CN108484609A - A kind of preparation and application of novel purine analogue jak kinase inhibitor - Google Patents

A kind of preparation and application of novel purine analogue jak kinase inhibitor Download PDF

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CN108484609A
CN108484609A CN201810328225.8A CN201810328225A CN108484609A CN 108484609 A CN108484609 A CN 108484609A CN 201810328225 A CN201810328225 A CN 201810328225A CN 108484609 A CN108484609 A CN 108484609A
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optionally substituted
unsubstituted
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hydrogen atom
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张大永
张天泰
陈成娟
殷缘
于汝南
舒蕾
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Institute of Materia Medica of CAMS
China Pharmaceutical University
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China Pharmaceutical University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The present invention provides can be used for preventing, treating and/or improve autoimmune disease (such as, psoriasis, rheumatoid arthritis, inflammatory bowel disease, siogren's syndrome, Behcet's disease, multiple sclerosis, systemic loupus erythematosus etc.) etc. drug, with excellent jak kinase (janus kinase) inhibitory activity.The present invention also provides the pharmaceutically acceptable compositions comprising the compound and the method for being used to prepare these compounds.

Description

Preparation and application of novel purine analogue JAK kinase inhibitor
The technical field is as follows:
the present invention relates to a heterocyclic compound having a JAK kinase inhibitory action, which is useful as an agent for preventing, treating and/or improving autoimmune diseases (e.g., Psoriasis (Psoriasis), rheumatoid arthritis (rheumatoid arthritis), inflammatory bowel disease (inflammatory bowel disease), sjogren's syndrome (sjogren's syndrome), behcet's disease, multiple sclerosis (multiple sclerosis), systemic lupus erythematosus (systemic lupus erythematosis) and the like), and a pharmaceutical composition containing the same, and the like.
Background art:
JAK kinase (janus kinase) and its downstream effector, signal transduction and transcriptional activator proteins (STATs) form an important cytokine signaling pathway, the JAK-STAT pathway (Science, 1994, 264: 1415-. The discovery of the pathway greatly improves the knowledge of researchers on gene regulation, and the researches discover that the JAK-STAT pathway can be activated by various cytokines, growth factors and receptors and participates in the processes of cell proliferation, differentiation, apoptosis, angiogenesis, immunoregulation and the like (World JGastroenterol, 2007, 13: 6478-.
The JAK kinase family plays a role in the cytokine-dependent regulation of cellular functions associated with growth and immune responses. In mammals, there are four JAK kinases: JAK-1 (also known as janus kinase 1), JAK-2 (also known as janus kinase 2), JAK-3 (also known as janus kinase 3), and TYK-2 (also known as tyrosine kinase 2). The JAK-STAT signaling pathway is a signaling pathway stimulated by multiple cytokine receptors, JAK kinases mediate signaling of most cytokines in cells (Prog Med Chem, 2013, 52: 153-. Among them, JAK-3 regulates cell signaling by binding to the gamma chain (yc) in the type I cytokine receptor complex such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Severe Combined Immunodeficiency (SCID) can result when JAK-3 is defective or gammac mutated, manifested as immune-restricted symptoms of T-cell and natural killer cell (NK) depletion, loss of B-cell function, etc. (Chinese J New Drug, 2015, 24: 39-45). When present in suitable amounts, these cytokines play an important role in the immune response. However, their overproduction is believed to be associated with a number of autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, and the like (Journal of Allergy and clinical Tmmurmmurgy 127, 3, 701-721.e70(2011), Cytoki ne & Growth Factor Reviews 19, 41-52(2008), Invest Ophthalmol Visi Sci.2008Jul; 49 (7): 3058-3064, Ann Rheumdis.2010Jul; 69 (7): 1325-1328). For example, in Europe, Ustekinumab, which is an anti-IL-12/23 monoclonal antibody, has been approved as a therapeutic drug for patients with moderate to severe psoriasis, and in addition, clinical trials for various diseases involved in the IL-12/23 signaling pathway have been conducted. From the above, JAK kinase inhibitors are potential therapeutic drugs for various autoimmune diseases (Front biosci.2011Jun 1; 17: 3214-32).
Examples of the compounds having a structure similar to that of the compounds described in the present specification include the following compounds.
(1) A compound represented by the formula:
(non-patent document 1).
(2) A compound represented by the formula:
(non-patent document 2).
(3) A compound represented by the formula:
(non-patent document 3).
(4) In the chemical abstracts, the following compounds were registered.
1) Registration number: 1808289-89-5
2) Registration number: 1422827-35-7
List of documents
Non-patent document
[ non-patent document 1] Zapf C W, Gerstenberger B S, Xing L, et al.Covalintinhibitors of interleukin-2 indicator T cell kinase (itk) with a nano porous a porous-blood assay [ J ]. Journal of medical chemistry, 2012, 55 (22): 10047-10063.
[ non-patent document 2] Li X, Wang A, Yu K, et al.discovery of (R) -1- (3- (4-Amino-3- (4-phenoxypheny1) -1H-pyrazolo [3, 4-d ] pyrimid-1-y 1) pidin-1-y 1) -2- (dimethylamine) ethane (CHMFL-FLT3-122) as a patent and Available approach FLT3Kinase Inhibitor for FLT3-ITD Positive acid Myeloid Leukamia [ J ]. Journal of media, 2015, 58 (24): 9625-9638.
[ non-patent document 3] Engel J, Becker C, Lategahn J, et al. insight into the introduction of Drug-Resistant Mutants of the Receptor type Kinase EGFR [ J ]. Angewandte Chemie International Edition, 2016, 55 (36): 10909-10912.
Summary of the invention
Problems to be solved by the invention
It is an object of the present invention to provide a medicament for preventing, treating and/or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus and the like) and the like, which has an excellent JAK-1 and/or JAK-3 inhibitory effect.
Means for solving the problems
The present inventors have conducted intensive studies in an attempt to solve the above problems, and have found that a compound (I) represented by the following formula has an excellent JAK-1 and/or JAK-3 inhibitory effect, thereby completing the present invention.
Accordingly, the present invention provides the following.
