JP2005536517A - Pyrazolopyrimidines as kinase inhibitors - Google Patents

Abstract

The present invention relates generally to inhibitors of kinases and more particularly to novel pyrazolopyrimidine compounds.

Description

The present invention relates generally to inhibitors of kinases such as GSK3 or TIE2, and more particularly to novel pyrazolopyrimidine compounds.

BACKGROUND OF THE INVENTION The present invention provides compounds that are useful drugs for disease states mediated by protein kinase inhibition or antagonism, such as those alleviated thereby. In particular, the invention relates to compounds that demonstrate protein tyrosine kinase and / or protein serine / threonine kinase inhibition.

Protein kinases are ADDIN ENRef (Hanks, et al., Science , 1988, 241, 42-42), which represents a large family of proteins that play a central role in the regulation of various cellular processes and the maintenance of cell function. 52). Loss of control of cellular regulation often results in abnormal cell function or death, and often results in the pathological state of the host organism. A list of some of these kinases includes: ab1, ATK, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R , CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, GSK3, Hck, IGF-1R , INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, TIE1, TIE2, TRK, Yes, and Zap70. Examples of kinase therapy include, but are not limited to: (1) c-Src ADDIN ENRef (Brickell, Critical Reviews in Oncogenesis 1992, 3, 401-46; Courtneidge, Seminars in Cancer Biology 1994 , 5, 239-46), raf ADDIN ENRef (Powis, Pharmacology & Therapeutics 1994, 62, 57-95) and cyclin-dependent kinases (CDK) 1, 2 and 4 ADDIN ENRef (Pines, Current Opinion in Cell Biology 1992 , 4, 144-8; Lees, Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell 1994, 79, 573-82), (2) CDK2 or PDGF-R during restenosis Kinase inhibition ADDIN ENRef (Buchdunger et al., Proceedings of the National Academy of Science USA 1995, 92, 2258-62), (3) Inhibition of CDK5 and GSK3 kinases for Alzheimer's disease ADDIN ENRef (Hosoi et al., Journal of Biochemistry (Tokyo) 1995, 117, 741-9; Aplin et al., Journal of Neurochemistry 1996, 67, 699-707), (4) Inhibition of c-Src kinase in osteoporosis ADDIN ENRef (Tanaka et al., Nature 1996, 383, 528-31), (5) Inhibition of GSK-3 kinase in type 2 diabetes ADDIN ENRef (Borthwick et al., Biochemical & Biophysical Research Communications 1995, 210, 738-45), which is described in detail below; (6 ) Inhibition of inflammation with p38 kinase ADDIN ENRef (Badger et al., The Journal of Pharmacology and Experimental Therapeutics 1996, 279, 1453-61); (7) VEGF-R 1-3 and TIE- in diseases involving angiogenesis Inhibition of 1 and -2 kinases ADDIN ENRef (Shawver et al., Drug Discovery Today 1997, 2, 50-63); (8) Inhibition of UL97 kinase in viral infections ADDIN ENRef (He et al., Journal of Virology 1997, 71, 405 -11); (9) Inhibition of CSF-1R kinase in bone and hematopoietic diseases ADDIN ENRef (Myers et al., Bioorganic & Medicinal Chemistry Letters 1997, 7, 421-4), and (10) in autoimmune diseases and transplant rejection ADDIN ENRef (Myers et al., Bioorganic & Medicinal Chemistry Letters 1997, 7, 417-20).

  Some inhibitors of kinases may also have utility in the treatment of diseases where the kinase is not misregulated, but is essential for maintaining the disease state. In this case, inhibition of kinase activity serves either to treat or alleviate these diseases. For example, many viruses, such as human papillomavirus, interfere with the cell cycle and induce cells into the S-phase of the cell cycle ADDIN ENRef (Vousden, FASEB Journal 1993, 7, 872-9). Inhibition of cells from progression to DNA synthesis after viral infection by inhibiting essential S-phase initiation activity, such as through kinase inhibition, appears to interfere with the viral life cycle by inhibiting viral replication. Using this same principle, ADDIN ENRef (Stone et al., Cancer Research 1996, 56, 3199-202; Kohn et al.) Appears to be able to protect living cells from the toxicity of cycle-specific chemotherapeutic agents. , Journal of Cellular Biochemistry 1994, 54, 440-52).

  As described above, GSK3 (glycogen synthase kinase) has been identified as a useful kinase for the treatment of type II diabetes. GSK3 inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby activating glycogen synthase and possibly allowing other insulin-dependent events.

  Type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), is initially characterized by a decrease in sensitivity to insulin (insulin resistance) and an increase in circulating insulin concentration as a compensation. The increase in insulin levels is due to an increase in secretion from pancreatic beta cells aimed at overcoming insulin resistance. The resulting hyperinsulinemia is associated with various cardiovascular complications.

  As insulin resistance worsens, the need for pancreatic beta cells steadily increases and the pancreas can no longer supply adequate insulin levels, resulting in elevated blood glucose levels. Thus, diabetes leads to impaired glucose transport into skeletal muscle and increased hepatic glucose production, as well as an inappropriate insulin response. Diseases and symptoms associated with hyperglycemia and hyperlipidemia include cardiovascular disease, renal failure and blindness.

  Inhibition of GSK3 is useful for the treatment of diseases and conditions such as type II diabetes that stimulate insulin-dependent processes and consequently are mediated by GSK3 activity or more particularly characterized by the need for inhibition of GSK3.

For example, Klein et al., PNAS 93: 8455-9 (1996) report that lithium ions inhibit GSK3 activity. Lithium has been reported to have antidiabetic effects such as lowering plasma glucose levels, increasing glycogen uptake, enhancing insulin, and stimulating glycogen synthesis in skin, muscle and adipocytes. However, since lithium acts on molecular targets other than GSK3, it is not a widely accepted therapy for diabetics.

  GSK3 is a proline-specific serine / threonine kinase. Other examples of diseases or symptoms mediated by GSK3 include, but are not limited to: various CNS disorders such as obesity, Alzheimer's disease, manic depression and schizophrenia, and neurotrauma such as acute stroke , Immune enhancement, baldness or hair loss, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, ischemia, brain trauma or injury, immune dysfunction, and cancer. See, for example, published PCT application WO00 / 38675. The background of this invention is incorporated herein by reference.

In addition, other tyrosine kinases, TIE and the like are also included in the compounds of the present invention. The acronym TIE means “tyrosine kinase containing Ig and EGF homology domains”. TIE is used to identify a class of receptor tyrosine kinases that are expressed exclusively in vascular endothelial cells and early hematopoietic cells. Angiopoieten 1 (Ang1), a ligand for the endothelium-specific receptor tyrosine kinase TIE-2, is an angiogenic factor. See: Davis et al., Cell , 1996, 87: 1161-1169; Partanen et al . , Mol. Cell Biol , 12: 1698-1707 (1992); US Pat. Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831. Ang1 and its receptor TIE-2 function during the late stages of vascular development, ie, vascular remodeling (remodeling refers to the formation of vascular lumens) and maturation. See Yancopoulos et al., Cell , 1998, 93: 661-664; Peters, KG, Circ. Res. , 1998, 83 (3): 342-3; Suri et al., Cell , 87, 1171-1180 ( 1996). In conclusion, inhibition of TIE-2 is expected to interfere with the remodeling and maturation of new angiogenesis initiated by angiogenesis, thereby preventing the angiogenic process. Thus, inhibition of TIE-2 should suppress tumor angiogenesis and delay or eradicate tumor growth. Thus, treatment of cancer or other diseases associated with inappropriate angiogenesis can be provided.

As used herein, angiogenesis is defined as involving: (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent basement membrane lysis and Extravasation of plasma components and consequent formation of transient fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells and formation of functional capillaries (Vi) formation of capillary loops; and (vii) basement membrane accumulation and recruitment of perivascular cells to newly formed blood vessels. Normal angiogenesis is activated during tissue growth from embryonic development to maturation, and then enters the relative stationary phase of the mature body stage. Normal angiogenesis is also activated during wound healing and at certain stages of the female reproductive cycle. Inappropriate angiogenesis has been implicated in several disease states including: retinopathy; ischemic disease; atherosclerosis; chronic inflammatory disorders; and cancer. The role of angiogenesis in disease states is discussed below: Fan et al., Trends in Pharmacol Sci . 16: 54-66; Shawver et al., DDT Vol. 2, No. 2 February 1997; Folkmann, 1995, Nature Medicine , 1: 27-31.

For example, in cancer, solid tumor growth has been shown to be angiogenesis-dependent. See Folkmann, J., J. Nat'l. Cancer Inst. , 1990, 82, 4-6. In conclusion, targeting the pro-angiogenic pathway in cancer treatment is one of the strategies that has been widely studied to provide new therapies in these areas of great unknown medical demand. It is. The role of tyrosine kinases involved in angiogenesis and angiogenesis of solid tumors appears to prove useful in the creation of effective drugs.

  Thus, it is believed that the compounds of the present invention are useful in a variety of disease states, each characterized as being mediated by protein kinase inhibition or antagonism.

SUMMARY OF THE INVENTION The present invention provides a compound of formula (I):

Wherein A is H, alkyl, or aryl;
R ¹ is D ¹ , D ² , D ³ , D ⁴ , or D ⁵ ,
Said D ¹ is:

R ³ and R ⁴ are each independently H, alkyl, alkyl, alkylsulfonyl, or —C (O) — (CH ₂ ) _x —R ⁵ ;
R ⁵ is alkyl, acyl, alkoxy,-(O)-(CH ₂ ) _x- (O) -alkyl, or -NR ⁶ R ⁷ ;
R ⁶ and R ⁷ are each independently H or alkyl, or R ⁶ and R ⁷ are combined to form a 5- or 6-membered ring, which ring optionally further contains one or more heteroatoms. Optionally containing one or more degrees of unsaturation and optionally substituted one or more times by alkyl, hydroxy, carboxy, acyl, alkoxy or halogen,
Alternatively, R ³ and R ⁴ combine to form a 5- or 6-membered ring, which optionally further contains one or more heteroatoms, and optionally contains one or more degrees of unsaturation, Substituted one or more times by alkyl, hydroxy, carboxy, alkoxy, acyl or halogen;
D ² is:

And R ⁸ is alkyl or —NR ⁹ R ¹⁰ ;
R ⁹ and R ¹⁰ are each independently selected from H, alkyl, or — (CH ₂ ) _x —NR ⁶ R ⁷ ;
R ⁶ and R ⁷ are each independently H or alkyl, or R ⁶ and R ⁷ are combined to form a 5- or 6-membered ring, which ring optionally further contains one or more heteroatoms. Optionally containing one or more degrees of unsaturation and optionally substituted one or more times by alkyl, hydroxy, carboxy, acyl, alkoxy or halogen;
Said D ³ is:

And the dotted line represents any double bond;
When R ¹¹ is — (CH ₂ ) _x , there is no double dotted double bond, and R ¹² is alkylsulfonyl or —NR ¹³ R ¹⁴ ,
R ¹³ and R ¹⁴ are each independently selected from H, alkyl,-(CH ₂ ) _x -R ¹⁷ (R ¹⁷ is alkoxy or -NR ¹⁵ R ¹⁶ );
R ¹⁵ and R ¹⁶ are each independently H or alkyl;
Or R ¹³ and R ¹⁴ combine to form a 5- or 6-membered ring, optionally further containing one or more heteroatoms, optionally containing one or more degrees of unsaturation, Substituted one or more times by alkyl or — (CH ₂ ) _x —OH by
When R ¹¹ is-(CH)-, there is an optional dotted double bond, and R ¹² is-(CH) -C (O) -OH;
Said D ⁴ is:

And R ¹⁷ is hydroxy, alkoxy, or —NR ¹⁸ R ¹⁹ ,
R ¹⁸ and R ¹⁹ are each independently selected from H, alkyl, — (CH ₂ ) _x —R ²⁰ ,
R ²⁰ is alkylsulfonyl, hydroxy, aryl (aryl is optionally substituted with hydroxy or alkoxy), heteroaryl, or —NR ²¹ R ²² ;
R ²¹ and R ²² are each independently selected from H, acyl, and alkyl, or R ²¹ and R ²² combine to form a 5- or 6-membered ring, optionally further comprising one or more rings Contains a heteroatom, optionally contains one or more degrees of unsaturation and is optionally substituted by alkyl or — (CH ₂ ) _x —OH;
Alternatively, R ¹⁸ and R ¹⁹ combine to form a 5- or 6-membered ring, optionally containing one or more heteroatoms, optionally containing one or more degrees of unsaturation, Substituted by-(CH ₂ ) _x -R ²³ by
R ²³ is alkoxy, hydroxy, —C (O) —R ²⁴ (R ²⁴ is a 5- or 6-membered ring, this ring optionally further containing one or more heteroatoms and optionally one or more unsaturateds. Or -NR ²⁵ R ²⁶ (R ²⁵ and R ²⁶ are each independently H or alkyl);
D ⁵ is
A 5- or 6-membered ring, optionally further containing one or more heteroatoms, optionally containing one or more degrees of unsaturation, and optionally another 5- or 6-membered ring ( This ring optionally further contains one or more heteroatoms and optionally contains one or more degrees of unsaturation),
Said ring or fused ring system is optionally: halogen, alkyl, haloalkyl, alkylsulfonyl, alkylthio, hydroxy, alkoxy, oxo, sulfonyl, sulfate, nitro, cyano, carboxy, alkoxycarbonyl, aryl (aryl is optionally sulfamoyl) Optionally substituted), heteroaryl (heteroaryl optionally substituted with alkyl), or —NR ²⁷ R ²⁸ ,
(Wherein R ²⁷ and R ²⁸ are each independently H, alkyl, acyl, alkoxy, alkoxycarbonyl, carboxy, or — (CH ₂ ) _x —NR ²⁹ R ³⁰ (R ²⁹ and R ³⁰ are each independently H and Selected from alkyl) or
Or R ²⁷ and R ²⁸ combine to form a 5- or 6-membered ring, which optionally further contains one or more heteroatoms, and optionally contains one or more degrees of unsaturation, Is substituted with one or more alkyl, hydroxy, carboxy, acyl, alkoxy, or halogen. )
Alternatively,-(O) _y- (CH ₂ ) _x -R ³¹ (wherein R ³¹ is hydroxy, alkoxy, haloalkyl, aryl (optionally substituted with halogen), or -NR ²⁷ R ²⁸ (R ²⁷ and R ²⁸ is as defined above) and may be substituted one or more times by
For each of the above cases, x is independently 0, 1, 2, or 3;
For each of the above cases, y is independently 0 or 1; and
R ² is phenyl, substituted with one or more alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ³¹ R ³² ;
R ³¹ and R ³² are each independently selected from H, alkyl, acyl, or-(CH ₂ ) _z -R ³³ ;
Said z is 0, 1, or 2; and
R ³³ is cycloalkyl. ]
And the salts, solvates, and pharmaceutically acceptable derivatives thereof.

Preferably R ¹ is D ⁵ . More preferably, D ⁵ is pyridyl. More preferably, D ⁵ is 4-pyridyl.

Preferably R ² is phenyl substituted with alkoxy. More preferably, the alkoxy is methoxy.

Preferably R ² is:

Preferably in each case the alkyl is C ₁ -C ₆ alkyl.

Preferably, R ¹ is D ³ and R ¹¹ and R ¹² are combined to form — (CH) ═ (CH) —C (O) —OH.

  In a preferred embodiment, the stereochemical configuration is cis.

  In another preferred embodiment, the stereochemical configuration is trans.

  Preferably A is H.

In another embodiment, preferably A is alkyl. More preferably, A is C _1-6 alkyl. More preferably A is selected from propyl or isopropyl.

  Another aspect of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention.

  Preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carrier (s), diluent (s), or excipient (s).

  In another aspect of the invention, a method of treating a mammalian disorder characterized by misregulation of one or more protein kinases, comprising administering to the mammal a therapeutically effective amount of a compound of the invention. , Is included. Preferably, the kinase is a serine / threonine kinase. More preferably, the kinase is GSK3. Alternatively, the kinase may be a tyrosine kinase. In that case, preferably the kinase is TIE2.

  Another aspect of the present invention includes a compound of the present invention for use in therapy. Another aspect includes the use of a compound of the invention in the preparation of a medicament for use in the treatment of a disorder characterized by misregulation of one or more protein kinases.

  Another embodiment of the present invention includes methods for treating the following disorders by administration of a therapeutically effective amount of a compound of the present invention to a mammal: Type 2 diabetes, hyperlipidemia, obesity, CNS disorders, nerves Trauma, immune enhancement, baldness or hair loss, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, ischemia, immune dysfunction, and cancer.

  Another aspect of the present invention includes a method of treating a type II diabetes disorder by administering to a mammal a therapeutically effective amount of a compound of the present invention and at least one other antidiabetic agent.

Other embodiments of the present invention include intermediates such as compounds of formula (II), and salts, solvates and pharmaceutically functional derivatives thereof:

Wherein A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2; and
R ^d is cycloalkyl.

Yet another embodiment of the present invention includes compounds of formula (III), and salts, solvates and pharmaceutically functional derivatives thereof:

Wherein A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2; and
R ^d is cycloalkyl.

Yet another embodiment of the present invention includes compounds of formula (IV), and salts, solvates and pharmaceutically functional derivatives thereof:

Wherein A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2; and
R ^d is cycloalkyl.

Yet another aspect of the present invention includes compounds of formula (V), and salts, solvates and pharmaceutically functional derivatives thereof:

Wherein A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2;
R ^d is cycloalkyl; and
^Re is H or —C (O) — (O) —C— (CH ₃ ) ₃ .

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The term “alkyl” refers to a straight or branched chain hydrocarbon that may be optionally substituted and that may be substituted multiple times. Examples of “alkyl” include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl, isopropyl, and the like. The term “C _x -C _y alkyl” represents an alkyl group as defined above containing a specified number of carbon atoms.

  The term “alkylene” refers to a straight or branched chain unsaturated aliphatic hydrocarbon radical that may be optionally substituted and that may be substituted in multiple ways. Examples of “alkylene” include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

The term “aryl” refers to an optionally substituted benzene ring, or an optionally substituted benzene that is fused with one or more optionally substituted benzene rings to form, for example, an anthracene, phenanthrene, or naphthalene ring system. Represents a ring system. Examples of “aryl” groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, and substituted derivatives thereof. The term “aralkyl” further represents a group —R _a R _b , where R _a is alkylene as defined herein, and R _b is aryl as defined herein. Exemplary “aralkyl” groups include C _1-6 alkylene-aryl, benzyl, and the like.

The term “heteroaryl” refers to a monocyclic aromatic ring system or a fused bicyclic aromatic ring system comprising two or more aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen atoms, in which case N-oxides and sulfur oxides and dioxides are possible heteroatom substitutions, and sometimes multiple times Replacement is possible. Examples of “heteroaryl” groups as used herein include: furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, Pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, and substitutional variants thereof. The term “heteroaralkyl” further represents the group —R _a R _b , where R _a is alkylene as defined herein, and R _b is heteroaryl as defined herein.

The term “acyl” as used herein refers to the group —C (O) R _a , where R _a is H, alkyl, or aryl. Non-limiting examples of “acyl” groups include formyl, acetyl, benzoyl, and the like.

The term “alkoxy” refers to the group —OR _a , where R _a is alkyl as defined above. Non-limiting examples of “alkoxy” groups include methoxy, ethoxy, and the like.

  The term “oxo” as used herein represents the group ═O.

  As used herein, the term “hydroxy” refers to the group —OH.

  The term “carboxy” as used herein represents the group —COOH.

  The term “halogen” represents fluorine, chlorine, bromine or iodine.

  The term “haloalkyl” represents an alkyl group, as defined herein, substituted with at least one halogen. Non-limiting examples of “haloalkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, and independently substituted with one or more halogens such as fluorine, chlorine, bromine, and / or iodine. t-Butyl is included. The term “haloalkyl” should be construed to include substituents such as perfluoroalkyl.

The term “haloalkoxy” represents the group —OR _{a, where} R _a is haloalkyl as defined above.

The term “sulfonyl” as used herein refers to the group —S (O) ₂ —.

The term “alkylsulfonyl” as used herein represents a group —S (O) ₂ R _{a, where} R _a is alkyl as defined above.

As used herein, the term “alkylthio” refers to the group —SR _{a, where} R _a is alkyl as defined above.

The term “sulfamoyl” as used herein refers to the group —SO ₂ —NH ₂ .

The term “carbamoyl” as used herein refers to the group —C (O) NH ₂ .

The term “carboxamide” as used herein refers to the group —C (O) N (R _a ) _{2, where} R _a is alkyl or aryl as defined herein.

The term “alkoxycarbonyl” as used herein refers to the group —C (O) OR _{a, where} R _a is alkyl or aryl as defined herein.

The compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism. Such polymorphic forms (“polymorphs”) are within the scope of the invention. Polymorphism generally can occur as a response to changes in temperature or pressure, or both, and can also occur as a result of changes in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as x-ray diffraction patterns, solubility, and melting point.

  Some of the compounds described herein can contain one or more chiral centers or exist as multiple stereoisomers. Within the scope of the present invention are mixtures of stereoisomers with purified enantiomers, or mixtures enriched as enantiomers or as diastereomers. Also, all individual isomers of the compounds, as well as fully or partially equilibrated mixtures thereof, are within the scope of the invention. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers of the compounds of the present invention in which one or more chiral centers are inverted.

  As mentioned above, the present invention includes salts, solvates, and pharmaceutical functional derivatives of the compounds of the present invention. Salts include addition salts, metal salts, or optionally alkylated ammonium salts. Examples of such salts include hydrochloric acid, bromic acid, iodic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, maleic acid, pyruvic acid, malonic acid, succinic acid, citric acid, mandelic acid, benzoic acid, Salts such as cinnamic acid, methanesulfonic acid, ethanesulfonic acid, picric acid are included. Other salts include lithium, sodium, potassium, magnesium and the like. See also: JournalofPharmaceuticalScience, 1997, 66,2, the association with salts, which is incorporated herein by reference.

  The term “solvate” as used herein refers to various stoichiometric complexes formed by a solute or salt thereof or a pharmaceutically functional derivative and a solvent. For the purposes of the present invention, such solvents should not interfere with the biological activity of the solute. Examples of solvents include but are not limited to water, methanol, ethanol and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol and acetic acid.

The term “pharmaceutically functional derivative” refers to any pharmaceutically acceptable derivative of a compound of the invention, eg, when administered to a mammal, the compound of the invention or an active metabolite thereof (directly or indirectly). An ester or an amide capable of feeding). Such derivatives can be recognized by those skilled in the art without undue experimentation. However, reference should be made to the following teachings: Burger's Medicinal Chemistryand Drug Discovery, 5 th Edition, Vol1: Principlesand Practice. The scope of teaching of pharmaceutically functional derivatives is hereby incorporated by reference.

  While it is possible for a compound of the present invention to be administered as the raw chemical, preferably the compound of the present invention is provided as an active ingredient in a pharmaceutical formulation, as is known in the art. . Accordingly, the present invention further includes pharmaceutical formulations comprising a compound of the present invention, or a salt, solvate, or functional derivative thereof, together with one or more pharmaceutically acceptable carriers. In some cases, this pharmaceutical preparation may contain other therapeutic and / or prophylactic ingredients. For example, the compounds of the present invention can be formulated with another agent, including but not limited to: one or more other antidiabetic agents such as insulin, alpha glucosidase inhibitors, biguanides, sulfonylureas An insulin secretagogue such as thiazolidinedione, and / or a dipeptidyl peptidase inhibitor.

  Formulations of the present invention include those formulated specifically for oral, buccal, parenteral, transdermal, inhalation, nasal, transmucosal, implant, or rectal administration. Of the various modes of administration, oral administration is typically preferred. For oral administration, tablets, capsules, and caplets can contain conventional excipients such as binders, fillers, lubricants, disintegrants, and / or wetting agents. Non-limiting examples of binders include: syrup, gum arabic, gelatin, sorbitol, tragacanth, starch paste, or polyvinylpyrrolidone (PVP). Non-limiting examples of bulking agents include, for example: lactose, sucrose, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol. Non-limiting examples of lubricants include, for example: magnesium stearate, stearic acid, talc, polyethylene glycol or silica. Non-limiting examples of disintegrants include, for example: potato starch or sodium starch glycolate. One non-limiting example of a wetting agent includes sodium lauryl sulfate. The tablets may be further coated by methods known in the art.

  Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. In addition, formulations containing these compounds can be provided as a dry product for composition with water or other suitable vehicle prior to use. Liquid preparations can contain conventional additives. Non-limiting examples of such additives include suspending agents such as: sorbitol syrup, methylcellulose, glucose / sucrose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated food fat. In addition, emulsifiers, lecithin, sorbitan monooleate, gum arabic, etc .; non-aqueous vehicles (including edible oils), almond oil, fractionated coconut oil, oily esters, propylene glycol, ethyl alcohol, etc. . In addition, preservatives such as methyl or propyl p-hydroxybenzoic acid or sorbic acid may be incorporated into the preparation. Such preparations can also be formulated as suppositories, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

  Moreover, the formulations of the present invention can be formulated for parenteral administration by injection or continuous infusion. Injectable formulations may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. . Alternatively, the active ingredient can be in powder form for composition with a suitable vehicle, eg, sterilized, pyrogen-free water, before use.

  The preparation according to the invention can also be formulated as a depot preparation. Such long acting formulations may be administered, for example, by subcutaneous or intramuscular implant, or by intramuscular injection. Therefore, the compound of the present invention can be formulated with a polymer or hydrophobic substance such as an acceptable emulsion in oil or ion exchange resin, or as a poorly soluble derivative such as a hardly soluble salt.

  The pharmaceutical formulations can be provided as unit dosage forms containing a predetermined amount of the active ingredient per unit dose. Such a unit may contain a certain amount of a compound of the invention depending on the condition being treated, the route of administration, age, weight, and condition of the patient. Preferred unit dosage forms are those containing a predetermined dosage of the active ingredient, such as a daily dose or an appropriate divided dose thereof. Such pharmaceutical preparations can be prepared by any method well known in the pharmacology field.

  As used herein, the term “effective amount” refers to an amount of a drug or pharmaceutical agent that elicits a biological or medical response of a tissue, organ system, animal or human, as determined by, for example, a researcher or medical professional. Means. Furthermore, the term “therapeutically effective amount” refers to an improvement in treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or disease or disorder compared to a corresponding subject that did not receive that amount. Means any amount that results in a decrease in the speed of progression. The term also includes amounts effective to enhance normal physiological function.

  A “therapeutically effective amount” of a compound of the present invention depends on a number of factors, such as: the age and weight of the animal, the specific symptoms and severity required of treatment, the nature of the formulation, and Route of administration. The therapeutic effectiveness is ultimately at the discretion of the attending physician or veterinarian. An effective amount of a salt or solvate, or pharmaceutically functional derivative thereof, is determined as an amount proportional to the effective amount of the compound itself.

