CN114149437A

CN114149437A - Pyrrolopyrimidine five-membered nitrogen heterocyclic derivative and preparation method and application thereof

Info

Publication number: CN114149437A
Application number: CN202111595389.5A
Authority: CN
Inventors: 杜永磊; 朱满洲; 孟祥明
Original assignee: Anhui University
Current assignee: Anhui University
Priority date: 2021-12-24
Filing date: 2021-12-24
Publication date: 2022-03-08

Abstract

The invention relates to a pyrrolopyrimidine five-membered nitrogen heterocyclic derivative, a preparation method and application thereof.

Description

Pyrrolopyrimidine five-membered nitrogen heterocyclic derivative and preparation method and application thereof

Technical Field

The invention relates to a pyrrolopyrimidine five-membered nitrogen heterocyclic derivative, a preparation method thereof and application thereof in preparing medicines for indications related to JAK kinase functions.

Background

JAK kinases (Janus kinases) are a family of intracellular non-receptor tyrosine kinases with proteins of approximately 110kDa to 140kDa, and 4 family members are currently found: JAK1, JAK2, JAK3 and TYK2, of which JAK1, JAK2 and TYK2 are widely present in various tissues and cells, while JAK3 is expressed only in lymphocytes and bone marrow. Specific binding of JAK proteins to different receptors can exert specific physiological functions. Researches show that JAK1 is a target of diseases such as inflammation, cancer and immunity, JAK2 is a target of diseases related to a blood system, and JAK3 is a hot target of autoimmune diseases. By far, there are 10 JAK kinase inhibitor products approved for marketing worldwide. Including six first generation JAK inhibitors, Ruxolitinib (Ruxolitinib) of nova/Incyte, Tofacitinib (Tofacitinib) of feverfew/Incyte, barnitinib (barcitinib) of feverfew/Incyte, olatinib (ocacitinib) of feverfew, pefitinib (peicitinib) of astalate (astella), digotitinib (delgocetinib) of Japan tobaco, respectively; and four second-generation JAK inhibitors, new base phenanthrotinib (Fedratinib), upaactinib (upaactinib) of ibowei and filgoninib (Filgotinib) of gillidae, respectively. The indications include rheumatoid arthritis, myelofibrosis, psoriatic arthritis, ulcerative colitis, graft-versus-host disease, atopic dermatitis, etc. In addition, at present, dozens of JAK inhibitors are in the clinical development stage, most of the JAK inhibitors are new-generation therapies, and 10 products enter the phase III clinical stage. Wherein aprepitinib (Abrocitinib) of pyroxene and pasiretinib (Pacritinib) of CTI BioPharma have filed new drug marketing applications (NDA) to FDA. However, most of the already approved JAK inhibitors and the JAK candidates under development face safety and tolerability challenges. Therefore, the development of candidate drugs with high selectivity, good curative effect and good safety in the field has very important significance and good application prospect.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a pyrrolopyrimidine five-membered nitrogen heterocyclic derivative, and a preparation method and application thereof. The pyrrolopyrimidine five-membered nitrogen heterocyclic derivative disclosed by the invention is simple and efficient in synthesis method, and can be used for preparing medicaments for treating inflammatory diseases, autoimmune diseases and cancer related diseases.

The pyrrolopyrimidine five-membered nitrogen heterocyclic ring derivative has a structure shown in a formula I or a formula II:

wherein X is selected from C or N; y is selected from C or N;

R₁is selected from

R₂Selected from SO₂R₃、S(O)R₃Or C (O) R₃；

R₃Is selected from

Or C1-C6 alkyl, wherein R₃R is C1-C6 alkyl₂Is S (O) R₃；

R₄Selected from C3-C8 cycloalkyl, substituted or unsubstituted phenyl, six-membered heterocyclic groupOr a bridged ring group;

R₅is composed of

R₆Is SO₂R₇Or C (O) R₇；R₇Is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, a five or six membered heteroaryl, a bridged or fused ring group, wherein the alkyl, cycloalkyl, phenyl, heteroaryl, bridged or fused ring group may be optionally substituted with 1, 2 or 3 independent substituents of F, Cl, CN, Ph or C1-C4 alkyl;

indicates that the spatial configuration is S or R optical purity or racemate thereof.

In the present invention, as a preferred embodiment, in formula I or formula II:

x is selected from C or N; y is selected from C or N;

R₁is selected from

R₂Selected from SO₂R₃、S(O)R₃Or C (O) R₃；

R₃Is selected from

Or ethyl, wherein R₃R in the case of ethyl₂Is S (O) R₃；

R₄Is C3-C8 cycloalkyl, substituted or unsubstituted phenyl, tetrahydropyranyl or a bridged cyclic group;

R₅is composed of

R₆Is SO₂R₇Or C (O) R₇；R₇Is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or fused ring group, wherein said alkyl, cycloalkyl, phenyl or fused ring group may be optionally substituted with 1, 2 or 3 independent substituents of F, Cl, CN, Ph or C1-C4 alkyl.

In the present invention, as a further preferred embodiment, in the formula I or the formula II,

x is selected from C or N; y is selected from N;

R₁is selected from

R₂Selected from SO₂R₃、S(O)R₃Or C (O) R₃；

R₃Is selected from

Or ethyl, wherein R₃R in the case of ethyl₂Is S (O) R₃；

R₄Is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or 4-nitrophenyl, tetrahydro-2H-pyran-4-yl, 7-dimethyl-2-oxobicyclo [2.2.1]]Hept-1-yl;

R₅is composed of

R₆Is SO₂R₇Or C (O) R₇；R₇Is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 4-methylphenyl, 4-tert-butylphenyl, benzyl, phenyl, cyanoethyl or naphthalene ring group.

In the present invention, as a particularly preferred technical solution, the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative is any one of structural compounds shown in table 1 below:

TABLE 1

The term "C1-C6 alkyl" as used herein refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like. The term "C1-C4 alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like. The term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

In the present invention, C1-C6, C1-C4, C3-C8 and the like before the specific group indicate the number of carbon atoms contained in the group, for example, C1-C6 indicates a group in which the number of carbon atoms may be 1, 2,3, 4,5 or 6, C1-C4 indicates a group in which the number of carbon atoms may be 1, 2,3 or 4, and C3-C8 indicates a group in which the number of carbon atoms may be 3, 4,5, 6, 7 or 8.

The invention also provides a preparation method of the pyrrolopyrimidine five-membered nitrogen heterocyclic ring derivative, and the preparation route is as follows:

the groups in the preparation route are as defined above, unless otherwise indicated.

Wherein: z is selected from chlorine, bromine or iodine; r₈Selected from an alkoxyamino protecting group or a silanylamino protecting group; PG represents a protecting group selected from

X、Y、R₁And R₅The definition of the substituents is the same as above and will not be described herein.

The preparation method of the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative comprises the following steps:

step 1: reacting the compound shown in the formula 1 with an amino protecting reagent under an alkaline condition to generate a compound shown in a formula 2;

the reaction described in step 1 is carried out under the action of an amino protecting reagent and a base. The amino protecting reagent is selected from 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl), di-tert-butyl dicarbonate (Boc)₂O), chloromethyl pivalate, benzyl chloroformate (CbzCl), p-toluenesulfonyl chloride, triphenylmethyl bromide or a combination of at least two thereof; the base is organic base or inorganic base, and the organic base is selected from any one or the combination of at least two of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the inorganic base is selected from any one or combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydride.

Preferably, the molar ratio of the compound of formula 1 to the amino protecting reagent and base is 1:1.0-2.0:1.0-2.0, such as 1:1.0:1.0, 1:1.1:1.1, 1:1.2:1.2, 1:1.3:1.3, 1:1.4:1.4, 1:1.5:1.5, 1:1.6:1.6, 1:1.7:1.7, 1:1.8:1.8, 1:1.9:1.9 or 1:2.0: 2.0.

Preferably, the reaction solvent of step 1 is selected from any one of toluene, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or hexamethylphosphoric triamide or a combination of at least two thereof.