[1] A compound represented by the formula (I):
wherein
X1Is a nitrogen atom or-CH-;
X2is a nitrogen atom or-CH-;
R1is a hydrogen atom, a halogen atom, a cyano group, an acryloyl group, a 2-cyanoacetyl group, an optionally substituted C1-6A hydrocarbyl or optionally substituted cyclic group;
R2is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C1-6An alkyl group;
R3、R4independently selected from hydrogen atom, halogen atom, cyano group, optionally substituted C1-6A hydrocarbyl or optionally substituted cyclic group; r5Is L1-A-L2-G, wherein,
L1is optional and when present is a bond, optionally substituted or unsubstituted C1-6Hydrocarbyl, optionally substituted or unsubstituted C3-8Cycloalkyl, optionally substituted or unsubstituted C2-7Alkenyl, optionally substituted or unsubstituted C2-7An alkynyl group;
a is optional and, when present, is a bond, -O-, -C (═ O) -, -S (═ O)2-、-NH-、-NR10-、-NHC(O)-、-C(O)NH-、-NR10C(O)-、-C(O)NR10-、-S(＝O)2NH-、-NHS(＝O)2-、-S(＝O)2NR10-、-NR10S(＝O)2-、-OC(O)NH-、-NH C(O)O-、-O C(O)NR10-、-NR10C(O)O-、-CH＝NO-、-ON＝CH-、-NR11C(O)NR11-, heteroaryl-, aryl-, -NR11C(＝NR12)NR11-、-NR11C(＝NR12)-、-C(＝NR12)NR11-、OC(＝NR12) -or-C (═ NR)12)O-；
L2Is optional and when present is a bond, optionally substituted or unsubstituted C1-6Hydrocarbyl, optionally substituted or unsubstituted C3-8Cycloalkyl, optionally substituted or unsubstituted C2-7Alkenyl, optionally substituted or unsubstituted C2-7Alkynyl, substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl, substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl, substituted or unsubstituted 4-, 5-, 6-, 7-or 8-membered heterocycle;
or L1A and L2Together form a nitrogen-containing heterocyclic ring;
g is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy,
Wherein,
b is independently selected from hydrogen atom, halogen, cyano, hydroxyl;
R6、R7、R8and R9Independently selected from hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted C1-6Hydrocarbyl or substituted or unsubstituted C1-6Heterohydrocarbyl or substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C3-8A heterocycloalkyl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl group;
each R10Independently selected from a hydrogen atom, substituted or unsubstituted C1-6A hydrocarbon group, and substituted or unsubstituted C3-8A cyclic hydrocarbon group;
each R11Independently a hydrogen atom, substituted or unsubstituted C1-6A hydrocarbon group, or a substituted or unsubstituted C3-8A cyclic hydrocarbon group; or two R11The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or
R11And R12May together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or
Each R12Independently selected from a hydrogen atom or substituted or unsubstituted C1-6A hydrocarbyl group;
[2] the compound of the above [1] or a salt thereof, wherein,
R1is that
(1) A hydrogen atom, and a nitrogen atom,
(2) a halogen atom,
(3) the cyano group(s),
(4) an acryl group,
(5) 2-cyanoacetyl group,
(6) c optionally substituted with 1 to 3 substituents selected from the group consisting of1-6Alkyl groups: (a) hydrogen atom, (b) halogen atom, (C) hydroxyl group, (d) C1-6Alkoxy, (e) C3-8Cycloalkyl, (f) C1-6Alkyl-carbonyl mono-or di-substituted amino,
(7) c optionally substituted with 1 to 3 substituents selected from the group consisting of2-7Alkenyl: (a) a hydrogen atom, (b) a halogen atom, (C) an optionally substituted C1-6An alkyl group, a carboxyl group,
(8) c optionally substituted with 1 to 3 substituents selected from the group consisting of2-7Alkynyl: (a) a hydrogen atom, (b) a halogen atom, (C) an optionally substituted C1-6An alkyl group, a carboxyl group,
(9) c optionally substituted with 1 to 3 substituents selected from the group consisting of3-10Cycloalkyl groups: (a) halogen atom, (b) C1-6An alkyl group;
(10) a 3 to 8 membered monocyclic non-aromatic heterocyclic group, or
(11) A 5-or 6-membered monocyclic aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom, (b) a cyano group; r2Is a hydrogen atom, a halogen atom or a cyano group;
R3、R4is independently selected from
(1) A hydrogen atom, and a nitrogen atom,
(2) a halogen atom,
(3) the cyano group(s),
(4) an acryl group,
(5) 2-cyanoacetyl group,
(6) c optionally substituted with 1 to 3 substituents selected from the group consisting of1-6Alkyl groups: (a) hydrogen atom, (b) halogen atom, (C) hydroxyl group, (d) C1-6Alkoxy, (e) C3-8Cycloalkyl, (f) C1-6Alkyl-carbonyl mono-or di-substituted amino,
(7) c optionally substituted with 1 to 3 substituents selected from the group consisting of2-6Alkenyl: (a) a hydrogen atom, (b) a halogen atom, (C) an optionally substituted C1-6An alkyl group, a carboxyl group,
(8) c optionally substituted with 1 to 3 substituents selected from the group consisting of3-10Cycloalkyl groups: (a) halogen atom, (b) C1-6An alkyl group, a carboxyl group,
(9) c optionally substituted with 1 to 3 substituents selected from the group consisting of6-14Aryl: (a) a halogen atom, (b) optionally substituted by 1 to 3 halogen atomsSubstituted C1-6Alkyl, (C) cyano, (d) optionally substituted by C1-6Alkyl-carbonyl mono-or disubstituted amino, (e) C1-6An alkoxy group,
(10) a 3 to 8 membered monocyclic non-aromatic heterocyclic group, or
(11) A 5-or 6-membered monocyclic aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom, (b) a cyano group; r5Is that
[3]Above-mentioned [1]To [2]]The use of any one of, wherein L1A and L2Together form a nitrogen-containing heterocyclic ring.
[4] The use as described in the above [3], wherein the heterocycle containing nitrogen is an azetidinyl group, a pyrrolidine group or a piperidine group.
[5]Above-mentioned [1]To [4]]The use of any one of, wherein G is cyano,
[6] The medicament according to claims 1 to 5, which is a JAK-1 and/or JAK-3 inhibitor.
[7] The pharmaceutical agent as claimed in claim 6, which is an agent for preventing, treating and/or ameliorating an autoimmune disease.
[8] A medicament as claimed in claim 7, wherein the autoimmune disease is psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis or systemic lupus erythematosus.
[9] Use of the compound of claim 1 or a salt thereof for the production of a medicament for preventing and/or ameliorating an autoimmune disease.
[10] The use of claim 9, wherein the autoimmune disease is psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, or systemic lupus erythematosus.
Effects of the invention
The compound (I) has an excellent JAK-1 and/or JAK-3 inhibitory action and is useful as an agent for preventing, treating or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis, etc.), Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.), and the like.
Detailed description of the invention
In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
In the present specification, "C" or "C" is used1-6By "hydrocarbyl (group)" is meant C1-6Alkyl radical, C2-7Alkenyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C1-6Alkyl-carbonyl mono-or di-substituted aminoaryl, and the like.
In the present specification, "C" or "C" is used1-6Alkyl (group) "means, for example, methyl, ethyl, isopropyl, butyl, sec-butyl, pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, isohexyl, 1-dimethylbutyl, 3-dimethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, 1, 2-dimethylpropyl, and the like.
In the present specification, "C" or "C" is used2-7Alkenyl "means, for example, ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 4-methyl-3-pentenyl, 3-hexenyl, 5-hexenyl, and the like.
In the present specification, "C" or "C" is used2-7Alkynyl "means, for example, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 1-pentynyl, 1-dimethylprop-2-yn-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.
In the present specification, "C" or "C" is used1-6Alkoxy "means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like.