The following examples illustrate embodiments of the invention but should not be construed as limiting. Except as otherwise noted, all starting materials were obtained from commercial suppliers or by synthetic methods known to those skilled in the art. As used herein, the symbols and boilerplate used in these processes, schemes and examples are consistent with those used in modern scientific literature, for example: The Journal of the American Chemical Society Or The Journal of Biological Chemistry. In particular, the following abbreviations are used in the examples and throughout the specification:
g (grams); mg (milligrams);
L (liter); mL (milliliter);
μL (microliter); psi (pounds / (inch) ² );
M (molar concentration); mM (molar concentration);
iv (intravenous); hz (hertz);
MHz (megahertz); mol (mol);
mmol (mmol); RT (room temperature);
min (minutes); h (hours);
mp (melting point); TLC (thin layer chromatography);
Tr (retention time); RP (reverse phase);
MeOH (methanol); I-PrOH (isopropanol);
TEA (triethylamine); TFA (trifluoroacetic acid);
TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);
DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate);
DCE (dichloroethane); DMF (N, N-dimethylformamide);
HOAc (acetic acid); EDC (ethyl carbodiimide hydrochloride);
mCPBA (meta-chloroperbenzoic acid);
BOC (tert-butyloxycarbonyl); CBZ (benzyloxycarbonyl);
DCC (dicyclohexylcarbodiimide); Me (methyl);
Ac (acetyl); atm (atmospheric pressure);
TMSE (2- (trimethylsilyl) ethyl); TMS (tomethylsilyl);
TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);
DMAP (4-dimethylaminopyridine);
HPLC (high pressure liquid chromatography);
Et (ethyl); tBu (tert-butyl).

  All ether designations refer to diethyl ether; brine represents a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C (degrees Centigrade). Unless otherwise stated, all reactions were performed at room temperature under an inert atmosphere.

¹ HNMR spectra were recorded on a Varian VXR-300, VarianUnity-300, VarianUnity-400 instrument, or General Electric QE-300. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). The split pattern indicates the apparent multiplicity and is displayed as s (singlet), d (doublet), t (triplet), q (quadruple), m (multiplet), br (wide) To do.

  Low resolution mass spectra (MS) were recorded on a JOELJMS-AX505HA, JOELSX-102, or SCIEX-APIiii spectrometer; high resolution MS was acquired using a JOELSX-102A spectrometer. Full mass spectra were obtained by electrospray ionization (ESI), chemical ionization (CI), electron impact (EI), or by fast atom bombardment (FAB) methods. Infrared (IR) spectra were acquired on a Nicolet 510 FT-IR spectrometer using a 1-mm NaCl cell. All reactions were monitored by thin layer chromatography visualized with UV light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution on 0.25 mm E. Merck silica gel plates (60F-254). Flash column chromatography was performed on silica gel (230-400 mesh, Merck). The optical rotation was obtained using a PerkinElmerModel241Polarimeter. Melting points were measured using a Mel-Temp II instrument, but this is uncorrected.

  The IUPAC name is also used to further identify specific compounds of the invention. The scope of the present invention should not be limited in any way by the IUPAC names used herein.

Scheme 1:

a: ethoxymethylenemalononitrile (1 eq), triethylamine (1.2 eq), ethanol; b: formic acid; c: phosphorus oxychloride; d: hydrazine hydrate (6 eq), ethanol; e: suitable aldehyde (1 eq) ), Pyrrolidine (catalyst), ethanol.

Scheme 2:

a: suitable amine (1.5 eq), diethyl cyanophosphonate (2 eq), triethylamine (3 eq), DMF
Scheme 3:

a: suitable amine, diisopropylethylamine; b: i: sodium hydride (12 eq), suitable alcohol (18 eq), THFii: DMSO

Example
Intermediate Example A
4-Hydrazino-1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- (3-methylphenyl) -1H-pyrazole-4-carbonitrile

To 1- (3-methylphenyl) hydrazine hydrochloride (2.00 g, 12.61 mmol) in 25 mL of ethanol was added 2- (ethoxymethylene) malononitrile (1.54 g, 12.61 mmol) and triethylamine (2.3 mL, 16.39 mmol). The mixture was refluxed for about 3 h, concentrated under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The product was isolated as a white solid (1.135 g, 45%) by flash chromatography.
¹ HNMR (CDCl ₃ ) δ 7.63 (s, 1H), 7.40 (t, 1H), 7.26 (m, 3H), 4.58 (s, 2H), 2.42 (s, 3H) ppm.

b. 1- (3-Methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

5-Amino-1- (3-methylphenyl) -1H-pyrazole-4-carbonitrile (a, above) (1.13 g, 5.71 mmol) was dissolved in 50 mL formic acid and refluxed for about 24 h. The mixture was cooled to RT and diluted with ether. The resulting solid was collected by filtration and washed with ether to give the product as a white solid (0.99 g, 77%).
¹ HNMR (DMSO) δ12.44 (s, 1H), 8.31 (s, 1H), 8.20 (d, 1H), 7.85 (s, 1H), 7.82 (d, 1H), 7.43 (t, 1H), 7.21 (d, 1H), 2.39 (s, 3H) ppm.

c. 4-Chloro-1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine

1- (3-Methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (0.98 g, 4.32 mmol) was dissolved in phosphorus oxychloride (5 mL) and DMF2-3 Drops were added. The mixture was heated at reflux for about 3.5 h. The mixture was concentrated under reduced pressure, quenched in an ice / sodium bicarbonate mixture and extracted with methylene chloride. The organic phase was washed with aqueous sodium bicarbonate and concentrated to give the product as a white solid (0.95 g, 90%).
¹ HNMR (DMSO) δ8.98 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.93 (d, 1H), 7.48 (t, 1H), 7.25 (d, 1H), 2.42 (s, 3H) ppm. ES-MSm / z245 (MH ⁺ ).

d.4-Hydrazino-1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine

4-Chloro-1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (c, above) (0.50 g, 2.05 mmol) was dissolved in ethanol (25 mL) to give hydrazine monohydrate. (0.60 mL, 12.3 mmol) was added. The mixture was heated at 45 ° C. for about 18 h and concentrated under reduced pressure. The resulting solid was triturated with aqueous sodium bicarbonate to give the product as a white solid (0.45 g, 91%).
ES-MSm / z241 (MH ⁺ ).

Intermediate Example B
1- (3-Bromophenyl) -4-chloro-1H-pyrazolo [3,4-d] pyrimidine
a. 1- (3-Bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

A solution of 5-amino-1- (3-bromophenyl) -1H-pyrazole-4-carbonitrile (1.47 g, 5.59 mmol) in 50 mL of 88% formic acid was heated at 100 ° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The precipitated solid was collected by filtration, washed with ether and dried under vacuum to give 1.37 g (84%) of product as a white solid.
¹ HNMR (DMSO) δ 12.50 (brs, 1H), 8.35 (m, 2H), 8.25 (m, 1H), 8.10 (m, 1H), 7.60 (m, 1H), 7.50 (t, 1H) ppm. ES-MSm / z291 (M + 2) ⁺
b. 1- (3-Bromophenyl) -4-chloro-1H-pyrazolo [3,4-d] pyrimidine

A suspension of 1- (3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (a, above) (1.36 g, 4.67 mmol) in 5 mL of phosphorus oxychloride at 100 ° C. Heated for 4 h. The reaction mixture was cooled to room temperature, poured into ice and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give 0.84 g (58%) of product as a white solid.
¹ HNMR (DMSO) Δ9.05 (s, 1H), 8.80 (s, 1H), 8.45 (m, 1H) 8.20 (d, 1H), 7.45 (d, 1H), 7.40 (t, 1H).

c. 1- (3-Bromophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine hydrochloride

To a solution of 1- (3-bromophenyl) -4-chloro-1H-pyrazolo [3,4-d] pyrimidine (b, above) in 5 mL of absolute ethanol is added hydrazine hydrate (0.094 mL, 1.93 mmol). Added. The mixture was heated at reflux overnight, cooled to room temperature, and the solvent was evaporated to give 0.095 g of product as a white solid.
ES-MSm / z307 (M + 2), 308.
Intermediate Example C
4-Hydrazino-1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- (2-methoxyphenyl) -1H-pyrazole-4-carbonitrile

2-Methoxyphenylhydrazine hydrochloride (1.00 g, 5.70 mmol) was prepared as described for 5-amino-1- (3-methylphenyl) -1H-pyrazole-4-carbonitrile (intermediate Example A). Treatment with ethoxymethylenemalononitrile (0.698 g, 5.70 mmol) and triethylamine (0.95 mL, 6.80 mmol) gave 0.46 g (38%) of product as an off-white solid.
¹ HNMR (DMSO) δ 7.65 (s, 1H), 7.45 (t, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 7.05 (t, 1H), 6.35 (brs, 2H), 3.80 (s, 3H) ppm.

b. 1- (2-Methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

5-amino-1- (2-methoxyphenyl) as described for 1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (intermediate example A) -1H-pyrazole-4-carbonitrile (a, above) (0.43 g, 2.01 mmol) was treated with 88% formic acid to give 0.302 g (62%) of product as an off-white solid.
¹ HNMR (DMSO) δ 12.25 (brs, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.50 (m, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.10 (m, 1H), 3.75 (s, 3H) ppm. ES-MSm / z243 (MH ⁺ ).

c. 4-Chloro-1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

As described for 4-chloro-1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example A), 1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (0.296 g, 1.22 mmol) was treated with phosphorus oxychloride to give the product 0.230 (72%) as a white solid.
¹ HNMR (DMSO) δ8.85 (s, 1H), 8.70 (s, 1H), 7.60 (t, 1H), 7.50 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 3.70 (s, 3H) ppm.

d.4-Hydrazino-1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

4-Hydrazino-1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example A) as described for 4-chloro-1- (2-methoxyphenyl) Treatment of -1H-pyrazolo [3,4-d] pyrimidine (c, above) (0.228 g, 0.87 mmol) with hydrazine hydrate (0.25 mL, 5.25 mmol) yields 0.349 g of product as an off-white solid did.
ES-MSm / z256 (MH ⁺ )
Intermediate Example D
4-Hydrazino-1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- (3-nitrophenyl) -1H-pyrazole-4-carbonitrile

2- (3-Nitrophenyl) hydrazine hydrochloride (3.00 g, 15.82 mmol) in 40 mL of ethanol was added 2- (ethoxymethylene) malononitrile (1.93 g, 15.82 mmol) and triethylamine (2.9 mL, 20.6 mmol). Added. The mixture was refluxed for about 6 h. After cooling to RT, the resulting solid was collected and the product was obtained as a yellow solid (2.15 g, 59%).
¹ HNMR (CDCl ₃ ): δ 8.47 (t, 1H), 8.31 (dd, 1H), 7.95 (d, 1H), 7.76 (t, 1H), 7.71 (s, 1H), 4.66 (s, 2H) ppm.

b. 1- (3-Nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

5-Amino-1- (3-nitrophenyl) -1H-pyrazole-4-carbonitrile (a, above) (2.00 g, 8.73 mmol) was dissolved in 40 mL formic acid and refluxed for about 30 h. The mixture was cooled to RT and diluted with ether. The resulting solid was collected by filtration and washed with ether to give the product as a white solid (2.10 g, 100%).
¹ HNMR (DMSO): δ 12.62 (s, 1H), 9.03 (t, 1H), 8.57 (dd, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.23 (dd, 1H), 7.87 (t, 1H) ppm.

c. 4-Chloro-1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidine

1- (3-Nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (2.1 g, 8.73 mmol) was dissolved in phosphorus oxychloride (25 mL) and DMF2-3 Drops were added. The mixture was heated at reflux for about 5 h. The mixture was concentrated under reduced pressure, quenched in an ice / sodium bicarbonate mixture and extracted with methylene chloride. The organic phase was washed with aqueous sodium bicarbonate and concentrated to give the product as a white solid (2.1 g, 87%).
¹ HNMR (DMSO) δ 9.11 (t, 1H), 9.09 (s, 1H), 8.88 (s, 1H), 8.66 (dd, 1H), 8.28 (dd, 1H), 7.93 (t, 1H) ppm.

d. tert-butyl 2- [1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate

4-chloro-1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidine (c, above) (1.00 g, 3.63 mmol) and tert-butyl hydrazine carboxylate (0.58 g, 4.35 mmol) ) Was dissolved in ethanol (200 mL). Triethylamine (0.76 mL, 5.44 mmol) was added. The mixture was refluxed for about 18 h and concentrated under reduced pressure. The residue was partitioned between methylene chloride and aqueous sodium bicarbonate to give the product as a white solid (1.2 g, 89%).
ES-MSm / z372 (MH ⁺ ).

e.4-Hydrazino-1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidine

tert-Butyl 2- [1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (d, above) (0.60 g, 1.6 mmol) was added to methylene chloride ( 50 mL) and trifluoroacetic acid (15 mL). The mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in 4N hydrochloric acid in methylene chloride (50 mL) and dioxane (8 mL). The solvent was removed under reduced pressure to give the product as the hydrochloride salt (0.62 g, 98%).
ES-MSm / z272 (MH ⁺ ).

Intermediate Example E
N- [3- (4-hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] acetamide
tert-butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate

Tert-Butyl 2- [1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (Intermediate Example D) (0.70) in ethanol (150 mL) g, 1.89 mmol) was added palladium on carbon (10%, 0.6 g). The mixture was stirred for 3 h under 1 atm of hydrogen. The mixture was flushed with nitrogen, filtered and concentrated to give the product as a white foam (0.67 g, 99%).
ES-MSm / z342 (MH ⁺ ).

b. tert-butyl 2- [3- (acetylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate

Tert-Butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (a, above) (100 mg, 0.29 mmol) in THF (8 mL) ) Was added triethylamine (0.51 mL, 0.37 mmol) and acetyl chloride (0.021 mL, 0.29 mmol). The mixture was stirred at RT for 40 min and then partitioned between ethyl acetate and aqueous sodium bicarbonate to give the product as a white solid (110 mg, 100%).
^{ES-MSm / z382 (MH -} ).

cN- [3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] acetamide

tert-Butyl 2- [3- (acetylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate (b, above) (0.10 g, 0.27 mmol) in methylene chloride (20 mL) and trifluoroacetic acid (10 mL). The mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in 4N hydrochloric acid in methylene chloride (20 mL) and dioxane (5 mL). The solvent was removed under reduced pressure to give the product as the hydrochloride salt (0.82 g, 95%).
ES-MSm / z284 (MH ⁺ ).

Intermediate Example F
N- [3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] butanamide
a. tert-butyl 2- [3- (butyrylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate

Tert-Butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (Intermediate Example E) (100 mg) in THF (8 mL) , 0.29 mmol) was added triethylamine (0.51 mL, 0.37 mmol) and butyryl chloride (31 mg, 0.29 mmol). The mixture was stirred at RT for 1 h and then partitioned between ethyl acetate and aqueous sodium bicarbonate to give the product as a clear solid (120 mg, 100%).
^{ES-MSm / z410 (MH -} ).

bN- [3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] butanamide

tert-Butyl2-1- [3- (butyrylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate (a, above) (0.12 g, 0.29 mmol) was added to methylene chloride ( 20 mL) and trifluoroacetic acid (8 mL). The mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in 4N hydrochloric acid in methylene chloride (20 mL) and dioxane (4 mL). The solvent was removed under reduced pressure to give the product as the hydrochloride salt (0.10 g, 100%).
ES-MSm / z312 (MH ⁺ ).

Intermediate Example G
N- [3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] benzamide
a. tert-butyl 2- [3- (benzoylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate

Tert-Butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (Intermediate Example E) (100 mg) in THF (8 mL) , 0.29 mmol) was added triethylamine (0.51 mL, 0.37 mmol) and benzoyl chloride (41 mg, 0.29 mmol). The mixture was stirred at RT for 3 days and then partitioned between ethyl acetate and aqueous sodium bicarbonate to give the crude product as a white solid. The product was purified by silica gel chromatography (2: 1 ethyl acetate: hexanes) to give the product as a white solid (82 mg, 64%).
^{ES-MSm / z444 (MH -} ).

bN- [3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] benzamide

tert-Butyl 2- [3- (benzoylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate (a, above) (0.75 g, 0.17 mmol) in methylene chloride (10 mL) and trifluoroacetic acid (8 mL). The mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in 4N hydrochloric acid in methylene chloride (10 mL) and dioxane (4 mL). The solvent was removed under reduced pressure to give the product as the hydrochloride salt (0.65 g, 100%).
ES-MSm / z346 (MH ⁺ ).

Intermediate Example H
3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-pentylaniline
a. tert-butyl 2- [3- (pentylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate

Tert-Butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (Intermediate Example E) (150 mg) in methanol (7 mL) , 0.44 mmol) was added pentanal (45 mg, 0.53 mmol). The mixture was stirred at RT for about 30 minutes and cyanoborohydride (300 mg, about 1.0 mmol) conjugated to the resin was added. The resulting mixture was stirred at RT for about 18 h. The mixture was filtered and partitioned between methylene chloride and aqueous sodium bicarbonate to obtain the crude product. The crude product was purified by silica gel chromatography (1: 3 ethyl acetate: hexanes) to obtain the product (55 mg, 30%).
ES-MSm / z412 (MH ⁺ ).

b. 3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-pentylaniline

tert-butyl 2- [3- (pentylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate (a, above) (50 mg, 0.12 mmol) was added to methylene chloride ( 5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at RT for 1.5 h. The solvent was removed under reduced pressure and the residue was dissolved in 1N hydrochloric acid in methylene chloride (5 mL) and diethyl ether (5 mL). The solvent was removed under reduced pressure to obtain the product as the hydrochloride salt (0.42 g, 100%).
ES-MSm / z312 (MH ⁺ ).

Intermediate Example I
N- (Cyclopropylmethyl) -3- (4-hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) aniline
a. tert-butyl 2- (1-3-[(cyclopropylmethyl) amino] phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazinecarboxylate

Tert-Butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (Intermediate Example E) (150 mg) in methanol (6 mL) , 0.44 mmol) was added sodium acetate (ca. 20 mg) and cyclopropanecarbaldehyde (39 mg, 0.55 mmol). The mixture was stirred at RT for about 1 h and cyanoborohydride (500 mg, about 1.7 mmol) conjugated to the resin was added. The resulting mixture was stirred at RT for about 6 h. The mixture was filtered and partitioned between methylene chloride and aqueous sodium bicarbonate to obtain the crude product. The crude product was purified by silica gel chromatography (1: 3 ethyl acetate: hexanes) to give the product (60 mg, 35%).
ES-MSm / z396 (MH ⁺ ).

bN- (Cyclopropylmethyl) -3- (4-hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) aniline

tert-Butyl 2- (1-3-[(cyclopropylmethyl) amino] phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazinecarboxylate (a, above) (57 mg, 0.14 mmol) Was dissolved in methylene chloride (8 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at RT for 1.5 h. The solvent was removed under reduced pressure and the residue was dissolved in 4N hydrochloric acid in methylene chloride (8 mL) and dioxane (4 mL). The solvent was removed under reduced pressure to give the product as the hydrochloride salt (48 mg, 100%).

ES-MSm / z296 (MH ⁺ ).

Intermediate Example J
3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-propylaniline
a. tert-butyl 2- [3- (propylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate

Tert-Butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (Intermediate Example E) (150 mg) in methanol (6 mL) , 0.44 mmol) was added sodium acetate (about 20 mg) and propionaldehyde (39 mg, 0.55 mmol). The mixture was stirred at RT for about 1 h and cyanoborohydride (500 mg, about 1.7 mmol) conjugated to the resin was added. The resulting mixture was stirred at RT for about 6 h. The mixture was filtered and partitioned between methylene chloride and aqueous sodium bicarbonate to obtain the crude product. The crude product was purified by silica gel chromatography (1: 3 ethyl acetate: hexanes) to give the product (65 mg, 39%).
ES-MSm / z384 (MH ⁺ ).

b. 3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-propylaniline

tert-Butyl 2- [3- (propylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate (a, above) (60 mg, 0.16 mmol) was added to methylene chloride ( 8 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at RT for 1.5 h. The solvent was removed under reduced pressure and the residue was dissolved in 4N hydrochloric acid in methylene chloride (8 mL) and dioxane (4 mL). The solvent was removed under reduced pressure to give the product as the hydrochloride salt (51 mg, 100%).
ES-MSm / z284 (MH ⁺ ).

Intermediate Example K
3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-isobutylaniline
a. tert-butyl 2- [3- (isobutylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate

Tert-Butyl 2- [1- (3-aminophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazinecarboxylate (middle Example E) in methylene chloride (12 mL) To 150 mg, 0.44 mmol) was added 2-methylpropanal (48 mg, 0.66 mmol). The mixture was stirred at RT for about 1.5 h and sodium triacetoxyborohydride (0.28 g, 1.32 mmol) was added. The resulting mixture was stirred at RT for about 2 days. The mixture was partitioned between methylene chloride and aqueous sodium bicarbonate to obtain the crude product. The crude product was purified by silica gel chromatography (1: 3 ethyl acetate: hexanes) to give the product (76 mg, 44%).
ES-MSm / z398 (MH ⁺ ).

b. 3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-isobutylaniline

tert-butyl 2- [3- (isobutylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazinecarboxylate (a, above) (72 mg, 0.18 mmol) was added to methylene chloride ( 8 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at RT for 1.5 h. The solvent was removed under reduced pressure and the residue was dissolved in 4N hydrochloric acid in methylene chloride (8 mL) and dioxane (4 mL). The solvent was removed under reduced pressure to give the product as the hydrochloride salt (60 mg, 100%).
ES-MSm / z298 (MH ⁺ ).

Intermediate Example L
1- (3-Ethoxyphenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- (3-ethoxyphenyl) -1H-pyrazole-4-carbonitrile

To a solution of 3-ethoxyphenylhydrazine (1.40 g, 9.21 mmol) in 50 mL of absolute ethanol was added ethoxymethylenemalononitrile (1.12 g, 9.21 mmol). The mixture was heated at reflux for 1 hour. Upon cooling to room temperature, a crystalline solid was formed. The mixture was refrigerated overnight, filtered and the crystals were washed with hexane and dried under vacuum to give 1.20 g (57%) of pure product.
¹ HNMR (DMSO) δ 7.75 (s, 1H), 7.40 (t, 1H), 7.02 (d, 1H), 6.98 (m, 1H), 6.95 (dd, 1H), 6.65 (brs, 2H), 4.05 (q, 2H), 1.30 (t, 3H) ppm; ES-MSm / z360 (MH ^<+> ).

b. 1- (3-Ethoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

A solution of 5-amino-1- (3-ethoxyphenyl) -1H-pyrazole-4-carbonitrile (a, above) (1.20 g, 5.26 mmol) in 30 mL of 88% formic acid was heated at 100 ° C. overnight. Upon cooling to room temperature, the precipitated crude product was filtered, washed with diethyl ether and dried under vacuum to give 0.88 g (65%) of product as a white solid.
¹ HNMR (DMSO) δ 12.50 (brs, 1H), 8.40 (s, 1H), 8.25 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H), 7.00 (d, 1H), 4.10 (q, 2H), 1.40 (t, 3H) ppm; ES-MSm / z257 (MH ^<+> ).

c. 4-Chloro-1- (3-ethoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

A suspension of 1- (3-ethoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (0.88 g, 3.43 mmol) in 5 mL of phosphorus oxychloride at 100 ° C. Heated for 30 minutes. The reaction mixture was cooled to room temperature, poured into ice and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under vacuum to give 0.94 g of product as an off-white solid.
¹ HNMR (DMSO) δ9.05 (s, 1H), 8.80 (s, 1H), 7.79 (m, 2H), 7.50 (t, 1H), 7.05 (d, 1H), 4.15 (q, 2H), 1.40 (t, 3H) ppm.

d. 1- (3-Ethoxyphenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine

Hydazine hydration was performed on a suspension of 4-chloro-1- (3-ethoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (c, above) (0.94 g, 3.42 mmol) in 25 mL of absolute ethanol. Product (1.0 mL, 20.5 mmol) was added. The mixture was heated at reflux for 1.5 h. After removal of the solvent under vacuum, the crude solid product was suspended in saturated aqueous sodium bicarbonate, filtered, washed with water and dried under vacuum to give 0.81 g (88%) of the product as a white solid Acquired as.
ES-MSm / z271 (MH ⁺ ).

Intermediate Example M
4-Hydrazino-1- [3- (trifluoromethoxy) phenyl] -1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- [3- (trifluoromethoxy) phenyl] -1H-pyrazole-4-carbonitrile

To a solution of 3-trifluoromethoxyphenylhydrazine (2.71 g, 14.1 mmol) in 75 mL of absolute ethanol was added ethoxymethylenemalononitrile (1.72 g, 14.1 mmol). The mixture was heated at reflux for 1 hour, cooled and the solvent removed in vacuo. The solid residue was recrystallized from hexane / ethyl acetate to obtain 2.43 g (64%) of pure product.
¹ HNMR (DMSO) δ 7.86 (s, 1H), 7.68 (t, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7.46 (d, 1H), 6.90 (brs, 2H) ppm.

b. 1- [3- (Trifluoromethoxy) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ol

As described for 1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (Intermediate Example C), 5-amino-1- [3- (trifluoro Methoxy) phenyl] -1H-pyrazole-4-carbonitrile (a, above) (2.42 g, 9.03 mmol) was treated with formic acid to give 1.50 g (56%) of product.
¹ HNMR (DMSO) δ 12.60 (brs, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 8.20 (m, 2H), 7.75 (t, 1H), 7.45 (d, 1H) ppm; ES-MSm / z297 (MH ⁺ ).

c. 4-Chloro-1- [3- (trifluoromethoxy) phenyl] -1H-pyrazolo [3,4-d] pyrimidine

1- [3- (trifluoromethoxy) phenyl] as described for 4-chloro-1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example C) Treatment of -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (1.49 g, 5.03 mmol) with phosphorus oxychloride gives 1.45 g (92%) of product as a white solid did.
¹ HNMR (DMSO) δ 9.05 (s, 1H), 8.85 (s, 1H), 8.30 (d, 1H), 8.25 (s, 1H), 7.80 (t, 1H), 7.45 (d, 1H) ppm.

d.4-Hydrazino-1- [3- (trifluoromethoxy) phenyl] -1H-pyrazolo [3,4-d] pyrimidine

As described for 4-hydrazino-1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example C), 4-chloro-1- [3- (trifluoro Methoxy) phenyl] -1H-pyrazolo [3,4-d] pyrimidine (c, above) (1.45 g, 4.61 mmol) was treated with hydrazine hydrate (1.3 mL, 27.6 mmol) to give 0.996 g of product ( 70%) was obtained as a white solid.
ES-MSm / z311 (MH ⁺ ).

Intermediate Example N
4-Hydrazino-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- (4-methoxyphenyl) -1H-pyrazole-4-carbonitrile.

A mixture of 4-methoxyphenylhydrazine hydrochloride (5.00 g, 28.6 mmol), ethoxymethylenemalononitrile (3.49 g, 28.6 mmol) and triethylamine (4.8 mL, 34.3 mmol) in 75 mL of absolute ethanol was heated at reflux overnight. . The solvent was removed in vacuo and the residue was extracted between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography in hexane / ethyl acetate to give 4.88 g (80%) of product as an off-white crystalline solid.
¹ HNMR (DMSO) δ 7.70 (s, 1H), 7.35 (d, 2H), 7.05 (d, 2H), 6.50 (brs, 2H), 3.80 (s, 3H) ppm.

b. 1- (4-Methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

A solution of 5-amino-1- (4-methoxyphenyl) -1H-pyrazole-4-carbonitrile (a, above) (4.88 g, 22.8 mmol) in 100 mL 88% formic acid was heated at 100 ° C. overnight. Upon cooling to room temperature, a solid precipitated. The solid was collected by filtration, washed with diethyl ether and dried under vacuum to give 3.30 g (60%) of product as a white powder.
¹ HNMR (DMSO) δ 12.20 (brs, 1H), 8.25 (s, 1H), 8.10 (m, 1H), 7.85 (d, 2H), 7.05 (d, 2H), 3.80 (s, 3H) ppm.

c. 4-Chloro-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

A suspension of 1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (3.30 g, 13.6 mmol) in 10 mL of phosphorus oxychloride at 100 ° C. Heated for 2 hours. The mixture was cooled to room temperature, poured into ice and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and the solvent was removed to give 3.30 g (67%) of product as a white solid.
¹ HNMR (DMSO) δ 8.90 (s, 1H), 8.65 (s, 1H), 7.95 (s, 2H), 7.15 (d, 2H), 3.80 (s, 3H) ppm.

d.4-Hydrazino-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

Hydazine hydration was performed on a suspension of 4-chloro-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (c, above) (3.30 g, 12.7 mmol) in 100 mL of absolute ethanol. Product (3.7 mL, 76. mmol) was added. The mixture was heated at reflux for 2 hours. The solvent was evaporated to give 4.40 g of white solid.
ES-MSm / z257 (MH ⁺ ).