Preferably, the reaction temperature in step 1 is 0 ℃ or higher and not higher than the boiling point of the reaction solvent, for example, 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or the reaction is carried out under the reflux state which is the boiling point of the solvent; the reaction time is 0.5 to 48 hours, for example, 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

Step 2: carrying out Suzuki coupling reaction on the compound of the formula 2 and the compound of the formula 3 under the conditions of a catalyst and alkali to obtain a compound of a formula 4, and carrying out hydrolysis reaction on the compound of the formula 4 under an acidic condition to obtain a compound of a formula 5; or the compound of the formula 2 and the compound of the formula 3 are subjected to Suzuki coupling reaction under the conditions of a catalyst and alkali to directly obtain the compound of the formula 5;

the reaction in the step 2 is carried out under the action of a catalyst and a base. The catalyst is selected from any one or the combination of at least two of a copper catalyst, a palladium-copper alloy catalyst, a nickel catalyst and a platinum catalyst; the base is organic base or inorganic base, and the organic base is selected from any one or the combination of at least two of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the inorganic base is selected from any one or combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydride.

Preferably, the molar ratio of the compound of formula 2 to the compound of formula 3, catalyst and base is 1:1.0-1.5:0.01-0.1:1.0-5.0, such as 1:1.0:0.01:1.0, 1:1.1:0.02:2.0, 1:1.2:0.04:3.0, 1:1.3:0.06:4.0, 1:1.4:0.08:5.0 or 1:1.5:0.1: 5.0.

Preferably, the reaction solvent of step 2 is selected from any one of toluene, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-methylpyrrolidone, water or N-butanol, or a combination of at least two thereof.

Preferably, the reaction temperature in step 2 is 0 ℃ or higher and not higher than the boiling point of the reaction solvent, such as 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 100 ℃, 120 ℃, 140 ℃, 150 ℃ or the like, or the reaction is carried out under the reflux state of the boiling point of the solvent; the reaction time is 0.5 to 48 hours, for example, 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

In addition, in step 2, the compound of formula 4 undergoes hydrolysis under acidic conditions to give the compound of formula 5. The hydrolysis reaction is carried out in any one or a mixed solvent of at least two of water, methanol, ethanol, tetrahydrofuran and 1, 4-dioxane.

Preferably, the hydrolysis reaction is carried out in the presence of an acidic medium selected from any one or a combination of at least two of hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid.

Preferably, the acidic medium is used in an amount of 1 to 5 times, e.g., 1 time, 1.3 times, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, or 5 times the molar amount of the compound of formula 4.

Preferably, the hydrolysis reaction temperature is greater than or equal to 0 ℃ and less than or equal to the boiling point of the reaction solvent, such as 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, or in the solvent boiling point, i.e. the reflux state reaction.

And step 3: carrying out addition reaction on the compound shown in the formula 5 and the compound shown in the formula 6 under an alkaline condition to obtain a compound shown in a formula III;

the addition reaction in step 3 is carried out in the presence of a basic substance selected from any one of triethylamine, N-diisopropylethylamine, pyridine or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), or a combination of at least two thereof.

Preferably, the molar ratio of the compound of formula 5 to the compound of formula 6 and base is 1:1.0-2.0:1.0-2.0, such as 1:1.0:1.0, 1:1.1:1.1, 1:1.2:1.2, 1:1.3:1.3, 1:1.4:1.4, 1:1.5:1.5, 1:1.6:1.6, 1:1.7:1.7, 1:1.8:1.8, 1:1.9:1.9 or 1:2.0: 2.0.

Preferably, the addition reaction in step 3 is carried out in any one or a mixed solvent of at least two of dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone.

Preferably, the reaction temperature in step 3 is greater than or equal to-10 ℃ and less than or equal to the boiling point of the reaction solvent, such as-10 ℃, -5 ℃,0 ℃, 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or the reaction is carried out under the condition of the boiling point of the solvent, i.e. the reflux state; the reaction time is 0.5 to 48 hours, for example, 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

And 4, step 4: and (3) removing the protecting group PG from the compound in the formula III under acidic or basic conditions to obtain the compound in the formula I.

The reaction in step 4 is carried out in any one or a mixed solvent of at least two of dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, water, methanol and ethanol.

Preferably, the reaction of step 4 is carried out in the presence of an acidic substance, preferably acetic acid or trifluoroacetic acid, or a basic substance, preferably any one or a combination of at least two of triethylamine, N-diisopropylethylamine, pyridine, ethylenediamine, aqueous ammonia, sodium hydroxide, lithium hydroxide, or potassium hydroxide.

Preferably, the acidic or basic substance is used in an amount of 1-10 times, e.g., 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times the molar amount of the compound of formula III.

Preferably, the reaction temperature in step 4 is 0 ℃ or higher and 0 ℃ or lower than the boiling point of the reaction solvent, for example, 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or the reaction is carried out under the reflux state which is the boiling point of the solvent; the reaction time is 0.5 to 48 hours, for example, 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

And 5: carrying out substitution reaction on the compound of the formula 2 and the compound of the formula 7 under an acidic condition to obtain a compound of a formula IV;

preferably, the substitution reaction in step 5 is carried out in any one or a mixed solvent of at least two of dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, acetic acid, trifluoroacetic acid, or water.

Preferably, the molar ratio of the compound of formula 7 to the compound of formula 2 is 1:1.0 to 1.5, such as 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1: 1.5.

Preferably, the reaction temperature in step 5 is 0 ℃ or higher and not higher than the boiling point of the reaction solvent, for example, 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or the reaction is carried out under the reflux state which is the boiling point of the solvent; the reaction time is 0.5 to 48 hours, for example, 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

Step 6: and (3) removing the protecting group PG from the compound in the formula IV under acidic or basic conditions to obtain a compound in a formula II.

The reaction in step 6 is carried out in any one or a mixed solvent of at least two of dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide, water, methanol and ethanol.

Preferably, the reaction of step 6 is carried out in the presence of an acidic substance, preferably acetic acid or trifluoroacetic acid, or a basic substance, preferably any one or a combination of at least two of triethylamine, N-diisopropylethylamine, pyridine, ethylenediamine, aqueous ammonia, sodium hydroxide, lithium hydroxide, or potassium hydroxide.

Preferably, the acidic or basic substance is used in an amount of 1-10 times, e.g., 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times the molar amount of the compound of formula IV.

Preferably, the reaction temperature in step 6 is 0 ℃ or higher and not higher than the boiling point of the reaction solvent, for example, 25 ℃,30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or the reaction is carried out under the reflux state which is the boiling point of the solvent; the reaction time is 0.5 to 48 hours, for example, 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours, or 48 hours.

The application of the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative, the tautomer, the enantiomer and the diastereomer of the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative or the pharmaceutically acceptable salt of the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative is application in preparing medicines for preventing and/or treating JAK kinase function-related indications.

The indications related to JAK kinase function include inflammatory, autoimmune and cancer-related diseases, wherein the inflammatory, autoimmune and cancer diseases include: rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, ulcerative colitis, psoriasis, alopecia areata, vitiligo, asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis or neurodermatitis.

In the invention, the tautomer, enantiomer, diastereomer or pharmaceutically acceptable salt of the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative can also play the same role and effect as the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative.

Wherein, the pharmaceutically acceptable salt is formed by reacting the compound shown in the formula I or the formula II with inorganic acid or organic acid to form the conventional pharmaceutically acceptable salt. For example, conventional pharmaceutically acceptable salts can be prepared by reacting a compound of formula I or formula II with an inorganic or organic acid, including hydrochloric, hydrobromic, sulfuric, nitric, sulfamic, phosphoric and the like, and the organic acid includes citric, tartaric, lactic, pyruvic, acetic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, naphthalenesulfonic, ethanesulfonic, naphthalenedisulfonic, maleic, malic, malonic, fumaric, succinic, propionic, oxalic, trifluoroacetic, stearic, pamoic, hydroxymaleic, phenylacetic, benzoic, salicylic, glutamic, ascorbic, p-aminobenzenesulfonic, 2-acetoxybenzoic, isethionic and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I or formula II with an inorganic base; or the methylamine salt, ethylamine salt or ethanolamine salt of the compound of formula I or formula II with an organic base.