In the present specification, "C" or "C" is used2-6The "alkenyloxy group" means, for example, an ethyleneoxy group, a 1-propylenyloxy group, a 2-methyl-1-propylenyloxy group, a 1-butenyloxy group, a 2-butenyloxy group, a 4-methyl-3-pentenyloxy group, a 1-hexenyloxy group, a 3-hexenyloxy group, a 5-hexenyloxy group, etc.
In the present specification, "C" or "C" is used1-6Alkyl-carbonyl mono-or di-substituted aminoaryl "means, for example, N, N-dimethylformyl, N, N-dimethylacetyl, and the like.
In the present specification, "C" or "C" is used6-14Aryl (group) "means, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.
In the present specification, examples of the "monocyclic aromatic heterocyclic group" include 5 to 7-membered (preferably 5 or 6-membered) monocyclic aromatic heterocyclic groups containing, as ring constituting atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom (optionally oxidized) in addition to a carbon atom, for example, furyl (e.g., 2-furyl, 3-furyl) and the like
In the present specification, "non-aromatic heterocyclic group" means a monocyclic non-aromatic heterocyclic group and a condensed non-aromatic heterocyclic group.
In the present specification, examples of the "monocyclic non-aromatic heterocyclic group" include a 3-to 8-membered (preferably 5-or 6-membered) monocyclic non-aromatic heterocyclic group containing, as a ring constituting atom, 1 to 4 atoms selected from an oxygen atom, a sulfur atom (optionally oxidized), and the like, in addition to a carbon atom.
In the present specification, examples of the "fused non-aromatic heterocyclic group" include 8 to 22-membered fused non-aromatic heterocyclic groups, specifically, groups derived from fused rings, among which, corresponding to the above-mentioned 3 to 3Ring of 8-membered monocyclic non-aromatic heterocyclic group and C6-14The fusion of aromatic hydrocarbons; groups derived from fused rings, and the like.
When compound (I) is in the form of a salt, examples thereof include: metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
Among them, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), etc., ammonium salts, etc., and when the compound has a basic functional group, examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, p-toluenesulfonic acid, etc.
Preparation method
The process for producing the compound (I) or a salt thereof of the present invention is described below.
The compound (I) and the starting compound can be prepared according to methods known per se, for example, the methods shown in the following reaction schemes, and the like. In each step of the following preparation method, "room temperature" generally means 5 to 40 ℃, unless otherwise specified, each symbol in the chemical formula described in the reaction scheme is as described above. In the compounds of the formula, each compound includes a salt, and examples of such a salt include salts similar to the salt of the compound (I), and the like.
Among the compounds (I), the compounds represented by the formula (I-A)
Wherein each symbol in the chemical formula is as described above,
(hereinafter, abbreviated as compound (I-A)) can be produced according to the following method A, method B, method C or a method similar thereto. In each step of the preparation process, the starting compounds may be in the form of salts. Examples of the salts include those similar to the salts of compound (I).
Method A
Wherein Y is a halogen atom, Z is-B (OH)2OR-B (OR) (OR '), wherein R and R' are each independently C1-6An alkyl group; or adjacent R and R' are optionally combined, e.g., to form 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl, with the other symbols as described above.
In this method, the compound (II) and the compound (IX) used as starting materials may be commercially available products, or may also be prepared according to a method known per se or a method similar thereto.
Step A-1
This step is a step of converting compound (II) into compound (III) by reacting compound (II) with hydrazine.
The hydrazine is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (II).
Examples of hydrazines used include: hydrazine hydrate (concentration 5% -95%), hydrazine, etc., among which 60% hydrazine hydrate, 80% hydrazine hydrate and 85% hydrazine hydrate are preferable.
In this step, the solvent is not particularly limited, and a solvent may be used or may not be used as long as the reaction can proceed.
In this step, the reaction temperature is usually from about-50 ℃ to about 200 ℃, preferably from about-10 ℃ to about 100 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.
The compound (III) thus obtained can be isolated and purified by using a known separation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Further, the compound (III) can be used directly in the next reaction without purification.
Step A-2
This step is a step of converting compound (III) into compound (IV) by reacting compound (III) with an amide.
The amide is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 30mol, per 1mol of the compound (III).
Examples of the amide used include: formamide, acetamide, and the like, among which formamide is preferred.
In this step, the solvent is not particularly limited, and a solvent may be used or may not be used as long as the reaction can proceed.
In this step, the reaction temperature is usually about-50 ℃ to about 250 ℃, preferably about 50 ℃ to about 250 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.
The compound (IV) thus obtained can be isolated and purified by using a known separation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Further, the compound (IV) can be used directly in the next reaction without purification.
Step A-3
This step is a step of converting compound (IV) into compound (V) by subjecting compound (IV) to a halogenation reaction with a halogenating agent.
The halogenating agent is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (IV).
Examples of the halogenated agents used include: fluorine, chlorine, bromine, iodine, NBS, NIS, etc., and among them, bromine and iodine are preferable.
In this step, the solvent is not particularly limited as long as the reaction can proceed.
In this step, the reaction temperature is usually about-50 ℃ to about 200 ℃, preferably about 50 ℃ to about 200 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.
In this step, the reaction gas shielding is not particularly limited, and gas shielding may be performed or not, as long as the reaction can be performed. The shielding gas includes: nitrogen, argon, and the like.
The compound (V) thus obtained can be isolated and purified by using a known isolation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, acid-soluble base precipitation and the like. Further, the compound (V) can be used directly in the next reaction without isolation.
Step A-4
This step is a step of converting the compound (V) into the compound (VI) by subjecting the compound (V) to a substitution reaction with a substitution reagent.
The substitution reagent is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (VI).
In this step, the solvent is not particularly limited as long as the reaction can proceed.
In this step, the reaction temperature is generally from about-50 ℃ to about 250 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.
In this step, the reaction gas shielding is not particularly limited, and gas shielding may be performed or not, as long as the reaction can be performed. The shielding gas includes: nitrogen, argon, and the like.
The compound (VI) thus obtained can be isolated and purified by using a known isolation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, acid-soluble base precipitation and the like. Further, the compound (VI) can be used directly in the next reaction without isolation.
Step A-5
This step is a step of subjecting the compound (VI) to a coupling reaction with the compound (VII) and a transition metal catalyst, converting the compound (VI) and the compound (I-A).
The reaction with the transition metal catalyst may be carried out according to a method known per se [ e.g., Chemical Reviews, 1995, vol.95, page 2457, etc. ], for example, in the presence of a transition metal catalyst and a base in a solvent which does not adversely affect the reaction.
The compound (VII) is used in an amount of about 1mol to about 100mol, preferably about 1mol to about 10mol, per 1mol of the compound (VI).
Examples of the transition metal catalyst used include: palladium catalysts (e.g., palladium (II) acetate, etc.), nickel catalysts (e.g., nickel chloride, etc.), and the like. If necessary, a ligand (e.g., 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl, etc.) may be added, and a metal oxide (e.g., copper oxide, silver oxide, etc.) may be used as a promoter. Meanwhile, the amount of the transition metal catalyst used varies depending on the kind of the catalyst, and generally, about 0.0001mol to about 1mol, preferably about 0.01mol to about 0.5mol, is used per 1mol of the compound (VI). The amount of the ligand or cocatalyst used is usually from about 0.0001mol to about 4mol, preferably from about 0.01mol to about 2mol, per 1mol of the compound (VI).