Intermediate Example O
4-Hydrazino-1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine

4-Chloro-1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (2.00 g, 8.18 mmol) was dissolved in ethanol (150 mL) and hydrazine monohydrate (2.47 mL, 49.1 mmol) was added. The mixture was heated at 45 ° C. for about 20 h and concentrated under reduced pressure. The resulting solid was triturated with aqueous sodium bicarbonate to give the product as a white solid (1.83 g, 93%).
ES-MSm / z241 (MH ⁺ ).

Intermediate Example P
4-Hydrazino-1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- (3-propylphenyl) -1H-pyrazole-4-carbonitrile

To 1- (3-propylphenyl) hydrazine hydrochloride (1.00 g, 5.36 mmol) in 15 mL of ethanol was added 2- (ethoxymethylene) malononitrile (0.654 g, 5.36 mmol) and triethylamine (0.97 mL, 6.97 mmol). . The mixture was refluxed for about 3.5 h, concentrated under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The product was isolated as a white solid (0.79 g, 65%) by flash chromatography.
¹ HNMR (CDCl ₃ ) δ 7.64 (s, 1H), 7.43 (t, 1H), 7.29 (m, 3H), 4.58 (s, 2H), 2.66 (t, 2H), 1.66 (m, 2H), 0.96 (t, 3H) ppm.

b. 1- (3-Propylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

5-Amino-1- (3-propylphenyl) -1H-pyrazole-4-carbonitrile (a, above) (0.78 g, 3.45 mmol) was dissolved in 45 mL formic acid and refluxed for about 24 h. The mixture was cooled to RT, concentrated under reduced pressure and diluted with ether. The resulting solid was collected by filtration and washed with ether to give the product as a white solid (0.53 g, 60%).
¹ HNMR (DMSO) δ12.44 (s, 1H), 8.31 (s, 1H), 8.20 (d, 1H), 7.85 (m, 2H), 7.44 (t, 1H), 7.22 (d, 1H), 2.64 (t, 2H), 1.64 (m, 2H), 0.91 (t, 3H) ppm.

c. 4-Chloro-1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidine

1- (3-Propylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (0.52 g, 2.03 mmol) was dissolved in phosphorus oxychloride (10 mL) and DMF2-3 Drops were added. The mixture was heated at reflux for about 3.5 h. The mixture was concentrated under reduced pressure, quenched in an ice / sodium bicarbonate mixture and extracted with methylene chloride. The organic phase was washed with aqueous sodium bicarbonate and concentrated to give the product as a white solid (0.53 g, 96%).
¹ HNMR (DMSO) δ8.99 (s, 1H), 8.75 (s, 1H), 7.96 (m, 2H), 7.51 (t, 1H), 7.27 (d, 1H), 2.67 (t, 2H), 1.64 (m, 2H), 0.92 (t, 3H) ppm. ES-MSm / z273 (MH ^<+> ).

d.4-Hydrazino-1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidine

4-Chloro-1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (c, above) (0.55 g, 2.02 mmol) was dissolved in ethanol (50 mL) and hydrazine monohydrate (0.60 mL, 12.3 mmol) was added. The mixture was heated at 45 ° C. for about 19 h and concentrated under reduced pressure. The resulting solid was triturated with aqueous sodium bicarbonate to give the product as a white solid (0.48 g, 90%).
ES-MSm / z269 (MH ⁺ ).

Intermediate Example Q
4-Hydrazino-1- (2-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride
a. 1- (2-Methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

  Using the method described for 1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (intermediate Example N), 5-amino-1- (2- Prepared from methylphenyl) -1H-pyrazole-4-carbonitrile.

b. 4-Chloro-1- (2-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine

Using the method described for 4-chloro-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example N), 1- (2-methylphenyl)- Prepared from 1H-pyrazolo [3,4-d] pyrimidin-4-ol (a, above).
¹ HNMR (300 MHz, DMSO) δ 8.84 (s, 1H), 8.72 (s, 1H), 7.39-7.48 (m, 4H), 2.04 (s, 3H) ppm. ES-MSm / z245 (MH ⁺ ).

c.4-Hydrazino-1- (2-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride

Using the method described for 4-hydrazino-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example N), 4-chloro-1- (2- Prepared from methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (b, above).
¹ HNMR (300 MHz, DMSO) δ 9.28 (s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.38-7.45 (m, 4H), 5.04 (s, 2H), 2.08 (s, 3H) ppm. ES-MSm / z241 (MH ⁺ ).

Intermediate Example R
1- (3-Fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine
a. 1- (3-Fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

  Using the method described for 1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (intermediate Example N), 5-amino-1- (3- Prepared from fluorophenyl) -1H-pyrazole-4-carbonitrile.

b. 4-Chloro-1- (3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidine

  Using the method described for 4-chloro-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example N), 1- (3-fluorophenyl)- Prepared from 1H-pyrazolo [3,4-d] pyrimidin-4-ol (a, above).

c. 1- (3-Fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine

  Using the method described for 1- (4-methoxyphenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate Example N), 4-chloro-1- (3- Prepared from fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidine (b, above).

Intermediate Example S
1- (3-Chlorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine
a. 1- (3-Chlorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

Using the method described for 1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (intermediate Example N), 5-amino-1- (3- Prepared from chlorophenyl) -1H-pyrazole-4-carbonitrile.
¹ HNMR (400MHz, DMSO) δ12.50 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.16 (m, 1H), 8.01 (d, 1H), 7.55 (t, 1H) , 7.41 (d, 1H) ppm. ES-MSm / z247 (MH ⁺ ).

b. 4-Chloro-1- (3-chlorophenyl) -1H-pyrazolo [3,4-d] pyrimidine

  Using the method described for 4-chloro-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example N), 1- (3-chlorophenyl) -1H -Prepared from pyrazolo [3,4-d] pyrimidin-4-ol (a, above).

c. 1- (3-Chlorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine

  Using the method described for 1- (4-methoxyphenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate Example N), 4-chloro-1- (3- Prepared from chlorophenyl) -1H-pyrazolo [3,4-d] pyrimidine (b, above).

Intermediate Example T
4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine
a. 5-Amino-1- (3-methoxyphenyl) -1H-pyrazole-4-carbonitrile

A mixture of 3-methoxyphenylhydrazine hydrochloride (5.00 g, 28.6 mmol), ethoxymethylenemalononitrile (3.49 g, 28.6 mmol), and triethylamine (4.8 mL, 34.3 mmol) in 75 mL of absolute ethanol was heated at reflux for 18 hours. did. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was extracted between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was concentrated under vacuum to obtain a brown paste. Flash chromatography on silica gel with hexane: ethyl acetate (70:30) gave 4.54 g (74%) of product as a light tan solid.
¹ HNMR (400MHz, DMSO) δ7.80 (s, 1H), 7.40 (t, 1H), 7.05 (d, 1H), 7.00 (s, 1H), 6.95 (d, 1H), 6.65 (brs, 2H) 3.80 (s, 3H) ppm.

b. 1- (3-Methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

A solution of 5-amino-1- (3-methoxyphenyl) -1H-pyrazole-4-carbonitrile (a, above) (4.50 g, 21.0 mmol) in 100 mL of 88% formic acid was heated at 100 ° C. under nitrogen for 18 hours. did. The reaction mixture was cooled to room temperature and diluted with 100 mL diethyl ether. The resulting precipitate was filtered, washed with ether and dried under vacuum to give 3.67 g (72%) of product as an off-white solid.
¹ HNMR (400MHz, DMSO) δ 12.50 (brs, 1H), 8.40 (s, 1H), 8.25 (m, 1H), 7.70 (m, 2H), 7.50 (t, 1H), 7.0 (dd, 1H) 3.9 (s, 3H) ppm.

c. 4-Chloro-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

A suspension of 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (b, above) (3.38 g, 13.9 mmol) in 15 mL of phosphorus oxychloride at 100 ° C. Heated for 30 minutes. After cooling to room temperature, the reaction mixture was poured into ice and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give 3.49 g (96%) of product as a light tan solid.
¹ HNMR (400MHz, DMSO) δ9.0 (s, 1H), 8.75 (s, 1H), 7.75 (m, 2H), 7.50 (t, 1H), 7.0 (d, 1H), 3.85 (s, 3H) ppm.

d.4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

To a suspension of 4-chloro-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (c, above) in 100 mL of absolute ethanol was added hydrazine hydrate (3.9 mL, 80.4 mmol). ) Was added. The mixture was heated at reflux for 2.5 hours. The resulting solution was cooled to room temperature and the solvent was removed under vacuum. The residue was suspended in saturated aqueous sodium bicarbonate and stirred for 10 minutes. The mixture was filtered and the solid was washed with water and dried under vacuum for 18 hours to give 2.91 g (85%) of product as a white solid.
ES-MSm / z257 (MH ⁺ ).

Intermediate Example U
N- [2- (Dimethylamino) ethyl] -4-formylbenzenesulfonamide
a.4-Cyano-N- [2- (dimethylamino) ethyl] benzenesulfonamide

(U16945 / 187/1)
To a solution of 4-cyanobenzenesulfonyl chloride (2.50 g; 12.40 mmol) in THF (25 mL) was added N, N-dimethylethylenediamine (3.40 mL; 31.10 mmol) at RT. After 16 h, saturated NaHCO ₃ (100 mL) and ethyl acetate (250 mL) were added. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (3.00 g; 96%).
¹ HNMR (300MHz, CDCl3) δ7.98 (s, 2H), 7.80 (d, 2H), 5.25 (sbr, 1H), 2.98 (t, 2H), 2.33 (t, 2H), 2.07 (s, 6H) .

bN- [2- (Dimethylamino) ethyl] -4-formylbenzenesulfonamide

(U16945 / 187/2)
To a solution of 4-cyano-N- [2- (dimethylamino) ethyl] benzenesulfonamide (a, above) (1.10 g; 4.35 mmol) in toluene (50 mL) under N ₂ at RT in hexanes. Of 1 M diisobutylaluminum hydride (9.57 mL; 9.57 mmol) was added slowly. After 3 h, an aqueous solution of 5% H ₂ SO ₄ (50 mL) was added and the mixture was stirred for 1 h. Saturated NaHCO ₃ (100 mL) and ethyl acetate (200 mL) were added. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to obtain the title compound (0.89 g; 80%).
¹ HNMR (300 MHz, CDCl3) δ 10.09 (s, 1H), 8.04-7.99 (m, 4H), 4.96 (sbr, 1H), 2.99 (t, 2H), 2.32 (t, 2H), 2.06 (s, 6H).

Intermediate Example V
4- (Diethoxymethyl) -2- (methylsulfonyl) pyridine
a.4- (Diethoxymethyl) -2- (methylthio) pyridine

To 2-chloro-4- (diethoxymethyl) pyridine (0.214 g, 1.0 mmol) in THF was added sodium thiomethoxide ((0.35 g, 5 mmol) and the mixture was refluxed for about 16 h. Quenched in aqueous sodium and extracted with ethyl acetate The product was purified by silica gel chromatography (20: 1 hexanes: ethyl acetate) to give the product as a clear oil (0.12 g, 54%).
¹ HNMR (CDCl ₃ ): δ 8.43 (d, 1H), 7.27 (s, 1H), 7.08 (d, 1H), 5.43 (s, 1H), 3.56 (m, 4H), 2.57 (s, 3H) , 1.24 (t, 6H) ppm.

b. 4- (Diethoxymethyl) -2- (methylsulfonyl) pyridine

4- (Diethoxymethyl) -2- (methylthio) pyridine (a, above) (0.12 g, 0.522 mmol) in methylene chloride (10 mL) was cooled in a 0C bath and MCPBA (75%, 0.24 g, 1.04). mmol) was added in 4 portions in 10 minutes. The mixture was stirred at 0 ° C. for about 2.5 h and then partitioned between aqueous sodium bicarbonate and methylene chloride. The product was purified by silica gel chromatography (1: 1 ethyl acetate: hexanes) to give the product as a clear oil (0.12 g, 89%).
¹ HNMR (CDCl ₃ ): δ 8.73 (d, 1H), 8.20 (s, 1H), 7.67 (d, 1H), 5.56 (s, 1H), 3.59 (m, 4H), 3.25 (s, 3H) , 1.27 (t, 6H) ppm.

Intermediate Example W
4-[(4-Methylpiperazin-1-yl) methyl] benzaldehyde
a.4-[(4-Methylpiperazin-1-yl) methyl] benzonitrile

4-[(Diethylamino) methyl] benzonitrile (250 mg, 1.28 mmol) in DMF (25 mL) was treated with 1-methylpiperazine (191 mg, 1.91 mmol) followed by potassium carbonate (177 mg, 1.28 mmol). The mixture was stirred at RT for about 18h. The reaction was concentrated and then partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give the pure product as a white solid (189 mg, 69% yield).
¹ HNMR (300 MHz, DMSO) δ 7.78 (d, 2H), 7.49 (d, 2H), 3.53 (s, 2H), 2.44-2.21 (m, 8H), 2.14 (s, 3H).

b.4-[(4-Methylpiperazin-1-yl) methyl] benzaldehyde

4-[(4-Methylpiperazin-1-yl) methyl] benzonitrile (189 mg, 0.88 mmol) in toluene (15 mL) was treated with DIBAL (1M in heptane, 1.93 mL) and stirred at RT for 1 h. An aqueous solution of 5% H ₂ SO ₄ (30 mL) was added and the reaction was stirred for about 18 h. The pH was adjusted with aqueous sodium bicarbonate and extracted with ethyl acetate and then with chloroform: isopropanol (4: 1). The organic layers were combined, dried and concentrated to obtain the pure product as viscous oil (187 mg, 97% yield).
¹ HNMR (300 MHz, DMSO) δ 9.98 (s, 1H), 7.86 (d, 2H), 7.52 (d, 2H), 3.54 (s, 2H), 2.44-2.21 (m, 8H), 2.14 (s, 3H).

Intermediate Example X
4- (Pyrrolidin-1-ylmethyl) benzaldehyde
a.4- (Pyrrolidin-1-ylmethyl) benzonitrile

4-[(Diethylamino) methyl] benzonitrile (250 mg, 1.28 mmol) was converted to pyrrolidine (250 mg, 1.28 mmol) as described for 4-[(4-methylpiperazin-1-yl) methyl] benzonitrile (Intermediate Example W). The pure product was obtained as a yellow oil (112 mg, 47% yield) by treatment with 136 mg, 1.19 mmol).
¹ HNMR (300 MHz, DMSO) δ 7.77 (d, 2H), 7.50 (d, 2H), 3.65 (s, 2H), 2.50-2.35 (m, 4H), 1.75-1.65 (m, 4H).

b. 4- (Pyrrolidin-1-ylmethyl) benzaldehyde

4-((4-Methylpiperazin-1-yl) methyl] benzaldehyde (Intermediate Example W) as described for 4- (pyrrolidin-1-ylmethyl) benzonitrile (112 mg, 0.60 mmol) in DIBAL Upon processing, the pure product was obtained as viscous oil (111 mg, 98% yield).
¹ HNMR (300 MHz, DMSO) δ 9.98 (s, 1H), 7.76 (d, 2H), 7.53 (d, 2H), 3.66 (s, 2H), 2.47-2.38 (m, 4H), 1.75-1.65 ( m, 4H).

Intermediate Example Y
N ¹ -[4- (Diethoxymethyl) benzyl] -N ² , N ² -Dimethylethane-1,2-diamine

A solution of 4- (diethoxymethyl) benzaldehyde (500 mg, 2.4 mmol), methanol (10 mL), THF (10 mL), and N, N-dimethylethane-1,2-diamine (0.39 mL, 3.6 mmol) at RT. Stir for 3 h. Sodium borohydride (230 mg, 6.0 mmol) was added and the reaction was refluxed for 3 h. The resulting mixture was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to obtain the pure product (595 mg, 89% yield).
¹ HNMR (300 MHz, DMSO) δ 7.31 (s, 2H), 7.30 (s, 2H), 5.45 (s, 1H), 3.68 (s, 2H), 3.58-3.42 (m, 4H), 2.56-2.46 ( m, 2H), 2.24-2.36 (m, 2H), 2.09 (s, 6H), 2.13 (s, 6H).

Intermediate Example Z
N- [4- (Diethoxymethyl) benzyl] ethanamine

U17724 / 152/1
A solution of 4- (diethoxymethyl) benzaldehyde (0.48 mL, 2.4 mmol), methanol (10 mL), THF (10 mL), and 2N ethylamine / THF (3.15 mL, 3.6 mmol) was stirred at RT for 2 h. Sodium borohydride (230 mg, 6.0 mmol) was added and the reaction was stirred overnight at RT. The resulting mixture was basified with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to obtain the pure product as an oil (345 mg, 61% yield).
Intermediate Example AA
N ^1- (4-formylphenyl) -N ² , N ² -dimethylglycinamide
aN ^1- [4- (hydroxymethyl) phenyl] -N ² , N ² -dimethylglycinamide

A mixture of (4-aminophenyl) methanol (200 mg, 1.10 mmol), N, N-dimethylglycyl chloride (200 mg, 1.65 mmol) and triethylamine (0.43 mL, 3.3 mmol) in dichloromethane (5 mL) was stirred at RT for 1 h. did. The reaction mixture was concentrated and purified by silica gel flash chromatography (gradient elution: 100% → 99% → 95% dichloromethane in methanol) to give the title compound as a yellow solid (182 mg, 79% yield).
¹ HNMR (400 MHz, DMSO): δ 9.67 (s, 1H), 7.56 (d, 2H), 7.21 (d, 2H), 5.07 (t, 1H), 4.40 (d, 2H), 3.08 (s, 2H ), 2.28 (s, 6H).

bN ^1- (4-formylphenyl) -N ² , N ² -dimethylglycinamide

N ^1- [4- (hydroxymethyl) phenyl] -N ² , N ² -dimethylglycinamide (a, above) (182 mg, 0.873 mmol) and manganese dioxide (IV) (1.52 g, 17.48) in dichloromethane (10 mL) mmol) was stirred at RT for 18 h. The reaction mixture was filtered through a Celite545 ™ pad and the filtrate was concentrated to give the product as a brown oil (106 mg, 60% yield).
¹ HNMR (400 MHz, DMSO): Δ10.14 (s, 1H), 9.86 (s, 1H), 7.85 (m, 4H), 3.11 (s, 2H), 2.26 (s, 6H).

Intermediate Example BB
N- (4-formylphenyl) -2-morpholin-4-ylacetamide
a. 2-Chloro-N- [4- (hydroxymethyl) phenyl] acetamide

A mixture of (4-aminophenyl) methanol (500 mg, 4.06 mmol) and chloroacetyl chloride (1.41 mL, 17.86 mmol) in acetonitrile (150 mL) was stirred at RT for 15 min. The reaction was then partitioned between ethyl acetate and saturated aqueous NaHCO ₃ solution. The organic layer was dried (Na ₂ SO ₄ ), concentrated, and the residue was purified by silica gel flash chromatography (40% ethyl acetate in hexanes) to give the product as a yellow solid (1.3 g, 40% yield) Acquired as.
¹ HNMR (400 MHz, DMSO): δ 10.24 (s, 1H), 7.51 (d, 2H), 7.24 (d, 2H), 5.11 (s, 1H), 4.41 (s, 2H) 4.22 (s, 2H) .

bN- [4- (Hydroxymethyl) phenyl] -2-morpholin-4-ylacetamide

A mixture of 2-chloro-N- [4- (hydroxymethyl) phenyl] acetamide (a, above) (128 mg, 0.641 mmol) and morpholine (0.2 mL, 1.923 mmol) in ethanol (10 mL) was heated at 100 ° C. for 2 h. did. The reaction was then cooled to RT and concentrated to give the product (160 mg, 100% yield) as a yellow oil (160 mg, 100% yield).
¹ HNMR (400 MHz, DMSO): δ 9.68 (s, 1H), 7.55 (d, 2H), 7.21 (d, 2H), 5.09 (s, 1H), 4.41 (s, 2H), 3.62 (m, 4H ), 3.09 (s, 2H), 2.88 (t, 4H).

cN- (4-Formylphenyl) -2-morpholin-4-ylacetamide

A solution of dimethyl sulfoxide (206 μL, 2.66 mmol) and oxalyl chloride (2 M in dichloromethane, 670 μL) in dichloromethane (6 mL) by cannula transfer at −78 ° C. by N- [4- (hydroxymethyl ) Phenyl] -2-morpholin-4-ylacetamide (b, above) (334 mg, 1.33 mmol) was added. The reaction mixture was stirred at this temperature for 15 minutes and then at −40 ° C. for 40 minutes. Triethylamine (610 μL, 4.39 mmol) was added and the reaction was stirred at this temperature for 5 minutes and then warmed to RT. The mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (Na ₂ SO ₄ ), concentrated and the residue was purified by silica gel flash chromatography (4% methanol in dichloromethane) to give the product as a yellow oil (112 mg, 34% yield).
¹ HNMR (400 MHz, DMSO): δ 10.14 (s, 1H), 9.85 (s, 1H), 7.84 (s, 4H), 3.61 (t, 4H), 3.33 (s, 2H), 3.14 (t, 4H ). ES-MSm / z249 (MH ⁺ ).

Intermediate Example CC
N- (4-formylphenyl) -2-methoxyacetamide
aN- [4- (1,3-Dioxolan-2-yl) phenyl] -2-methoxyacetamide

To a mixture of 4- (1,3-dioxolan-2-yl) aniline (500 mg, 3.03 mmol) and pyridine (0.6 mL, 6.36 mmol) in diethyl ether (10 mL) at 0 ° C. was added methoxyacetyl chloride (0.6 mL, 6.36 mmol) was added. The reaction was stirred at this temperature for 20 minutes and then partitioned between ethyl acetate and saturated aqueous NaHCO ₃ solution. The organic layer was dried (MgSO ₄ ), concentrated, and the residue was purified by silica gel flash chromatography (30% ethyl acetate in hexanes) to give the product as a yellow solid (434 mg, 64% yield).
¹ HNMR (400 MHz, DMSO): δ9.81 (s, 1H), 7.65 (d, 2H), 7.33 (d, 2H), 5.63 (s, 1H), 4.00 (m, 2H), 3.97 (s, 3H ), 3.90 (m, 2H).

bN- (4-Formylphenyl) -2-methoxyacetamide

N- [4- (1,3-Dioxolan-2-yl) phenyl] -2-methoxyacetamide (a, above) (200 mg, 0.895 mmol) and four odors in water (1.79 mL) and acetonitrile (0.89 mL) A mixture of carbonized carbon (59 mg, 0.179 mmol) was heated at 90 ° C. for 3 h. The reaction was then diluted with water and extracted with diethyl ether. The organic layer was dried (MgSO ₄ ) and concentrated to give the product as an orange oil (160 mg, 100% yield).
¹ HNMR (400 MHz, DMSO): Δ10.18 (s, 1H), 9.85 (s, 1H), 7.85 (dd, 4H), 4.03 (s, 3H).

Intermediate Example DD
N ^1- (4-formylphenyl) -N ³ , N ³ -dimethyl-β-alaninamide
a. 3-Chloro-N- [4- (1,3-dioxolan-2-yl) phenyl] propanamide

To a mixture of 4- (1,3-dioxolan-2-yl) aniline (1.0 g, 6.05 mmol) and pyridine (1.5 mL, 18.15 mmol) in diethyl ether (25 mL) at 0 ° C. in dichloromethane (1 mL). Of chloropropionyl chloride (0.64 mL, 6.65 mmol) was added. The reaction was stirred at this temperature for 10 minutes and then partitioned between ethyl acetate and saturated aqueous NaHCO ₃ solution. The organic layer was dried (MgSO ₄ ), concentrated, and the residue was purified by silica gel flash chromatography (30% ethyl acetate in hexanes) to give the product as a yellow solid (730 mg, 47% yield).
¹ HNMR (400 MHz, DMSO): δ 10.12 (s, 1H), 7.58 (d, 2H), 7.34 (d, 2H), 5.63 (s, 1H), 4.00 (m, 2H), 3.88 (m, 4H ), 2.80 (t, 2H). ES-MSm / z256 (MH ⁺ ).

bN ^1- [4- (1,3-Dioxolan-2-yl) phenyl] -N ³ , N ³ -dimethyl-β-alaninamide

3-Chloro-N- [4- (1,3-dioxolan-2-yl) phenyl] propanamide (a, above) (200 mg, 0.782 mmol), N-ethyl-N-isopropyl in dimethylformamide (10 mL) A mixture of propan-2-amine (0.41 mL, 2.364 mmol) and 2M dimethylamine (0.78 mL, 1.564) was stirred at 60 ° C. for 1 h. More 2M dimethylamine (0.78 mL, 1.564, 2 eq) was added and the reaction was stirred at this temperature for 3 h. The reaction was then cooled to RT and concentrated to give the product as a yellow oil (207 mg, 100% yield).
¹ HNMR (400 MHz, DMSO): δ 10.38 (s, 1H), 7.60 (d, 2H), 7.35 (d, 2H), 5.63 (s, 1H), 4.00 (m, 2H), 3.92 (m, 2H ), 3.31 (t, 2H), 2.85 (t, 2H), 2.74 (s, 6H).

cN ^1- (4-formylphenyl) -N ³ , N ³ -dimethyl-β-alaninamide

N ^1- [4- (1,3-Dioxolan-2-yl) phenyl] -N ³ , N ³ -dimethyl-β-alaninamide (b, above) in water (1.56 mL) and acetonitrile (0.78 mL) A mixture of (207 mg, 0.782 mmol) and carbon tetrabromide (52 mg, 0.156 mmol) was heated at 90 ° C. for 4 h. The reaction was then diluted with water and concentrated to give the product as an orange oil (172 mg, 100% yield).
¹ HNMR (400 MHz, DMSO): δ 10.78 (s, 1H), 9.86 (s, 1H), 7.84 (quartet, 4H), 3.36 (s, 6H), 2.92 (t, 2H), 2.75 (d, 1H ), 2.46 (d, 1H). ES-MS m / z 221 (MH ⁺ ).

Intermediate Example EE
N- (4-Formylphenyl) -2- (2-methoxyethoxy) acetamide

To a mixture of 4- (1,3-dioxolan-2-yl) aniline (250 mg, 1.513 mmol) and pyridine (245 μL, 3.026 mmol) in dichloromethane (10 mL) at 0 ° C. in dichloromethane (2 mL) (2 A solution of -methoxyethoxy) acetyl chloride (231 mg, 1.513 mmol) was added dropwise. The reaction mixture was stirred at this temperature for 1 h and then at RT for 1.5 h. The mixture was then concentrated and the residue was purified by silica gel flash chromatography (25% ethyl acetate in hexanes) to give the product as a yellow oil (70 mg, 26% yield).
¹ HNMR (400 MHz, DMSO): δ 10.06 (s, 1H), 9.86 (s, 1H), 7.84 (m, 4H), 4.11 (s, 2H), 3.65 (dd, 2H), 3.50 (dd, 2H ), 3.26 (s, 3H).

