2380-63-4

Usage

Uses

Used in Pharmaceutical Industry:
4-Aminopyrazolo[3,4-d]pyrimidine is used as a therapeutic agent for the treatment of hypercholesterolemia in rats. It has been shown to decrease serum cholesterol markedly, which can be beneficial in managing and reducing the risk of cardiovascular diseases associated with high cholesterol levels.
Used in Chemical Research:
As a heterocyclic compound with a unique structure, 4-Aminopyrazolo[3,4-d]pyrimidine can be used as a building block or intermediate in the synthesis of more complex molecules for various applications in the chemical industry. Its reactivity and functional groups can be exploited to create novel compounds with specific properties and potential uses.
Used in Drug Design and Development:
The biological activity of 4-Aminopyrazolo[3,4-d]pyrimidine makes it a promising candidate for drug design and development. Researchers can use 4-Aminopyrazolo[3,4-d]pyrimidine as a starting point to develop new drugs targeting various diseases and conditions, particularly those related to cholesterol metabolism and cardiovascular health.

InChI:InChI=1/C5H5N5/c6-4-3-1-9-10-5(3)8-2-7-4/h1-2H,(H3,6,7,8,9,10)

Synthetic route

3-Amino-4-cyanopyrazole (16617-46-2) + formamide (77287-34-4, 77287-35-5, 60100-09-6) → 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4)

Conditions	Yield
at 180℃;	100%
at 170℃; for 5h; Inert atmosphere;	94%
for 1h; Reflux;	93%

formamide (77287-34-4, 77287-35-5, 60100-09-6) + 3-amino-4-cyano-2H-pyrazole (16617-46-2) → 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4)

Conditions	Yield
at 180℃; Inert atmosphere;	95%
at 180℃; for 2h; Microwave irradiation;	93%
at 180℃; for 2h; Microwave irradiation;	93%

3-Amino-4-cyanopyrazole (16617-46-2) → 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4)

Conditions	Yield
In formamide	87%

3-Amino-4-cyanopyrazole (16617-46-2) → lH-pyrazolo[3,4-d]pyrimidin-4-ylamine + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4)

Conditions	Yield
In formamide	A n/a B 87%

formamidine acetic acid (3473-63-0) + 3-amino-4-cyano-2H-pyrazole (16617-46-2) → 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4)

Conditions	Yield
at 120℃; for 45h; Temperature; Concentration; Inert atmosphere;	84.1%
In ethanol for 5h; Reflux;	75%

N1,N1-dimethyl-N2-[4-cyanopyrazol-5-yl]formamidine (78972-81-3) → 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4)

Conditions	Yield
With ammonium hydroxide for 5h; Heating;	80%

4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 3-bromo-4-aminopyrazolo<3,4-d>pyrimidine (83255-86-1)

Conditions	Yield
With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃; for 3h;	100%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 80℃; for 5h;	92%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 60℃;	91%

4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (151266-23-8)

Conditions	Yield
With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃;	100%
With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 5h;	98%
With N-iodo-succinimide In N,N-dimethyl-formamide for 12h;	97%

4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) + Hexafluoroacetone (684-16-2) → 2,2,4,4-tetrakis(trifluoromethyl)-2,8-dihydro<1,3,5>oxadiazino<3,4-c>pyrazolopyrimidine (125509-32-2)

Conditions	Yield
In N,N-dimethyl-formamide at 80℃; for 24h;	95%

di-tert-butyl dicarbonate (24424-99-5) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → C15H21N5O4

Conditions	Yield
With dmap In tetrahydrofuran at 20℃; Inert atmosphere;	90%

[(3aR,4S,6R, 6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl] trifluoromethanesulfonate (1373333-65-3) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 1-((3aS,4R,6R,6aR)-2,2-dimethyl-6-vinyltetrahydro-3aHcyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Conditions	Yield
Stage #1: 4-Aminopyrazolo<3,4-d>pyrimidin With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Mitsunobu Displacement; Stage #2: [(3aR,4S,6R, 6aR)-2,2-dimethyl-6-vinyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl] trifluoromethanesulfonate In dichloromethane; N,N-dimethyl-formamide; mineral oil at 20℃; for 16h; Mitsunobu Displacement;	88%

N-iodo-succinimide (516-12-1) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (151266-23-8)