Examples of the base used include: organic amines (e.g., trimethylamine, triethylamine, etc.), alkali metal salts (e.g., sodium bicarbonate, etc.), metal hydrides (potassium hydride, etc.), alkali metal alcoholates (sodium methylate, etc.), alkali metal disilylamides (e.g., lithium disilylamide, etc.), and the like. Among them, alkali metal salts (sodium carbonate, potassium carbonate, cesium carbonate, etc.) are preferable.
The base is generally used in an amount of about 0.01mol to about 100mol, preferably about 0.1mol to about 10mol, per 1mol of the compound (VI).
In this step, the solvent is not particularly limited as long as the reaction can proceed.
In this step, the reaction temperature is usually from about-50 ℃ to about 200 ℃, preferably from about-50 ℃ to about 150 ℃. In this step, the reaction time is usually about 0.1 hour to about 100 hours.
In this step, the reaction gas shielding is not particularly limited, and gas shielding may be performed or not, as long as the reaction can be performed. The shielding gas includes: nitrogen, argon, and the like.
The compound (I-a) thus obtained can be isolated and purified by using a known isolation and purification method, for example, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, acid-soluble base precipitation and the like.
Examples
Hereinafter, the present invention is explained in more detail with reference to reference examples, experimental examples and formulation examples, but these examples do not limit the present invention and may be changed within the scope of the present invention.
In the examples below, "room temperature" generally means about 10 ℃ to about 35 ℃. The proportions indicated by the mixed solvents are volume mixing proportions unless otherwise specified. Unless otherwise specified,% means wt%.
In silica gel column chromatography, basic silica gel refers to silica gel bound with aminopropylsilane. In high performance liquid chromatography (HP1C), C18 refers to the use of octadecyl coupled silica gel. The ratio of elution solvents is a volume mixing ratio unless otherwise specified.
Reference example 1
1-methyl-4-pyrazole boronic acid pinacol ester
4-iodopyrazole (2g, 10.3mmol), potassium carbonate (2.14g), methyl iodide (1.72g) and 25mL of acetonitrile were reacted under reflux for 12 h. Spin-drying under reduced pressure, adding 50mL water, extracting with 50mL ethyl acetate for 3 times, mixing organic layers, washing with saturated saline, adding anhydrous Na into organic phase2SO4Drying, drying under reduced pressure to obtain 1-methyl-4-iodopyrazole (2.1 g).
Adding isopropyl magnesium chloride/lithium chloride solution (3.97mL) into 1-methyl-4-iodopyrazole (1.0g) and 10mL of THF slowly under the protection of nitrogen, wherein the temperature does not exceed 0 ℃ in the dropping process, stirring for 1h after adding, then slowly dropping isopropyl pinacol borate (1.11g) at the temperature of 0 ℃ to control the temperature to not exceed 0 ℃, stirring for 1.5h at room temperature after adding, dropping 10mL of saturated ammonium chloride solution after completely reacting, and quenching. Then adding 50mL ethyl acetate and 10mL saturated ammonium chloride solution, separating organic layer, extracting water layer with 50mL ethyl acetate twice, combining organic layers, adding anhydrous Na2SO4Drying and drying under reduced pressure gave the title product (1 g).
MS(ESI+)：[M+H]+209.3。
Reference example 2
1-Ethylmethyl ether-4-pyrazole boronic acid pinacol ester
The title compound was obtained from 4-iodopyrazole, 2-bromomethylethylether, isopropylmagnesium chloride/lithium chloride solution and isopropylpinacol borate by the same method as in reference example 1.
MS(ESI+)：[M+H]+253.4。
Reference example 3
1- (2-hydroxy) ethyl-4-pyrazoleboronic acid pinacol ester
The title compound was obtained from 4-iodopyrazole, 2-bromoethanol, isopropyl magnesium chloride/lithium chloride solution and isopropyl pinacol borate by the same method as in reference example 1.
MS(ESI+)：[M+H]+239.2。
Reference example 4
1-acryloyl-3-hydroxymethylpiperidine
To 3-hydroxymethylpiperidine (3g), triethylamine (3.16g) and 30mL of dichloromethane was added acryloyl chloride (2.48g) slowly at-10 ℃ and the reaction was then allowed to proceed for 2h with stirring at-10 ℃. After the reaction, the reaction mixture was dried under reduced pressure, 25mL of water was added, extraction was performed 3 times with 50mL of dichloromethane, the organic layers were combined, and anhydrous Na was added to the organic layer2SO4Drying, drying under reduced pressure and column chromatography on silica gel (basic silica gel, hexane/ethyl acetate) gave the title compound (3.8 g).
MS(ESI+)：[M+H]+170.1。
Reference example 5
1-acryloyl-3-hydroxypiperidine
The title compound was obtained from 3-hydroxypiperidine and acryloyl chloride by the same method as in reference example 9.
MS(ESI+)：[M+H]+156.5。
Reference example 6
1-acryloyl-4-hydroxymethylpiperidine
The title compound was obtained from 4-hydroxymethylpiperidine and acryloyl chloride using the same method as in reference example 9.
MS(ESI+)：[M+H]+170.1。
Reference example 7
1-acryloyl-3-hydroxypiperidine
The title compound was obtained from 4-hydroxypiperidine and acryloyl chloride by the same method as in reference example 9.
MS(ESI+)：[M+H]+156.5。
Reference example 8
1-acryloyl-3-hydroxymethyl-pyrrolidine
The title compound was obtained from 3-hydroxymethylpyrrolidine and acryloyl chloride using the same method as in reference example 9.
MS(ESI+)：[M+H]+156.2。
Reference example 9
1-acryloyl-3-hydroxypyrrolidine
The title compound was obtained from 3-hydroxypyrrolidine and acryloyl chloride using the same method as in reference example 9.
MS(ESI+)：[M+H]+142.6。
Reference example 10
1-acryloyl-3-hydroxyazetidines
The title compound was obtained from 3-hydroxyazetidine and acryloyl chloride using the same procedures as in reference example 9.
MS(ESI+)：[M+H]+128.3。
Reference example 11
1-cyano-3-hydroxymethylpiperidine
To 3-hydroxymethylpiperidine (3g), potassium carbonate (5.4g) and 30mL of methanol was added bromocyanogen (3.3g) at 0 ℃ and the reaction was then carried out for 12 hours with stirring at room temperature. After the reaction was completed, it was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to obtain the title compound (3.5 g).
MS(ESI+)：[M+H]+141.1。
Reference example 12
1-cyanoacetyl-3-hydroxypiperidine
Cyanoacetic acid (2.1g), HATU (18.8g), DIEA (15.3g) and 30mL of methylene chloride were reacted at 0 ℃ for 0.5 hour with stirring, and then 3-hydroxypiperidine (2g) was added to the mixture and reacted at room temperature for 12 hours with stirring. After the reaction was completed, it was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to obtain the title compound (2.5 g).