Intermediate Example FF
N- (4-formylphenyl) -2- (4-methylpiperazin-1-yl) acetamide
a. 2-Chloro-N- [4- (1,3-dioxolan-2-yl) phenyl] acetamide

Mixture of 4- (1,3-dioxolan-2-yl) aniline (1.0 g, 6.05 mmol), chloroacetyl chloride (0.5 mL, 6.66 mmol) and pyridine (1.5 mL, 18.15 mmol) in diethyl ether (10 mL) Was stirred at 0 ° C. for 30 minutes. The reaction was partitioned between ethyl acetate and saturated aqueous NaHCO ₃ solution. The organic layer was dried (MgSO ₄ ), concentrated, and the residue was purified by silica gel flash chromatography (30% ethyl acetate in hexanes) to give the product as a yellow solid (810 mg, 55% yield).
¹ HNMR (400 MHz, DMSO): δ 10.36 (s, 1H), 7.58 (d, 2H), 7.37 (d, 2H), 5.65 (s, 1H), 4.23 (s, 2H), 4.01 (m, 2H) ), 3.90 (m, 2H).

bN- [4- (1,3-Dioxolan-2-yl) phenyl] -2- (4-methylpiperazin-1-yl) acetamide

2-Chloro-N- [4- (1,3-dioxolan-2-yl) phenyl] acetamide (a, above) (200 mg, 0.827 mmol), 1-methylpiperazine (0.28 mL, 2.481) in ethanol (20 mL) mmol) and pyridine (0.13 mL, 1.654 mmol) were heated at reflux for 7 h. The reaction was concentrated and the residue was purified by silica gel flash chromatography (20% methanol in dichloromethane) to give the product as a yellow solid (189 mg, 80% yield).
¹ HNMR (400 MHz, DMSO): δ9.73 (s, 1H), 7.61 (d, 2H), 7.34 (d, 2H), 5.63 (s, 1H), 4.01 (m, 2H), 3.94 (m, 2H ), 3.10 (m, 6H), 2.35 (m, 2H), 2.15 (s, 3H).

cN- (4-Formylphenyl) -2- (4-methylpiperazin-1-yl) acetamide

N- [4- (1,3-Dioxolan-2-yl) phenyl] -2- (4-methylpiperazin-1-yl) acetamide (b, above) in water (1.24 mL) and acetonitrile (0.62 mL) A mixture of (189 mg, 0.619 mmol) and carbon tetrabromide (41 mg, 0.124 mmol) was heated at 90 ° C. for 4 h. The reaction was then diluted with water and concentrated to give the product as an orange oil (162 mg, 100% yield).

¹ HNMR (400 MHz, DMSO): δ 10.19 (s, 1H), 9.86 (s, 1H), 7.83 (m, 4H), 4.43 (s, 2H), 3.28 (m, 4H), 2.74 (m, 2H) ), 2.63 (s, 3H). ES-MSm / z262 (MH ⁺ ).

Intermediate Example GG
4- [2- (Dimethylamino) ethoxybenzaldehyde

To a mixture of 4-hydroxybenzaldehyde (1.34 g, 10.97 mmol) and 2-dimethylaminoethyl chloride hydrochloride (1.95 g, 13.54 mmol) in DMF (12 mL) was added K ₂ CO ₃ (6.04 g, 3.23 mmol). did. The mixture was heated at reflux for 12 h. The residue was partitioned between H ₂ O and EtOAc. The organic layer was dried (MgSO ₄ ), filtered and concentrated. The crude material was purified by flash chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 4- [2- (dimethylamino) ethoxybenzaldehyde (220 mg, 10%) as an orange liquid.
¹ HNMR (400 MHz, CDCl ₃ ) δ 9.87 (s, 1H), 7.82 (d, 2H), 7.01 (d, 2H), 4.16 (t, 2H), 2.79 (t, 2H), 2.37 (s, 6H ).

Intermediate Example HH
4-[(Methylsulfonyl) methyl] benzaldehyde

U18806 / 48/1
A mixture of 4- (bromomethyl) benzaldehyde (100 mg, 0.503 mmol) and sodium methanesulfinate (56 mg, 0.553 mmol) in ethanol (5 mL) was heated at 100 ° C. for 2 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried (Na ₂ SO ₄ ) and concentrated to give the product as a white solid (85 mg, 85% yield).
¹ HNMR (400 MHz, DMSO) δ 10.01 (s, 1H), 7.93 (d, 2H), 7.62 (d, 2H), 4.62 (s, 2H), 2.93 (s, 3H).

Intermediate Example JJ
3-methylisonicotinaldehyde

To 3- (methylthio) isonicotinonitrile (0.510 g, 3.75 mmol) in toluene (25 mL) was added a solution of Dibal-H (5.62 mL, 5.62 mmol) in THF. After 2 h, 5% H ₂ SO ₄ solution (50 mL) was added and stirred for 16 h. A solution of 1N NaOH was added to make the pH basic, after which the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to obtain the title compound in LC / MS purity ˜40%.
Intermediate Example KK
4-Hydrazino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine
a.2- (1-Ethoxybutylidene) malononitrile

A mixture of triethyl orthobutyrate (6.9 mL, 31.9 mmole) and malonitrile (2.00 mL, 31.8 mmole) was heated at 140 ° C. for 30 minutes. During the course of the reaction, ethanol was removed by distillation. The reaction mixture was cooled and the product was obtained as a yellow oil (5.02 g, 96%).
¹ HNMR (CDCl ₃ ): Δ4.42 (q, 2H), 2.60 (t, 2H), 1.67 (m, 2H), 1.44 (t, 3H), 1.04 (t, 3H) ppm.

b. 5-Amino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazole-4-carbonitrile

To a solution of 2- (1-ethoxybutylidene) malononitrile (a, above) (2.836 g, 17.3 mmole) in ethanol (65 mL) was added 3-methoxyphenylhydrazine hydrochloride (3.016 g, 17.3 mmole) and triethylamine (5.00 mL, 35.9 mmole) was added. The resulting solution was heated at reflux for 3 h, then cooled to RT and concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (2: 1, 150 mL). The aqueous layer was extracted with ethyl acetate (1x50 mL) and the combined organics were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography to obtain the product as a red oil (3.49 g, 79%).
¹ HNMR (DMSO): δ 7.38 (t, 1H), 7.04 (dd, 1H), 7.00 (m, 1H), 6.94 (dd, 1H), 6.63 (s, 2H), 3.79 (s, 3H), 2.48 (t, 2H), 1.64 (m, 2H), 0.92 (t, 3H) ppm.

c. 1- (3-Methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-ol

While refluxing a solution of 5-amino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazole-4-carbonitrile (b, above) (3.49 g, 13.6 mmole) in formic acid (50 mL) Heated overnight. After cooling to RT, the solution was concentrated. The residue was triturated with ether to give the product as a pale pink solid (2.32 g, 60%).
¹ HNMR (DMSO): δ 12.36 (s, 1H), 8.13 (m, 1H), 7.62 (m, 2H), 7.42 (t, 1H), 6.92 (dd, 1H), 3.80 (s, 3H), 2.85 (t, 2H), 1.76 (m, 2H), 0.94 (t, 3H) ppm.

d. 4-Chloro-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine

  A solution of 1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-ol (c, above) (2.32 g, 8.16 mmole) in phosphorus oxychloride (20 mL) Was heated at reflux for 3 h. The solution was cooled to RT and poured slowly onto ice. The resulting mixture was extracted with methylene chloride (4 × 50 mL). The organics were dried (MgSO4) and concentrated to give the product as a brown solid (2.70 g), which was used without further purification.

¹ HNMR (CDCl ₃ ): δ 8.80 (s, 1H), 7.77 (m, 2H), 7.43 (t, 1H), 6.90 (dd, 1H), 3.90 (s, 3H), 3.15 (t, 2H) 1.90 (m, 2H), 1.09 (t, 3H) ppm.

e.4-Hydrazino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine

To a solution of 4-chloro-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (d, above) (2.70 g, 8.92 mmole) in ethanol (50 mL), Hydrazine hydrate (1.70 mL, 54.6 mmole) was added. The solution was heated at reflux for 3 h, then cooled to RT and concentrated. The residue was stirred with saturated aqueous sodium bicarbonate (50 mL) for 2 h and then filtered. The solid was washed with water and dried to give the product as a tan solid (2.19 g, 82%).
¹ HNMR (CDCl ₃ ): δ 8.50 (s, 1H), 7.71 (m, 2H), 7.37 (t, 1H), 6.83 (dd, 1H), 3.87 (s, 3H), 2.94 (t, 2H) 1.85 (m, 2H), 1.06 (t, 3H) ppm.

Intermediate Example LL
4-Hydrazino-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine
a.2- (1-Hydroxy-2-methylpropylidene) malononitrile

  To a suspension of sodium hydride (60% dispersion in mineral oil, 3.71 g, 92.8 mmole) in THF (50 mL) at 0 ° C. with a solution of THF (10 mL) malonitrile (2.90 mL, 46.1 mmole). Added (gas evolution!). The resulting mixture was stirred for 15 minutes and isobutyryl chloride (4.80 mL, 45.8 mmole) was added. The resulting solution was stirred at 0 ° C. for 3 h and then at RT overnight. Saturated aqueous monobasic potassium phosphate (100 mL) was added and the mixture was extracted with ethyl acetate (2 × 50 mL). The organic layer was dried (MgSO4) and concentrated to give the product as a yellow solid that was used without further purification.

¹ HNMR (DMSO): δ 2.72 (m, 1H), 0.90 (d, 6H) ppm.

b. 2- (1-Methoxy-2-methylpropylidene) malononitrile

To a solution of 2- (1-hydroxy-2-methylpropylidene) malononitrile (a, above) in dioxane / water (6: 1, 100 mL) was added solid sodium bicarbonate (19.374 g, 231 mmole) and dimethyl sulfate (20.0 mL). , 211 mmole) was added. The resulting mixture was heated at 80 ° C. for 5.5 hours. The mixture was cooled to RT and poured into brine (50 mL) and water (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried (MgSO4) and concentrated. The obtained residue was dissolved in chloroform (100 mL) and filtered through a celite pad. The resulting filtrate was concentrated to give the product as a red oil (7.53 g, 63%).
¹ HNMR (CDCl ₃ ): δ 4.35 (s, 3H), 3.16 (m, 1H), 1.16 (d, 6H) ppm.

c. 5-Amino-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazole-4-carbonitrile

2- (1- (3-methoxyphenyl) -3-propyl-1H-pyrazole-4-carbonitrile (intermediate example KK) as described for 2- (1- Prepared from methoxy-2-methylpropylidene) malononitrile (b, above) (6.46 g, 43.0 mmole), 3-methoxyphenylhydrazine hydrochloride (7.53 g, 43.1 mmole) and triethylamine (12.0 mL, 86.1 mmole) The product was obtained as an orange oil (4.76 g, 43%).
¹ HNMR (CDCl ₃ ): δ 7.38 (t, 1H), 7.04 (dd, 1H), 7.01 (m, 1H), 6.92 (dd, 1H), 4.61 (s, 2H), 3.83 (s, 3H) , 3.04 (m, 1H), 1.34 (d, 6H) ppm.

d. 3-Isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol

As described for 1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-ol (intermediate example KK), 5- Prepared from amino-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazole-4-carbonitrile (c, above) (4.76 g, 18.6 mmole) to give the product as a white solid (2.92 g, 55 %).
¹ HNMR (DMSO): δ 12.36 (s, 1H), 8.14 (d, 1H), 7.62 (m, 2H), 7.42 (t, 1H), 6.92 (dd, 1H), 3.80 (s, 3H), 3.31 (m, 1H), 1.33 (d, 6H) ppm.

e. 4-Chloro-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

As described for 4-chloro-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (intermediate example KK), 3-isopropyl-1- (3 -Methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (2.92 g, 10.3 mmole) and phosphorus oxychloride (50 mL) to prepare the product as a white solid (3.03 g, 97% ).
¹ HNMR (CDCl ₃ ): δ 8.79 (s, 1H), 7.81 (m, 2H), 7.43 (t, 1H), 6.89 (dd, 1H), 3.90 (s, 3H), 3.74 (m, 1H) 1.50 (d, 6H) ppm.

f.4-Hydrazino-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

4-Hydrazino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (intermediate example KK) as described for 4- (4) in ethanol (65 mL). Prepared from chloro-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (3.03 g, 10.0 mmole) and hydrazine hydrate (1.95 mL, 62.6 mmole) The product was obtained as a white solid (2.67 g, 90%).
¹ HNMR (DMSO): δ 8.36 (s, 1H), 7.81 (m, 1H), 7.76 (d, 1H), 7.40 (t, 1H), 6.86 (dd, 1H), 3.80 (s, 3H), 3.66 (m, 1H), 1.29 (d, 6H) ppm.

Intermediate Example MM
4-Hydrazino-3-ethyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine
b. 2- (1-Ethoxypropylidene) malononitrile

Prepared from malonitrile (6.30Ml, 100mmole) and triethylorthopropionate (20.0mL, 99.4mmole) as described for 2- (1-ethoxybutylidene) malononitrile (intermediate example KK) Material was obtained as a yellow oil (15.832 g, 100%).
¹ HNMR (CDCl ₃ ): d4.45 (q, 2H), 2.64 (q, 2H), 1.44 (t, 3H), 1.25 (t, 3H) ppm.

c. 5-Amino-3-ethyl-1- (3-methoxyphenyl) -1H-pyrazole-4-carbonitrile

2- (1-ethoxypropylidene) as described above for 5-amino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazole-4-carbonitrile (intermediate example KK) Prepared from malononitrile (2.584g, 17.2mmole) and 3-methoxyphenylhydrazine (2.998g, 17.2mmole), the product was obtained as a yellow solid (1.85g, 44%).
¹ HNMR (DMSO): δ 7.38 (t, 1H), 7.02 (d, 1H), 6.99 (m, 1H), 6.94 (dd, 1H), 6.63 (s, 2H), 3.79 (s, 3H), 2.51 (q, 2H), 1.18 (t, 3H) ppm.

d. 1- (3-Methoxyphenyl) -3-ethyl-1H-pyrazolo [3,4-d] pyrimidin-4-ol

5- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-ol (intermediate example KK) as described for 5- Prepared from amino-3-ethyl-1- (3-methoxyphenyl) -1H-pyrazole-4-carbonitrile (c, above) (1.0 g, 4.13 mmole) to give the product as a white solid (0.9 g, 81 %).
¹ HNMR (DMSO): δ 12.36 (s, 1H), 8.14 (s, 1H), 7.63 (m, 2H), 7.42 (t, 1H), 6.93 (dd, 1H), 3.80 (s, 3H), 2.89 (q, 2H), 1.29 (t, 3H) ppm.

e. 4-Chloro-3-ethyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

As described for 4-chloro-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (intermediate example KK), 3-ethyl-1- (3 -Methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-ol (0.9 g, 3.3 mmole) and phosphorus oxychloride (3.7 mL) to give the product as a white solid (913 mg, 95% ).
¹ HNMR (DMSO): δ8.92 (s, 1H), 7.74 (m, 2H), 7.49 (t, 1H), 6.98 (dd, 1H), 3.83 (s, 3H), 3.15 (q, 2H), 1.38 (t, 3H) ppm.

f.4-Hydrazino-3-ethyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine

4-Hydrazino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (intermediate example KK) as described for 4- (4) in ethanol (20 mL). Prepared from chloro-3-ethyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (913 mg, 3.12 mmole) and hydrazine hydrate (0.9 mL, 18.72 mmole) Material was obtained as a white solid (0.81 g, 91%).
¹ HNMR (DMSO): δ 8.37 (s, 1H), 7.78 (m, 2H), 7.40 (t, 1H), 6.86 (dd, 1H), 4.76 (broads, 2H), 3.80 (s, 3H), 3.03 (q, 2H), 1.24 (t, 3H) ppm.

Nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

To a solution of 4-hydrazino-1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (52 mg, 0.22 mmol) (intermediate Example A) in ethanol (5 ml) under stirring Nicotinaldehyde (28 mg, 0.26 mmol) and pyrrolidine were added. The resulting mixture was refluxed for about 3 h, cooled to RT and filtered to obtain the product as a white solid (30 mg, 41%).
¹ HNMR (DMSO) δ 12.39 (s, 1H), 8.91 (s, 1H), 8.64 (s, 1H), 8.62 (d, 1H), 8.50 (s, 1H), 8.33 (s, 1H), 8.30 (d, 1H), 8.03 (s, 1H), 7.99 (d, 1H), 7.52 (dd, 1H), 7.44 (t, 1H), 7.17 (d, 1H), 2.41 (s, 3H) ppm; ES-MSm / z330 (MH ⁺ ).

6-chloronicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example A) and 6-chloronicotinaldehyde.
¹ HNMR (300MHz, DMSO) δ 12.45 (s, 1H), 8.75 (d, 1H), 8.64 (s, 1H), 8.51 (s, 1H), 8.38 (dd, 1H), 8.32 (s, 1H) 8.02 (s, 1H), 7.99 (d, 1H), 7.61 (d, 1H), 7.43 (t, 1H), 7.18 (d, 1H), 2.40 (s, 3H) ppm.

6-Methoxynicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

6-chloronicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (0.075 g; 0.21 mmol) in DMSO (3 mL) (Example 2) And sodium methoxide (0.080 g; 1.51 mmol) was heated at 105 ° C. for 1 h. The solution was cooled to RT, then water (25 mL) and 1N HCl (15 mL) were added. The solid was filtered, washed with MeOH (3 mL) then Et ₂ O (5 mL) and dried to give the title compound (34 mg) as an off-white powder (45%).
¹ HNMR (300MHz, DMSO) δ 12.29 (s, 1H), 8.67 (s, 1H), 8.51 (s, 2H), 8.36-8.33 (m, 2H), 8.07-8.02 (m, 2H), 7.48 ( t, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 3.95 (s, 3H), 2.56 (s, 3H) ppm.

4-((E)-[1- (3-Methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example A) and 4-formylbenzoic acid.
¹ HNMR (300 MHz, DMSO) δ 13.26-12.10 (mbr, 2H), 8.67 (s, 1H), 8.53 (s, 1H), 8.37 (s, 1H), 8.10-7.99 (m, 4H), 7.97- 7.94 (m, 1H), 7.46 (t, 1H), 7.21 (d, 2H), 2.43 (s, 3H) ppm; ES-MSm / z373 (MH ⁺ ).

N- [2- (dimethylamino) ethyl] -4-((E)-[1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide

4-((E)-[1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 4) (45 mg, 0.120 mmol) in a solution of N, N-dimethylethane-1,2-diamine (0.02 mL, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). ) Was added. The solution was stirred at RT for 1 h, after which water and diethyl ether were added. The formed precipitate was collected by filtration to obtain a pure product (18 mg, yield 34%).
¹ HNMR (300 MHz, DMSO) δ 12.34 (s, 1H), 8.66 (s, 1H), 8.54-8.48 (m, 2H), 8.35 (s, 1H), 8.09-7.84 (m, 6H), 7.45 ( t, 1H), 7.20 (d, 1H), 3.46-3.32 (m, 2H), 2.55-2.50 (m, 2H), 2.42 (s, 3H), 2.23 (s, 6H) ppm; ES-MSm / z443 (MH ⁺ ).

4-((E)-[1- (3-Methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- [2- (methylsulfonyl) ethyl] benzamide

4-((E)-[1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 4) To a solution of (45 mg, 0.12 mmol) was added 2- (methylsulfonyl) ethanamine hydrochloride (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). . The solution was stirred at RT for about 16 h, after which water and diethyl ether were added. The resulting precipitate was collected by filtration to obtain a pure product (48 mg, 84% yield).
¹ HNMR (300 MHz, DMSO) δ 12.37 (s, 1H), 8.83 (t, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.09-7.96 (m, 2H), 7.94 (s, 4H), 7.46 (t, 1H), 7.24-7.19 (m, 1H), 3.70 (q, 2H), 3.41 (q, 2H), 3.05 (s, 3H), 2.42 (s , 3H) ppm; ES-MSm / z478 (MH ⁺ ).

4-((E)-[1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- (3-pyrrolidin-1-ylpropyl) Benzamide

4-((E)-[1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 4) (45 mg, 0.12 mmol) in a solution of 3-pyrrolidin-1-ylpropan-1-amine (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 ml, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol) Was added. The solution was stirred at RT for 3 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (5 mg, yield 9%).
¹ HNMR (300MHz, DMSO) δ 12.36 (s, 1H), 8.69-8.62 (m, 2H), 8.52 (s, 1H), 8.35 (s, 1H), 8.09-8.00 (m, 2H), 7.99- 7.88 (m, 4H), 7.46 (t, 1H), 7.25-7.18 (m, 1H), 3.40-3.25 (m, 2H), 2.55-2.44 (m, 6H), 2.42 (s, 3H), 1.75- 1.63 (m, 6H) ppm. ES-MS m / z 483 (MH ⁺ ).

Nicotinaldehyde [1- (3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Suspension of 1- (3-bromophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example B) (0.095 g, 0.28 mmol) in 15 mL of absolute ethanol To this was added nicotinaldehyde (0.031 mL, 0.33 mmol) and 2 drops of pyrrolidine. The mixture was heated at reflux for 3 h. After cooling to room temperature, diethyl ether was added and the precipitated solid was collected by filtration and dried under vacuum to give 0.081 g (67%) of product as a white solid.
¹ HNMR (DMSO) δ8.90 (s, 1H), 8.70 (s, 1H), 8.65 (m, 1H), 8.55 (m, 2H), 8.35 (s, 1H), 8.30 (dd, 2H), 7.50 (m, 4H) ppm; ES-MSm / z394 (M ⁺ ), 396 (M + 2).

Isonicotinaldehyde [1- (3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

As described for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1- (3-bromo Phenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example B) (0.070 g, 0.23 mmol) was treated with isonicotinaldehyde (0.073 g, 0.68 mmol) in absolute ethanol. The product, 66 mg (73%), was obtained as an off-white solid.
¹ HNMR (DMSO) δ 12.60 (brs, 1H), 8.70 (s, 1H), 8.67 (d, 2H), 8.55 (d, 2H), 8.26 (m, 2H), 7.79 (d, 2H), 7.54 (m, 2H) ppm; ES-MSm / z396 (M + 2)

6-chloronicotinaldehyde [1- (3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

1- (3-Bromophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example B) (0.100 g, 0.33 mmol), 6-chloronicotinaldehyde (0.046 g , 0.33 mmol), and 10 mL of absolute ethanol were heated at reflux for 18 h. After cooling to room temperature, the solid product was collected by filtration, washed with ethanol, and dried under vacuum to obtain 0.115 g (82%) of a yellow powder.
¹ HNMR (DMSO) δ 12.50 (brs, 1H), 8.75 (s, 1H), 8.70 (s, 1H), 8.55 (d, 2H), 8.40 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.65 (d, 1H), 7.55 (m, 2H) ppm.

6-Methoxynicotinaldehyde [1- (3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Of 6-chloronicotinaldehyde [1- (3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 10) (0.114 g, 0.27 mmol) in 5 mL of dimethyl sulfoxide To the suspension was added sodium methoxide (0.086 g, 1.59 mmol). The mixture was heated at 100 ° C. for 2 hours to produce a homogeneous solution. After cooling to room temperature, water (5 mL) was added and the precipitated solid was collected by filtration, washed with water, methanol and diethyl ether and dried under vacuum for 2 hours to give 73 mg (64%) of a tan solid. I got it.
¹ HNMR (DMSO) δ 12.30 (brs, 1H), 8.64 (s, 1H), 8.51 (d, 2H), 8.45 (s, 1H), 8.26 (m, 3H), 7.52 (m, 2H), 6.93 (d, 1H), 3.90 (s, 3H) ppm; ES-MSm / z424 (M), 426 (M + 2)

4-Hydroxy-3-methoxybenzaldehyde [1- (3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from bromophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example B) and 4-hydroxy-3-methoxybenzaldehyde.
¹ HNMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 8.26 (d, 1H), 8.17 (s, 1H), 7.48-7.51 (m, 2H), 7.32 (s, 1H), 7.19 (d, 1H), 6.85 (d, 1H), 3.86 (s, 3H) ppm ES-MSm / z440 (MH ⁺ )

4-((E)-[1- (3-Bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(3-bromophenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (intermediate example B) and 4-formylbenzoic acid.
¹ HNMR (300 MHz, DMSO) δ 13.27-12.37 (mbr, 2H), 8.71 (s, 1H), 8.57 (s, 2H), 8.37 (s, 1H), 8.32-7.24 (m, 1H), 8.04 ( d, 2H), 7.95 (d, 2H), 7.60-7.48 (m, 2H) ppm; ES-MSm / z439 (MH ^<+> ).

4-((E)-[1- (3-Bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- [2- (dimethylamino) ethyl] benzamide

4-((E)-[1- (3-Bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 13) (45 mg, 0.120 mmol) in a solution of N, N-dimethylethane-1,2-diamine (0.02 mL, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). ) Was added. The solution was stirred at RT for 1 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (37 mg, yield 61%).
¹ HNMR (300MHz, DMSO) δ 12.44 (s, 1H), 8.69 (s, 1H), 8.65-8.52 (m, 2H), 8.35 (s, 1H), 8.33-8.22 (m, 1H), 8.10- 7.85 (m, 5H), 7.59-7.50 (m, 2H), 3.46-3.32 (m, 2H), 2.62-2.50 (m, 2H), 2.30 (s, 6H) ppm; ES-MSm / z509 (MH ⁺ ).

4-((E)-[1- (3-Bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- [2- (methylsulfonyl) ethyl] benzamide

4-((E)-[1- (3-Bromophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 13) To a solution of (53 mg, 0.12 mmol) was added 2- (methylsulfonyl) ethanamine hydrochloride (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 ml, 0.360 mmol). The solution was stirred at RT for 16 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (45 mg, yield 69%).
¹ HNMR (300 MHz, DMSO) δ 12.44 (s, 1 H), 8.84 (t, 1 H), 8.72 (s, 1 H), 8.56 (s, 1 H), 8.36 (s, 1 H), 8.33-8.26 (m, 1H), 7.94 (s, 5H), 7.59-7.53 (m, 2H), 3.71 (q, 2H), 3.42 (q, 2H), 3.05 (s, 3H) ppm; ES-MSm / z544 (MH ⁺ ) .

Nicotinaldehyde [1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (2-methoxy) as described for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1) Phenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example C) (0.0647 g, 0.22 mmol) was treated with nicotinaldehyde (0.025 mL, 0.26 mmol) in absolute ethanol, 0.051 g (61%) of product was obtained as an off-white solid.
¹ HNMR (DMSO) δ 12.30 (brs, 1H), 8.90 (s, 1H), 8.60 (m, 2H), 8.30 (m, 3H), 7.50 (m, 2H), 7.40 (d, 1H), 7.30 (d, 1H) 7.10 (t, 1H), 3.70 (s, 3H) ppm.ES-MSm / z346 (MH ⁺ )

Isonicotinaldehyde [1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (2-methoxy) as described for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1) Phenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example C) (0.070 g, 0.24 mmol) was treated with isonicotinaldehyde (0.068 mL, 0.72 mmol) to give the product 0.0335. g was obtained as a light yellow solid.
¹ HNMR (400MHz, DMSO) δ12.40 (brs, 1H), 8.67 (d, 2H), 8.60 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.77 (d, 2H) , 7.53 (t, 1H), 7.41 (dd, 1H) 7.25 (d, 1H), 7.11 (t, 1H), 3.75 (s, 3H) ppm; ES-MSm / z345 (MH ⁺ ).

tert-butyl 4-((E)-[1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) piperidine-1-carboxylate

4-Hydrazino-1- (2-methoxy) as described for isonicotinaldehyde [1- (2-methoxyphenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 17) (Phenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example C) (0.070 g, 0.24 mmol) in tert-butyl 4-formylpiperidine-1-carboxylate in 7 mL of absolute ethanol ( 0.102 g, 0.48 mmol) and 1 drop of pyrrolidine. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel with dichloromethane: methanol / 95: 5 to give 49 mg (45%) of pure product.
¹ HNMR (DMSO) δ 11.75 (brs, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.57 (d, 1H), 7.51 (t, 1H), 7.37 (d, 1H), 7.24 (d, 1H), 7.09 (t, 1H), 3.97 (d, 2H), 3.68 (s, 3H), 2.90 (brm, 2H), 2.50 (m, 2H), 1.89 (d, 2H), 1.38 ( s, 9H) ppm; APCI-MSm / z451 (MH ⁺ ).