The pharmaceutical preparation may be prepared using a pharmaceutically acceptable carrier, in particular one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers

Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

Synthetic examples

Synthesis example 1: preparation of 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (Compound No. I-1)

(1) The preparation method of (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) methyl pivalate comprises the following steps:

reacting 4-chloro-7H-pyrrolo [2,3-d]Pyrimidine (5.00g,32.56mmol,1.0eq) was dissolved in N, N-dimethylformamide (50mL), potassium carbonate (4.50g,32.56mmol,1.0eq) was added at room temperature, and after stirring for 10min, chloromethyl pivalate (5.88g,39.07mmol,1.2eq) was slowly added dropwise, followed by reaction at room temperature for 2h, and the reaction was terminated when the reaction of the starting material was complete by TLC. Adding 35mL of water into the system, separating out the solid, filtering, drying the filter cake to obtain a white solid product (4-chloro-7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) pivalic acid methyl ester (7.94g, yield: 91%).¹H NMR(400MHz,DMSO-d₆)δ8.71(s,1H),7.83(d,J＝3.7Hz,1H),6.72(d,J＝3.7Hz,1H),6.24(s,2H),1.07(s,9H).HRMS(ESI)calcd for C₁₂H₁₄ClN₃O₂[M+H⁺]:268.0847,found:268.0893.

(2) The preparation method of methyl 4- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-yl) pivalate comprises the following steps:

the compound (4-chloro-7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) pivalic acid methyl ester (5.00g,18.68mmol,1.0eq) was dissolved in 1, 4-dioxane/water 2:1(30mL), and after stirring at room temperature for 15min, potassium carbonate (7.74g,56.03mmol,3.0eq), 1- (1-ethoxyethyl) -4-pyrazoleboronic acid pinacol ester (5.72g,21.48mmol,1.15eq), and tetrakis (triphenylphosphine) palladium (431.64mg,373.54 μmol,0.02eq), N, were added in that order₂Heating to 90 ℃ under protection, and carrying out reflux reaction for 12 h. After completion of the TLC detection reaction, the system was cooled to room temperature, quenched with water, extracted with ethyl acetate (20 mL. multidot.2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatographyPurifying (eluent is petroleum ether, ethyl acetate is 4:1) to obtain colorless oily product (4- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) which is changed into solid after long-time standing]Pyrimidin-7-yl) pivalic acid methyl ester (5.00g, yield: 72.05%).¹H NMR(400MHz,DMSO-d₆)δ8.81(s,1H),8.79(s,1H),8.36(s,1H),7.73(d,J＝3.8Hz,1H),7.15(d,J＝3.8Hz,1H),6.24(s,2H),5.67(q,J＝6.0Hz,1H),3.55–3.42(m,1H),3.30–3.21(m,1H),1.68(d,J＝6.0Hz,3H),1.07(s,9H),1.06(s,3H).HRMS(ESI)calcd for C₁₉H₂₅N₅O₃[M+H⁺]:372.2030,found:372.2124.

(3) The preparation method of (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-yl) methyl pivalate comprises the following steps:

the compound (4- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) pivalic acid methyl ester (5.00g,13.46mmol,1.0eq) was dissolved in tetrahydrofuran (30mL), 11mL of 6M hydrochloric acid solution was slowly added dropwise, the reaction was carried out at room temperature for 1.5h, and the reaction was terminated when the starting material reaction was complete as monitored by TLC. Adjusting the pH value of the system to 9 by using 1M aqueous solution of sodium hydroxide, precipitating a large amount of solid at the moment, evaporating most of solvent, continuously stirring the suspension at room temperature for 1H, filtering, washing a filter cake by using water, drying the filter cake, and finally obtaining a white solid product (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) pivalic acid methyl ester (3.63g, yield: 90%).¹H NMR(400MHz,DMSO-d₆)δ13.41(s,1H),8.77(s,1H),8.67(s,1H),8.35(s,1H),7.70(d,J＝3.9Hz,1H),7.12(d,J＝3.9Hz,1H),6.23(s,2H),1.08(s,9H).HRMS(ESI)calcd for C₁₅H₁₇N₅O₂Na[M+Na⁺]:322.1274,found:322.2517.

(4) Preparation of methyl (4- (1- (3- (cyanomethyl) -1- (cyclopropylmethyl) sulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate by the following specific preparation method:

the compound 2- (1- ((cyclopropylmethyl) sulfonyl) azetidin-3-ylidene) acetonitrile (200.00mg, 942.20. mu. mol,1.0eq) was dissolved in N, N-dimethylformamide (20mL) and the compound (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) -was added at room temperature]Pyrimidine-7-yl) methyl pivalate (282.03mg, 942.20. mu. mol,1.0eq) is stirred and dissolved for 15min, then cooled to 10-15 ℃,1, 8-diazabicycloundecen-7-ene (10.04mg, 65.95. mu. mol,0.07eq) is slowly dropped in, the temperature is kept around 15 ℃ for reaction for 90min, and then the temperature is raised to 25 ℃ for continuous reaction for 4 h. After TLC monitoring of the completion of the reaction of the starting materials, the reaction was terminated, quenched with water (30mL), extracted with ethyl acetate (30 mL. times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate: 1) to give the product (4- (1- (3- (cyanomethyl) -1- (cyclopropylmethyl) sulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) as a white solid]Pyrimidin-7-yl) pivalic acid methyl ester (272.00mg, yield: 56.43%).¹H NMR(400MHz,DMSO-d₆)δ8.97(s,1H),8.82(s,1H),8.50(d,J＝0.6Hz,1H),7.77(d,J＝3.8Hz,1H),7.21(d,J＝3.8Hz,1H),6.25(s,2H),4.63(d,J＝9.1Hz,2H),4.26(d,J＝9.2Hz,2H),3.68(s,2H),3.21(d,J＝7.2Hz,2H),1.08(s,9H),1.07–0.99(m,1H),0.63–0.52(m,2H),0.39–0.31(m,2H).HRMS(ESI)calcd for C₂₄H₂₉N₇O₄S[M+H⁺]:512.2074,found:512.2337.

(5) The preparation method of 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile comprises the following steps:

the compound methyl (4- (1- (3- (cyanomethyl) -1- (cyclopropylmethyl) sulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate (200.00mg, 390.93. mu. mol,1.0eq) was dissolved in methanol (20mL) and 1M aqueous sodium hydroxide (23.45mg, 586.40. mu. mol,1.5eq) was added thereto at room temperature and stirred at room temperature for 2H. After the TLC monitoring of the raw material reaction is finished, the reaction is finished. Adding water to quench the reaction, adjusting the pH value of the system to about 7 by using 1M hydrochloric acid, separating out a white solid, removing most of the solvent by spinning, filtering, and drying a filter cake to obtain a white solid product, namely 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (119.19mg, yield: 76.71%).