MS(ESI+)：[M+H]+169.1。
Example 1
1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2-propen-1-one
A) 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidines
To 4-aminopyrazolo [3, 4-d at room temperature]Pyrimidine (2g) and H2To O25 mL, bromine (2g) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 1 hour, followed by reaction under reflux for 1 hour, followed by spin-drying under reduced pressure, dissolution in water, PH adjustment to 7, precipitation, suction filtration, and washing to obtain the title compound (2.5 g).
1H NMR(300MHz，CDCl3)δ＝6.7to 6.9(m，2H)，8.3(s，1H)，13.2(s，1H).
B)1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2-propen-1-one
Diisopropyl azodicarboxylate (5.6g) was added dropwise to 200mL of 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidine (2g), triphenylphosphine (7.3g), 1- (3-hydroxypiperidinyl) -2-propen-1-one (1.7g) and tetrahydrofuran at 0 ℃ and then the mixture was stirred at room temperature for 16 hours, dried under reduced pressure and purified by silica gel column chromatography to give the title compound (2 g).
1H NMR(300MHz，CDCl3)δ＝1.6(m，2H)，1.9(m，1H)，2.1(m，1H)，3.1(m，2H)，4.2(m，2H)，4.6(m，1H)，4.7(m，1H)，5.7(dd，1H)，6.1(t，1H)，6.7to 6.9(m，2H)，8.2(s，1H).
C)1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2-propen-1-one
Adding 1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) -1-piperidinyl]-2-propen-1-one (0.2g), potassium carbonate (0.19g), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.25g) and 10mL of 1, 4-dioxane and 2mL of water, tetrakis (triphenylphosphine) palladium (0.035g) were stirred overnight at 100 ℃ and N was carried out2After completion of the reaction by protection, the reaction mixture was dried under reduced pressure and purified by silica gel column chromatography to give the title compound (0.15 g).
MS(ESI+)：[M+H]+353.2。
Examples 2 to 7
In examples 2 to 7, 1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d) obtained by the step B of example 1 was obtained in the same manner as in example 1]Pyrimidin-1-yl) -1-piperidinyl]-2-propen-1-one and optionally substituted by 1 to 3 substituents selected from halogen atoms, cyano, amino, 2-cyanoacetyl, C1-6Alcohol, C1-6Alcohol ether, C1-6Alkyl of (C)2-8Cycloalkylalkyl of (C)2-6Alkenyl and C2-6Alkynyl and the likeA group-substituted 5-or 6-membered monocyclic heterocycle (e.g., pyrazole, pyrrole, etc.) (corresponding to the compounds of examples 2 to 7) to obtain the title compound. The MS in the table is an observed value.
TABLE 1
Example 8
1- [3- ((4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) methyl) -1-piperidinyl ] -2-propen-1-one
A) 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidines
To 4-aminopyrazolo [3, 4-d at room temperature]Pyrimidine (2g) and H2To O25 mL, bromine (2g) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 1 hour, followed by reaction under reflux for 1 hour, followed by spin-drying under reduced pressure, dissolution in water, PH adjustment to 7, precipitation, suction filtration, and washing to obtain the title compound (2.5 g).
1H NMR(300MHz，CDCl3)δ＝6.7to 6.9(m，2H)，8.3(s，1H)，13.2(s，1H).
B)1- [3- ((4-amino-3-bromo-1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) methyl) -1-piperidinyl ] -2-propen-1-one
Diisopropyl azodicarboxylate (5.6g) was added dropwise to 200mL of 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidine (2g), triphenylphosphine (7.3g), 1- (3-hydroxymethylpiperidinyl) -2-propen-1-one (1.9g) and tetrahydrofuran at 0 ℃ and then the mixture was stirred at room temperature for 16 hours, dried under reduced pressure and purified by silica gel column chromatography to give the title compound (2.1 g).
1H NMR(300MHz，CDCl3)δ＝1.5(m，2H)，1.9(m，1H)，2.1(m，1H)，3.1(m，2H)，3.6-3.8(m，2H)4.2(m，2H)，4.6(m，1H)，4.7(m，1H)，5.7(dd，1H)，6.1(t，1H)，6.9to 7.1(m，2H)，8.3(s，1H).
C)1- [3- ((4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) methyl) -1-piperidinyl ] -2-propen-1-one
Adding 1- [3- ((4-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) methyl) -1-piperidinyl]-2-propen-1-one (0.2g), potassium carbonate (0.19g), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.25g) and 10mL of 1, 4-dioxane and 2mL of water, tetrakis (triphenylphosphine) palladium (0.035g) were stirred overnight at 100 ℃ and N was carried out2After completion of the reaction by protection, the reaction mixture was dried under reduced pressure and purified by silica gel column chromatography to give the title compound (0.15 g).
MS(ESI+)：[M+H]+367.5。
Examples 9 to 14
In examples 9 to 14, 1- [3- ((4-amino-3-bromo-1H-pyrazolo [3, 4-d) obtained by the step B of example 8 was obtained by the same method as in example 8]Pyrimidin-1-yl) methyl) -l-piperidinyl]-2-propen-1-one and optionally substituted by 1 to 3 substituents selected from halogen atoms, cyano, amino, 2-cyanoacetyl, C1-6Alcohol, C1-6Alcohol ether, C1-6Alkyl of (C)2-8Cycloalkylalkyl of (C)2-6Alkenyl and C2-6And the like (corresponding to the compounds of examples 9 to 14) to obtain the title compound. The MS in the table is an observed value.
TABLE 2
Example 15
1- [4- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2-propen-1-one
A) 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidines
To 4-aminopyrazolo [3, 4-d at room temperature]Pyrimidine (2g) and H2To O25 mL, bromine (2g) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 1 hour, followed by reaction under reflux for 1 hour, followed by spin-drying under reduced pressure, dissolution in water, PH adjustment to 7, precipitation, suction filtration, and washing to obtain the title compound (2.5 g).
1H NMR(300MHz，CDCl3)δ＝6.7to 6.9(m，2H)，8.3(s，1H)，13.2(s，1H).
B)1- [4- (4-amino-3-bromo-1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2-propen-1-one
Diisopropyl azodicarboxylate (5.6g) was added dropwise to 200mL of 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidine (2g), triphenylphosphine (7.3g), 1- (4-hydroxypiperidinyl) -2-propen-1-one (1.7g) and tetrahydrofuran at 0 ℃ and then the mixture was stirred at room temperature for 16 hours, dried under reduced pressure and purified by silica gel column chromatography to give the title compound (2 g).
1H NMR(300MHz，CDCl3)δ＝2.0(m，4H)，3.7(m，1H)，4.2(m，4H)，4.7(m，1H)，5.7(dd，1H)，6.1(t，1H)，7.2(m，2H)，8.2(s，1H).
C)1- [4- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2-propen-1-one
Adding 1- [4- (4-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) -1-piperidinyl]-2-propen-1-one (0.2g), potassium carbonate (0.19g), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.25g) and 10mL of 1, 4-dioxane and 2mL of water, tetrakis (triphenylphosphine) palladium (0.035g) were stirred overnight at 100 ℃ and N was carried out2After completion of the reaction by protection, the reaction mixture was dried under reduced pressure and purified by silica gel column chromatography to give the title compound (0.15 g).
