatography on the obtained residue to obtain a compound 2- (5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b)]-4-yl) hydrazino tert-butyl ester (4.56g, 75% yield). 1 H NMR(400MHz,CDCl 3 )δ9.73(s,1H),9.11(s,1H),8.06(d,J＝8.4Hz,2H),7.61(d,J＝4.1Hz,1H),7.31(d,J＝8.1Hz,2H),6.96(d,J＝4.1Hz,1H),6.68(s,1H),2.40(s,3H),1.46(s,9H).LCMS ESI(+)m/z：448.1(M+1).
And B:
the compound 2- (5-nitro-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b)]-4-yl) hydrazino tert-butyl ester (4.56g, 10.2mmol) was dissolved in 250mL of methanol and 10% palladium on carbon (2.78g) was added under nitrogen. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered and washed 2 times with methanol (20 mL). Evaporating the filtrate under reduced pressure to remove the solvent to obtain compound 2- (5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b)]-4-yl) hydrazino tert-butyl ester (4.25g, 100% yield). 1 H NMR(400MHz,CDCl 3 )δ7.99(d,J＝8.3Hz,2H),7.87(s,1H),7.49(d,J＝4.1Hz,1H),7.23(d,J＝8.2Hz,3H),6.69(d,J＝4.1Hz,1H),6.56(s,2H),2.36(s,4H),1.43(s,9H).LCMS ESI(+)m/z：418.1(M+1).
And C:
the compound 2- (5-amino-1-p-toluenesulfonyl-1H-pyrrolo [2, 3-b)]-4-yl) hydrazino tert-butyl ester (4.25g, 10.2mmol), triethyl orthoformate (1.81g, 12.2mmol) and pyridine hydrochloride (116mg, 1.0mmol) were added to 150mL toluene. The temperature was raised to 115 ℃ under nitrogen and stirred for 2 hours. After the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. Performing silica gel column chromatography on the obtained residue to obtain a compound tert-butyl (6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) carbamate (4.35g, 100% yield). 1 H NMR(400MHz,CDCl 3 )δ8.77(s,1H),8.05(d,J＝8.3Hz,2H),7.91(brs,1H),7.91(s,1H),7.58(d,J＝2.8Hz,1H),7.25(d,J＝8.4Hz,1H),6.58(d,J＝2.8Hz,1H),2.35(s,3H),1.49(s,9H).LCMS ESI(+)m/z：428.1(M+1).
Step D:
the compound tert-butyl (6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) carbamate (3.69g, 8.63mmol) was dissolved in 400mL of acetone, and sodium hydroxide (726mg, 13.0mmol) powder was added thereto, followed by stirring at room temperature for 10 minutes. Ethyl 2-bromobutyrate (5.05g, 25.9mmol) was added to the reaction solution, which was stirred at room temperature for 1.5 hours. The reaction solution was filtered with suction and the filter cake was washed with dichloromethane (50 mL). Concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography to obtain compound ethyl 2- ((tert-butoxycarbonyl) (6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) amino) butanoic acid methyl ester (4.08g, 87% yield). 1 H NMR(400MHz,CDCl 3 )δ8.89(s,1H),8.38(s,1H),8.14(d,J＝8.4Hz,2H),7.78(d,J＝4.0Hz,1H),7.29(d,J＝8.3Hz,2H),6.69(d,J＝3.9Hz,1H),4.98-4.79(m,1H),4.33(q,J＝7.1Hz,2H),2.38(s,3H),1.59-1.48(m,2H),1.36(t,J＝9.2,5.1Hz,3H),1.33-1.12(m,9H),0.81(t,J＝7.4Hz,3H).LCMS ESI(+)m/z：542.2(M+1).