6-Aminonicotinaldehyde [1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone = trifluoroacetate

4-hydrazino-1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example C) (0.070 g, 0.24 mmol), tert-butyl 5-formylpyridine- A mixture of 2-ylcarbamate (0.106 g, 0.48 mmol), 1 drop of pyrrolidine, and 7 mL of absolute ethanol was heated at reflux for 6 hours. The cooled reaction mixture was filtered. The collected solid was washed with ethanol, dried under vacuum, treated with 1 mL of trifluoroacetic acid for 30 minutes at room temperature and then evaporated to dryness. The residue was taken up in methanol and the mixture was filtered. The filtrate was evaporated and the residue was purified by reverse phase HPLC (C18 column, 5-50% acetonitrile / water / 0.1% formic acid gradient) to give 5 mg of pure product.
¹ HNMR (DMSO) δ8.58 (d, 1H), 8.52 (dd, 1H), 8.30 (m, 2H), 8.19 (s, 1H), 7.53 (t, 1H), 7.40 (dd, 1H), 7.26 (d, 1H), 7.10 (m, 2H), 5.40 (brs, 2H), 3.70 (s, 3H) ppm; ES-MSm / z361 (MH ^<+> ).

6-Chloronicotinaldehyde [1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (intermediate example C) and 6-chloronicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.37 (s, 1 H), 8.75 (s, 1 H), 8.58 (s, 1 H), 8.38 (d, 1 H), 8.33 (s, 1 H), 8.31 (s, 1 H) 7.61 (d, 1H), 7.53 (t, 1H), 7.40 (d, 1H), 7.26 (d, 1H), 7.11 (t, 1H), 3.70 (s, 3H) ppm.

6-Methoxynicotinaldehyde [1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

6-chloronicotinaldehyde [1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 20) in DMSO (3 mL) (0.075 g; 0.20 mmol) And sodium methoxide (0.080 g; 1.51 mmol) was heated at 105 ° C. for 1 h. The solution was cooled to RT, then water (25 mL) and 1N HCl (15 mL) were added. The solid was filtered, washed with MeOH (3 mL) then Et ₂ O (5 mL) and dried to give the title compound (41 mg) as an off-white powder (55%).
¹ HNMR (300 MHz, DMSO) δ 12.30 (s, 1H), 8.59 (s, 1H), 8.51 (d, 1H), 8.39-8.31 (m, 3H), 7.56 (t, 1H), 7.45 (d, 1H), 7.30 (d, 1H), 7.15 (t, 1H), 6.99 (d, 1H), 3.94 (s, 3H), 3.74 (s, 3H) ppm.

4-((E)-[1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

4-Hydrazino-1- (2-methoxy) as described for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1) Phenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example C) (0.070 g, 0.24 mmol) was treated with 4-carboxybenzaldehyde (0.108 g, 0.72 mmol). The crude solid product was triturated with methanol and dried under vacuum to give 14 mg (15%) pure product as a light yellow solid.
¹ HNMR (DMSO) δ8.60 (s, 1H), 8.34 (d, 2H), 8.04 (s, 1H), 8.02 (d, 2H), 7.93 (d, 2H), 7.53 (t, 1H), 7.42 (d, 1H), 7.26 (d, 1H), 7.11 (t, 1H), 3.75 (s, 3H) ppm; APCI-MSm / z388 (MH ^<+> ).

4-((E)-[1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- [2- (methylsulfonyl) ethyl] benzamide Hydrochloride

4-((E)-[1- (2-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 22) To a solution of (47 mg, 0.12 mmol) was added 2- (methylsulfonyl) ethanamine hydrochloride (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). . The solution was stirred at RT for 16 h and then partitioned between water and diethyl ether. The aqueous layer was acidified with 1N HCl and then concentrated. The resulting solid was washed with ethanol and diethyl ether and collected by filtration to obtain the pure product (48 mg, 81% yield).
¹ HNMR (300 MHz, DMSO) δ 12.83-12.08 (sbr, 1H), 8.89-8.83 (m, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 8.35 (s, 1H), 7.94 ( s, 4H), 7.90-7.82 (m, 2H), 7.48 (t, 1H), 6.99-6.92 (m, 1H), 3.84 (s, 3H), 3.71 (q, 2H), 3.42 (q, 2H) , 3.05 (s, 3H) ppm; ES-MSm / z494 (MH ⁺ ).

N- [2- (dimethylamino) ethyl] -4-((E)-[1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzene Sulfonamide

According to the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1- ( 3-Nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (Intermediate Example D) (65 mg, 0.21 mmol) and N- [2- (dimethylamino) ethyl] -4-formylbenzene The title compound was prepared from the sulfonamide (Intermediate Example U) (162 mg, 0.0.63 mmol) to give the product as a white solid (81 mg, 76%).
¹ HNMR (DMSO) 12.58 (s, 1H), 10.11 (s, 1H), 9.22 (t, 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.39 (s, 1H), 8.19 (m , 2H), 8.07 (d, 2H), 7.94 (d, 2H), 7.88 (t, 1H), 3.15 (s, 4H), 2.76 (s, 6H) δ ppm; ES-MSm / z510 (MH ⁺ ).

4-((E)-[1- (3-Nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidine hydrochloride (intermediate example D) and 4-formylbenzoic acid.
¹ HNMR (300MHz, DMSO) δ12.67-12.31 (sbr, 1H), 9.23 (s, 1H), 8.80-8.72 (m, 2H), 8.61 (s, 1H), 8.37 (s, 1H), 8.24- 8.18 (m, 1H), 8.08-8.00 (m, 2H), 7.98-7.84 (m, 3H) ppm.

N- [2- (dimethylamino) ethyl] -4-((E)-[1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide

4-((E)-[1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 25) (39 mg, 0.10 mmol) in a solution of N, N-dimethylethane-1,2-diamine (0.02 mL, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). ) Was added. The solution was stirred at RT for 1 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (23 mg, yield 40%).
¹ HNMR (300 MHz, DMSO) δ 12.46 (s, 1H), 9.23 (s, 1H), 8.80-8.72 (m, 2H), 8.60 (s, 1H), 8.58-8.50 (m, 1H), 8.36 ( s, 1H), 8.26-8.15 (m, 1H), 7.98-7.84 (m, 5H), 3.46-3.32 (m, 2H), 2.62-2.50 (m, 2H), 2.25 (s, 6H) ppm; ES -MSm / z474 (MH ⁺ ).

N- [2- (methylsulfonyl) ethyl] -4-((E)-[1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide

4-((E)-[1- (3-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 25) To a solution of (48 mg, 0.12 mmol) was added 2- (methylsulfonyl) ethanamine hydrochloride (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). . The solution was stirred at RT for 16 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (49 mg, yield 80%).
¹ HNMR (300 MHz, DMSO) δ 12.45 (s, 1H), 9.22 (s, 1H), 8.84 (t, 1H), 8.78-8.70 (m, 2H), 8.60 (s, 1H), 8.35 (s, 1H), 8.21-8.16 (m, 1H), 7.94 (s, 4H), 7.92-7.83 (m, 1H), 3.70 (q, 2H), 3.46-3.38 (m, 2H), 3.05 (s, 3H) ppm; ES-MSm / z509 (MH ⁺ ).

N- (3-4-[(2E) -2- (pyridin-4-ylmethylene) hydrazino] -1H-pyrazolo [3,4-d] pyrimidin-1-ylphenyl) acetamide

According to the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), N- [3- (4 From -hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] acetamide hydrochloride (intermediate example E) (80 mg, 0.25 mmol) and isonicotinaldehyde (90 mg, 0.85 mmol), The title compound was prepared and the product was obtained as a white solid (53 mg, 57%).
¹ HNMR (DMSO) δ 12.52 (s, 1H), 10.19 (s, 1H), 8.69 (m, 3H), 8.52 (d, 2H), 8.28 (s, 1H), 7.93 (d, 1H), 7.80 (d, 2H), 7.57 (d, 1H), 7.47 (t, 1H), 2.08 (s, 3H) ppm. ES-MSm / z373 (MH ^<+> ).

N- (3-4-[(2E) -2- (pyridin-4-ylmethylene) hydrazino] -1H-pyrazolo [3,4-d] pyrimidin-1-ylphenyl) butanamide

According to the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), N- [3- (4 From -hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] butanamide hydrochloride (Intermediate Example F) (100 mg, 0.25 mmol) and isonicotinaldehyde (100 mg, 0.94 mmol), The title compound was prepared and the product was obtained as a pale yellow solid (95 mg, 95%).
¹ HNMR (DMSO) δ 12.51 (s, 1H), 10.12 (s. 1H), 8.68 (m, 3H), 8.51 (d, 2H), 8.29 (s, 1H), 7.92 (d, 1H), 7.79 (d, 2H), 7.60 (d, 1H), 7.47 (t, 1H), 2.33 (t, 2H), 1.63 (m, 2H), 0.93 (t, 3H) ppm; ES-MSm / z401 (MH ⁺ ).

N- (3-4-[(2E) -2- (pyridin-4-ylmethylene) hydrazino] -1H-pyrazolo [3,4-d] pyrimidin-1-ylphenyl) benzamide

According to the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), N- [3- (4 From -hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) phenyl] benzamide hydrochloride (intermediate example G) (65 mg, 0.17 mmol) and isonicotinaldehyde (100 mg, 0.94 mmol), The title compound was prepared and the product was obtained as a white solid (35 mg, 47%).
¹ HNMR (DMSO) δ 12.52 (s, 1H), 10.51 (s, 1H), 8.69 (m, 4H), 8.56 (s, 1H), 8.29 (s, 1H), 8.01 (m, 3H), 7.79 (m, 3H), 7.59 (m, 4H) ppm; ES-MSm / z435 (MH ^<+> ).

Isonicotinaldehyde 1- [3- (pentylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazone

Following the general procedure for isonicotinaldehyde [1- (2-methoxyphenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 17), 3- (4-hydrazino- From 1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-pentylaniline hydrochloride (intermediate example H) (42 mg, 0.12 mmol) and isonicotinaldehyde (50 mg, 0.47 mmol), the notation The compound was prepared to obtain the impure product as a green solid. The crude product was purified by silica gel chromatography (3% methanol in methylene chloride) to obtain the pure product (21 mg, 44%).
¹ HNMR (DMSO) δ 12.47 (s, 1H), 8.67 (m, 3H), 8.51 (s, 1H), 8.27 (s, 1H), 7.79 (d, 2H), 7.37 (d, 2H), 7.21 (t, 1H), 6.55 (d, 1H), 5.94 (t, 1H), 3.04 (q, 2H), 1.59 (t, 2H), 1.34 (brs, 4H), 0.89 (t, 3H) ppm; ES -MSm / z401 (MH ⁺ ).

Isonicotinaldehyde (1-3-[(cyclopropylmethyl) amino] phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone

According to the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), N- (cyclopropylmethyl) -3- (4-Hydrazino-1H-pyrazolo [3,4-d] pyrimidin-1-yl) aniline hydrochloride (Intermediate Example I) (48 mg, 0.14 mmol) and isonicotinaldehyde (55 mg, 0.52 mmol) ) To give the product as a tan solid (37 mg, 69%).
¹ HNMR (DMSO) δ 12.47 (s, 1H), 8.67 (m, 3H), 8.52 (s, 1H), 8.27 (s, 1H), 7.79 (d, 2H), 7.40 (d, 2H), 7.22 (t, 1H), 6.58 (d, 1H), 6.05 (brs, 1H), 2.95 (t, 2H), 1.07 (m, 1H), 0.48 (dd, 2H), 0.24 (dd, 2H) ppm; ES -MSm / z385 (MH ⁺ ).

Isonicotinaldehyde 1- [3- (propylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazone

According to the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 3- (4-hydrazino- From 1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-propylaniline hydrochloride (Intermediate Example J) (51 mg, 0.16 mmol) and isonicotinaldehyde (55 mg, 0.52 mmol), the notation The compound was prepared and the product was obtained as a tan solid (41 mg, 69%).
¹ HNMR (DMSO) δ 12.48 (s, 1H), 8.67 (m, 3H), 8.51 (s, 1H), 8.27 (s, 1H), 7.79 (d, 2H), 7.37 (d, 2H), 7.22 (t, 1H), 6.55 (d, 1H), 5.96 (brs, 1H), 3.02 (brs, 2H), 1.60 (m, 2H), 0.96 (t, 3H) ppm; ES-MSm / z373 (MH ⁺ ).

Isonicotinaldehyde 1- [3- (isobutylamino) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazone

According to the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 3- (4-hydrazino- From 1H-pyrazolo [3,4-d] pyrimidin-1-yl) -N-isobutylaniline hydrochloride (Intermediate Example K) (60 mg, 0.18 mmol) and isonicotinaldehyde (60 mg, 0.57 mmol), the notation The compound was prepared and the product was obtained as a tan solid (44 mg, 63%).
¹ HNMR (DMSO) δ 12.47 (s, 1H), 8.67 (m, 3H), 8.51 (s, 1H), 8.27 (s, 1H), 7.79 (d, 2H), 7.37 (d, 2H), 7.21 (t, 1H), 6.56 (d, 1H), 6.02 (t, 1H), 2.87 (t, 2H), 1.87 (m, 1H), 0.95 (d, 6H) ppm; ES-MSm / z387 (MH ⁺ ).

Isonicotinaldehyde [1- (3-ethoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

As described for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3-ethoxyphenyl) -4 -Hydrazino-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example L) (0.050 g, 0.185 mmol) was treated with isonicotinaldehyde (0.059 g, 0.55 mmol) to give 0.051 g of product ( 77%) was obtained as a white solid.
¹ HNMR (DMSO) δ 12.50 (brs, 1H), 8.75 (m, 3H), 8.58 (s, 1H), 8.30 (s, 1H), 7,85 (m, 4H), 7.49 (t, 1H) 6.96 (d, 1H), 4.14 (q, 2H), 1.40 (t, 3H) ppm; ES-MSm / z360 (MH ⁺ ).

Nicotinaldehyde [1- (3-ethoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

As described for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3-ethoxyphenyl) -4 -Hydrazino-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example L) (0.050 g, 0.185 mmol) was treated with nicotinaldehyde (0.059 g, 0.55 mmol) to give 0.057 g (86 %) Was obtained as a white solid.
¹ HNMR (DMSO) δ 12.45 (brs, 1H), 8.95 (s, 1H), 8.70 (s, 1H), 8.66 (d, 1H), 8.55 (s, 1H), 8.36 (m, 2H), 7.86 (m, 2H), 7.56 (dd, 1H), 7.49 (t, 1H), 6.96 (d, 1H), 4.14 (q, 2H), 1.40 (t, 3H) ppm; ES-MSm / z360 (MH ⁺ ).

Isonicotinaldehyde 1- [3- (trifluoromethoxy) phenyl] -1H-pyrazolo [3,4-d] pyrimidin-4-ylhydrazone

As described for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1- [3- ( Trifluoromethoxy) phenyl] -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example M) (0.050 g, 0.161 mmol) treated with isonicotinaldehyde (0.051 g, 0.48 mmol) to form 0.047 g (73%) of product was obtained as a pale yellow solid.
¹ HNMR (DMSO) δ 12.60 (brs, 1H), 8.77 (s, 1H), 8.71 (d, 2H), 8.63 (s, 1H), 8.39 (m, 2H), 8.32 (s, 1H), 7.83 (d, 2H), 7.76 (t, 1H), 7.41 (d, 1H) ppm; ES-MSm / z400 (MH ^<+> ).

Isonicotinaldehyde [1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example N) and isonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.49 (s, 1H), 8.67 (d, 2H), 8.63 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 8.03 (d, 2H) , 7.79 (d, 2H), 7.12 (d, 2H), 3.81 (s, 3H) ppm.

tert-butyl 4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) piperidine-1-carboxylate

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example N) and tert-butyl 4-formylpiperidine-1-carboxylate.
¹ HNMR (300 MHz, DMSO) δ 11.84 (s, 1H), 8.38 (s, 2H), 8.03 (d, 2H), 7.58 (d, 1H), 7.12 (d, 2H), 4.05-3.93 (m, 2H), 3.81 (s, 3H), 2.96-2.76 (m, 2H), 2.63-2.53 (m, 1H), 1.99-1.84 (m, 2H), 1.46-1.36 (m, 11H) ppm.

Piperidine-4-carbaldehyde [1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone = trifluoroacetate

tert-butyl 4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) piperidine-1-carboxylate (Example 39) ) (37 mg, 0.140 mmol), dichloromethane (10 mL), and TFA (0.5 mL) were stirred at RT for 3 h. The resulting mixture was concentrated, washed with dichloromethane and collected by filtration to give the product as a white solid (23 mg, 35% yield).
¹ HNMR (300 MHz, DMSO) δ 12.10-11.78 (sbr, 1H), 8.40 (d, 2H), 8.03 (d, 2H), 7.62 (s, 1H), 7.12 (d, 2H), 3.81 (s, 3H), 3.46-3.30 (m, 2H), 3.06-2.90 (m, 2H), 2.80-2.66 (m, 1H), 2.16-2.02 (m, 2H), 1.77-1.61 (m, 2H) ppm; ES -MSm / z352 (MH ⁺ ).

4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example N) and 4-formylbenzoic acid.
¹ HNMR (300MHz, DMSO) δ12.60-12.19 (sbr, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 8.12-8.01 (m, 4H), 7.97- 7.90 (m, 2H), 7.14 (d, 2H), 3.82 (s, 3H) ppm.

N- [2- (dimethylamino) ethyl] -4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide

4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 ml) (Example 41) (47 mg, 0.120 mmol) in a solution of N, N-dimethylethane-1,2-diamine (0.02 ml, 0.180 mmol), diethyl cyanophosphonate (0.036 ml, 0.240 mmol), and triethylamine (0.05 ml, 0.360 mmol). ) Was added. The solution was stirred at RT for 1 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (22 mg, yield 40%).
¹ HNMR (300 MHz, DMSO) δ 12.32 (s, 1H), 8.63 (s, 1H), 8.53 (t, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.10-7.99 (m, 2H), 7.97-7.89 (m, 4H), 7.13 (d, 2H), 3.82 (s, 3H), 3.46-3.32 (m, 2H), 2.55-2.50 (m, 2H), 2.25 (s, 6H) ppm; ES-MSm / z459 (MH ⁺ ).

4-((E)-[1- (4-Methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- [2- (methylsulfonyl) ethyl] benzamide

4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 ml) (Example 41) To a solution of (47 mg, 0.12 mmol) was added 2- (methylsulfonyl) ethanamine hydrochloride (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 ml, 0.240 mmol), and triethylamine (0.05 ml, 0.360 mmol). . The solution was stirred at RT for 16 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (45 mg, yield 76%).
¹ HNMR (400MHz, DMSO) δ 12.33 (s, 1H), 8.81 (t, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.04 (d, 2H) , 7.99-7.92 (m, 4H), 7.92 (d, 2H), 3.80 (s, 3H), 3.70-3.64 (m, 2H), 3.40-3.35 (m, 2H), 3.30 (s, 3H) ppm; ES-MSm / z494 (MH ⁺ ).

4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- (3-pyrrolidin-1-ylpropyl) Benzamide

4-((E)-[1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 ml) (Example 41) (47 mg, 0.12 mmol) in a solution of 3-pyrrolidin-1-ylpropan-1-amine (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 ml, 0.240 mmol), and triethylamine (0.05 ml, 0.360 mmol) Was added. The solution was stirred at RT for 3 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (18 mg, yield 21%).
¹ HNMR (300MHz, DMSO) δ 12.33 (s, 1H), 8.66-8.60 (m, 2H), 8.48 (s, 1H), 8.34 (s, 1H), 8.06 (d, 2H), 7.99-7.88 ( m, 4H), 7.13 (d, 2H), 3.82 (s, 3H), 3.35-3.28 (m, 2H), 2.55-2.25 (m, 6H), 1.75-1.63 (m, 6H) ppm; ES-MSm / z499 (MH ⁺ ).

tert-butyl 5-((E)-[1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) pyridin-2-ylcarbamate

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example O) and tert-butyl 5-formylpyridin-2-ylcarbamate.
¹ HNMR (300 MHz, DMSO) δ 12.26 (s, 1H), 10.08 (s, 1H), 8.64 (s, 1H), 8.57 (d, 1H), 8.47 (s, 1H), 8.32-8.28 (m, 2H), 8.08 (d, 2H), 7.95 (d, 1H), 7.37 (d, 2H), 2.37 (s, 3H), 1.48 (s, 9H) ppm; ES-MSm / z445 (MH ^<+> ).

6-Aminonicotinaldehyde [1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

tert-Butyl 5-((E)-[1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) pyridin-2-ylcarbamate (Examples) A solution of 45) (76 mg, 0.171 mg), dichloromethane (5 ml), and TFA (1 ml) was stirred at RT for 2 h. The mixture was concentrated, dichloromethane was added and the solution was filtered. The filtrate was concentrated to give the product as a solid (32 mg, 54% yield).
¹ HNMR (400MHz, DMSO) δ 12.31 (s, 1H), 8.64 (s, 1H), 8.46-8.43 (m, 2H), 8.72 (s, 1H), 8.18 (s, 1H), 8.17 (d, 3H), 7.36 (d, 2H), 7.01 (d, 1H), 2.36 (s, 3H) ppm; ES-MSm / z336 (MH ^<+> ).

4-((E)-[1- (4-Methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example O) and 4-formylbenzoic acid.
¹ HNMR (300 MHz, DMSO) δ 12.36 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 8.10-8.03 (m, 4H), 7.95 (d, 2H), 7.38 (d, 2H), 2.38 (s, 3H) ppm; AP-MSm / z373 (MH ^<+> ).

4-((E)-[1- (4-Methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- (3-pyrrolidin-1-ylpropyl) Benzamide

4-((E)-[1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 47) (45 mg, 0.12 mmol) in a solution of 3-pyrrolidin-1-ylpropan-1-amine (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 ml, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol) Was added. The solution was stirred at RT for 3 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (18 mg, yield 31%).
¹ HNMR (300 MHz, DMSO) δ 12.32 (s, 1H), 8.65 (s, 2H), 8.50 (s, 1H), 8.34 (s, 1H), 8.09 (d, 2H), 7.99-7.88 (m, 4H), 7.38 (d, 2H), 3.40-3.28 (m, 2H), 2.55-2.39 (m, 6H), 2.37 (s, 3H), 1.75-1.63 (m, 6H) ppm; ES-MSm / z483 (MH ⁺ ).

N- [2- (dimethylamino) ethyl] -4-((E)-[1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide

4-((E)-[1- (4-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 47) (45 mg, 0.120 mmol) in a solution of N, N-dimethylethane-1,2-diamine (0.02 mL, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). ) Was added. The solution was stirred at RT for 1 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (21 mg, yield 40%).
¹ HNMR (300 MHz, DMSO) δ 12.34 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 8.10 (d, 2H), 7.96-7.89 (m, 4H), 7.39 (d, 2H), 3.48-3.34 (m, 2H), 2.49-2.40 (m, 2H), 2.38 (s, 3H), 2.23 (s, 6H) ppm; ES-MSm / z443 (MH ⁺ ).

4-((E)-[1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example P) and 4-formylbenzoic acid.
¹ HNMR (400MHz, DMSO) δ 12.44 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.37 (s, 1H), 8.09-8.02 (m, 4H), 7.99-7.93 ( m, 2H), 7.48 (t, 1H), 7.22 (d, 1H), 2.68 (t, 2H), 1.72-1.61 (m, 2H), 0.94 (t, 3H) ppm; AP-MSm / z401 (MH ⁺ ).

N- [2- (Dimethylamino) ethyl] -4-((E)-[1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide

4-((E)-[1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 50) (43 mg, 0.120 mmol) in a solution of N, N-dimethylethane-1,2-diamine (0.02 mL, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol), and triethylamine (0.05 mL, 0.360 mmol). ) Was added. The solution was stirred at RT for 1 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (20 mg, yield 24%).
¹ HNMR (300 MHz, DMSO) δ 12.33 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.06-8.03 (m, 2H), 7.96-7.87 ( m, 4H), 7.47 (t, 1H), 7.21 (d, 1H), 3.45-3.34 (m, 2H), 2.72-2.62 (m, 2H), 2.50-2.44 (m, 2H), 2.23 (s, 3H), 1.65 (m, 2H), 0.94 (t, 3H) ppm; ES-MSm / z471 (MH ⁺ ).

4-Hydroxy-3-methoxybenzaldehyde [1- (2-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(2-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example Q) and 4-hydroxy-3-methoxybenzaldehyde.
¹ HNMR (400 MHz, DMSO) δ 12.10 (s, 1H), 9.58 (s, 1H), 8.55 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.33-7.44 (m, 5H), 7.21 (b, 1H), 6.87 (d, 1H), 3.86 (s, 3H), 2.05 (s, 3H) ppm. ES-MSm / z375 (MH ^<+> ).

3-Bromo-4-hydroxy-5-methoxybenzaldehyde [1- (2-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 4-hydrazino-1 Prepared from-(2-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example Q) and 3-bromo-4-hydroxy-5-methoxybenzaldehyde.
¹ HNMR (400 MHz, DMSO) δ 12.15 (s, 1H), 10.03 (s, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.37-7.46 (m, 6H), 3.93 (s, 3H), 2.05 (s, 3H). ES-MSm / z454 (MH ^<+> ).

4-Hydroxy-3-methoxybenzaldehyde [1- (3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example R) and 4-hydroxy-3-methoxybenzaldehyde.
¹ HNMR (400 MHz, DMSO) δ 12.14 (s, 1H), 9.59 (s, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.12-8.17 (m, 3H), 7.58 (d, 1H), 7.32 (s, 1H), 7.19 (m, 2H), 6.86 (d, 1H), 3.86 (s, 3H) ppm. ES-MSm / z379 (MH ⁺ ).

4-Hydroxybenzaldehyde [1- (3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example R) and 4-hydroxybenzaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.09 (s, 1H), 9.95 (s, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 8.12-8.17 (m, 3H), 7.55-7.64 ( m, 3H), 7.16 (t, 1H), 6.86 (d, 2H). ES-MSm / z349 (MH ^<+> ).

4-((E)-[1- (3-Fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example R) and 4-formylbenzoic acid.
¹ HNMR (400MHz, DMSO) δ11.85 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.12 (m, 2H), 8.00 (d, 2H) , 7.85 (d, 2H), 7.58 (m, 1H), 7.17 (t, 1H) ppm. ES-MSm / z377 (MH ⁺ ).

4-Vinylbenzaldehyde [1- (3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example R) and 4-vinylbenzaldehyde.
¹ HNMR (400MHz, DMSO) δ8.62 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 8.12 (m, 2H), 7.80 (d, 2H), 7.73 (d, 2H) 7.58 (m, 1H), 7.51 (d, 1H), 7.16 (m, 1H), 6.56 (d, 1H) ppm. ES-MSm / z403 (MH ⁺ ).