Conditions	Yield
In N,N-dimethyl-formamide at 80℃; for 12h;	86%
In N,N-dimethyl-formamide at 80℃; Concentration; Solvent;

4-phenoxyiodobenzene (2974-94-9) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (330786-24-8)

Conditions	Yield
With potassium tert-butylate In dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere;	82%

Cyclopentyl bromide (137-43-9) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (21254-14-8)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 110℃;	80%

1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (6974-32-9) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → (2R,3R,4R,5R)-2-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate (854020-39-6)

Conditions	Yield
With boron trifluoride diethyl etherate In nitromethane for 2h; Heating;	79%
With boron trifluoride diethyl etherate In nitromethane for 1.5h; Reflux;	59%
With boron trifluoride diethyl etherate In nitromethane Reflux;	42%

C16H18F4O5S + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 1-((3aS,4R,6S,6aR)-6-(4-fluorobenzyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Conditions	Yield
Stage #1: 4-Aminopyrazolo<3,4-d>pyrimidin With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: C16H18F4O5S In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h;	78%

2'-Deoxyguanosine (961-07-9) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine (17318-21-7)

Conditions	Yield
With purine nucleoside phosphorylase at 50℃; pH=7; aq. phosphate buffer; Enzymatic reaction;	77%

copper (II) carbonate hydroxide + (carboxymethyl(4-methylbenzyl)amino)acetic acid (166826-77-3) + water (7732-18-5) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → [Cu2(N-(p-methylbenzyl)iminodiacetate)2(μ2-N1,N8-4-aminopyrazolo[3,4-d]pyrimidine)(water)2]*4water

Conditions	Yield
Stage #1: copper (II) carbonate hydroxide; (carboxymethyl(4-methylbenzyl)amino)acetic acid In water at 50℃; Stage #2: water; 4-Aminopyrazolo<3,4-d>pyrimidin In isopropyl alcohol for 1h;	75%

1-(tert-Butoxycarbonyl)-3-(methanesulfonyloxy)piperidine (129888-60-4) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → tert-butyl 3-(4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1374250-98-2)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100℃;	72%
Stage #1: 4-Aminopyrazolo<3,4-d>pyrimidin With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 1-(tert-Butoxycarbonyl)-3-(methanesulfonyloxy)piperidine In N,N-dimethyl-formamide; mineral oil at 100℃; for 16h;	50%

[1,3]-dioxolan-2-one (96-49-1) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 9-(2'-hydroxyethyl)adenine (100524-24-1)

Conditions	Yield
With sodium hydroxide In N,N-dimethyl-formamide for 2h; Heating;	71%

copper (II) carbonate hydroxide + water (7732-18-5) + (carboxymethyl(4-fluorobenzyl)amino)acetic acid (1813-23-6) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → [Cu4(N-(p-fluorobenzyl)iminodiacetate)4(μ2-N8,N9-4-aminopyrazolo[3,4-d]pyrimidine)2(water)]*water

Conditions	Yield
Stage #1: copper (II) carbonate hydroxide; (carboxymethyl(4-fluorobenzyl)amino)acetic acid In water at 50℃; Stage #2: water; 4-Aminopyrazolo<3,4-d>pyrimidin In isopropyl alcohol for 1h;	65%

1-azido-2,3-epoxypropane (80044-09-3) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 1-(4-Amino-pyrazolo[3,4-d]pyrimidin-1-yl)-3-azido-propan-2-ol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;	64%

4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) + phenylboronic acid (98-80-6) → N-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (99973-41-8)

Conditions	Yield
With [2,2]bipyridinyl; copper diacetate; caesium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; Chan-Lam Coupling;	62%

1-methyl-piperazine (109-01-3) + formaldehyd (50-00-0) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 1-(N-methylpiperazinomethyl)-4-(N-methylpiperazinomethylamino)pyrazolo<3,4-d>pyrimidine (83255-90-7)

Conditions	Yield
In water	60%

2'-deoxyuridine (951-78-0) + 4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) → 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine (17318-21-7)

Conditions	Yield
With purine nucleoside phosphorylase In dimethyl sulfoxide at 50℃; for 72h; pH=7; aq. phosphate buffer; Enzymatic reaction;	60%
at 37℃; for 16h; alginate gel-entrapped cells of auxotrophic thymine-dependent strain of E. coli, ammonium acetate buffer pH 5.7;