Step E:
the compound ethyl 2- ((tert-butyloxycarbonyl) (6-p-toluenesulfonylimidazo [4,5 ]-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) amino) butyric acid methyl ester (4.08g, 7.53mmol) was dissolved in 33mL of a mixed solvent of dichloromethane and methanol (volume ratio: 10: 1), and a 4N dioxane solution (15mL) of hydrogen chloride was added dropwise thereto under ice bath. The mixture was warmed to room temperature under nitrogen and stirred for 16 hours. The reaction solution was concentrated under reduced pressure. 80mL of saturated sodium bicarbonate solution was added and stirred for 5 minutes. Extraction was performed with ethyl acetate (3X 50mL), and the organic phases were combined, washed with 50mL of saturated brine, and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate to obtain a compound ethyl 2- ((6-p-toluenesulfonyl imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) amino) butanoic acid methyl ester (3.10g, 93% yield). 1 H NMR(400MHz,CDCl 3 )δ8.85(s,1H),8.10(d,J＝8.4Hz,2H),8.03(s,1H),7.77(d,J＝3.9Hz,1H),7.27(s,1H),7.25(s,1H),6.91(d,J＝4.0Hz,1H),5.74(d,J＝7.8Hz,1H),4.33-4.16(m,2H),3.85-3.76(m,1H),2.35(s,3H),1.92-1.82(m,2H),1.26(t,J＝7.2Hz,3H),1.14(t,J＝7.4Hz,3H).LCMS ESI(+)m/z：442.1(M+1).
Step F:
the compound ethyl 2- ((6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) amino) butyric acid methyl ester (3.10g, 7.02mmol) was dissolved in 200mL of ethanol, and sodium borohydride (797mg,21.1mmol) was added under nitrogen protection in an ice bath and stirred at room temperature for 48 hours. A1N diluted hydrochloric acid solution was added dropwise to the reaction at O ℃ to adjust the reaction solution to neutrality. 50mL of water was added and the mixture was stirred at room temperature. The reaction mixture was neutralized with 1N diluted hydrochloric acid, and the solvent was distilled off under reduced pressure. Extracting with ethyl acetate (3 × 50mL), mixing organic phases, washing with 30mL saturated brine, drying with anhydrous sodium sulfate, removing solvent by evaporation under reduced pressure, and performing silica gel column chromatography to obtain compound 2- ((6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) amino) butyl-1-ol (1.97g, 69% yield). 1 H NMR(400MHz,DMSO-d 6 )δ8.69(s,1H),8.30(s,1H),8.02(d,J＝8.4Hz,2H),7.92(d,J＝4.0Hz,1H),7.40(d,J＝8.1Hz,2H),7.16(d,J＝4.0Hz,1H),6.95(d,J＝2.7Hz,1H),4.89(t,J＝5.0Hz,1H),3.54-3.44(m,1H),3.37-3.34(m,1H),3.23-3.15(m,1H),2.33(s,3H),1.42-1.32(m,2H),0.83(t,J＝7.5Hz,3H).LCMS ESI(+)m/z：400.1(M+1).
G:
adding the compound 2- ((6-p-toluenesulfonylimidazo [4, 5-d) into 120mL of toluene under ice bath cooling and nitrogen protection]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) amino) butyl-1-ol (1.72g, 4.31mmol), DBU (3.28g, 21.5mmol) and DPPA (3.55g, 12.9 mmol). The temperature was raised to 75 ℃ and stirred for 16 hours. Concentrating the reaction solution under reduced pressure, and performing silica gel column chromatography on the obtained residue to obtain a compound N- (1-azido-butyl-2-yl) -6-p-toluenesulfonyl imidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) -amine (1.10g, 60% yield). 1 H NMR(400MHz,CDCl 3 )δ8.88(s,1H),8.12(d,J＝8.4Hz,2H),7.96(s,1H),7.81(d,J＝4.0Hz,1H),7.27(d,J＝8.4Hz,2H),7.01(d,J＝4.0Hz,1H),5.41(s,1H),3.68(dd,J＝12.0,2.8Hz,1H),3.47-3.34(m,2H),1.52-1.41(m,2H),0.91(t,J＝7.5Hz,3H).LCMS ESI(+)m/z：425.1(M+1).