Isonicotinaldehyde [1- (3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example R) and isonicotinaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.45 (s, 1H), 8.64 (s, 3H), 8.52 (s, 1H), 8.22 (s, 1H), 8.10 (m, 2H), 7.73 (d, 2H) 7.58 (m, 1H), 7.17 (t, 1H) ppm. ES-MSm / z334 (MH ⁺ ).

3,4-Dimethoxybenzaldehyde [1- (3-fluorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

  Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from fluorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example R) and 3,4-dimethoxybenzaldehyde.

¹ HNMR (300MHz, DMSO) δ 12.24 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.23 (s, 1H), 8.17 (m, 2H), 7.62 (m, 1H) , 7.39 (s, 1H), 7.32 (d, 1H), 7.21 (t, 1H), 7.08 (d, 1H), 3.90 (s, 3H), 3.84 (s, 3H) ppm.ES-MSm / z393 ( MH ⁺ ).

4-((E)-[1- (3-Chlorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 1), 1- (3- Prepared from chlorophenyl) -4-hydrazino-1H-pyrazolo [3,4-d] pyrimidine (intermediate example S) and 4-formylbenzoic acid.
¹ HNMR (400MHz, DMSO) δ 12.34 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.20 (d, 1H) 8.00 (d, 2H), 7.89 (d, 2H), 7.57 (t, 1H), 7.39 (d, 1H) ppm.

4-((E)-[1- (3-Chlorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- (2-piperidin-1-ylethyl) benzamide

N- [2- (Dimethylamino) ethyl] -4-((E)-[1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide Using the method described for Example 51, 4-((E)-[1- (3-chlorophenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) Prepared from benzoic acid (Example 60) and 2-piperidin-1-ylethanamine.
¹ HNMR (400MHz, DMSO) δ 12.39 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.46 (m, 1H), 8.39 (m, 1H), 8.32 (s, 1H) , 8.22 (d, 1H), 7.82-7.92 (m, 4H), 7.58 (t, 1H), 7.40 (d, 1H), 3.36 (m, 2H), 2.36-2.46 (m, 6H), 1.47 (m , 4H), 1.35 (m, 2H) ppm. ES-MS m / z 504 (MH ⁺ ).

4- (4-Hydroxy-piperidin-1-yl) -benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone hydrochloride

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (50 mg, 0.17 mmol) in EtOH (3 mL) was added 4 -(4-Hydroxy-piperidin-1-yl) -benzaldehyde (62 mg, 0.25 mmol) was added. The reaction mixture was refluxed overnight. The cooled solution was filtered to collect the precipitate, which was dissolved in HCl-MeOH and evaporated in vacuo to give a solid (32.3 mg, 39% yield).
¹ HNMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.51 (s, 1H), 8.42 (s, 1H), 8.25-8.24 (m, 2H), 7.74 (d, 2H), 7.62 (t, 1H), 7.44 (d, 1H), 7.25 (d, 2H), 3.68 (m, 5H), 3.13 (m, 4H) ppm; ES-MSm / z448 (MH ^<+> ).

3-Imidazol-1-yl-benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone hydrochloride

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (50 mg, 0.17 mmol) in EtOH (3 mL) was added 3 -Imidazol-1-yl-benzaldehyde (52 mg, 0.25 mmol) was added. The reaction mixture was refluxed overnight. The cooled solution was filtered to collect the precipitate, which was dissolved in HCl-MeOH and evaporated in vacuo to give a solid (82.7 mg, 99% yield).
¹ HNMR (400 MHz, DMSO) δ 9.86 (brs, 1H), 8.59 (s, 1H9), 8.43 (br, 2H), 8.23-8.26 (m, 2H), 8.06 (d, 1H), 7.99 (s, 1H), 7.88 (d, 1H), 7.78 (t, 1H), 7.63 (t, 1H), 7.45 (d, 1H) ppm; ES-MSm / z415 (MH ⁺ ).

4-Dimethylaminomethyl-benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (50 mg, 0.17 mmol) in EtOH (3 mL) was added 4 -Dimethylaminomethyl-benzaldehyde (50 mg, 0.25 mmol) was added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (23.0 mg, 33% yield).
¹ HNMR (400MHz, DMSO) δ12.25 (brs, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.24 (d, 1H) , 7.78 (d, 2H), 7.61 (t, 1H), 7.41-7.43 (m3H) 3.44 (s, 2H), 2.17 (s, 6H) ppm; ES-MSm / z406 (MH ⁺ ).

6-Methoxy-pyridine-3-carbaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (50 mg, 0.17 mmol) in EtOH (3 mL) was added 6 -Methoxy-pyridine-3-carbaldehyde (42 mg, 0.25 mmol) was added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (56.8 mg, 88% yield).
¹ HNMR (400 MHz, DMSO) δ 12.34 (brs, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 8.30-8.34 (m, 2H), 8.27 (d, 1H), 8.62 (t, 1H), 7.45 (d, 1H), 6.97 (d, 1H), 3.93 (s, 3H) ppm; ES-MSm / z380 (MH ⁺ ).

5-Formyl-furan-2-sulfonic acid [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (50 mg, 0.17 mmol) in EtOH (3 mL) was added 5 -Formyl-furan-2-sulfonic acid sodium salt (60 mg, 0.25 mmol) was added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (69 mg, 92% yield).
¹ HNMR (400MHz, DMSO) δ12.32 (brs, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.28 (d, 1H), 8.16 (s, 1H) 7.61 (t, 1 H), 7.43 (d, 1 H), 6.99 (d, 1 H), 6.57 (d, 1 H) ppm; ES-MSm / z 419 (MH ⁺ ).

4- (4-Methyl-piperazin-1-ylmethyl) -benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone dihydrochloride

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (39 mg, 0.13 mmol) in EtOH (5 mL) was added 2N HCl. (0.5 mL) and 1- (4-diethoxymethyl-benzyl) -4-methyl-piperazine (42 mg, 0.14 mmol) were added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (66 mg, 95% yield).
¹ HNMR (400MHz, DMSO) δ 12.42 (brs, 1H), 8.71 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 8.25 (d, 1H) , 7.88-7.94 (m, 2H), 7.60-7.70 (m, 2H), 7.63 (t, 1H), 7.45 (d, 1H), 3.1-3.6 (br, 10H), 2.81 (s, 3H) ppm; ES-MSm / z461 (MH ⁺ ).

4-morpholin-4-ylmethyl-benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone hydrochloride

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (38 mg, 0.13 mmol) in EtOH (5 mL) was added 2N HCl. (0.5 mL) and 4- (4-diethoxymethyl-benzyl) -morpholine (39 mg, 0.14 mmol) were added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (45 mg, 71% yield).
¹ HNMR (400MHz, DMSO) δ 12.45 (brs, 1H), 10.60 (brs, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 8.37 (s, 1H) , 8.24 (d, 1H), 7.95 (d, 2H), 7.69 (d, 2H), 7.63 (t, 1H), 7.45 (d, 1H), 4.41 (m, 2H), 3.98 (m, 2H), 3.72 (m, 2H), 2.29 (m, 2H), 2.12 (m, 2H) ppm; ES-MSm / z448 (MH ^<+> ).

4- [Bis- (2-methoxy-ethyl) -amino] -methyl-benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone hydrochloride

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (32 mg, 0.11 mmol) in EtOH (5 mL) was added 2N HCl. (0.5 mL) and N- [4- (dimethoxymethyl) benzyl] -2-methoxy-N- (2-methoxyethyl) ethanamine (43 mg, 0.12 mmol) were added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (24 mg, 41% yield).
¹ HNMR (400MHz, DMSO) δ 12.45 (brs, 1H), 10.03 (brs, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H) , 8.24 (d, 1H), 7.95 (d, 2H), 7.71 (d, 2H), 7.62 (t, 1H), 7.43 (d, 1H), 4.47 (m, 2H), 3.70 (m, 4H), 3.31 (m, 4H), 3.31 (s, 6H) ppm; ES-MSm / z494 (MH ^<+> ).

4-[(2-Dimethylamino-ethyl) -methyl-amino] -methyl-benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone dihydrochloride salt

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (35 mg, 0.12 mmol) in EtOH (5 mL) was added 2N HCl. (0.5 mL) and N- (4-diethoxymethyl-benzyl) -N, N ′, N′-trimethyl-ethane-1,2-diamine (48 mg, 0.13 mmol) were added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (53 mg, 82% yield).
¹ HNMR (400MHz, DMSO) δ 12.45 (brs, 1H), 10.86 (brs, 1H), 10.50 (brs, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H) , 8.37 (s, 1H), 8.26 (d, 1H), 7.95 (m, 2H), 7.75 (m, 2H), 7.63 (t, 1H), 7.47 (d, 1H), 4.62 (m, 1H), 4.35 (m, 1H), 3.61 (m, 2H), 2.86 (s, 6H), 2.73 (m, 2H) ppm; ES-MSm / z463 (MH ⁺ ).

4- [4- (2-Hydroxy-ethyl) -piperazin-1-ylmethyl] -benzaldehyde [1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone Hydrochloride

To a solution of 4-hydrazino-1- (3-chloro-phenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example S) (34 mg, 0.11 mmol) in EtOH (5 mL) was added 2N HCl. (0.5 mL) and 2- [4- (4-diethoxymethyl-benzyl) -piperazin-1-yl] -ethanol (55 mg, 0.17 mmol) were added. The reaction mixture was refluxed overnight. The cooled solution was filtered to recover the pure product (58 mg, 94% yield).
¹ HNMR (400MHz, DMSO) δ12.40 (brs, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 8.26 (d, 1H) , 7.93 (d, 2H), 7.68 (m, 2H), 7.63 (t, 1H), 7.45 (d, 1H), 3.76 (m, 2H), 3.68 (m, 2H), 3.24 (m, 10H) ppm ; ES-MSm / z491,493 (MH ^<+> ).

Nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

To a suspension of 4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (0.200 g, 0.78 mmol) in 10 mL of absolute ethanol, Nicotinaldehyde (0.22 mL, 2.34 mmol) was added. The mixture was heated at reflux for 2 h. After cooling to room temperature, the solid product was collected by filtration, washed with ethanol and dried under vacuum to give a white solid 0.241 g (91%).
¹ HNMR (400MHz, DMSO) δ12.45 (brs, 1H), 8.91 (s, 1H), 8.66 (s, 1H), 8.60 (d, 1H), 8.50 (s, 1H), 8.33 (s, 1H) , 8.32 (d, 1H), 7.85 (m, 2H), 7.52 (dd, 1H), 7.46 (t, 1H), 6.94 (dd, 1H), 3.83 (s, 3H) ppm.ES-MSm / z309 ( MH ⁺ ).

Isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and isonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.51 (s, 1H), 8.68-8.66 (m, 3H), 8.54 (s, 1H), 8.26 (s, 1H), 7.84 (d, 2H), 7.77 (d, 2H), 7.47 (t, 1H), 6.94 (d, 1H), 3.83 (s, 3H) ppm.

tert-Butyl 5-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) pyridin-2-ylcarbamate

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and tert-butyl 5-formylpyridin-2-ylcarbamate.
¹ HNMR (300MHz, DMSO) δ 12.23 (s, 1H), 10.07 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.48 (s, 1H), 8.28 (d, 1H) , 8.26 (s, 1H), 7.93 (d, 1H), 7.86-7.83 (m, 2H), 7.46 (t, 1H), 6.93 (dd, 1H), 3.83 (s, 3H), 1.48 (s, 9H ) ppm.

6-Aminonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone = trifluoroacetate

Tert-Butyl 5- (E)-[1- (3-methoxyphenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazono] methylpyridine-2-CH ₂ Cl ₂ (5 mL) To a suspension of ilcarbamate (Example 74) (0.070 g; 0.15 mmol) was added trifluoroacetic acid (3 mL). The mixture was stirred at RT for 3 days, after which the solvent was removed to give the title compound (0.075 g) as a white solid (100%).
¹ HNMR (300 MHz, DMSO) δ 8.65-8.48 (m, 4H), 8.29 (s, 1H), 8.18 (s, 1H), 7.83 (m, 2H), 7.45 (m, 1H), 7.10-7.08 ( m, 1H), 6.92 (m, 1H), 3.82 (s, 3H) ppm; ES-MSm / z361 (MH ^<+> ).

6-chloronicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 6-chloronicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.49 (s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.41 (d, 1H), 8.33 (s, 1H) 7.90-7.86 (m, 2H), 7.63 (d, 1H), 7.49 (t, 1H), 6.97 (d, 1H), 3.86 (s, 3H) ppm.

6- (Methylthio) nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

6-chloronicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 76) in DMSO (5 mL) (0.138 g; 0.36 mmol) And sodium thiomethoxide (0.126 g; 1.82 mmol) was heated at 105 ° C. for 1 h. The solution was cooled to RT and then water (3 mL) and MeOH (3 mL) were added. The solid was filtered and dried to give the title compound (102 mg) as an off-white powder (72%).
¹ HNMR (300 MHz, DMSO) δ 12.33 (s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.20 (d, 1H) , 7.88-7.85 (m, 2H), 7.48 (t, 1H), 7.42 (d, 1H), 6.95 (d, 1H), 3.84 (s, 3H), 2.57 (s, 3H) ppm; ES-MSm / z390.0 (MH ^-).

6-Methoxynicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

6-chloronicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 76) (0.11 g; 0.29 mmol) in DMSO (5 mL) And sodium methoxide (0.11 g; 2.09 mmol) was heated at 105 ° C. for 1 h. The solution was cooled to RT and then water (25 mL) was added. The solid was filtered, washed with MeOH (3 mL) followed by Et ₂ O (5 mL) and dried to give the title compound (68 mg) as an off-white powder (63%).
¹ HNMR (300 MHz, DMSO) δ 12.30 (s, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.36-8.31 (m, 2H), 7.90-7.88 ( m, 2H), 7.50 (t, 1H), 6.99 (d, 2H), 3.94 (s, 3H), 3.87 (s, 3H) ppm; ES-MSm / z376.0 (MH ^<+> ).

Isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone 1-oxide

According to the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1- ( Prepare the title compound from 3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (100 mg, 0.39 mmol) and isonicotinaldehyde 1-oxide (85 mg, 0.69 mmol) The product was obtained as an orange solid (127 mg, 90%).
¹ HNMR (DMSO) δ12.47 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.24 (d, 3H), 7.86 (m, 4H), 7.48 (t, 1H), 6.94 (dd, 1H), 3.84 (s, 3H) ppm; ES-MSm / z362 (MH ^<+> ).

2- (Methylsulfonyl) isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone hydrochloride

4- (Diethoxymethyl) -2- (methylsulfonyl) pyridine (Intermediate Example V) (120 mg, 0.46 mmol) in THF (5 mL) was added to 4-hydrazino-1- (3-methoxyphenyl)- 1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (90 mg, 0.35 mmol) and 1N aqueous hydrochloric acid (5 mL) were added. The mixture was heated in a 90 C oil bath for about 1.75 h. After cooling to RT, the resulting solid was collected by filtration and washed with ether to give the product HCl salt as a white solid (93 mg, 57%).
¹ HNMR (DMSO) δ8.86 (d, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 8.42 (brs, 1H), 8.34 (brs, 1H), 8.16 (d, 1H), 7.84 (m, 2H), 7.48 (t, 1H), 6.96 (d, 1H), 5.11 (brs, 2H), 3.84 (s, 3H), 3.34 (s, 3H) ppm.ES-MSm / z424 (MH ⁺ ).

Methyl 2-chloro-4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) nicotinate hydrochloride

Methyl 2-chloro-4- (diethoxymethyl) nicotinate (95 mg, 0.35 mmol) in THF (5 mL) was added to 4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] Pyrimidine (intermediate Example T) (80 mg, 0.31 mmol) and 1N aqueous hydrochloric acid (5 mL) were added. The mixture was heated in a 90 C oil bath for about 3.5 h. After cooling to RT, the resulting solid was collected by filtration and washed with ether to give the product HCl salt as a white solid (60 mg, 41%).
¹ HNMR (DMSO) δ8.66 (s, 1H), 8.59 (m, 2H), 8.30 (s, 1H), 8.12 (d, 1H), 7.85 (m, 2H), 7.48 (t, 1H), 6.96 (dd, 1H), 4.91 (brs, 2H), 3.93 (s, 3H), 3.84 (s, 3H) ppm; ES-MSm / z438 (MH ^<+> ).

1H-indole-3-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 1H-indole-3-carbaldehyde.
¹ HNMR (300MHz, DMSO) δ 11.95 (s, 1H), 11.74 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H) 7.94-7.86 (m, 3H), 7.49-7.43 (m, 2H), 7.27-7.24 (m, 2H), 6.93 (m, 1H), 3.83 (s, 3H) ppm.

4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4-formylbenzoic acid.
¹ HNMR (300 MHz, DMSO) δ 12.90-12.49 (sbr, 2H), 8.67 (s, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.02 (d, 2H), 7.93 (d, 2H), 7.87-7.83 (m, 2H), 7.46 (t, 1H), 6.93 (d, 1H), 3.83 (s, 3H) ppm.

4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- [2- (methylsulfonyl) ethyl] benzamide

4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 83) To a solution of (47 mg, 0.12 mmol) was added 2- (methylsulfonyl) ethanamine hydrochloride (29 mg, 0.180 mmol), diethyl cyanophosphonate (0.036 mL, 0.240 mmol) and triethylamine (0.05 mL, 0.360 mmol). The solution was stirred at RT for 16 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (48 mg, yield 81%).
¹ HNMR (300MHz, DMSO) δ 12.39 (s, 1H), 8.83 (t, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.35 (s, 1H), 7.99-7.92 (m, 4H), 7.88-7.85 (m, 2H), 7.48 (t, 1H), 6.95 (dd, 1H), 3.84 (s, 3H), 3.70 (q, 2H), 3.47-3.33 (m, 2H), 3.05 (s, 3H) ppm; ES-MSm / z494 (MH ^<+> ).

4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- (3-pyrrolidin-1-ylpropyl) Benzamide

4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzoic acid in DMF (4 mL) (Example 83) (100 mg, 0.26 mmol) in a solution of 3-pyrrolidin-1-ylpropan-1-amine (0.13 mL, 1.03 mmol), diethyl cyanophosphonate (0.16 mL, 1.03 mmol), and triethylamine (0.11 mL, 0.77 mmol). ) Was added. The solution was stirred at RT for 3 h, after which water and diethyl ether were added. The produced precipitate was collected by filtration to obtain a pure product (86 mg, 66% yield).
¹ HNMR (300 MHz, DMSO) δ 12.49-12.21 (sbr, 1H), 8.68 (s, 1H), 8.65 (t, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 7.95-7.84 ( m, 6H), 7.48 (t, 1H), 6.95 (dd, 1H), 3.84 (s, 3H), 3.40-3.28 (m, 2H), 2.55-2.39 (m, 6H), 1.75-1.63 (m, 6H) ppm; ES-MSm / z499 (MH ^<+> ).

N- [2- (Dimethylamino) ethyl] -4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide Hydrochloride

N- [2- (Dimethylamino) ethyl] -4-((E)-[1- (3-propylphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzamide Using the general procedure for (Example 51), 4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydra Prepared from (zonomethyl) benzoic acid (Example 83).
¹ HNMR (300MHz, DMSO) δ 10.20 (s, 1H), 8.96 (s, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 8.02 (d, 2H) , 7.92 (d, 2H), 7.87-7.83 (m, 2H), 7.47 (t, 1H), 6.94 (d, 1H), 3.83 (s, 3H), 3.64 (m, 2H), 3.72 (m, 2H ), 2.81 (s, 6H) ppm.

2-Chloro-6-methylisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 2-chloro-6-methylisonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.51 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.91-7.86 (m, 2H), 7.67 (s, 1H), 6.62 (s, 1H ), 7.50 (t, 1H), 6.97 (d, 1H), 3.87 (s, 3H), 2.57 (s, 3H) ppm; ES-MSm / z392 (MH -).

2-Methoxy-6-methylisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

2-Chloro-6-methylisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone in DMSO (10 mL) (Example 87) (0.15 g; 0.38 mmol) and sodium methoxide (0.206 g; 3.81 mmol) were heated at 105 ° C. for 24 h. The solution was cooled to RT and then water (50 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (54 mg) as an off-white powder (37%).
¹ HNMR (300 MHz, DMSO) δ 12.36 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.13 (s, 1H), 7.84 (d, 1H), 7.81 (s, 1H) , 7.44 (t, 1H), 7.19 (s, 1H), 6.91 (d, 1H), 6.80 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.44 (s, 3H) ppm ; ES-MSm / z388 (MH -).

2,6-dichloroisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 2,6-dichloroisonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.66 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 7.84-7.80 (m, 4H), 7.44 (t, 1H), 6.92 (d, 1H), 3.82 (s, 3H) ppm.

2-Chloro-6-methoxyisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

2,6-dichloroisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone in DMSO (5 mL) (Example 89) (0.060 g; 0.15 mmol) and sodium methoxide (0.15 g; 2.78 mmol) were heated at 105 ° C. for 1 h. The solution was cooled to RT, then 1N HCl (5 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (37 mg; 60%).
¹ HNMR (300 MHz, DMSO) δ 12.59 (s, 1H), 8.55 (m, 2H), 8.19 (s, 1H), 7.83-7.81 (m, 2H), 7.48-7.44 (m, 2H), 7.12 ( s, 1H), 6.93 (d , 1H), 3.88 (s, 3H), 3.82 (s, 3H) ppm; ES-MSm / z408.5 (MH -).

2-morpholin-4-yl-1,3-thiazole-5-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2-morpholin-4-yl-1,3-thiazole-5-carbaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.24 (s, 1H), 8.47-2.46 (m, 2H), 8.36 (s, 1H), 7.91-7.85 (m, 2H), 7.66 (s, 1H), 7.49 ( t, 1H), 6.96 (d , 1H), 3.86 (s, 3H), 3.76 (m, 4H), 3.57 (m, 4H) ppm; ES-MSm / z435.6 (MH -).

2,3,5,6-Tetrafluoroisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 2,3,5,6-tetrafluoroisonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.72 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 7.82-7.78 (m, 2H), 7.44 (t, 1H), 6.92 (d, 1H), 3.82 (s, 3H) ppm.

Pyrimidine-4-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and pyrimidine-4-carbaldehyde.
¹ HNMR (300MHz, DMSO) δ12.60 (s, 1H), 9.21 (s, 1H), 8.85 (d, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H) , 8.13 (d, 1H), 7.84-7.82 (m, 2H), 7.45 (t, 1H), 6.92 (d, 1H), 3.82 (s, 3H) ppm; ES-MSm / z345.3 (MH -) .

2-Methylpyrimidine-4-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2-methylpyrimidine-4-carbaldehyde.
¹ HNMR (300MHz, DMSO) δ12.73 (s, 1H), 8.80 (d, 1H), 8.76 (s, 1H), 8.62 (s, 1H), 8.22 (s, 1H), 8.00 (d, 1H) 7.91-7.87 (m, 2H), 7.51 (t, 1H), 6.99 (d, 1H), 3.87 (s, 3H), 2.68 (s, 3H) ppm.

3- (Methylthio) isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 3- (methylthio) isonicotinaldehyde.
¹ HNMR (300MHz, DMSO) δ12.54 (s, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.49 (d, 1H) , 7.90 (d, 1H), 7.85-7.82 (m, 2H), 7.46 (t, 1H), 6.94 (d, 1H), 3.82 (s, 3H), 2.60 (s, 3H) ppm; ES-MSm / z390 (MH ^-).

2-Chloroisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2-chloroisonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.57 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H), 8.49 (d, 1H), 8.27 (s, 1H), 7.98-7.79 (m, 4H), 7.48 (t, 1H), 6.95 (d, 1H), 3.84 (s, 3H) ppm; ES-MSm / z381 (MH ^<+> ).

2-methoxyisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

2-chloroisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 96) in DMSO (2 ml) (50 mg, 0.13 mmol) To the solution was added sodium methoxide (50 mg). The mixture was stirred at 80 ° C. for 1 h. Cool to RT and add water. The resulting solid was collected by filtration, washed with water and air dried to obtain the pure product (33 mg, 68% yield).
¹ HNMR (300MHz, DMSO) δ 12.51 (s, 1H), 8.63 (s, 1H), 8.27-8.23 (m, 2H), 7.90-7.83 (m, 2H), 7.51-7.45 (m, 2H), 7.10 (s, 1H), 6.99-6.93 (m, 1H), 3.90 (s, 3H), 3.84 (s, 3H) ppm; ES-MSm / z376 (MH ⁺ ).

4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) -N- (3-pyrrolidin-1-ylpropyl) Benzenesulfonamide

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4-formyl-N- (3-pyrrolidin-1-ylpropyl) benzenesulfonamide .
¹ HNMR (300MHz, DMSO) δ 12.44 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H), 8.06 (d, 2H), 7.88 (t, 5H) , 7.49 (t, 1H), 6.95 (dd, 1H), 3.84 (s, 3H), 3.40-3.28 (m, 2H) 3.06-2.95 (m, 4H) 2.94-2.75 (m, 2H), 1.92-1.63 (m, 6H) ppm; ES-MSm / z535 (MH ⁺ ).

N- [2- (Dimethylamino) ethyl] -4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzene Sulfonamide

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 -(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and N- [2- (dimethylamino) ethyl] -4-formylbenzenesulfonamide (intermediate of Prepared from Example U).
¹ HNMR (300MHz, DMSO) δ 12.51 (s, 1H), 10.09 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.20 (m, 1H) , 8.09 (d, 2H), 7.98 (d, 2H), 7.75 (d, 1H), 7.52 (t, 1H), 7.00 (d, 1H), 3.87 (s, 3H), 3.18 (sbr, 4H), 2.79 (s, 6H) ppm; ES-MSm / z493 (MH -).

3,5-dichloroisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 3,5-dichloroisonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 8.74 (s, 2H), 8.58 (s, 2H), 8.56 (s, 1H), 7.84-7.78 (m, 2H), 7.46 (t, 1H), 6.94 (d, 1H), 3.82 (s, 3H) ppm; ES-MSm / z414 (MH ⁺ ).

2-Methylisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2-methylisonicotinaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.51 (s, 1H), 8.72 (s, 1H), 8.58 (s, 2H), 8.27 (s, 1H), 7.92-7.85 (m, 2H), 7.65-7.60 ( m, 2H), 7.51 (t, 1H), 7.00 (dd, 1H), 3.87 (s, 3H), 3.35 (s, 3H) ppm; ES-MSm / z360 (MH ^<+> ).

4-[[2- (Dimethylamino) ethyl] (methyl) amino] methylbenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4-[[2- (dimethylamino) ethyl] (methyl) amino] methylbenzaldehyde .
¹ HNMR (300 MHz, DMSO) δ 12.23 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.90-7.87 (m, 2H), 7.78 (d, 2H), 7.51-7.40 (m, 3H), 6.95 (dd, 1H), 3.85 (s, 3H), 3.53 (s, 2H), 2.55-2.39 (m, 4H), 2.14 (d, 9H) ppm; ES-MSm / z459 (MH ⁺ ).

4- (morpholin-4-ylmethyl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4- (morpholin-4-ylmethyl) benzaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.25 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.90-7.84 (m, 2H), 7.79 (d, 2H), 7.51-7.40 (m, 3H), 6.95 (dd, 1H), 3.85 (s, 3H), 3.61-3.56 (m, 4H), 3.52 (s, 2H) 2.40-2.34 (m, 4H) ppm ; ES-MSm / z444 (MH ⁺ ).

4-[(Dimethylamino) methyl] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4-[(dimethylamino) methyl] benzaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.24 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.90-7.84 (m, 2H), 7.78 (d, 2H), 7.51-7.40 (m, 3H), 6.95 (dd, 1H), 3.85 (s, 3H), 3.44 (s, 2H) 2.16 (s, 6H) ppm; ES-MSm / z402 (MH ⁺ ).