MS(ESI+)：[M+H]+353.2。
Examples 16 to 21
In examples 16 to 21, 1- [4- (4-amino-3-bromo-1H-pyrazolo [3, 4-d) obtained by the step B of example 15 was obtained in the same manner as in example 15]Pyrimidin-1-yl) -1-piperidinyl]-2-propen-1-one and optionally substituted by 1 to 3 substituents selected from halogen atoms, cyano, amino, 2-cyanoacetyl, C1-6Alcohol, C1-6Alcohol ether, C1-6Alkyl of (C)2-8Cycloalkylalkyl of (C)2-6Alkenyl and C2-6And the like (corresponding to the compounds of examples 16 to 21) to obtain the title compound. The MS in the table is an observed value.
TABLE 3
Example 22
1- [4- ((4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) methyl) -1-piperidinyl ] -2-propen-1-one
A) 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidines
To 4-aminopyrazolo [3, 4-d at room temperature]Pyrimidine (2g) and H2To O25 mL, bromine (2g) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 1 hour, followed by reaction under reflux for 1 hour, followed by spin-drying under reduced pressure, dissolution in water, PH adjustment to 7, precipitation, suction filtration, and washing to obtain the title compound (2.5 g).
1H NMR(300MHz，CDCl3)δ＝6.7to 6.9(m，2H)，8.3(s，1H)，13.2(s，1H).
B)1- [4- ((4-amino-3-bromo-1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) methyl) -1-piperidinyl ] -2-propen-1-one
Diisopropyl azodicarboxylate (5.6g) was added dropwise to 200mL of 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidine (2g), triphenylphosphine (7.3g), 1- (4-hydroxymethylpiperidinyl) -2-propen-1-one (1.9g) and tetrahydrofuran at 0 ℃ and then the mixture was stirred at room temperature for 16 hours, dried under reduced pressure and purified by silica gel column chromatography to give the title compound (2.1 g).
1H NMR(300MHz，CDCl3)δ＝2.0(m，4H)，3.7(m，1H)，3.6-3.8(m，2H)4.2(m，4H)，4.6(m，1H)，4.7(m，1H)，5.7(dd，1H)，6.1(t，1H)，6.9to 7.1(m，2H)，8.3(s，1H).
C)1- [4- ((4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) methyl) -1-piperidinyl ] -2-propen-1-one
Adding 1- [3- ((4-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) methyl) -1-piperidinyl]-2-propen-1-one (0.2g), potassium carbonate (0.19g), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.25g) and 10mL of 1, 4-dioxane and 2mL of water, tetrakis (triphenylphosphine) palladium (0.035g) were stirred overnight at 100 ℃ and N was carried out2After completion of the reaction by protection, the reaction mixture was dried under reduced pressure and purified by silica gel column chromatography to give the title compound (0.15 g).
MS(ESI+)：[M+H]+367.5。
Examples 23 to 14
In examples 23 to 28, 1- [4- ((4-amino-3-bromo-1H-pyrazolo [3, 4-d) obtained by the same procedure as in example 22 in step B of example 22 was used]Pyrimidin-1-yl) methyl) -1-piperidinyl]-2-propen-1-one and optionally substituted by 1 to 3 substituents selected from halogen atoms, cyano, amino, 2-cyanoacetyl, C1-6Alcohol, C1-6Alcohol ether, C1-6Alkyl of (C)2-8Cycloalkylalkyl of (C)2-6Alkenyl and C2-6And the like (corresponding to the compounds of examples 23 to 28) to obtain the title compound. The MS in the table is an observed value.
TABLE 4
Example 29
1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-pyrrolidinyl ] -2-propen-1-one
A) 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidines
To 4-aminopyrazolo [3, 4-d at room temperature]Pyrimidine (2g) and H2To O25 mL, bromine (2g) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 1 hour, followed by reaction under reflux for 1 hour, followed by spin-drying under reduced pressure, dissolution in water, PH adjustment to 7, precipitation, suction filtration, and washing to obtain the title compound (2.5 g).
1H NMR(300MHz，CDCl3)δ＝6.7to 6.9(m，2H)，8.3(s，1H)，13.2(s，1H).
B)1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-pyrrolidinyl ] -2-propen-1-one
Diisopropyl azodicarboxylate (5.6g) was added dropwise to 200mL of 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidine (2g), triphenylphosphine (7.3g), 1- (3-hydroxypyrrolidinyl) -2-propen-1-one (1.6g) and tetrahydrofuran at 0 ℃ and then the mixture was stirred at room temperature for 16 hours, dried under reduced pressure and purified by silica gel column chromatography to give the title compound (1.8 g).
1H NMR(300MHz，CDCl3)δ＝1.9(m，1H)，2.1(m，1H)，3.3(m，2H)，3.6(m，1H)，3.8(m，1H)，4.0(m，1H)，5.5(dd，1H)，6.1(t，1H)，6.6(m，1H)7.4(m，2H)，8.2(s，1H).
C)1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-pyrrolidinyl ] -2-propen-1-one
Adding 1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) -1-pyridinesPyrrolidinyl radical]-2-propen-1-one (0.2g), potassium carbonate (0.19g), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.25g) and 10mL of 1, 4-dioxane and 2mL of water, tetrakis (triphenylphosphine) palladium (0.035g) were stirred overnight at 100 ℃ and N was carried out2After completion of the reaction by protection, the reaction mixture was dried under reduced pressure and purified by silica gel column chromatography to give the title compound (0.13 g).
MS(ESI+)：[M+H]+339.6。
Examples 30 to 35
In examples 30 to 35, 1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d) obtained by the step B of example 29 is prepared in the same manner as in example 29]Pyrimidin-1-yl) -1-pyrrolidinyl]-2-propen-1-one and optionally substituted by 1 to 3 substituents selected from halogen atoms, cyano, amino, 2-cyanoacetyl, C1-6Alcohol, C1-6Alcohol ether, C1-6Alkyl of (C)2-8Cycloalkylalkyl of (C)2-6Alkenyl and C2-6And the like (corresponding to the compounds of examples 30 to 35) to obtain the title compound. The MS in the table is an observed value.
TABLE 5
Example 36
1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-azetidinyl ] -2-propen-1-one
A) 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidines
To 4-aminopyrazolo [3, 4-d at room temperature]Pyrimidine (2g) and H2To O25 mL, bromine (2g) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 1 hour, followed by reaction under reflux for 1 hour, followed by spin-drying under reduced pressure, dissolution in water, PH adjustment to 7, precipitation, suction filtration, and washing to obtain the title compound (2.5 g).
1H NMR(300MHz，CDCl3)δ＝6.7to 6.9(m，2H)，8.3(s，1H)，13.2(s，1H).