Step H:
the compound N- (1-azido-but-2-yl) -6-p-toluenesulfonylimidazo [4,5-d]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) -amine (1.10g, 2.59mmol) was dissolved in 200mL of methanol and 10% palladium on carbon (220mg) was added under nitrogen. The hydrogen gas was replaced, and the mixture was stirred at room temperature for 6 hours under a hydrogen gas atmosphere. The filter cake was filtered off with suction and washed with 20mL of methanol. Concentrating the filtrate under reduced pressure to obtain compound N 2 - (6-p-toluenesulfonylimidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) butane-1, 2-diamine (1.03g, 100% yield). 1 H NMR(400MHz,CDCl 3 )δ8.88(s,1H),8.12(d,J＝8.4Hz,2H),7.97(s,1H),7.76(d,J＝3.9Hz,1H),7.27(d,J＝8.0Hz,2H),7.12(d,J＝4.0Hz,1H),5.99(d,J＝2.0Hz,1H),3.15(s,1H),3.09(dd,J＝13.1,3.3Hz,1H),2.64(dd,J＝13.1,8.8Hz,1H),2.36(s,3H),1.44-1.27(m,3H),0.83(t,J＝7.5Hz,3H).LCMS ESI(+)m/z：399.1(M+1).
Step I:
compound N 2 - (6-p-toluenesulfonylimidazo [4,5-d ]]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) butane-1, 2-diamine (1.03g, 2.58mmol) was dissolved in 50mL of methanol and paraformaldehyde (101mg, 3.36mmol) was added. Heated to 70 ℃ and stirred for 16 hours. Cooled to room temperature, filtered with suction and washed with 10mL of methanol. The filtrate was evaporated under reduced pressure to remove the solvent, whereby 1- (5-ethylimidazolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] was obtained as a compound]Pyrrolo [2,3-b]Pyridine (1.06g, 100% yield). 1 H NMR(400MHz,CDCl 3 )δ8.94-8.77(m,1H),8.13-8.07(m,2H),7.79-7.67(m,1H),7.28-7.24(m,1H),7.08(m,1H),4.53-3.97(m,2H),3.80-3.37(m,3H),2.42-2.30(m,3H),1.83-1.59(m,2H),0.96-0.74(m,3H).LCMS ESI(+)m/z：411.1(M+1).
Step J:
compound 1- (5-Ethylimidazolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine (60mg, 0.15mmol) is dissolved in 3mL of methanol, and 2N sodium hydroxide solution (1.0mL,2.0mmol) is added. Stirred at room temperature for 16 hours. The reaction mixture was diluted with 10mL of water, and methanol was distilled off under reduced pressure. Extraction was performed with ethyl acetate (3X 5mL), the organic phases were combined, the organic phase was washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, filtered under suction, and the solvent was evaporated under reduced pressure. The crude compound, 1- (5-ethylimidazolidin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine (50mg, crude yield 100%), was obtained. LCMS ESI (+) m/z: 257.1(M +1).
Step H:
mixing the crude compound 1- (5-ethyl imidazolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (50mg, 0.2mmol) and triethylamine (33mg, 0.3mmol) were dissolved in 5mL of dichloromethane, and 3-cyanobenzenesulfonyl chloride (40mg,0.2mmol) was added dropwise at 0 ℃. After completion of the dropwise addition, the reaction solution was stirred at 0 ℃ for 4 hours. After the reaction was complete, quench with water (10mL), extract with dichloromethane (30mLx3) and combine the organic phases. Washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and spin-dried. Subjecting the crude compound to column chromatography and high performance liquid chromatography to obtain compound 3- ((4-ethyl-3- (imidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) imidazolin-1-yl) sulfonyl) benzonitrile (26mg, 31% yield). 1 H NMR(400MHz,CDCl3)δ9.49(s,1H),8.80(s,1H),8.23(t,J＝1.4Hz,1H),8.16(dt,J＝8.0,2.0Hz,1H),8.01(dt,J＝8.0,1.2Hz,1H),7.81(t,J＝8.0Hz,1H),7.37(s,1H),6.54(s,1H),4.90-4.74(m,2H),4.08-3.75(m,2H),3.93(s,1H),3.16(t,J＝9.6Hz,1H),1.55-1.22(m,2H),0.78(t,J＝6.8Hz,3H).LCMS ESI(+)m/z：422.1(M+1).