4-[(Diethylamino) methyl] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4-[(diethylamino) methyl] benzaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.24 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.90-7.84 (m, 2H), 7.78 (d, 2H), 7.51-7.40 (m, 3H), 6.95 (dd, 1H), 3.85 (s, 3H), 3.58 (s, 2H), 2.48 (q, 4H), 0.99 (t, 6H) ppm; ES- MS m / z 430 (MH ⁺ ).

4-[(Dipropylamino) methyl] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4-[(dipropylamino) methyl] benzaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.21 (s, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.90-7.84 (m, 2H), 7.78 (d, 2H), 7.51-7.40 (m, 3H), 6.95 (dd, 1H), 3.85 (s, 3H), 3.56 (s, 2H), 2.35 (t, 4H), 1.43 (q, 4H), 0.83 (t , 6H) ppm; ES-MSm / z458 (MH ^<+> ).

4-[(Diisopropylamino) methyl] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4-[(diisopropylamino) methyl] benzaldehyde.
¹ HNMR (300 MHz, DMSO) δ 12.21 (s, 1H), 8.66 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 7.88-7.84 (m, 2H), 7.75 (d, 2H), 7.51-7.43 (m, 3H), 6.95 (dd, 1H), 3.84 (s, 3H), 3.66 (s, 2H), 2.98 (quin, 2H), 0.99 (d, 12H) ppm; ES- MSm / z428 (MH ⁺ ).

4-[(4-Methylpiperazin-1-yl) methyl] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 -(3-Methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4-[(4-methylpiperazin-1-yl) methyl] benzaldehyde (intermediate example) W).
¹ HNMR (300 MHz, DMSO) δ 12.22 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.88-7.84 (m, 2H), 7.78 (d, 2H), 7.51-7.40 (m, 3H), 6.95 (dd, 1H), 3.84 (s, 3H), 3.50 (s, 2H), 2.45-2.56 (m, 6H), 2.15 (s, 3H) ppm; ES-MSm / z457 (MH ⁺ ).

4- (Pyrrolidin-1-ylmethyl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4- (pyrrolidin-1-ylmethyl) benzaldehyde (intermediate example X).
¹ HNMR (300MHz, DMSO) δ 12.24 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 8.30 (s, 1H), 7.90-7.84 (m, 2H), 7.78 (d, 2H), 7.51-7.40 (m, 3H), 6.95 (dd, 1H), 3.84 (s, 3H), 3.62 (s, 2H), 2.47-2.56 (m, 4H), 1.65-1.81 (m, 4H) ppm; ES-MSm / z428 (MH ⁺ ).

4-([2- (Dimethylamino) ethyl] aminomethyl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (25 mg, 0.10 mmol), N ^1- [4- (diethoxymethyl) A mixture of [benzyl] -N ² , N ² -dimethylethane-1,2-diamine (Intermediate Example Y) (27 mg, 0.10 mmol) and 6NHCl (5 mL) was stirred at 50 ° C. for 2 h. The mixture was cooled to RT and filtered. The resulting solid was partitioned between 1N NaOH and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the product (16 mg, 37% yield).
¹ HNMR (300 MHz, DMSO) δ 8.64 (s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 7.88-7.80 (m, 2H), 7.76 (d, 2H), 7.51-7.40 ( m, 3H), 6.93 (dd, 1H), 3.83 (s, 3H), 3.74 (s, 2H), 2.60-2.52 (m, 2H), 2.36-2.29 (m, 2H), 2.10 (s, 6H) ppm; ES-MSm / z445 (MH ⁺ ).

4-[(Ethylamino) methyl] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone hydrochloride

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (50 mg, 0.19 mmol), N- [4- (diethoxymethyl) benzyl A mixture of ethanamine (Intermediate Example Z) (45 mg, 0.19 mmol) and 6N HCl (5 mL) was stirred at 50 ° C. for 16 h. The cooled solution was filtered and the product was recovered as a white solid (58 mg, 70% yield).
¹ HNMR (300 MHz, CD3OH) δ 8.66 (s, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.15 (d, 2H), 7.75-7.69 (m, 4H), 7.51 (t, 1H), 7.07 (dd, 1H), 4.31 (s, 2H), 3.91 (s, 3H), 3.18 (q, 2H), 1.38 (t, 3H) ppm; ES-MSm / z402 (MH ⁺ ).

tert-Butyl 4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenylcarbamate

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (87.5 mg, 0.342 mmol), tert-butyl 4 in ethanol (20 mL) A mixture of formylphenylcarbamate (151 mg 0.683 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 21 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a yellow solid (133 mg, 85% yield).
¹ HNMR (400 MHz, DMSO): δ 12.16 (s, 1H), 9.63 (s, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 8.21 (s, 1H), 7.86 (d, 2H ), 7.72 (d, 2H), 7.58 (d, 2H), 7.46 (t, 1H), 6.93 (d, 1H), 3.83 (s, 3H), 1.48 (s, 9H) ppm; ES-MSm / z460 (MH ⁺ ).

4-Aminobenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

tert-Butyl 4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenylcarbamate (Example 112) (602 mg , 1.311 mmol) and a mixture of 20% trifluoroacetic acid in dichloromethane (10 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO ₃ and the organic layer was dried (MgSO ₄ ) and concentrated to give the product as a yellow solid (433 mg, 92% yield).
¹ HNMR (400 MHz, DMSO): δ 11.93 (s, 1 H), 8.60 (s, 1 H), 8.40 (s, 1 H), 8.10 (s, 1 H), 7.85 (m, 2 H), 7.46 (m, 3 H ), 6.92 (d, 1H), 6.63 (d, 2H), 5.70 (broads, 2H), 3.82 (s, 3H) ppm; ES-MSm / z360 (MH ⁺ ).

N- [4-((E) -2- [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl] acetamide

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (150 mg, 0.585 mmol), N- (4- A mixture of formylphenyl) acetamide (190 mg 1.17 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 21 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a white solid (150 mg, 64% yield).
¹ HNMR (400 MHz, DMSO): δ 12.18 (s, 1H), 10.16 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 7.85 (m, 2H) ), 7.73 (dd, 4H), 7.46 (t, 1H), 6.93 (dd, 1H), 3.83 (s, 3H), 2.06 (s, 3H) ppm; ES-MSm / z402 (MH ⁺ ).

N- [4-((E) -2- [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl] methanesulfonamide

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (43 mg, 0.167 mmol), N- (4- A mixture of formylphenyl) methanesulfonamide (40 mg 0.201 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 21 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a white solid (67 mg, 92% yield).
¹ HNMR (400MHz, DMSO) δ 12.22 (s, 1H), 10.08 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.82 (m, 4H) , 7.47 (t, 1H), 7.31 (d, 2H), 6.94 (d, 1H), 3.83 (s, 3H), 3.06 (s, 3H) ppm; ES-MSm / z438 (MH ⁺ ).

N ¹ -[4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl] -N ² , N ² -Dimethylglycinamide

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (109 mg, 0.428 mmol) in ethanol (20 mL), N ^1- (4 A mixture of -formylphenyl) -N ² , N ² -dimethylglycinamide (intermediate example AA) (106 mg 0.514 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 21 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a yellow solid (151 mg, 79% yield).
¹ HNMR (400 MHz, DMSO): δ 12.21 (s, 1H), 9.97 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.83 (m, 6H) ), 7.48 (t, 1H), 6.95 (dd, 1H), 3.84 (s, 3H), 3.10 (s, 2H), 2.28 (s, 6H) ppm; ES-MSm / z445 (MH ⁺ ).

N- [4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl] -2-morpholin-4-yl Acetamide

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (77 mg, 0.301 mmol), N- (4- A mixture of formylphenyl) -2-morpholin-4-ylacetamide (Intermediate Example BB) (112 mg 0.452 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 18 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a light yellow solid (114 mg, 78% yield).
¹ HNMR (400 MHz, DMSO): δ 12.19 (s, 1H), 9.97 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 7.85 (dd, 2H ), 7.77 (s, 4H), 7.46 (t, 1H), 6.92 (dd, 1H), 3.82 (s, 3H), 3.62 (t, 4H), 3.14 (s, 2H), 2.50 (t, 4H) ppm; ES-MSm / z487 (MH ⁺ ).

2-Methoxy-N- [4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl] acetamide

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (152 mg, 0.595 mmol), N- (4- A mixture of formylphenyl) -2-methoxyacetamide (Intermediate Example CC) (160 mg 0.893 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 18 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as an orange solid (236 mg, 91% yield).
¹ HNMR (400MHz, DMSO): δ12.18 (s, 1H), 9.99 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 7.80 (m, 6H ), 7.46 (t, 1H), 6.92 (d, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 3.36 (s, 2H) ppm; ES-MSm / z432 (MH ^<+> ).

4- (Methylsulfonyl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (100 mg, 0.390 mmol), 4- (methylsulfonyl) in ethanol (20 mL) ) A mixture of benzaldehyde (108 mg 0.585 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 3.5 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a light yellow solid (142 mg, 86% yield).
¹ HNMR (400MHz, DMSO) δ 12.48 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.37 (s, 1H), 8.08 (d, 2H), 8.00 (d, 2H) , 7.84 (m, 2H), 7.47 (t, 1H), 6.94 (dd, 1H), 5.73 (s, 3H), 3.83 (s, 3H) ppm; ES-MSm / z423 (MH ⁺ ).

3-Aminobenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (200 mg, 0.780 mmol), 3-aminobenzaldehyde (200 mL) in ethanol (20 mL) A mixture of 189 mg 1.560 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 3.5 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a light brown solid (209 mg, 75% yield).
¹ HNMR (400 MHz, DMSO): δ 12.13 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 7.86 (m, 2H), 7.46 (t, 1H ), 7.11 (m, 2H), 6.93 (d, 1H), 6.81 (d, 1H), 6.63 (d, 1H), 5.34 (s, 2H), 3.82 (s, 3H) ppm; ES-MSm / z360 (MH ⁺ ).

1H-imidazole-2-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (100 mg, 0.390 mmol), 1H-imidazole-2 in ethanol (10 mL) A mixture of carbaldehyde (75 mg 0.780 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 5 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a brown solid (72 mg, 55% yield).
¹ HNMR (400MHz, DMSO) δ 12.74 (s, 1H), 12.21 (s, 1H), 9.08 (s, 1H), 8.49 (s, 1H), 8.22 (s, 1H), 7.86 (m, 2H) , 7.47 (t, 1H), 7.39 (s, 1H), 7.13 (s, 1H), 6.94 (dd, 1H), 3.84 (s, 3H) ppm; ES-MSm / z335 (MH ^<+> ).

1H-imidazole-5-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (100 mg, 0.390 mmol), 1H-imidazole-5 in ethanol (10 mL) A mixture of carbaldehyde (75 mg 0.780 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 18 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with ethanol and ether to give the product as a brown solid (67 mg, 51% yield).
¹ HNMR (400MHz, DMSO) δ 12.91 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.84 (m, 3H), 7.61 (s, 1H) 7.46 (t, 1H), 6.93 (dd, 1H), 5.75 (s, 1H), 3.83 (s, 3H) ppm; ES-MSm / z336 (MH ^<+> ).

N ¹ -[4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl] -N ^Three , N ^Three -Dimethyl-γ-alaninamide

Ethanol (10 mL) solution of 4-hydrazino-1- (3-methoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine (Example of Intermediate T) (59mg, 0.226mmol), N 1 - (4 A mixture of -formylphenyl) -N ³ , N ³ -dimethyl-γ-alaninamide (Intermediate Example DD) (100 mg 0.453 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 18 h. The reaction was then cooled to RT and concentrated. The residue was triturated with diethyl ether and the solid was collected by filtration and washed with diethyl ether to give the product as a brown solid (16.8 mg, 17% yield).
¹ HNMR (400 MHz, DMSO): δ 12.18 (s, 1H), 10.31 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 7.85 (m, 2H) ), 7.75 (m, 4H), 7.46 (t, 1H), 6.93 (dd, 1H), 3.83 (s, 3H), 2.77 (s, 2H), 2.49 (s, 6H), 1.69 (s, 2H) ppm; ES-MSm / z460 (MH ⁺ ).

tert-Butyl (2R) -2-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) pyrrolidine-1-carboxylate

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (100 mg, 0.390 mmol), tert-butyl (2S) in ethanol (10 mL) A mixture of) -2-formylpyrrolidine-1-carboxylate (90 mg 0.452 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 18 h. The reaction was then cooled to RT and concentrated. The residue was triturated with diethyl ether and the solid was collected by filtration and washed with diethyl ether to give the product (107 mg, 63% yield) as a yellow solid.
¹ HNMR (400MHz, DMSO) δ11.90 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 7.81 (m, 2H), 7.54 (m, 1H), 7.44 (t, 1H) , 6.92 (d, 1H), 4.49 (d, 1H), 3.82 (s, 3H), 3.36 (m, 2H), 2.0 (m, 2H), 1.41 (m, 2H), 1.29 (s, 9H) ppm ; ES-MSm / z438 (MH ⁺ ).

(2R) -Pyrrolidine-2-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

tert-Butyl (2R) -2-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) pyrrolidine-1-carboxylate Example 127 A mixture of 20% trifluoroacetic acid in (80 mg, 0.182 mmol) and dichloromethane (10 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO ₃ solution. The organic layer was dried (MgSO ₄ ) and concentrated to give the product as a tan solid (49 mg, 80% yield).
¹ HNMR (400MHz, DMSO) δ11.98 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.84 (m, 2H), 7.52 (d, 1H), 7.46 (t, 1H) , 6.94 (d, 1H), 3.84 (s, 3H), 3.16 (s, 1H), 2.88 (t, 2H), 1.98 (m, 1H), 1.72 (m, 3H) ppm; ES-MSm / z338 ( MH ^-).

2- (2-methoxyethoxy) -N- [4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl Acetamide

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (38 mg, 0.147 mmol), N- (4- A mixture of formylphenyl) -2- (2-methoxyethoxy) acetamide (intermediate example EE) (70 mg, 0.294 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 3 h. The reaction was then cooled to RT and concentrated. The residue was triturated with diethyl ether and the solid was removed by filtration and washed with diethyl ether to give the product as a yellow solid (112 mg, 80% yield).
¹ HNMR (400MHz, DMSO) δ12.10 (s, 1H), 9.86 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.80 (m, 6H) , 7.46 (t, 1H), 6.93 (d, 1H), 4.10 (s, 3H), 3.83 (s, 3H), 3.67 (t, 2H), 3.52 (t, 2H), 3.27 (s, 2H) ppm ; ES-MSm / z476 (MH ^<+> ).

N- [4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) phenyl] -2- (4-methylpiperazine -1-yl) acetamide

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (80 mg, 0.31 mmol), N- (4- A mixture of formylphenyl) -2- (4-methylpiperazin-1-yl) acetamide (Intermediate Example FF) (162 mg, 0.62 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 18 h. The reaction was then cooled to RT and concentrated. The residue was triturated with diethyl ether and the solid was collected by filtration and washed with diethyl ether to give the product as a yellow solid (114 mg, 74% yield).
¹ HNMR (400MHz, DMSO) δ11.70 (s, 1H), 9.93 (s, 1H), 8.64 (s, 1H), 8.45 (s, 1H), 8.22 (m, 2H), 7.76 (d, 6H) , 7.45 (t, 1H), 6.92 (d, 1H), 3.81 (s, 3H), 3.35 (m, 2H), 3.14 (s, 2H), 3.06 (m, 2H), 2.52 (m, 2H), 2.21 (s, 3H), 1.80 (m, 2H) ppm; ES-MS m / z 500 (MH ⁺ ).

tert-butyl 2-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) piperidine-1-carboxylate

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (330 mg, 1.29 mmol), tert-butyl 2-ethanol in ethanol (25 mL) A mixture of formylpiperidine-1-carboxylate (550 mg, 2.58 mmol) and pyrrolidine (2 drops) was heated at 100 ° C. for 18 h. The reaction was then cooled to RT and the solid was collected by filtration and washed with diethyl ether and ethanol to give the product as a white solid (275 mg, 47% yield).
¹ HNMR (400MHz, DMSO) δ 11.96 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 7.81 (m, 2H), 7.44 (m, 2H), 6.91 (d, 1H) , 4.94 (m, 1H), 3.91 (d, 1H), 3.81 (s, 3H), 2.00 (d, 1H), 1.68 (m, 2H), 1.61 (m, 2H), 1.38 (s, 9H), 1.30 (m, 2H) ppm; ES-MS m / z 452 (MH ⁺ ).

Piperidine-2-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

tert-Butyl 2-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) piperidine-1-carboxylate (Example 135) ) (171 mg, 0.379 mmol, 1 eq) and a mixture of 20% trifluoroacetic acid in dichloromethane (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO ₃ solution. The organic layer was dried (MgSO ₄ ) and concentrated to give the product as a tan solid (101 mg, 76% yield).
¹ HNMR (400MHz, DMSO) δ11.88 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 7.81 (m, 2H), 7.49 (d, 1H), 7.44 (t, 1H) , 6.91 (d, 1H), 6.81 (d, 1H), 3.81 (s, 3H), 3.36 (m, 1H), 2.96 (m, 1H), 2.58 (t, 1H), 1.78 (m, 2H), 1.46 (m, 4H) ppm; ES-MS m / z 352 (MH ⁺ ).

2- (Methylsulfonyl) isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone hydrochloride

4- (Diethoxymethyl) -2- (methylsulfonyl) pyridine (Intermediate Example V) (120 mg, 0.46 mmol) in THF (5 mL) was added to 4-hydrazino-1- (3-methoxyphenyl)- 1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (90 mg, 0.35 mmol) and 1N aqueous hydrochloric acid (5 mL) were added. The mixture was heated in a 90 C oil bath for about 1.75 h. After cooling to RT, the resulting solid was collected by filtration and washed with ether to give the product HCl salt as a white solid (93 mg, 57%).
¹ HNMR (DMSO) δ8.86 (d, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 8.42 (brs, 1H), 8.34 (brs, 1H), 8.16 (d, 1H), 7.84 (m, 2H), 7.48 (t, 1H), 6.96 (d, 1H), 5.11 (brs, 2H), 3.84 (s, 3H), 3.34 (s, 3H) ppm; ES-MSm / z424 (MH ⁺ ).

Methyl 2-chloro-4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) nicotinate hydrochloride

Methyl 2-chloro-4- (diethoxymethyl) nicotinate (95 mg, 0.35 mmol) in THF (5 mL) was added to 4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] Pyrimidine (intermediate Example T) (80 mg, 0.31 mmol) and 1N aqueous hydrochloric acid (5 mL) were added. The mixture was heated in a 90 C oil bath for about 3.5 h. After cooling to RT, the resulting solid was collected by filtration and washed with ether to give the product HCl salt as a white solid (60 mg, 41%).
¹ HNMR (DMSO) δ8.66 (s, 1H), 8.59 (m, 2H), 8.30 (s, 1H), 8.12 (d, 1H), 7.85 (m, 2H), 7.48 (t, 1H), 6.96 (dd, 1H), 4.91 (brs, 2H), 3.93 (s, 3H), 3.84 (s, 3H) ppm; ES-MSm / z438 (MH ^<+> ).

4- (Dimethylamino) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (107 mg, 0.417 mmol), 4- (dimethylamino) in EtOH (10 mL) ) A mixture of benzaldehyde (76 mg, 0.511 mmol) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (130 mg, 81%) as a yellow solid.
¹ HNMR (400 MHz, DMSO) δ 12.01 (s, 1H), 8.60 (s, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.87-7.85 (m, 2H), 7.62 (d, 2H), 7.45 (t, 1H), 6.92 (m, 1H), 6.79 (d, 2H), 3.82 (s, 3H), 2.98 (s, 6H) ppm; ES-MSm / z388 (MH ⁺ ).

4- (Diethylamino) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (106 mg, 0.414 mmol), 4- (diethylamino) in EtOH (10 mL) A mixture of benzaldehyde (93 mg, 0.525 mmol) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (140 mg, 82%) as a yellow solid.
¹ HNMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 7.86-7.85 (d + s, 2H), 7.59 ( d, 2H), 7.45 (t, 1H), 6.92 (m, 1H), 6.74 (d, 2H), 3.82 (s, 3H), 3.39 (q, 4H), 1.11 (t, 6H) ppm; ES- MS m / z 416 (MH ⁺ ).

4-Pyrrolidin-1-ylbenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (100 mg, 0.391 mmol), 4- (1- A mixture of pyrrolidinyl) benzaldehyde (85 mg, 0.486 mmol) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (120 mg, 75%) as a yellow solid.
¹ HNMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.87-7.85 (m, 2H), 7.61 (d, 2H), 7.45 (t, 1H), 6.92 (m, 1H), 6.62 (d, 2H), 3.82 (s, 3H), 3.29-3.27 (m, 4H), 1.97-1.94 (m, 4H) ppm; ES-MSm / z414 (MH ⁺ ).

4-morpholin-4-ylbenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (105 mg, 0.410 mmol), 4- (4- A mixture of morpholinyl) benzaldehyde (105 mg, 0.549) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (137 mg, 76%) as a yellow solid.
¹ HNMR (400MHz, DMSO) δ 12.07 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.86-7.84 (m, 2H), 7.66 (d, 2H), 7.45 (t, 1H), 7.03 (d, 2H), 6.92 (m, 1H), 3.82 (s, 3H), 3.74-3.72 (m, 4H), 3.22-3.20 (m, 4H) ppm; ES-MSm / z430 (MH ⁺ ).

4-Piperidin-1-ylbenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (117 mg, 0.457 mmol), 4- (1- A mixture of piperidinyl) benzaldehyde (114 mg, 0.602 mmol) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (195 mg, 98%) as a yellow solid.
¹ HNMR (400 MHz, DMSO) δ 12.03 (s, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.86-7.84 (d + s, 2H), 7.62 ( d, 2H), 7.45 (t, 1H), 6.99 (d, 2H), 6.92 (m, 1H), 3.82 (s, 3H), 3.27 (m, 4H), 1.57 (m, 6H) ppm; ES- MSm / z428 (MH ⁺ ).

5-morpholin-4-ylthiophene-2-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (103 mg, 0.402 mmol), 5- (4- A mixture of morpholinyl) -2-thiophenecarbaldehyde (96 mg, 0.488 mmol) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (162 mg, 95%) as a yellow solid.
¹ HNMR (400MHz, DMSO) δ 12.05 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.86-7.82 (m, 2H), 7.45 (t, 1H), 7.20 (d, 1H), 6.91 (m, 1H), 6.19 (d, 1H), 3.82 (s, 3H), 3.74-3.72 (m, 4H), 3.23-3.21 (m, 4H) ppm; ES-MSm / z436 (MH ⁺ ).

4- (1H-Imidazol-1-yl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (106 mg, 0.415 mmol), 4- (1H--) in EtOH (10 mL) A mixture of imidazol-1-yl) benzaldehyde (86 mg, 0.501 mmol) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (148 mg, 87%) as a yellow solid.
¹ HNMR (400MHz, DMSO) δ 12.31 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 7.94 (d, 2H) , 7.86-7.82 (m, 3H), 7.76 (d, 2H), 7.45 (t, 1H), 7.13 (s, 1H), 6.92 (m, 1H), 3.82 (s, 3H) ppm; ES-MSm / z411 (MH ⁺ ).

5- (Dimethylamino) thiophene-2-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (100 mg, 0.392 mmol), 5- (dimethylamino) in EtOH (10 mL) A mixture of) -2-thiophenecarbaldehyde (77 mg, 0.499 mmol) and pyrrolidine (2 drops) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (142 mg, 95%) as a yellow solid.
¹ HNMR (400 MHz, DMSO) δ 11.97 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.87-7.83 (m, 2H), 7.44 (t, 1H), 7.16 (d, 1H), 6.91 (m, 1H), 5.90 (d, 1H), 3.82 (s, 3H), 3.00 (s, 6H) ppm; ES-MSm / z394 (MH ⁺ ).

4- [3- (Dimethylamino) propoxy] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (110 mg, 0.428 mmol), 4- [3- (dimethylamino) propoxy] A mixture of benzaldehyde (0.105 mL, 0.522 mmol) and pyrrolidine (2 drops) in EtOH (10 mL) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (170 mg, 89%) as a yellow solid.
¹ HNMR (400 MHz, DMSO) δ 12.11 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.86-7.83 (m, 2H), 7.74 (d, 2H), 7.45 (t, 1H), 7.02 (d, 2H), 6.92 (m, 1H), 4.04 (t, 2H), 3.82 (s, 3H), 2.35 (t, 2H), 2.13 (s, 6H ), 1.84 (m, 2H) ppm; ES-MSm / z446 (MH ⁺ ).

4- [2- (Diethylamino) ethoxy] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (106 mg, 0.412 mmol), 4- [2- (diethylamino) ethoxy] benzaldehyde A mixture of (132 mg, 0.595 mmol) and pyrrolidine (2 drops) in EtOH (10 mL) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (90 mg, 48%) as a yellow solid.
¹ HNMR (400 MHz, DMSO): δ 12.13 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 7.87-7.84 (m, 2H), 7.74 (d , 2H), 7.46 (t, 1H), 7.03 (d, 2H), 6.92 (m, 1H), 4.06 (t, 2H), 3.82 (s, 3H), 2.78 (m, 2H), 2.53 (m, 4H), 0.96 (t, 6H) ppm; ES-MSm / z460 (MH ^<+> ).

4- (2-Methoxyethoxy) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (104 mg, 0.405 mmol), 4- (2-methoxyethoxy) benzaldehyde (109 mg , 0.607 mmol), and a mixture of pyrrolidine (2 drops) in EtOH (10 mL) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (114 mg, 67%) as an off-white solid.
¹ HNMR (400 MHz, DMSO): δ 12.15 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 7.87-7.84 (m, 2H), 7.76 (d , 2H), 7.46 (t, 1H), 7.05 (d, 2H), 6.92 (m, 1H), 4.15 (t, 2H), 3.83 (s, 3H), 3.67 (t, 2H), 3.30 (s, 3H) ppm; ES-MSm / z419 (MH ⁺ ).

4- (4-tert-Butyl-1,3-thiazol-2-yl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example T) (108 mg, 0.423 mmol), 4- (4-tert-butyl-1, A mixture of 3-thiazol-2-yl) benzaldehyde (131 mg, 0.533 mmol) and pyrrolidine (2 drops) in EtOH (10 mL) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (164 mg, 82%) as a yellow solid.
¹ HNMR (400MHz, DMSO) δ12.35 (s, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 8.32 (s, 1H), 8.03 (d, 2H), 7.93 (d, 2H) , 7.87-7.84 (m, 2H), 7.47 (t, 1H), 7.37 (s, 1H), 6.93 (m, 1H), 3.83 (s, 3H), 1.35 (s, 9H) ppm; ES-MSm / z484 (MH ⁺ ).

4- [2- (Dimethylamino) ethoxy] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) (98 mg, 0.384 mmol), 4- [2- (dimethylamino) ethoxybenzaldehyde (Intermediate Example GG) (200 mg, 1.035 mmol) and a mixture of pyrrolidine (2 drops) in EtOH (10 mL) was heated at reflux for 12 h. The solid was filtered and washed with hexanes to give the product (114 mg, 67%) as a yellow solid.
¹ HNMR (400MHz, DMSO) δ 12.14 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 7.87-7.84 (m, 2H), 7.75 (d, 2H), 7.46 (t, 1H), 7.05 (d, 2H), 6.92 (m, 1H), 4.10 (t, 2H), 3.82 (s, 3H), 2.63 (t, 2H), 2.21 (s, 6H ) ppm; ES-MSm / z432 (MH ⁺ ).