B)1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-pyrrolidinyl ] -2-propen-1-one
To 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidine (2g), triphenylphosphine (7.3g), 1- (3-hydroxyazetidinyl) -2-propen-1-one (1.6g) and 200mL of tetrahydrofuran were added dropwise diisopropyl azodicarboxylate (5.6g) at 0 ℃ and the mixture was stirred at room temperature for 16 hours, dried under reduced pressure and purified by silica gel column chromatography to give the title compound (1.8 g).
1H NMR(300MHz，CDCl3)δ＝4.0(m，2H)，4.3(m，2H)，4.6(m，1H)，5.5(dd，1H)，6.1(t，1H)，6.6(m，1H)7.4(m，2H)，8.2(s，1H).
C)1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-azetidinyl ] -2-propen-1-one
Adding 1- [3- (4-amino-3-bromo-1H-pyrazolo [3, 4-d)]Pyrimidin-1-yl) -1-azacyclobutaneyl]-2-propen-1-one (0.2g), potassium carbonate (0.19g), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (0.25g) and 10mL of 1, 4-dioxane and 2mL of water, tetrakis (triphenylphosphine) palladium (0.035g) were stirred overnight at 100 ℃ and N was carried out2After completion of the reaction by protection, the reaction mixture was dried under reduced pressure and purified by silica gel column chromatography to give the title compound (0.13 g).
MS(ESI+)：[M+H]+325.3。
Example 37
1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2- (N, N-dimethylamino) ethanone propionitrile
A) 4-amino-3-bromopyrazolo [3, 4-d ] pyrimidines
To 4-aminopyrazolo [3, 4-d at room temperature]Pyrimidine (2g) and H2To O25 mL, bromine (2g) was added dropwise, and after completion of the addition, the reaction was stirred at room temperature for 1 hour, followed by reaction under reflux for 1 hour, followed by spin-drying under reduced pressure, dissolution in water, PH adjustment to 7, precipitation, suction filtration, and washing to obtain the title compound (2.5 g).
1H NMR(300MHz，CDCl3)δ＝6.7to 6.9(m，2H)，8.3(s，1H)，13.2(s，1H).
B)3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-4-amino
Adding 4-amino-3-bromopyrazolo [3, 4-d ] into a reaction bottle]Pyrimidine (2g), potassium carbonate (1.9g), 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2.5g) and 50mL of 1, 4-dioxane and 10mL of water, tetrakis (triphenylphosphine) palladium (0.35g), stirred at 100 ℃ overnight, and N was carried out2After protection and completion of the reaction, the reaction mixture was dried under reduced pressure and purified by silica gel column chromatography to obtain the title compound (2 g).
1H NMR(300MHz，CDCl3)δ＝3.9(s，3H)，6.7to 6.9(m，2H)，7.8(s，1H)，7.9(s，1H)，8.2(s，1H)，13.2(s，1H).
C)1- [3- (4-amino-3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl ] -2- (N, N-dimethylamino) ethanone
Diisopropyl azodicarboxylate (0.45g) was added dropwise to 20mL of 3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-4-amino (0.2g), triphenylphosphine (0.63g), 1- (3-hydroxypiperidinyl) -2- (N, N-dimethylamino) ethanone (0.2g) and tetrahydrofuran at 0 ℃ and the mixture was stirred at room temperature for 16 hours, dried under reduced pressure and purified by silica gel column chromatography to give the title compound (0.2 g).
MS(ESI+)：[M+H]+384.3。
Examples 38 to 48
In examples 38 to 48, the title compound was obtained from 3- (1-methyl-1H-4-pyrazolyl) -1H-pyrazolo [3, 4-d ] pyrimidin-4-amino obtained in step B of example 37 and the corresponding agent to the compound of examples 38 to 48 by the same method as example 37. The MS in the table is an observed value.
TABLE 6
Experimental example (JAK-1 and JAK-3 enzyme inhibition assay)
Purpose of the experiment:
compounds were evaluated for inhibition of JAK-1 and JAK-3 kinases.
The experimental principle is as follows:
proteolytic effects of fluorescence resonance energy transfer technology (FRET) -based coupled proteolytic enzymes on specific phosphorylated versus non-phosphorylated polypeptide substrates. Two ends of the polypeptide substrate are respectively marked as FRET energy donor coumarin and energy acceptor fluorescein, and then the donor and the acceptor can be excited to transfer energy when being close to each other.
In the Kinase Reaction (Kinase Reaction), JAK-1 or JAK-3 can transfer gamma-phosphate in ATP to single tyrosine residue of polypeptide substrate, if JAK-1 or JAK-3 inhibitor exists in the system, the gamma-phosphate group on ATP can not be transferred to the substrate polypeptide, and phosphorylation Reaction can not occur. An evaluation experiment of a kinase inhibitor is designed based on the principle, a substrate polypeptide is provided with a kinase phosphorylation site and a protein enzyme cutting site, two ends of the substrate polypeptide are respectively connected with 2 fluorescent groups which are respectively a donor and an acceptor, if the activity of the kinase is kept in a reaction system, a gamma-phosphate group is transferred to the enzyme cutting site of a substrate, so that the substrate polypeptide cannot be cut by protease and is separated into two sections, and under the excitation of laser with specific wavelength, the energy of one section of fluorescence can be transferred to the fluorescent group at the other end to emit energy. Otherwise, after the enzyme activity is inhibited, the phosphate group can not be transferred, the enzyme cutting site of the substrate can be cut by enzyme in the system, and the substrate is separated into two sections, so that the energy transfer of fluorescence can not occur. Based on this, the activity of the kinase was evaluated.
The experimental steps are as follows:
in this experiment, 10. mu.1 kinase reaction system was selected, and 2.5. mu.l of kinase (concentration: 1nM), 2.5. mu.l of polypeptide substrate (concentration: 2. mu.M), 2.5. mu.l of ATP (concentration: 10. mu.M) and 2.5. mu.l of compound were added to each system, and reacted at room temperature for 1 hour, then 5. mu.l of test solution was added, reacted at room temperature for 1 hour, and 5. mu.l of stop buffer was added. Fluorescence intensity (detection of coumarin emission at 445nm and fluorescein emission at 520nm under 400nm excitation) was measured using a microplate reader (Synergy H1, BioTek, USA). The inhibitory activity of each compound was calculated, wherein the fluorescence intensity of wells without enzyme was considered to be 100% inhibition.
TABLE 11
Formulation example 1 (preparation of tablets)
The total amount of 1), 2), 3) and 4) (30g) were stirred with water, dried under vacuum and sieved. The sieved powder was mixed with 4) (14g) and 5) (1g) and the mixture was pressed with a tablet press, whereby 1000 tablets each containing 30mg of the compound of example 1 were obtained.
Formulation example 2 (preparation of capsules)
Mixing 1), 2), 3) and 4) and filling into capsules.
The compound of the present invention has an excellent JAK-1 and/or JAK-3 inhibitory action and is useful as a medicament for preventing, treating or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.) and the like.