Example 38
Figure BDA0002251731350000551
1- (3- (cyclopropylsulfonyl) -5-ethylimidazolin-1-yl) -1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine
The specific implementation mode is as follows:
Figure BDA0002251731350000552
step A:
1- (5-ethylimidazolidin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (40mg, 0.16mmol) was dissolved in 5mL dichloromethane and cyclopropylsulfonyl chloride (24mg, 0.17mmol) and pyridine (25mg, 0.31mmol) were added sequentially under nitrogen and ice bath. Stirred at room temperature for 16 hours. Additional cyclopropylsulfonyl chloride (24mg, 0.17mmol) and pyridine (25mg, 0.31 mmol). Stirred at room temperature for 6 hours. The reaction was quenched with 10mL of water. Extracting with dichloromethane (3 × 10mL), mixing organic phases, washing with 15mL saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing high performance liquid chromatography to obtain compound 1- (3- (cyclopropylsulfonyl) -5-ethylimidazolin-1-yl) -1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b ] s]Pyridine (6mg, yield 11%). 1 H NMR(400MHz,DMSO-d 6 )δ11.89(s,1H),8.85-8.24(m,2H),7.46(s,1H),6.75(s,1H),4.90-4.62(m,2H),4.02-3.84(m,2H),3.05-2.98(m,1H),1.52-1.37(m,2H),1.26-1.22(m,1H),1.14-1.03(m,4H),0.75(t,J＝7.4Hz,3H).LCMS ESI(+)m/z：361.1(M+1).
Example 39
Figure BDA0002251731350000553
4-ethyl-3- (imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) -N- (2,2, 2-trifluoroethyl) imidazoline-1-carboxamide
The specific implementation mode is as follows:
Figure BDA0002251731350000554
step A:
trifluoroethylamine (15mg, 0.15mmol) was dissolved in 6mL of dichloromethane and a solution of pyridine (96mg, 1.2mmol) and triphosgene (43mg, 0.15mmol) in dichloromethane (2mL) was added under ice bath and nitrogen blanket. The mixture was stirred for 1 hour at 35 ℃ and then for 2 hours at room temperature. Adding the reaction solution to compound 1- (5-ethylimidazolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d]Pyrrolo [2,3-b]Pyridine (50mg, 0.12mmol) in dichloromethane (2mL) was stirred at 60 ℃ for 2 hours. The reaction liquid is decompressed and evaporated to remove the solvent, and the compound 4-ethyl-3- (6-tosylimidazo [4,5-d ] is obtained by silica gel column chromatography]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) -N- (2,2, 2-trifluoroethyl) imidazolidine-1-carboxamide (53mg, yield 81%). 1 H NMR(400MHz,DMSO-d 6 )δ8.86(s,1H),8.74(s,1H),8.04(d,J＝8.4Hz,2H),7.92(s,1H),7.42(d,J＝8.1Hz,2H),7.23-7.17(m,1H),7.10(s,1H),4.82(d,J＝6.2Hz,1H),4.73-4.62(m,1H),3.95-3.80(m,4H),3.29-3.26(m,1H),2.33(s,4H),1.31-1.25(m,3H),0.72(t,J＝7.4Hz,3H).LCMS ESI(+)m/z：536.2(M+1).
And B:
the compound 4-ethyl-3- (6-p-toluenesulfonyl imidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) -N- (2,2, 2-trifluoroethyl) imidazolidine-1-carboxamide (53mg, 0.1mmol) was dissolved in 4.5mL of methanol, and 2N sodium hydroxide solution (1.5mL,3.0mmol) was added. Stirred at room temperature for 7 hours. The reaction mixture was diluted with 10mL of water, and methanol was distilled off under reduced pressure. Extraction was carried out with ethyl acetate (3X 20mL), the organic phases were combined, the organic phase was washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was evaporated under reduced pressure. Preparing the residue by using a high performance liquid phase to obtain the compound 4-ethyl-3- (imidazo [4, 5-d)]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) -N- (2,2, 2-trifluoroethyl) imidazoline-1-carboxamide (20mg, 53% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),8.59(s,1H),7.46(s,1H),7.30-7.18(m,1H),6.68(s,1H),4.84(d,J＝6.0Hz,1H),4.75(s,1H),4.01-3.81(m,4H),3.37-3.27(m,1H),1.48-1.33(m,2H),0.74(t,J＝7.4Hz,3H).LCMS ESI(+)m/z：382.1(M+1).