Of Compound I-1¹H NMR(400MHz,DMSO-d₆)δ12.14(s,1H),8.93(s,1H),8.71(s,1H),8.48(s,1H),7.62(d,J＝3.6Hz,1H),7.08(d,J＝3.6Hz,1H),4.63(d,J＝9.0Hz,2H),4.25(d,J＝9.0Hz,2H),3.68(s,2H),3.21(d,J＝7.1Hz,2H),1.08–0.99(m,1H),0.58(d,J＝6.0Hz,2H),0.35(d,J＝4.2Hz,2H).HRMS(ESI)calcd for C₁₈H₁₉N₇O₂S[M+H⁺]398.1394, found 398.1868. Synthesis example 2: 2- (3- (4- (7H-pyrrolo [2, 3-d))]Preparation of pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile (Compound No. I-2)

(1) Preparation of methyl (4- (1- (3- (cyanomethyl) -1- (2-cyclopropylacetyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate by the following specific preparation method:

the compound 2- (1- (2-cyclopropylacetyl) azetidin-3-ylidene) acetonitrile (200.00mg,1.13mmol,1.0eq) was dissolved in N, N-dimethylformamide (20mL), and the compound (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) -was added at room temperature]Pyrimidine-7-yl) methyl pivalate (339.73mg,1.13mmol,1.0eq) is stirred and dissolved for 15min, then cooled to 10-15 ℃,1, 8-diazabicycloundecen-7-ene (12.09mg,79.45 μmol,0.07eq) is slowly dropped into the solution, the temperature is kept around 15 ℃ for reaction for 90min, and the temperature is raised to 25 ℃ for continuous reaction for 3.5 h. TLC monitoring starting material after completion of reaction, reaction was terminated, quenched with water (30mL), acetic acidEthyl ester extraction (30mL x 3), washing of the organic layer with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography of the residue (ethyl acetate as eluent) to give (4- (1- (3- (cyanomethyl) -1- (2-cyclopropylacetyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) -a pale yellow solid]Pyrimidin-7-yl) pivalic acid methyl ester (512.74mg, yield: 95.00%).¹H NMR(400MHz,DMSO-d₆)δ8.95(s,1H),8.81(s,1H),8.48(d,J＝0.6Hz,1H),7.77(d,J＝3.8Hz,1H),7.21(d,J＝3.8Hz,1H),6.25(s,2H),4.79(d,J＝9.5Hz,1H),4.49(dd,J＝9.9,4.6Hz,2H),4.23(d,J＝10.0Hz,1H),3.69(s,2H),2.09(d,J＝6.9Hz,2H),1.08(s,9H),0.97–0.86(m,1H),0.50–0.39(m,2H),0.15–0.10(m,2H).HRMS(ESI)calcd for C₂₅H₂₉N₇O₃[M+H⁺]:476.2405,found:476.2580.

(2) The preparation method of 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile comprises the following steps:

the compound methyl (4- (1- (3- (cyanomethyl) -1- (2-cyclopropylacetyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate (350.00mg, 736.00. mu. mol,1.0eq) was dissolved in methanol (20mL) and 1M aqueous sodium hydroxide (44.16mg,1.10mmol,1.5eq) was added at room temperature and stirred at room temperature for 2H. After the TLC monitoring of the raw material reaction is finished, the reaction is finished. Adding water to quench the reaction, adjusting the pH value of the system to about 7 by using 1M hydrochloric acid, separating out a white solid, removing most of the solvent by spinning, filtering, and drying a filter cake to obtain a white solid product, namely 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile (148.95mg, yield: 56.00%).

Of Compound I-2¹H NMR(400MHz,DMSO-d₆)δ12.14(s,1H),8.91(d,J＝0.7Hz,1H),8.70(s,1H),8.46(d,J＝0.6Hz,1H),7.62(dd,J＝3.6,2.2Hz,1H),7.08(dd,J＝3.7,1.5Hz,1H),4.79(d,J＝9.5Hz,1H),4.49(dd,J＝9.9,5.4Hz,2H),4.23(d,J＝10.5Hz,1H),3.69(s,2H),2.09(d,J＝6.8Hz,2H),0.99–0.90(m,1H),0.48–0.41(m,2H),0.15–0.10(m,2H).HRMS(ESI)calcd for C₁₉H₁₉N₇O[M+H⁺]:362.1724,found:362.1949.

Synthetic example 3: preparation of 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (ethylsulfinyl) azetidin-3-yl) acetonitrile (Compound No. I-3)

(1) Preparation of methyl (4- (1- (3- (cyanomethyl) -1- (ethylsulfinyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate by the following specific preparation method:

the compound (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d)]Dissolving methyl pyrimidin-7-yl) pivalate (193.42mg, 646.18. mu. mol,1.1eq) in acetonitrile (30mL), slowly adding 2- (1- (ethylsulfinyl) azetidin-3-ylidene) acetonitrile (100.00mg, 587.43. mu. mol,1.0eq) and 1, 8-diazabicycloundec-7-ene (89.43mg, 587.43. mu. mol,1.0eq) dropwise at-5 ℃ under the protection of nitrogen, and continuing the reaction for 2h at-5 ℃ after the addition of the raw material system is finished. After TLC monitoring of the completion of the reaction of the starting materials, the reaction was terminated, quenched with water (30mL), extracted with ethyl acetate (20 mL. times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate: 1:2) to give (4- (1- (3- (cyanomethyl) -1- (ethylsulfinyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) pivalic acid methyl ester (55.17mg, yield: 20.00%).¹H NMR(600MHz,DMSO-d₆)δ8.94(s,1H),8.82(s,1H),8.48(s,1H),7.78(d,J＝3.8Hz,1H),7.20(d,J＝3.8Hz,1H),6.26(s,2H),4.55(d,J＝9.1Hz,1H),4.35(d,J＝9.0Hz,1H),4.13(d,J＝9.2Hz,1H),3.92(d,J＝9.0Hz,1H),3.66(s,2H),2.65–2.60(m,2H),1.12(t,J＝7.5Hz,3H),1.09(s,9H).HRMS(ESI)calcd for C₂₂H₂₇N₇O₃S[M+H⁺]:470.1969,found:470.1977.

(2) The preparation method of 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- (ethylsulfinyl) azetidin-3-yl) acetonitrile comprises the following steps:

the compound methyl (4- (1- (3- (cyanomethyl) -1- (ethylsulfinyl) azetidin-3-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate (50.00mg, 106.48. mu. mol,1.0eq) was dissolved in methanol (20mL), and a 1M aqueous solution of sodium hydroxide (6.39mg, 159.72. mu. mol,1.5eq) was added thereto at room temperature and stirred at room temperature for 2H. After the TLC monitoring of the raw material reaction is finished, the reaction is finished. Adding water to quench the reaction, adjusting the pH value of the system to about 7 by using 1M hydrochloric acid, separating out a light yellow solid, removing most of the solvent by spinning, filtering, and drying a filter cake to obtain a light yellow solid product, namely 2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazole-1-yl) -1- (ethylsulfinyl) azetidin-3-yl) acetonitrile (29.41mg, yield: 77.70%).

Of Compound I-3¹H NMR(400MHz,DMSO-d₆)δ12.14(s,1H),8.89(s,1H),8.70(s,1H),8.45(s,1H),7.62(dd,J＝3.6,2.3Hz,1H),7.06(dd,J＝3.6,1.7Hz,1H),4.54(d,J＝9.0Hz,1H),4.35(d,J＝9.0Hz,1H),4.12(d,J＝9.0Hz,1H),3.91(d,J＝9.0Hz,1H),3.65(s,2H),2.62(qd,J＝7.1,6.5,1.4Hz,2H),1.11(t,J＝7.5Hz,3H).HRMS(ESI)calcd for C₁₆H₁₇N₇OS[M+H⁺]:356.1288,found:356.1296.

Synthetic example 4: preparation of 2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. I-4)

(1) The preparation method of 4-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine comprises the following steps:

will hydrogenateSodium (1.56g,65.12mmol,2.0eq) was dissolved in N, N-dimethylformamide (40mL) and 4-chloro-7H-pyrrolo [2,3-d ] was slowly added dropwise at 0 deg.C]After the pyridine (5.00g,32.56mmol,1.0eq) in DMF (20mL) was allowed to react for 1.5h, 2- (trimethylsilyl) ethoxymethyl chloride (6.51g,39.07mmol,1.2eq) was added slowly and the reaction was completed at room temperature for 1h with the addition of the starting material system, and the reaction was completed when the starting material was completely reacted as monitored by TLC. Adding 30mL of water into the system to quench the reaction, extracting with ethyl acetate (30mL of 3), washing the organic layer with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography (the eluent is petroleum ether: ethyl acetate 4:1) to obtain a light yellow oily product 4-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidine (6.45g, yield: 69.80%).¹H NMR(400MHz,CDCl₃)δ8.64(s,1H),7.37(d,J＝3.7Hz,1H),6.64(d,J＝3.7Hz,1H),5.63(s,2H),3.53–3.49(m,2H),0.91–0.87(m,2H),0.08(s,9H).HRMS(ESI)calcd for C₁₂H₁₈ClN₃OSi[M+H⁺]:284.0980,found:284.2168.