Claims (10)

1. A compound represented by the formula (I):
wherein
X1Is a nitrogen atom or-CH-;
X2is a nitrogen atom or-CH-;
R1is a hydrogen atom, a halogen atom, a cyano group, an acryloyl group, a 2-cyanoacetyl group, an optionally substituted C1-6A hydrocarbyl or optionally substituted cyclic group;
R2is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C1-6An alkyl group;
R3、R4independently selected from hydrogen atom, halogen atom, cyano group, optionally substituted C1-6A hydrocarbyl or optionally substituted cyclic group;
R5is L1-A-L2-G, wherein,
L1is optional and when present is a bond, optionally substituted or unsubstituted C1-6Hydrocarbyl, optionally substituted or unsubstituted C3-8Cycloalkyl, optionally substituted or unsubstituted C2-7Alkenyl, optionally substituted or unsubstituted C2-7An alkynyl group;
a is optional and, when present, is a bond, -O-, -C (═ O) -, -S (═ O)2-、-NH-、-NR10-、-NHC(O)-、-C(O)NH-、-NR10C(O)-、-C(O)NR10-、-S(＝O)2NH-、-NHS(＝O)2-、-S(＝O)2NR10-、-NR10S(＝O)2-、-OC(O)NH-、-NH C(O)O-、-O C(O)NR10-、-NR10C(O)O-、-CH＝NO-、-ON＝CH-、-NR11C(O)NR11-, heteroaryl-, aryl-, -NR11C(＝NR12)NR11-、-NR11C(＝NR12)-、-C(＝NR12)NR11-、OC(＝NR12) -or-C (═ NR)12)O-；
L2Is optional and when present is a bond, optionally substituted or unsubstituted C1-6Hydrocarbyl, optionally substituted or unsubstituted C3-8Cycloalkyl, optionally substituted or unsubstituted C2-7Alkenyl, optionally substituted or unsubstituted C2-7Alkynyl, substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl, substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl, substituted or unsubstituted 4-, 5-, 6-, 7-or 8-membered heterocycle;
or L1A and L2Together form a nitrogen-containing heterocyclic ring;
g is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, Wherein,
b is independently selected from hydrogen atom, halogen, cyano, hydroxyl;
R6、R7、R8and R9Independently selected from hydrogen atom, halogen, cyano, hydroxy, substituted or unsubstituted C1-6Hydrocarbyl or substituted or unsubstituted C1-6Heterohydrocarbyl or substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C3-8A heterocycloalkyl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered aryl group, a substituted or unsubstituted 5-, 6-, 7-or 8-membered heteroaryl group;
each R10Independently selected from a hydrogen atom, substituted or unsubstituted C1-6A hydrocarbon group, and substituted or unsubstituted C3-8A cyclic hydrocarbon group;
each R11Independently a hydrogen atom, substituted or unsubstituted C1-6A hydrocarbon group, or a substituted or unsubstituted C3-8A cyclic hydrocarbon group; or two R11The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or
R11And R12May together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or
Each R12Independently selected from a hydrogen atom or substituted or unsubstituted C1-6A hydrocarbyl group.
2. The compound of claim 1 or a salt thereof, wherein,
R1is that
(1) A hydrogen atom, and a nitrogen atom,
(2) a halogen atom,
(3) the cyano group(s),
(4) an acryl group,
(5) 2-cyanoacetyl group,
(6) c optionally substituted with 1 to 3 substituents selected from the group consisting of1-6Alkyl groups: (a) hydrogen atom, (b) halogen atom, (C) hydroxyl group, (d) C1-6Alkoxy, (e) C3-8Cycloalkyl, (f) C1-6Alkyl-carbonyl mono-or di-substituted amino,
(7) c optionally substituted with 1 to 3 substituents selected from the group consisting of2-7Alkenyl: (a) a hydrogen atom, (b) a halogen atom, (C) an optionally substituted C1-6An alkyl group, a carboxyl group,
(8) c optionally substituted with 1 to 3 substituents selected from the group consisting of2-7Alkynyl: (a) a hydrogen atom, (b) a halogen atom, (C) an optionally substituted C1-6An alkyl group, a carboxyl group,
(9) c optionally substituted with 1 to 3 substituents selected from the group consisting of3-10Cycloalkyl groups: (a) halogen atom, (b) C1-6An alkyl group;
(10) a 3 to 8 membered monocyclic non-aromatic heterocyclic group, or
(11) A 5-or 6-membered monocyclic aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom, (b) a cyano group;
R2is a hydrogen atom, a halogen atom or a cyano group;
R3、R4is independently selected from
(1) A hydrogen atom, and a nitrogen atom,
(2) a halogen atom,
(3) the cyano group(s),
(4) an acryl group,
(5) 2-cyanoacetyl group,
(6) c optionally substituted with 1 to 3 substituents selected from the group consisting of1-6Alkyl groups: (a) hydrogen atom, (b) halogen atom, (C) hydroxyl group, (d) C1-6Alkoxy, (e) C3-8Cycloalkyl, (f) C1-6Alkyl-carbonyl mono-or di-substituted amino,
(7) c optionally substituted with 1 to 3 substituents selected from the group consisting of2-6Alkenyl: (a) a hydrogen atom, (b) a halogen atom, (C) an optionally substituted C1-6Alkyl radical，
(8) C optionally substituted with 1 to 3 substituents selected from the group consisting of3-10Ring-burning base: (a) halogen atom, (b) C1-6An alkyl group, a carboxyl group,
(9) c optionally substituted with 1 to 3 substituents selected from the group consisting of6-14Aryl: (a) a halogen atom, (b) C optionally substituted by 1 to 3 halogen atoms1-6Alkyl, (C) cyano, (d) optionally substituted by C1-6Alkyl-carbonyl mono-or disubstituted amino, (e) C1-6An alkoxy group,
(10) a 3 to 8 membered monocyclic non-aromatic heterocyclic group, or
(11) A 5-or 6-membered monocyclic aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the group consisting of: (a) a halogen atom, (b) a cyano group.
3. The use according to any one of claims 1-2, wherein L1A and L2Together form a nitrogen-containing heterocyclic ring.
4. Use according to claim 3, wherein the nitrogen containing heterocycle is an azetidine group, a pyrrolidine group or a piperidine group.
5. The use according to any one of claims 1-4, wherein G is cyano,
6. The medicament according to claims 1 to 5, which is a JAK-1 and/or JAK-3 inhibitor.
7. The pharmaceutical agent as claimed in claim 6, which is an agent for preventing, treating and/or ameliorating an autoimmune disease.
8. A medicament as claimed in claim 7, wherein the autoimmune disease is psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis or systemic lupus erythematosus.
9. Use of the compound of claim 1 or a salt thereof for the production of a medicament for preventing and/or ameliorating an autoimmune disease.
10. The use of claim 9, wherein the autoimmune disease is psoriasis, rheumatoid arthritis, inflammatory bowel disease, sjogren's syndrome, behcet's disease, multiple sclerosis, or systemic lupus erythematosus.
CN201810328225.8A 2018-04-10 2018-04-10 A kind of preparation and application of novel purine analogue jak kinase inhibitor Pending CN108484609A (en)

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Publication number Priority date Publication date Assignee Title
CN113214265A (en) * 2020-01-21 2021-08-06 江苏先声药业有限公司 Pyrimido five-membered ring compounds
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