4-Aminopyrazolo<3,4-d>pyrimidin (2380-63-4) + benzyl alcohol (100-51-6) → N-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (58360-86-4)

Conditions	Yield
With samarium diiodide; potassium tert-butylate In tetrahydrofuran; toluene at 140℃; for 1.5h; Microwave irradiation; Inert atmosphere;	59%

Upstream product

• 16617-46-2 3-Amino-4-cyanopyrazole 
• 77287-34-4 formamide 
• 5399-92-8 4-chloro-1H-pyrazolo[3,4-d]pyrimidine 
• 78972-81-3 N¹,N¹-dimethyl-N²-[4-cyanopyrazol-5-yl]formamidine 
• 3258-05-7 4-amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine 
• 16617-46-2 3-amino-4-cyano-2H-pyrazole 
• 315-30-0 Allopurinol 
• 50-00-0 formaldehyd 
• 3473-63-0 formamidine acetic acid 

Downstream Products

• 100524-24-1 9-(2'-hydroxyethyl)adenine 
• 58791-75-6 3-(4-chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine 
• 1340540-90-0 1-butyl-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 
• 186895-90-9 C₁₆H₁₉N₅ 
• 1340540-91-1 C₁₅H₁₇N₅ 
• 1340540-92-2 C₁₅H₁₆ClN₅ 
• 1340540-93-3 C₁₆H₁₉N₅ 
• 1340540-94-4 C₁₅H₁₇N₅ 
• 1340540-95-5 C₁₆H₁₉N₅O 
• 1340540-96-6 C₁₅H₁₆FN₅ 
• 1340540-97-7 C₁₅H₁₆ClN₅ 
• 1340540-98-8 C₁₅H₁₆ClN₅ 
• 1340541-00-5 C₁₅H₁₅Cl₂N₅ 
• 1340541-01-6 C₁₅H₁₆BrN₅ 

Relevant academic research and scientific papers

Discovery of novel selective Janus kinase 2 (JAK2) inhibitors bearing a 1H-pyrazolo[3,4-d]pyrimidin-4-amino scaffold

Janus kinases (JAKs) regulate various cancers and immune responses and are targets for the treatment of cancers and immune diseases. A new series of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives were synthesized and optimized by introducing a functional 3,5-disubstituted-1H-pyrazole moiety into the C-3 moiety of pyrazole template, and then were biologically evaluated as potent Janus kinase 2 (JAK2) inhibitors. Among these molecules, inhibitors 11f, 11g, 11h and 11k displayed strong activity and selectivity against the JAK2 kinase, with IC50 values of 7.2 nM, 6.5 nM, 8.0 nM and 9.7 nM, respectively. In particular, the cellular inhibitory assay and western blot analysis further support the JAK2 selectivity of compound 11g also in cells. Furthermore, compound 11g also exhibited potent inhibitory activity in lymphocytes proliferation assay and delayed hypersensitivity assay. Taken together, the novel JAK2 selective inhibitors discovered in this study may be potential lead compounds for new drug discovery via further development of more potent and selective JAK2 inhibitors.

NEW COMPOUND HAVING FGFR INHIBITORY ACTIVITY AND PREPARATION AND APPLICATION THEREOF

The present invention relates to a new compound having an FGFR inhibitory activity and preparation and application thereof. In particular, the compound according to the present invention has a structure as shown in formula I, wherein each group and substituent are as defined in the description. Also disclosed in the present invention are a preparation method for the compound and a use thereof in preparation of a drug for treating and/or preventing a tumor-related disease and/or an FGFR-related disease.

Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors

Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 μM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.

CYCLIC DI-NUCLEOTIDE COMPOUNDS AND METHODS OF USE

Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.

Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii

Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.

Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase

Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC50 for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice.

MTOR MODULATORS AND USES THEREOF

The present invention provides methods and compositions for selective modulation of certain protein kinases, and especially mTor complexes. The methods and compositions are particularly useful in inhibiting mTor selectively for therapeutic applications.

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

A PROCESS FOR THE PREPARATION OF IBRUTINIB

The present invention provides processes for the preparation of ibrutinib, intermediate compounds of Formula VI and Formula VIII, and salts thereof. The processes of the present invention are commercially viable, cost-effective, environmentally friendly, and make use of inexpensive, non-hazardous, safe chemicals that are easy to handle.