(2) The preparation method of 4- (1H-pyrrole-3-yl) -7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine comprises the following steps:

the compound 4-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidine (5.00g,17.62mmol,1.0eq) was dissolved in 1:1(50mL) N-butanol/water, and 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1- (triisopropylsilyl) -1H-pyrrole (7.36g,21.14mmol,1.2eq), potassium carbonate (6.09g,44.04mmol,2.5eq), and tetrakis (triphenylphosphine) palladium (1.02g,880.81 μmol,0.05eq), N, were added sequentially at room temperature₂Heating to 100 ℃ under protection, and carrying out reflux reaction for 12 h. After completion of the TLC detection reaction, the system was cooled to room temperature, quenched with water, extracted with ethyl acetate (30 mL. times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate: 2:1) to give a pale yellow solidThe product 4- (1H-pyrrol-3-yl) -7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidine (3.77g, yield: 68.05%).¹H NMR(400MHz,DMSO-d₆)δ11.40(s,1H),8.66(s,1H),7.78–7.76(m,1H),7.64(d,J＝3.7Hz,1H),6.99(d,J＝3.7Hz,1H),6.93–6.89(m,2H),5.60(s,2H),3.55–3.50(m,2H),0.85–0.80(m,2H),0.10(s,9H).HRMS(ESI)calcd for C₁₆H₂₂N₄OSi[M+H⁺]:315.1636,found:315.1818.

(3) Preparation of 2- (1- ((cyclopropylmethyl) sulfonyl) -3- (3- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) azetidin-3-yl) acetonitrile, as follows:

the compound 4- (1H-pyrrol-3-yl) -7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidine (1.00g,3.18mmol,1.0eq) was dissolved in acetonitrile (50mL), and 2- (1- ((cyclopropylmethyl) sulfonyl) azetidin-3-ylidene) acetonitrile (810.04mg,3.82mmol,1.2eq) and 1, 8-diazabicycloundecen-7-ene (726.19mg,4.77mmol,1.5eq) were added sequentially at room temperature and reacted at 70 ℃ for 5 h. After TLC monitoring of the completion of the reaction of the starting materials, the reaction was terminated, the reaction was quenched with water (30mL), extracted with ethyl acetate (30 mL. times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate 1:1) to give 2- (1- ((cyclopropylmethyl) sulfonyl) -3- (3- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] as a pale yellow solid product]Pyrimidin-4-yl) -1H-pyrrol-1-yl) azetidin-3-yl) acetonitrile (777.34mg, yield: 46.27%).¹H NMR(400MHz,DMSO-d₆)δ8.71(s,1H),7.97(s,1H),7.71(d,J＝3.7Hz,1H),7.20(t,J＝2.6Hz,1H),7.10(d,J＝3.7Hz,1H),7.00(dd,J＝3.0,1.6Hz,1H),5.62(s,2H),4.49(d,J＝9.1Hz,2H),4.23(d,J＝8.8Hz,2H),3.58(s,2H),3.53(t,J＝8.0Hz,2H),3.19(d,J＝7.1Hz,2H),1.06–0.99(m,1H),0.83(t,J＝8.0Hz,2H),0.61–0.55(m,2H),0.36–0.32(m,2H),0.10(s,9H).HRMS(ESI)calcd for C₂₅H₃₄N₆O₃SSi[M+H⁺]:527.2255,found:527.2559.

(4) The preparation method of 2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrrole-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile comprises the following steps:

to a 50mL round bottom flask was added 7.9mL of trifluoroacetic acid, a solution of 2- (1- ((cyclopropylmethyl) sulfonyl) -3- (3- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) azetidin-3-yl) acetonitrile (200.00mg, 379.70. mu. mol,1.0eq) in dichloromethane (30mL) was added slowly at 0 ℃, the system was allowed to react at room temperature for 1H after addition of the starting material, the system was concentrated under reduced pressure, dissolved in methanol (30mL), ethylenediamine (1.58mL) was added at room temperature and the reaction was allowed to warm for 2H, after completion of the starting material reaction was monitored by TLC, the system was adjusted to pH 7 by the addition of 3M hydrochloric acid, and the reaction was quenched with water (30mL), extraction with ethyl acetate (30mL × 3), washing of the organic layer with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by column chromatography (eluent was ethyl acetate) gave the product 2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (86.14mg, yield: 57.22%) as a white solid.

Of Compound I-4¹H NMR(400MHz,DMSO-d₆)δ11.99(s,1H),8.64(s,1H),7.94(t,J＝2.0Hz,1H),7.53(dd,J＝3.6,2.3Hz,1H),7.18(dd,J＝3.0,2.3Hz,1H),6.99(dd,J＝3.2,1.7Hz,2H),4.49(d,J＝9.1Hz,2H),4.23(d,J＝9.1Hz,2H),3.58(s,2H),3.20(d,J＝7.1Hz,2H),1.10–0.96(m,1H),0.62–0.53(m,2H),0.37–0.32(m,2H).HRMS(ESI)calcd for C₁₉H₂₀N₆O₂S[M+H⁺]:397.1441,found:397.1904.

Synthesis example 5: preparation of 2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile (Compound No. I-5)

(1) Preparation of 2- (1- (2-cyclopropylacetyl) -3- (3- (7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) azetidin-3-yl) acetonitrile, the specific preparation method is as follows:

the compound 4- (1H-pyrrol-3-yl) -7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidine (200.00mg, 636.02. mu. mol,1.0eq) was dissolved in acetonitrile (50mL), and 2- (1- (2-cyclopropylacetyl) azetidin-3-ylidene) acetonitrile (168.11mg, 954.02. mu. mol,1.5eq) and 1, 8-diazabicycloundecen-7-ene (145.24mg, 954.02. mu. mol,1.5eq) were added in this order at room temperature, and the reaction was carried out for 4 hours at 70 ℃ after the completion of the addition of the starting materials. TLC (thin layer chromatography) to monitor the completion of the reaction of the starting materials, the reaction was terminated, the reaction was quenched with water (30mL), extracted with ethyl acetate (30 mL. about.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent was petroleum ether: ethyl acetate: 1) to give 2- (1- (2-cyclopropylacetyl) -3- (3- (7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] as a pale yellow solid product]Pyrimidin-4-yl) -1H-pyrrol-1-yl) azetidin-3-yl) acetonitrile (196.05mg, yield: 62.82%).¹H NMR(400MHz,DMSO-d₆)δ8.70(s,1H),7.95(t,J＝2.0Hz,1H),7.71(d,J＝3.7Hz,1H),7.19(dd,J＝3.0,2.3Hz,1H),7.09(d,J＝3.7Hz,1H),6.99(dd,J＝3.1,1.7Hz,1H),5.62(s,2H),4.71(d,J＝9.5Hz,1H),4.46(d,J＝9.5Hz,1H),4.38(d,J＝10.5Hz,1H),4.22(d,J＝10.5Hz,1H),3.57(s,2H),3.57–3.47(m,2H),2.08(d,J＝6.9Hz,2H),1.00–0.88(m,1H),0.88–0.78(m,2H),0.50–0.39(m,2H),0.15–0.10(m,2H),0.10(s,9H).HRMS(ESI)calcd for C₂₆H₃₄N₆O₂Si[M+H⁺]:491.2585,found:491.2732.

(2) The preparation method of 2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrrole-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile comprises the following steps:

adding 15.4mL of trifluoroacetic acid into a 100mL round bottom flask, slowly adding a dichloromethane (30mL) solution of 2- (1- (2-cyclopropylacetyl) -3- (3- (7- (2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) azetidin-3-yl) acetonitrile (150.00mg, 305.70. mu. mol,1.0eq) at 0 ℃, moving the added raw material system to room temperature for reaction for 1H, concentrating the system under reduced pressure, dissolving the system with methanol (30mL), adding ethylenediamine (1.28mL) at room temperature and keeping the temperature for reaction for 2H, after TLC monitors that the raw material is reacted completely, adding 3M hydrochloric acid to adjust the pH of the system to about 7, and quenching the reaction with water (30mL), extraction with ethyl acetate (30mL × 3), washing of the organic layer with saturated brine, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by column chromatography (eluent was ethyl acetate) gave the product 2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile (61.83mg, yield: 56.12%) as a white solid.