Example 40
Figure BDA0002251731350000561
1- (4-ethyl-3- (imidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) imidazolin-1-yl) -2- (1H-1,2,4 triazol-1-yl) ethanone
The specific implementation mode is as follows:
Figure BDA0002251731350000562
step A:
the compound 1- (5-ethylimidazolidin-1-yl) -6-p-toluenesulfonyl-1, 6-dihydroimidazo [4,5-d ] pyrrolo [2,3-b ] pyridine (58mg, 0.14mmol) was dissolved in 5mL of dichloromethane, and the compound 1H-1,2, 4-triazole-1-acetic acid (30mg, 0.24mmol), HOBT (32mg, 0.24mmol), DMAP (48mg, 0.38mmol) and EDCI (64mg, 0.38mmol) were added under nitrogen protection in ice bath and stirred at room temperature for 16 hours. Concentrated under reduced pressure, and subjected to silica gel column chromatography to give the compound 1- (4-ethyl-3- (6-p-toluenesulfonylimidazo [4,5-d ] pyrrolo [2,3-b ] pyridin-1 (6H) -yl) -imidazolidin-1-yl) -2- (1H-1,2, 4-triazol-1-yl) ethanone (71mg, yield 95%). LCMS ESI (+) m/z: 520.1(M +1).
And B:
the compound 1- (4-ethyl-3- (6-tosylimidazo [4,5-d ])]Pyrrolo [2,3-b]Pyridin-1 (6H) -yl) -imidazolidin-1-yl) -2- (1H-1,2, 4-triazol-1-yl) ethanone (71mg, 0.12mmol) was dissolved in 3mL of methanol, and 1N sodium hydroxide solution (1.0mL,2.0mmol) was added. Stirred at room temperature for 16 hours. The reaction mixture was diluted with 15mL of water, and methanol was distilled off under reduced pressure. Extraction was carried out with ethyl acetate (3X 5mL), the organic phases were combined, the organic phase was washed with 5mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was evaporated under reduced pressure. Subjecting the residue to high performance liquid chromatography to obtain compound 1- (4-ethyl-3- (imidazo [4, 5-d)]Pyrrolo [2,3-b ] s]Pyridin-1 (6H) -yl) imidazolin-1-yl) -2- (1H-1,2, 4-triazol-1-yl) ethanone (6mg, 14% yield). 1 H NMR(400MHz,DMSO-d 6 )δ12.24(s,1H),9.09-8.57(m,2H),8.51(d,J＝11.9Hz,1H),8.01(d,J＝12.5Hz,1H),7.59(s,1H),6.85(s,1H),5.49-4.79(m,4H),4.31-3.89(m,2H),3.68-3.32(m,1H),1.60-1.29(m,2H),0.89-0.70(m,3H).LCMS ESI(+)m/z：366.1(M+1).