Of Compound I-5¹H NMR(400MHz,DMSO-d₆)δ11.98(s,1H),8.64(s,1H),7.93(t,J＝2.0Hz,1H),7.53(dd,J＝3.6,2.3Hz,1H),7.18(t,J＝2.7Hz,1H),7.02–6.95(m,2H),4.71(d,J＝9.5Hz,1H),4.46(d,J＝9.5Hz,1H),4.37(d,J＝10.5Hz,1H),4.23(d,J＝10.5Hz,1H),3.57(s,2H),2.09(d,J＝6.9Hz,2H),1.00–0.90(m,1H),0.49–0.41(m,2H),0.17–0.09(m,2H).HRMS(ESI)calcd for C₂₀H₂₀N₆O[M+H⁺]:361.1771,found:361.2097.

Synthetic example 6: preparation of 2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) piperidin-4-yl) acetonitrile (Compound No. I-6)

(1) Preparation of methyl (4- (1- (4- (cyanomethyl) -1- (2-cyclopropylacetyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate by the following specific preparation method:

the compound 2- (1- (2-cyclopropylacetyl) piperidin-4-ylidene) acetonitrile (204.73mg,1.00mmol,1.5eq) was dissolved in acetonitrile (30mL), and the compound (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) was added successively at room temperature]Pyrimidin-7-yl) neopentanoic acid methyl ester (200.00mg, 668.16. mu. mol,1.0eq) and 1, 8-diazabicycloundecen-7-ene (152.58mg,1.00mmol,1.5eq) were reacted at about 70 ℃ for 4h after completion of the addition of the starting material system. After TLC monitoring of the completion of the reaction of the starting materials, the reaction was terminated, quenched with water (30mL), extracted with ethyl acetate (30 mL. times.3), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate: 1) to give the product (4- (1- (4- (cyanomethyl) -1- (2-cyclopropylacetyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) as a white solid]Pyrimidin-7-yl) pivalic acid methyl ester (201.89mg, yield: 60.00%).¹H NMR(400MHz,DMSO-d₆)δ8.87(s,1H),8.83(s,1H),8.48(s,1H),7.77(d,J＝3.8Hz,1H),7.22(d,J＝3.8Hz,1H),6.27(s,2H),4.09–4.02(m,1H),3.75(d,J＝14.0Hz,1H),3.29(s,2H),3.18(t,J＝12.0Hz,1H),2.95(t,J＝11.7Hz,1H),2.70(t,J＝15.7Hz,2H),2.30(d,J＝6.7Hz,2H),2.08–1.97(m,2H),1.10(s,9H),0.98–0.94(m,1H),0.48–0.43(m,2H),0.15–0.10(m,2H).HRMS(ESI)calcd for C₂₇H₃₃N₇O₃[M+H⁺]:504.2718,found:504.2935.

(2) The preparation method of 2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) piperidine-4-yl) acetonitrile comprises the following steps:

the compound methyl (4- (1- (4- (cyanomethyl) -1- (2-cyclopropylacetyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate (150.00mg, 297.86. mu. mol,1.0eq) was dissolved in methanol (30mL), and a 1M aqueous solution of sodium hydroxide (17.87mg, 446.79. mu. mol,1.5eq) was added thereto at room temperature and stirred at room temperature for 2 hours. After the TLC monitoring of the raw material reaction is finished, the reaction is finished. Water was added to quench the reaction, and the pH of the system was adjusted to about 7 with 1M hydrochloric acid, a pale yellow solid precipitated, most of the solvent was removed by rotation, suction filtration and drying of the filter cake gave a pale yellow solid product, 2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) piperidin-4-yl) acetonitrile (83.80mg, yield: 72.24%).

Of Compound I-6¹H NMR(400MHz,DMSO-d₆)δ12.13(s,1H),8.81(s,1H),8.70(s,1H),8.44(s,1H),7.64–7.56(m,1H),7.16–6.99(m,1H),4.10–3.98(m,1H),3.73(d,J＝14.0Hz,1H),3.28(s,2H),3.17(t,J＝12.6Hz,1H),3.00–2.87(m,1H),2.69(t,J＝16.1Hz,2H),2.29(d,J＝6.7Hz,2H),2.07–1.91(m,2H),1.41–1.33(m,1H),0.90–0.83(m,2H),0.44(d,J＝7.9Hz,2H).HRMS(ESI)calcd for C₂₁H₂₃N₇O[M+H⁺]:390.2037,found:390.2386.

Synthetic example 7: preparation of 2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) piperidin-4-yl) acetonitrile (Compound No. I-7)

(1) Preparation of methyl (4- (1- (4- (cyanomethyl) -1- (cyclopropylmethyl) sulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate by the following specific preparation method:

the compound 2- (1- ((cyclopropylmethyl) sulfonyl) piperidin-4-ylidene) acetonitrile (240.86mg,1.00mmol,1.5eq) was dissolved in N, N-dimethylformamide (30mL), and the compound (4- (1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) -was added at room temperature]Pyrimidine-7-yl) methyl pivalate (200.00mg,668.16 mu mol,1.0eq), after stirring and dissolving for 15min, cooling to 10-15 ℃, then slowly dropping 1, 8-diazabicycloundecen-7-ene (101.72mg,668.16 mu mol,1.0eq), keeping the temperature at about 15 ℃ for reaction for 90min, then raising the temperature to 25 ℃ for further reaction for 12 h. TLC monitoring the reaction completion of the starting material, reaction was stopped, quenched with water (30mL), extracted with ethyl acetate (30 mL. about.3), and the organic layer was saturated with common saltWashed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography (eluent was petroleum ether: ethyl acetate ═ 1:1) to give the product (4- (1- (4- (cyanomethyl) -1- (cyclopropylmethyl) sulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2, 3-d) as a white solid]Pyrimidin-7-yl) pivalic acid methyl ester (87.08mg, yield: 24.15%).¹H NMR(400MHz,DMSO-d₆)δ8.85(s,1H),8.81(s,1H),8.47(s,1H),7.76(d,J＝3.8Hz,1H),7.22(d,J＝3.8Hz,1H),6.26(s,2H),3.59–3.52(m,2H),3.28(s,2H),2.97(d,J＝7.0Hz,2H),2.96–2.86(m,2H),2.83(d,J＝14.1Hz,2H),2.14–2.06(m,2H),1.09(s,9H),0.94–0.89(m,1H),0.51–0.45(m,2H),0.24–0.18(m,2H).HRMS(ESI)calcd for C₂₆H₃₃N₇O₄S[M+H⁺]:540.2387,found:540.2797.

(2) The preparation method of 2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) piperidin-4-yl) acetonitrile comprises the following steps:

the compound methyl (4- (1- (4- (cyanomethyl) -1- (cyclopropylmethyl) sulfonyl) piperidin-4-yl) -1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate (80.00mg, 148.24. mu. mol,1.0eq) was dissolved in methanol (20mL), and a 1M aqueous solution of sodium hydroxide (8.89mg, 222.37. mu. mol,1.5eq) was added thereto at room temperature and stirred at room temperature for 2 hours. After the TLC monitoring of the raw material reaction is finished, the reaction is finished. Adding water to quench the reaction, adjusting the pH value of the system to about 7 by using 1M hydrochloric acid, separating out a light yellow solid, removing most of the solvent by spinning, filtering, and drying a filter cake to obtain a light yellow solid product, namely 2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) piperidin-4-yl) acetonitrile (56.77mg, yield: 90.00%).

Of Compound I-7¹H NMR(400MHz,DMSO-d₆)δ12.12(s,1H),8.81(s,1H),8.70(s,1H),8.45(s,1H),7.61(dd,J＝3.6,2.4Hz,1H),7.08(dd,J＝3.6,1.8Hz,1H),3.62–3.51(m,2H),3.27(s,2H),2.97(d,J＝7.0Hz,2H),2.96–2.89(m,2H),2.83(d,J＝14.1Hz,2H),2.15–2.06(m,2H),0.93–0.88(m,1H),0.52–0.44(m,2H),0.24–0.18(m,2H).HRMS(ESI)calcd for C₂₀H₂₃N₇O₂S[M+H⁺]:426.1707,found:426.2116.

Synthesis example 8: preparation of 2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (methylsulfonyl) azetidin-3-yl) acetonitrile (Compound No. II-1)

(1) Preparation of methyl (4- ((1- (3- (cyanomethyl) -1- (methylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate by the following specific method:

reacting (4-chloro-7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) methyl pivalate (500.00mg,1.87mmol,1.0eq) was dissolved in acetic acid/water (20mL:20mL), 2- (3- (4-amino-1H-pyrazol-1-yl) -1- (methylsulfonyl) azetidin-3-yl) acetonitrile (476.81mg,1.87mmol,1.0eq) was added at room temperature, the reaction was completed at 70 ℃ for 5-7H, and the completion of the reaction was monitored by TLC. Adjusting pH to 8-9 with 10% NaOH aqueous solution, extracting with ethyl acetate (30 mL. times.3), washing the organic layer with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue with column chromatography (the eluent is ethyl acetate) to obtain light brown oily product (4- ((1- (3- (cyanomethyl) -1- (methylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) pivalic acid methyl ester (426.46mg, yield: 46.93%).¹H NMR(400MHz,DMSO-d₆)δ9.73(s,1H),8.44(s,1H),8.38(s,1H),7.85(s,1H),7.36(d,J＝3.6Hz,1H),6.75(s,1H),6.15(s,2H),4.46(d,J＝9.2Hz,2H),4.22(d,J＝9.1Hz,2H),3.61(s,2H),3.11(s,3H),1.09(s,9H).HRMS(ESI)calcd for C₂₁H₂₆N₈O₄S[M+H⁺]:487.1870,found:487.2060.

(2) The preparation method of 2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -1H-pyrazol-1-yl) -1- (methylsulfonyl) azetidin-3-yl) acetonitrile comprises the following steps:

the compound methyl (4- ((1- (3- (cyanomethyl) -1- (methylsulfonyl) azetidin-3-yl) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate (200.00mg,411.06 μmol,1.0eq) was dissolved in methanol (20mL), and 1M aqueous sodium hydroxide (24.66mg,616.59 μmol,1.5eq) was added thereto at room temperature and stirred at room temperature for 2H. After the TLC monitoring of the raw material reaction is finished, the reaction is finished. Adding water to quench the reaction, adjusting the pH value of the system to about 7 by using 1M hydrochloric acid, separating out a light yellow solid, removing most of the solvent by spinning, performing suction filtration, and drying a filter cake to obtain a light yellow solid product, namely 2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -1H-pyrazole-1-yl) -1- (methylsulfonyl) azetidin-3-yl) acetonitrile (77.95mg, yield: 50.92%).

Of compound II-1¹H NMR(400MHz,DMSO-d₆)δ11.70(s,1H),9.60(s,1H),8.44(s,1H),8.28(s,1H),7.85(s,1H),7.19(t,J＝2.9Hz,1H),6.69(s,1H),4.46(d,J＝9.1Hz,2H),4.23(d,J＝9.1Hz,2H),3.61(s,2H),3.12(s,3H).HRMS(ESI)calcd for C₁₅H₁₆N₈O₂SNa[M+Na⁺]:395.1009,found:395.1332.

Synthetic example 9: preparation of 2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1-benzoylazetidin-3-yl) acetonitrile (Compound No. II-10)

(1) Preparation of methyl (4- ((1- (1-benzoyl-3- (cyanomethyl) azetidin-3-yl) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate by the following specific preparation method:

reacting (4-chloro-7H-pyrrolo [2, 3-d)]Pyrimidin-7-yl) pivalic acid methyl ester (500.00mg,1.87mmol,1.0eq) was dissolved in acetic acid/water (20mL:20mL), and 2- (3- (4-amino-1H-pyrazol-1-yl) -1-benzoylazetidine was added at room temperatureAlkyl-3-yl) acetonitrile (525.40mg,1.87mmol,1.0eq), and the reaction was terminated by TLC when the feed system was added and the reaction was completed at 70 deg.C for 5-7 h. Adjusting the PH to 8-9 with 10% aqueous NaOH, extracting with ethyl acid (30mL × 3), washing the organic layer with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography (eluent dichloromethane: methanol 10:1) to obtain (4- ((1- (1-benzoyl-3- (cyanomethyl) azetidin-3-yl) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2, 3-d) as a pale yellow oily product]Pyrimidin-7-yl) pivalic acid methyl ester (880.52mg, yield: 91.98%).¹H NMR(400MHz,DMSO-d₆)δ9.73(s,1H),8.46(s,1H),8.38(s,1H),7.84(s,1H),7.72–7.69(m,2H),7.57–7.53(m,1H),7.51–7.46(m,2H),7.36(d,J＝3.6Hz,1H),6.76(s,1H),6.15(s,2H),4.91(d,J＝9.6Hz,1H),4.63(d,J＝9.5Hz,1H),4.57(d,J＝10.8Hz,1H),4.42(d,J＝10.7Hz,1H),3.64(s,2H),1.08(s,9H).HRMS(ESI)calcd forC₂₇H₂₈N₈O₃[M+H⁺]:513.2357,found:513.2538.

(2) The preparation method of 2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) -1H-pyrazol-1-yl) -1-benzoyl azetidin-3-yl) acetonitrile comprises the following steps:

the compound methyl (4- ((1- (1-benzoyl-3- (cyanomethyl) azetidin-3-yl) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pivalate (500.00mg,975.49 μmol,1.0eq) was dissolved in methanol (20mL), and a 1M aqueous solution of sodium hydroxide (58.53mg,1.46mmol,1.5eq) was added thereto at room temperature and stirred for 2H at room temperature. After the TLC monitoring of the raw material reaction is finished, the reaction is finished. Adding water to quench the reaction, adjusting the pH value of the system to about 7 by using 1M hydrochloric acid, separating out a light yellow solid, removing most of the solvent by spinning, filtering, and drying a filter cake to obtain a light yellow solid product, namely 2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1-benzoyl azetidin-3-yl) acetonitrile (91.49mg, yield: 23.54%).

Of Compound II-10¹H NMR(400MHz,DMSO-d₆)δ11.69(s,1H),9.54(s,1H),8.45(s,1H),8.28(s,1H),7.83(s,1H),7.70(d,J＝7.5Hz,2H),7.60–7.51(m,1H),7.49(t,J＝7.4Hz,2H),7.19(s,1H),6.66(s,1H),4.90(d,J＝9.5Hz,1H),4.63(d,J＝9.4Hz,1H),4.57(d,J＝10.6Hz,1H),4.42(d,J＝10.7Hz,1H),3.64(s,2H).HRMS(ESI)calcd for C₂₁H₁₈N₈O[M+H⁺]:399.1676,found:399.2090.

In addition to the compounds described above, other compounds in Table 1 can be prepared by a method similar to that in synthetic examples 1-9, and nuclear magnetic and high resolution mass spectrometry data of a part of the compounds synthesized by reference to synthetic examples 1-9 are given in Table 2 below.

TABLE 2

Other compounds of formula I or formula II of the present invention may be synthesized by methods described above.

Pharmacological Activity test examples

EXAMPLE 1 Compounds physicochemical parameters are given in Table 3 below

TABLE 3 parameters relating to physicochemical Properties of the Compounds

Note: the physicochemical properties (LogP, CLogP and tPSA values) of the compounds are predicted values for Chemdraw software in the chemfice software package.

The results show that the physicochemical properties (LogP, CLOGP, tPSA and the like) of the compounds are equivalent to that of a positive drug Baricitinib (Baricitinib), and the compounds have good drug properties.