Activity detection of JAK kinase small molecule inhibitors
Experimental protocol
1. Reagent preparation
Kinase reaction buffer
Preparing a kinase reaction buffer solution, which comprises the following components: 50mM HEPES, pH 7.5, 1mM EGTA, 10mM MgCl 2 ，2mM DTT，0.01％Tween20
1X detection buffer
Preparing a detection buffer solution, deionized water 9: 1 Dilute 10 Xdetection buffer to 1X
4X kinase solution
Kinase reaction buffer diluted JAK kinase to 4X final concentration (JAK 1: 40nM, JAK 2: 0.5nM)
4X substrate solution
Dilution of ULight with kinase reaction buffer TM JAK-1(Tyr1023) substrate to 200nM (final concentration: 50nM)
4XATP solution
Kinase reaction buffer diluted ATP to 4X final concentration (JAK 1: 160. mu.M, JAK 2: 40. mu.M)
4X test Compound solution
DMSO dissolves test compounds into 10mM stock, 3-fold gradient diluted to the desired concentration, setting 10 concentration points per compound, with test compounds in the final concentration range: 10 μ M-0.5nM
4 Xenzyme reaction stop solution:
1 Xthe assay buffer dissolved EDTA to 40mM (final EDTA concentration: 10mM)
4X detection antibody solution
1 Xdetection buffer solution Eu-labeled detection antibody (anti-phosphotyrosine (PT66)) was diluted to 8nM (final antibody concentration: 2nM)
2. Experimental procedures
To a 384 well plate were added 2.5. mu.L, 4X kinase solution, and 2.5. mu.L of 4X test compound solution diluted to different concentrations, each concentration being set at 2 multiple wells, and an enzyme solution blank control and a negative control (DMSO group) were set simultaneously
Shaking 384 multi-well plate, mixing enzyme and compound, 1000 rpm, centrifuging for 1 min, incubating at room temperature for 60 min
Add 2.5. mu.L of 4 Xsubstrate solution to 384 Multi-well plates and centrifuge for 1 min at 1000 rpm
To 384 Multi-well plates, 2.5. mu.L of a 4XATP solution was added, and centrifugation was carried out at 1000 rpm for 1 minute to initiate an enzymatic reaction
JAK1 was reacted at room temperature for 2 hours, JAK2 was reacted at room temperature for 1 hour
The final concentrations of each component of the JAK1 reaction were: JAK 1: 10nM, substrate: 50nM, ATP: 40uM, final concentration range of test compound: 10 μ M-0.5nM
The final concentrations of each component of the JAK2 reaction were: JAK 2: 0.125nM, substrate: 50nM, ATP: 10 μ M, final concentration range of test compound: 10 μ M-0.5nM
After completion of the enzyme reaction, 5. mu.L of 4 Xenzyme reaction stop solution was added to each well of 384 multi-well plates, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 5 minutes
Add 5. mu.L of 4X detection antibody solution (final concentration of detection antibody 2nM) to each well of 384 multi-well plate at 1000 rpm, centrifuge for 1 min, incubate at room temperature for 1 hr
After the antibody incubation was completed, the signal value of each well was measured on an Envision plate reader
3. Data analysis
Calculating the percentage inhibition rate corresponding to each concentration of the detection compound by taking the enzyme solution blank control group as 100% inhibition rate and the negative control group (DMSO group) as 0% inhibition rate
Nonlinear regression analysis of the log concentration values and corresponding percent inhibition of the test compounds in GraphPad Prism software to obtain the median Inhibitory Concentration (IC) of the test compounds 50 ) The results of the experiments are listed in the following table:
Figure BDA0002251731350000581

Claims (7)

1. an amide or sulfonamide substituted hydrazine derivative characterized by: the amide or sulfonamide substituted hydrazine derivative is selected from compounds represented by the following structures:
Figure FDA0003697997850000011
Figure FDA0003697997850000021
2. an amide or sulfonamide substituted hydrazine derivative as claimed in claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0003697997850000022
3. an amide or sulfonamide substituted hydrazine derivative of claim 1 wherein the compound is:
Figure FDA0003697997850000023
4. an amide or sulfonamide substituted hydrazine derivative as claimed in claim 1, wherein the compound is:
Figure FDA0003697997850000031
5. an amide or sulfonamide substituted hydrazine derivative as claimed in claim 1, wherein the compound is:
Figure FDA0003697997850000032
6. an amide or sulfonamide substituted hydrazine derivative of claim 1 wherein the compound is:
Figure FDA0003697997850000033
7. an amide or sulfonamide substituted hydrazine derivative as claimed in any of claims 1 to 6 wherein:
is used as a JAK enzyme inhibitor.
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