Example 2: in vitro inhibitory Activity of Compounds on JAK kinases

Experimental materials: jaktide Peptide substrate, IRStide Peptide substrate, kinases JAK1/JAK2/JAK3/TYK2, Adenosine Triphosphate (ATP), positive control Baricitinib and the like

An experimental instrument: equipment Caliper of PerkinElmer

The experimental method comprises the following steps: fluorescence detection method

The experimental principle is as follows: the half inhibitory concentration IC of the compound was determined by Mobility Shift Assay (Mobility Shift Assay)₅₀(concentration of compound that inhibited enzyme activity to 50%). The EZ Reader of PerkinElmer company can be used for detecting the phosphorylation level of a polypeptide substrate catalyzed by kinase, the device is based on a micro-control fluid separation technology, the substrate and a product which are marked by fluorescence can be directly detected, and the separation step is realized in a microfluidic chip by controlling the pressure and the electric field intensity. The reaction is introduced into the bottom of the chip through the molten silicon pore by using vacuum pressure, the polypeptide substrate with fluorescent label and the reaction product are separated due to different charges because of the potential difference applied to the separation channel in the chip, then the excitation and detection of signals are carried out in the detection window, the signals of the substrate and the product can be simultaneously seen when each sample is detected, and the actual conversion rate can be obtained by comparing the peak heights of the polypeptide product and the polypeptide substrate. The results of the experiment are shown in table 4 below:

TABLE 4 study of JAK kinase inhibition by Compounds

The positive compound has the following structure:

and (4) experimental conclusion: in the evaluation of biological activity, Baricitinib is selected as a positive control drug, and test results show that a part of synthesized compounds have better inhibitory activity and IC (integrated Circuit) for JAK1 and JAK2₅₀The value is at nanomolar level, wherein the compound I-7 with the best activity is equivalent to the activity of a positive control drug, and has the potential efficacy of treating diseases related to the target.

The pyrrolopyrimidine five-membered nitrogen heterocyclic derivatives of the present invention, their production and use are illustrated by the above-mentioned teaching, but the present invention is not limited thereto. It will be apparent to those skilled in the art that various changes and modifications can be made herein, and equivalents may be made thereto without departing from the scope of the invention defined in the appended claims.

Claims

1. A pyrrolopyrimidine five-membered nitrogen heterocycle derivative is characterized in that the pyrrolopyrimidine five-membered nitrogen heterocycle derivative has a structure shown as formula I or formula II:

wherein X is selected from C or N; y is selected from C or N;

R₁is selected from

R₂Selected from SO₂R₃、S(O)R₃Or C (O) R₃；

R₃Is selected from

Or C1-C6 alkyl, wherein R₃R is C1-C6 alkyl₂Is S (O) R₃；

R₄Selected from the group consisting of C3-C8 cycloalkyl, substituted or unsubstituted phenyl, a six membered heterocyclic group, or a bridged ring group;

R₅is composed of

2. The pyrrolopyrimidine five-membered nitrogen heterocyclic derivative according to claim 1, wherein:

in formula I or formula II:

x is selected from C or N; y is selected from C or N;

R₁is selected from

R₂Selected from SO₂R₃、S(O)R₃Or C (O) R₃；

R₃Is selected from

Or ethyl, wherein R₃R in the case of ethyl₂Is S (O) R₃；

R₅is composed of

R₆Is SO₂R₇Or C (O) R₇；

R₇Is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, or fused ring group, wherein said alkyl, cycloalkyl, phenyl, or fused ring group may be optionally substituted with 1, 2, or 3 independent substituents selected from F, Cl, CN, Ph, or C1-C4 alkyl;

3. The pyrrolopyrimidine five-membered nitrogen heterocycle derivative according to claim 1, characterized in that the pyrrolopyrimidine five-membered nitrogen heterocycle derivative is any one of the following compounds:

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. I-1);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile (compound No. I-2);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (ethylsulfinyl) azetidin-3-yl) acetonitrile (compound No. I-3);

2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. I-4);

2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- (2-cyclopropylacetyl) azetidin-3-yl) acetonitrile (compound No. I-5);

2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopropylacetyl) piperidin-4-yl) acetonitrile (compound No. I-6);

2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- ((cyclopropylmethyl) sulfonyl) piperidin-4-yl) acetonitrile (compound No. I-7);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (cyclohexylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. I-8);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-phenylacetyl) azetidin-3-yl) acetonitrile (compound No. I-9);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (benzylsulfonyl) azetidin-3-yl) acetonitrile (compound No. I-10);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (cyclobutylmethyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. I-11);

2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- (benzylsulfonyl) azetidin-3-yl) acetonitrile (compound No. I-12);

2- (3- (3- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrrol-1-yl) -1- (2-phenylacetyl) azetidin-3-yl) acetonitrile (compound No. I-13);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (4-nitrobenzyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. I-14);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- ((((1S) -7, 7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. I-15);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclohexylacetyl) azetidin-3-yl) acetonitrile (compound No. I-16);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-cyclopentylacetyl) azetidin-3-yl) acetonitrile (compound No. I-17);

2- (3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) acetyl) azetidin-3-yl) acetonitrile (compound No. I-18);

2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (benzylsulfonyl) piperidin-4-yl) acetonitrile (compound No. I-19);

2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (((1R) -7, 7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methyl) sulfonyl) piperidin-4-yl) acetonitrile (compound No. I-20);

2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2-phenylacetyl) piperidin-4-yl) acetonitrile (compound No. I-21);

2- (4- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -1- (2- (tetrahydro-2H-pyran-4-yl) acetyl) piperidin-4-yl) acetonitrile (compound No. I-22);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (methanesulfonyl) azetidin-3-yl) acetonitrile (compound No. II-1);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (ethylsulfonyl) azetidin-3-yl) acetonitrile (compound No. II-2);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (propylsulfonyl) azetidin-3-yl) acetonitrile (compound No. II-3);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (isopropylsulfonyl) azetidin-3-yl) acetonitrile (compound No. II-4);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (cyclopropylsulfonyl) azetidin-3-yl) acetonitrile (compound No. II-5);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1-tosylazetidin-3-yl) acetonitrile (compound No. II-6);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- ((4- (tert-butyl) phenyl) sulfonyl) azetidin-3-yl) acetonitrile (compound No. II-7);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (naphthalen-2-ylsulfonyl) azetidin-3-yl) acetonitrile (compound No. II-8);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (benzylsulfonyl) azetidin-3-yl) acetonitrile (compound No. II-9);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1-benzoylazetidin-3-yl) acetonitrile (compound No. II-10);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1-acetoacetazepan-3-yl) acetonitrile (compound No. II-11);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (2-phenylacetyl) azetidin-3-yl) acetonitrile (compound No. II-12);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1- (cyclopropanecarbonyl) azetidin-3-yl) acetonitrile (compound No. II-13);

2- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -1-pivaloyl azetidin-3-yl) acetonitrile (compound No. II-14);

3- (3- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-1-yl) -3- (cyanomethyl) azetidin-1-yl) -3-oxopropanenitrile (compound No. II-15).

4. A method for preparing a pyrrolopyrimidine five-membered nitrogen heterocyclic derivative according to claim 1, characterized in that the preparation route is as follows:

5. The method according to claim 4, characterized by comprising the steps of:

6. Use of a pyrrolopyrimidine five-membered nitrogen heterocyclic derivative according to claim 1, characterized in that:

the pyrrolopyrimidine five-membered nitrogen heterocyclic derivative, the tautomer, the enantiomer and the diastereomer thereof or the pharmaceutically acceptable salt thereof are used for preparing the medicine for preventing and/or treating the indication related to the JAK kinase function.

7. Use according to claim 6, characterized in that:

the indications associated with JAK kinase function include inflammatory diseases, autoimmune diseases, and cancer-related diseases.

8. Use according to claim 7, characterized in that:

the indications related to the JAK kinase function comprise rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, ulcerative colitis, psoriasis, alopecia areata, vitiligo, asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis or neurodermatitis and other indications.