3-Fluorobenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 3-fluorobenzaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.35 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 7.83 (m, 2H), 7.64 (m, 2H) , 7.54 (m, 1H), 7.46 (t, 1H), 7.27 (dt, 1H), 6.93 (dd, 1H), 3.82 (s, 3H) ppm; ES-MSm / z363 (MH ⁺ ).

3,4-Difluorobenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 3,4-difluorobenzaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.27 (s, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.85 (m, 3H), 7.69 (m, 1H) , 7.53 (m, 1H), 7.46 (t, 1H), 6.93 (dd, 1H), 3.82 (s, 3H) ppm; ES-MSm / z381 (MH ⁺ ).

4-Fluorobenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4-fluorobenzaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.35 (s, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 7.86 (m, 4H), 7.45 (t, 1H) , 7.31 (t, 2H), 6.93 (dd, 1H), 3.82 (s, 3H) ppm; ES-MSm / z363 (MH ^<+> ).

2-Furaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2-furaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.21 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.84 (m, 3H), 7.45 (t, 1H) , 7.03 (d, 1H), 6.92 (d, 1H), 6.66 (m, 1H), 3.82 (s, 3H) ppm; ES-MSm / z335 (MH ⁺ ).

3-Furaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 3-furaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.14 (s, 1H), 8.62 (s, 1H), 8.45 (s, 1H), 8.23 (m, 2H), 7.83 (m, 3H), 7.46 (t, 1H) , 7.08 (s, 1H), 6.92 (dd, 1H), 3.82 (s, 3H) ppm; ES-MSm / z335 (MH ⁺ ).

5- (Methylsulfonyl) thiophene-2-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 5- (methylsulfonyl) thiophene-2-carbaldehyde.
¹ HNMR (400 MHz, DMSO) δ 12.60 (s, 1H), 8.83 (s, 2H), 8.48 (s, 1H), 7.83 (m, 2H), 7.79 (d, 1H), 7.62 (d, 1H) 7.47 (t, 1H), 6.94 (dd, 1H), 3.82 (s, 3H), 3.42 (s, 3H) ppm; ES-MSm / z335 (MH ⁺ ).

4-[(Methylsulfonyl) methyl] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4-[(methylsulfonyl) methyl] benzaldehyde (intermediate example HH).
¹ HNMR (400MHz, DMSO) δ 12.29 (s, 1H), 8.67 (s, 1H), 8.50 (s, 1H), 8.31 (s, 1H), 7.86 (m, 4H), 7.53 (m, 2H) 7.47 (t, 1H), 6.94 (dd, 1H), 4.56 (s, 2H), 3.82 (s, 3H), 2.93 (s, 3H) ppm; ES-MSm / z437 (MH ⁺ ).

4-Hydroxy-3-methoxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 4-hydroxy-3-methoxybenzaldehyde.
¹ HNMR (400MHz, DMSO) δ12.08 (s, 1H), 9.59 (s, 1H), 8.57 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 7.82 (m, 2H) , 7.43 (t, 1H), 7.32 (s, 1H), 7.20 (d, 1H), 6.85-6.91 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H) ppmES-MSm / z391 ( MH ⁺ ).

3-Bromo-4-hydroxy-5-methoxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate example T) and 3-bromo-4-hydroxy-5-methoxybenzaldehyde.
¹ HNMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 7.82-7.86 (m, 2H), 7.43 (t, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 6.90 (m, 1H), 3.83 (s, 3H), 3.81 (s, 3H) ppm; ES-MSm / z470 (MH ^<+> ).

4- [3- (Dimethylamino) propoxy] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for nicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone (Example 72), 4-hydrazino-1 Prepared from-(3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4- [3- (dimethylamino) propoxy] benzaldehyde.
¹ HNMR (400MHz, DMSO) δ 12.17 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 8.24 (s, 1H), 7.82 (m, 2H), 7.76 (d, 2H) , 7.44 (m, 1H), 7.04 (d, 2H), 6.91 (m, 1H), 4.10 (m, 2H), 3.81 (s, 3H), 3.19 (m, 2H), 2.75 (s, 6H), 2.14 (m, 2H) ppm; ES-MS m / z 483 (MH ⁺ ).

5- (Methylsulfonyl) -2-furaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T).
¹ HNMR (400MHz, DMSO) δ 12.51 (s, 1H), 8.60 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.84 (m, 2H), 7.45 (t, 1H) 7.42 (d, 1H), 7.27 (d, 1H), 6.93 (d, 1H), 3.82 (s, 3H), 3.39 (s, 3H). ES-MSm / z412 (MH ⁺ ).

4-Fluoro-3-methoxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T).
¹ HNMR (400MHz, DMSO) δ 12.32 (s, 1H), 8.61 (s, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 7.85 (m, 2H), 7.54 (d, 1H) , 7.46 (t, 1H), 7.41 (m, 1H), 7.32 (dd, 1H), 6.93 (dd, 1H), 3.95 (s, 3H), 3.83 (s, 3H) .ES-MSm / z392 (MH ⁺ ).

4- (Allyloxy) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4- (allyloxy) benzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.14 (s, 1 H), 8.62 (s, 1 H), 8.46 (s, 1 H), 8.23 (s, 1 H), 7.87 (m, 1 H), 7.86-7.84 (m , 1H), 7.76 (d, 2H, J = 8.8), 7.46 (t, 1H, J = 8.2), 7.06 (d, 2H, J = 8.8), 6.94-6.91 (m, 1H), 6.05 (m, 1H), 5.41 (m, 1H), 5.27 (m, 1H), 4.63 (m, 2H), 3.83 (s, 3H). ES-MSm / z401 (MH ⁺ ).

2,3-Dihydro-1-benzofuran-5-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2,3-dihydro-1-benzofuran-5-carbaldehyde.
¹ HNMR (400MHz, DMSO): δ12.07 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.87 (m, 1H), 7.85-7.83 (m , 1H), 7.77 (m, 1H), 7.49-7.43 (m, 2H), 6.93-6.90 (m, 1H), 6.84 (d, 1H, J = 8.3), 4.59 (t, 2H, J = 8.7) 3.82 (s, 3H), 3.28-3.23 (m, 2H). ES-MSm / z396 (MH ^<+> ).

4-Hydroxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4-formylphenyl phenylcarbamate.
¹ HNMR (400MHz, DMSO): δ12.06 (s, 1H), 9.95 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 8.19 (s, 1H), 7.87-7.84 (m , 2H), 7.65 (d, 2H, J = 8.6), 7.45 (t, 1H, J = 8.0), 6.93-6.91 (m, 1H), 6.87 (d, 2H, J = 8.6), 3.82 (s, 3H). ES-MSm / z361 (MH ^<+> ).

4-[(4-Fluorobenzyl) oxy] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4-[(4-fluorobenzyl) oxy] benzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.15 (s, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.87-7.84 (m + m, 2H), 7.77 (d, 2H, J = 8.8), 7.54-7.50 (m, 2H), 7.46 (t, 1H, J = 8.2), 7.25-7.20 (m, 2H), 7.12 (d, 2H, J = 8.6), 6.94-6.91 (m, 1H), 5.15 (s, 2H), 3.83 (s, 3H). ES-MSm / z469 (MH ⁺ ).

4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) benzonitrile

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 4-formylbenzonitrile.
¹ HNMR (400 MHz, DMSO): δ 12.48 (s, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.01 (d, 2H, J = 8.4), 7.92 (d, 2H, J = 8.5), 7.87-7.82 (m + m, 2H), 7.47 (t, 1H, J = 8.2), 6.95-6.92 (m, 1H), 3.83 (s, 3H) .ES- MS m / z 370 (MH ⁺ ).

1,1'-biphenyl-4-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 1,1′-biphenyl-4-carbaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.31 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.91 (d, 2H, J = 8.5), 7.88 -7.85 (m, 2H), 7.80 (d, 2H, J = 8.3), 7.73 (m, 2H), 7.51-7.45 (m, 3H), 7.39 (t, 1H, J = 7.3), 6.95-6.93 ( m, 1H), 3.83 (s, 3H). ES-MSm / z421 (MH ^<+> ).

3-Fluoro-4- (trifluoromethyl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 3-fluoro-4- (trifluoromethyl) benzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.49 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.31 (s, 1H), 7.90-7.81 (m, 5H), 7.45 (t , 1H, J = 8.2), 6.94-6.91 (m, 1H), 3.82 (s, 3H). ES-MSm / z431 (MH ⁺ ).

3-Fluoro-4-methoxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 3-fluoro-4-methoxybenzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.21 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 7.86-7.83 (m, 2H), 7.70-7.67 (m, 1H), 7.58-7.57 (m, 1H), 7.46 (t, 1H, J = 8.1), 7.26 (t, 1H, J = 8.6), 6.94-6.91 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H). ES-MSm / z393 (MH ^<+> ).

1-Benzylpiperidine-4-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 1-benzylpiperidine-4-carbaldehyde.
¹ HNMR (400 MHz, DMSO): δ 11.80 (s, 1H), 8.41 (s, 2H), 7.84-7.80 (m, 2H), 7.58 (d, 1H, J = 4.1), 7.44 (t, 1H, J = 8.1), 7.33-7.28 (m, 4H), 7.25-7.19 (m, 1H), 6.92-6.90 (m, 1H), 3.81 (s, 3H), 3.46 (s, 2H), 2.86-2.84 ( m, 2H), 2.41-2.32 (m, 1H), 2.03 (m, 2H), 1.89-1.85 (m, 2H), 1.57-1.48 (m, 2H). ES-MSm / z442 (MH ^<+> ).

2-Fluoro-4-methoxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2-fluoro-4-methoxybenzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.18 (s, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 7.97 (m, 1H), 7.86-7.82 (m , 2H), 7.45 (t, 1H, J = 8.1), 6.96-6.91 (m, 3H), 3.82 (s, 6H). ES-MSm / z393 (MH ^<+> ).

2,4-Bis (trifluoromethyl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2,4-bis (trifluoromethyl) benzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.61 (s, 1H), 8.65 (s, 1H), 8.63 (s, 1H), 8.58-8.54 (m, 2H), 8.15 (d, 1H, J = 7.4) , 8.08 (s, 1H), 7.84-7.81 (m, 2H), 7.45 (t, 1H, J = 7.9), 6.94-6.91 (m, 1H), 3.81 (s, 3H) .ES-MSm / z481 ( MH ⁺ ).

tert-butyl 4-((E)-[1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazonomethyl) piperidine-1-carboxylate

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and tert-butyl 4-formylpiperidine-1-carboxylate.
¹ HNMR (400 MHz, DMSO): δ 11.83 (s, 1H), 8.41 (s, 2H), 7.83-7.81 (m, 2H), 7.57 (m, 1H), 7.44 (t, 1H, J = 8.0) , 6.91 (m, 1H), 3.97 (m, 2H), 3.81 (s, 3H), 2.84 (m, 2H), 2.56 (m, 1H), 1.89 (m, 2H), 1.38 (s + m, 10H ). ES-MSm / z452 (MH ⁺ ).

3- (Methylsulfonyl) benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 3- (methylsulfonyl) benzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.46 (s, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 8.27 (m, 1H), 8.22 (d, 1H , J = 8.1), 7.99-7.97 (m, 1H), 7.88-7.86 (m, 1H), 7.84 (m, 1H), 7.77 (t, 1H, J = 7.8), 7.45 (t, 1H, J = 8.2), 6.95-6.93 (m, 1H), 3.83 (s, 3H), 3.30 (s, 3H). ES-MSm / z423 (MH ^<+> ).

3-Chloro-4- [2- (dimethylamino) ethoxy] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 3-chloro-4- [2- (dimethylamino) ethoxy] benzaldehyde.
¹ HNMR (400 MHz, DMSO): δ12.20 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.86-7.82 (m, 3H), 7.76-7.74 (m, 1H), 7.45 (t, 1H, J = 8.1), 7.26 (d, 1H, J = 8.6), 6.93-6.91 (m, 1H), 4.19 (t, 2H, J = 5.7), 3.82 ( s, 3H), 2.67 (t, 2H, J = 5.7), 2.23 (s, 6H). ES-MSm / z466 (MH ^<+> ).

2-Chloro-4- [2- (dimethylamino) ethoxy] benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) and 2-chloro-4- [2- (dimethylamino) ethoxy] benzaldehyde.
¹ HNMR (400 MHz, DMSO): δ 12.27 (s, 1H), 8.60 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 7.86-7.82 (m, 3H), 7.45 (t , 1H, J = 8.1), 7.12 (m, 1H), 7.08-7.05 (m, 1H), 6.93-6.91 (m, 1H), 4.11 (t, 2H, J = 5.7), 3.82 (s, 3H) 2.61 (t, 2H, J = 5.6), 2.19 (s, 6H). ES-MSm / z466 (MH ⁺ ).

2-Fluorobenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T).
¹ HNMR (400MHz, DMSO) δ 12.34 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 8.50 (s, 1H), 8.08 (t, 1H), 7.84 (m, 2H) 7.50 (m, 2H), 7.32 (m, 2H), 6.94 (dd, 1H), 3.83 (s, 3H). ES-MSm / z363 (MH ⁺ ).

4-Methoxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T).
¹ HNMR (400MHz, DMSO) δ12.09 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.86 (m, 2H), 7.77 (d, 2H) 7.46 (t, 1H), 7.05 (d, 2H), 6.93 (d, 1H), 3.83 (s, 3H), 3.81 (s, 3H). ES-MSm / z375 (MH ⁺ ).

3-methoxybenzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T).
¹ HNMR (400MHz, DMSO) δ 12.26 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 7.84 (m, 2H), 7.46 (t, 1H) , 7.41 (m, 2H), 7.31 (s, 1H), 7.02 (m, 1H), 6.93 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H) .ES-MSm / z375 (MH ⁺ ).

Pyridine-2-carbaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

Using the general procedure for isonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl) hydrazone (Example 73), 4-hydrazino- Prepared from 1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T).
¹ HNMR (400MHz, DMSO) δ12.50 (s, 1H), 8.73 (s, 1H), 8.64 (d, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 8.20 (d, 1H) 7.95 (t, 1H), 7.85 (m, 2H), 7.47 (m, 2H), 6.95 (dd, 1H), 3.84 (s, 3H). ES-MSm / z335 (MH ⁺ ).

Benzaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

To a solution of 4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (100 mg, 0.39 mmol) in ethanol (5 mL) under stirring , Benzaldehyde (46 mg, 0.43 mmol) and pyrrolidine (1 drop) were added to give the desired product as a white solid (91 mg, 68%).
¹ HNMR (DMSO) δ 12.31 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 7.92-7.86 (m, 4H), 7.57-7.48 (m, 4H), 6.98 (d, 1H ), 3.87 (s, 3H) ppm; ES-MSm / z343 (MH -).

3-Methylisonicotinaldehyde [1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

To a solution of 4-hydrazino-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate Example T) (100 mg, 0.39 mmol) in ethanol (5 mL) under stirring 3-methylisonicotinaldehyde (52 mg, 0.43 mmol) (Intermediate Example JJ) and pyrrolidine (1 drop) were added to give the desired product as a white solid (119 mg, 85%).
¹ HNMR (DMSO) δ 12.37 (s, 1H), 8.61 (s, 1H), 8.51-8.48 (m, 4H), 7.87-7.81 (m, 3H), 7.45 (t, 1H), 6.91 (d, 1H), 3.81 (s, 3H ), 2.40 (s, 3H) ppm; ES-MSm / z358 (MH -).

Isonicotinaldehyde [3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example LL) (100 mg, 0.335 mmol) in ethanol (3 ml) with stirring ) Was added to the solution of isonicotinaldehyde (47 mL, 0.499 mmol) and pyrrolidine. The resulting mixture was refluxed for about 3 hours, cooled to RT and filtered to obtain the product as a white solid (94.1 mg, 73%).
¹ HNMR (DMSO) δ 12.15 (s, 1H), 8.64 (d, 2H), 8.43 (s, 1H), 8.03 (s, 1H), 7.90 (d, 2H), 7.63 (m, 2H), 7.43 (t, 1H), 6.92 ( dd, 1H), 3.81 (s, 3H), 3.53 (m, 1H), 1.37 (d, 6H) ppm;. ES-MSm / z388 (MH +) analysis .C ₂₁ Calculated as H ₂₁ N ₇ O; C: 65.1%; H: 5.5%; N: 25.3%. Found: C: 65.32%; H: 5.33%; N: 25.53%.

4- (Methylsulfonyl) benzaldehyde [3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example LL) (100 mg, 0.335 mmol) in ethanol (3 ml) with stirring ) Was added 4- (methylsulfonyl) benzaldehyde (89.7 mg, 0.487 mmol) and pyrrolidine. The resulting mixture was refluxed for about 3 hours, cooled to RT and filtered to obtain the product as a white solid (104.8 mg, 67%).
¹ HNMR (DMSO) δ 12.13 (s, 1H), 8.53 (s, 1H), 8.22 (d, 2H), 8.02 (s, 1H), 7.97 (d, 2H), 7.63 (m, 2H), 7.43 (t, 1H), 6.92 (dd, 1H), 3.81 (s, 3H), 3.55 (m, 1H), 3.23 (s, 3H), 1.37 (d, 6H) ppm; ES-MSm / z465 (MH ⁺ .) analysis calculated value as _{.C 23 H 24 N 6 O 3} S; C: 59.5%; H: 5.2%; N: 18.1%. Found: C: 59.39%; H: 5.22%; N: 17.51%.

3-Fluorobenzaldehyde [3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-3-isopropyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example LL) (100 mg, 0.335 mmol) in ethanol (3 ml) with stirring ) Was added 3-fluorobenzaldehyde (54 mL, 0.503 mmol) and pyrrolidine. The resulting mixture was refluxed for about 3 hours, cooled to RT and filtered to give the product as a white solid (75.7 mg, 56%).
¹ HNMR (DMSO) δ 12.06 (s, 1H), 8.45 (s, 1H), 7.95 (m, 2H), 7.71 (d, 1H), 7.62 (d, 2H), 7.46 (m, 1H), 7.44 (m, 1H), 7.22 (t, 1H), 6.92 (dd, 1H), 3.81 (s, 3H), 3.48 (m, 1H), 1.36 (d, 6H) ppm; ES-MSm / z405 (MH ⁺ .) analysis calculated value as _{.C 22 H 21 FN 6 O;} C: 65.3%; H: 5.2%; N: 20.8%. Found: C: 65.21%; H: 5.25%; N: 20.76%.

4-Fluorobenzaldehyde [1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example KK) (100 mg, 0.335 mmol) in ethanol (2 ml) with stirring ) Was added 4-fluorobenzaldehyde (0.075 mL, 0.699 mmol) and pyrrolidine. The resulting mixture was refluxed for about 3 hours, cooled to RT and filtered to obtain the product as a white solid (75 mg, 55%).
¹ HNMR (DMSO) δ 11.98 (d, 1H), 8.41 (s, 1H), 8.02 (dd, 2H), 7.93 (d, 1H), 7.62 (m, 2H), 7.41 (t, 1H), 7.29 (m, 2H), 6.90 (dd, 1H), 3.80 (s, 3H), 2.90 (t, 2H), 1.78 (q, 2H), 0.97 (t, 3H), 2.41 (s, 3H) ppm; ES . -MSm / z405 (MH ⁺⁾ analysis calculation value as _{.C 22 H 21 FN 6 O;} C: 65.3%; H: 5.2%; N: 20.8%. Found: C: 65.31%; N: 5.34%; N: 20.83%.

4- (Methylsulfonyl) benzaldehyde [1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example KK) (100 mg, 0.335 mmol) in ethanol (2 ml) with stirring ) Was added 4- (methylsulfonyl) benzaldehyde (123 mg, 0.668 mmol) and pyrrolidine. The resulting mixture was refluxed for about 3 hours, cooled to RT and filtered to obtain the product as a white solid (121 mg, 78%).
¹ HNMR (DMSO) δ12.15 (s, 1H), 8.50 (s, 1H), 8.21 (d, 2H), 8.00 (d, 1H), 7.96 (d, 2H), 7.62 (m, 2H), 7.41 (t, 1H), 6.91 (dd, 1H), 3.81 (s, 3H), 3.25 (s, 3H), 2.93 (t, 2H), 1.79 (q, 2H), 0.98 (t, 3H) ppm; ES . -MSm / z465 (MH ⁺⁾ analysis calculation value as _{.C 23 H 24 N 6 O 3} S; C: 59.5%; H: 5.2%; N: 18.1%. Found: C: 59.29%; H: 5.29%; N: 17.83%.

Isonicotinaldehyde [1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -3-propyl-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example KK) (52 mg, 0.22 mmol) in ethanol (5 ml) with stirring ) Was added with isonicotinaldehyde (63 mL, 0.669 mmol) and pyrrolidine. The resulting mixture was refluxed for about 3 hours, cooled to RT and filtered to obtain the product as a white solid (88 mg, 68%).
¹ HNMR (DMSO) δ 12.15 (s, 1H), 8.63, (d, 2H), 8.41 (s, 1H), 8.01 (s, 1H), 7.90 (d, 2H), 7.62 (m, 2H), 7.41 (t, 1H), 6.91 (dd, 1H), 3.81 (s, 3H), 2.92 (t, 2H), 1.80 (m, 2H), 0.97 (t, 3H) ppm; ES-MSm / z388 (MH ^+); Anal value .C ₂₁ H ₂₁ N ₇ O as calculated value: C; 65.1%; H: 5.5%; N: 25.3%. Found: C: 65.31%; H: 5.36%; N: 25.60%.

3-Fluorobenzaldehyde [3-ethyl-1- (3-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -3-ethyl-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example MM) (100 mg, 0.35 mmol) in ethanol (10 ml) with stirring ) Was added 3-fluorobenzaldehyde (75 μL, 0.70 mmol) and pyrrolidine. The resulting mixture was refluxed for about 18 hours, cooled to RT and concentrated. The residue was purified by silica gel flash chromatography (20% ethyl acetate in hexanes) to give the product as a white solid (76 mg, 56%).
¹ HNMR (DMSO) δ 12.06 (s, 1H), 8.43, (m, 1H), 7.93 (m, 2H), 7.65 (m, 3H), 7.45 (m, 2H), 7.23 (t, 1H), 6.92 (dd, 1H), 3.81 (s, 3H), 2.95 (q, 2H), 1.31 (t, 3H) ppm; ES-MSm / z391 (MH ⁺ ).

4-Fluorobenzaldehyde [3-ethyl-1- (3methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -3-ethyl-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example MM) (100 mg, 0.35 mmol) in ethanol (10 ml) with stirring ) Was added 4-fluorobenzaldehyde (58 μL, 0.70 mmol) and pyrrolidine. The resulting mixture was refluxed for about 18 hours, cooled to RT and concentrated. The residue was purified by silica gel flash chromatography (10% ethyl acetate in hexanes → 20% ethyl acetate) to give the product as a white solid (95 mg, 69%).
¹ HNMR (DMSO) δ 12.00 (s, 1H), 8.43, (m, 1H), 8.01 (m, 2H), 7.61 (m, 2H), 7.40 (m, 3H), 6.90 (m, 1H), 6.60 (m, 1H), 3.80 (s, 3H), 2.94 (q, 2H), 1.30 (t, 3H) ppm; ES-MSm / z391 (MH ⁺ ).

Isonicotinaldehyde [3-ethyl-1- (3-methoxyphenyl) -3a, 7a-dihydro-1H-pyrazolo [3,4-d] pyrimidin-4-yl] hydrazone

4-Hydrazino-1- (3-methoxyphenyl) -3-ethyl-1H-pyrazolo [3,4-d] pyrimidine (Intermediate Example MM) (100 mg, 0.35 mmol) in ethanol (10 ml) with stirring ) Was added with isonicotinaldehyde (67 μL, 0.70 mmol) and pyrrolidine. The resulting mixture was refluxed for about 18 hours, cooled to RT and filtered to obtain the product as a white solid (76 mg, 58%).
¹ HNMR (DMSO) δ 12.16 (s, 1H), 8.64, (d, 2H), 8.43 (s, 1H), 8.02 (s, 1H), 7.91 (m, 2H), 7.63 (m, 2H), 7.42 (t, 1H), 6.93 (dd, 1H), 3.81 (s, 3H), 2.97 (q, 2H), 1.31 (t, 3H) ppm; ES-MSm / z374 (MH ⁺ ); Analytical value C20H19N7O As calculated; C; 64.3%; H: 5.1%; N: 26.3%. Found: C: 64.10%; H: 5.01%; N: 26.20%.

Biological data
GSK-3
The compounds of the invention elicit important and measurable pharmacological responses. In assessing these responses, the present invention also demonstrated unexpected beneficial biological and pharmacological properties. Briefly stated, the present invention provides unexpectedly superior performance characteristics not previously known.

The protocol used to demonstrate the pharmacological response of the present invention is based on the ability of the kinase to phosphorylate one biotinylated peptide. This sequence is derived from the phosphorylation site of glycogen synthase, and the sequence is biotin-Ahx-AAAKRREILSRRPS (PO ₃ ) YR-amide. The phosphorylated biotinylated peptide is then captured on a scintillation proximity assay (SPA) bead at Amersham Technology, where the ³³ P signal is amplified by the scintillant contained in the bead.

  Although GSK-3β is commercially available, it can also be cloned and expressed in Ecoli using standard techniques to produce a soluble active protein. The production of active protein involves two purification steps using metal chelates and ion exchange chromatography. Proteins that elute by ion exchange are provided as> 90% pure product, which can then be concentrated for use in high throughput screening.

Kinase is 100 mM MHEPES containing 10 mM magnesium chloride, 0.1 mg / mL bovine serum albumin, 1 mM dithiothreitol, 0.3 mg / mL heparin, 2.8 uM peptide substrate, 2.5 uMATP and 0.2 uCi / well [γ- ³³ P] -ATP. At a final concentration of 20 nM in pH 7.2. After 40 minutes incubation at room temperature, the reaction was stopped by the addition of 1 mM solution in 100 mM EDTA and 100 mM HEPES, pH 7.2, followed by the addition of a dilute solution of streptavidin-coated SPA beads in PBS, pH 7.2. The final concentration was 0.25 mg beads per assay well in a 96-well microtiter plate.

  As a first step in the screening process, a 10 mM stock solution of the compound of the invention in 100% DMSO is made. The second stage relates to the creation of dose response plates, in which case these compounds are diluted 10-fold in 100% DMSO to a concentration of 1 mM and then 100% continuously between plates by automated liquid handling. Dilute 3 fold in DMSO to give a final top concentration of inhibitor in the 30 uL kinase assay of 0.033 mM. The third stage relates to the production of the assay plate. This is performed by transferring 1 uL of compound to the assay plate with automated liquid handling. In the fourth step, the assay is performed as described and the plate results are counted in a PackardTopCountNXT microplate scintillation and luminescence counter.

The final stage is data acquisition and analysis. In this case, the curve data for each compound is normalized to the equation 100 * (U1-C2) / (C1-C2) (U1 is the cpm value, C2 is the background value, and C1 is the maximum number of counts) The IC ₅₀ value is calculated by fitting the measured data to the equation y = Vmax * (1- (x / (K + x))). Converting the an IC ₅₀ value pIC ₅₀ values, i.e. -log IC ₅₀ in molar concentration. This data is shown in Table 1 below.

Test compounds are used in free or salt form.

TIE-2 enzyme assay (TIE2-E)
In the TIE-2 enzyme assay, LANCE method (Wallac) and GST-TIE2, a recombinant construct of the intracellular domain of human TIE2 expressed in baculovirus (amino acids 762-1104, GenBank Accession # L06139) tagged with GST), It was used. In this method, the ability of the purified enzyme to catalyze the transfer of γ-phosphate from ATP to a tyrosine residue in a biotinylated synthetic peptide, D1-15 (biotin-C6-LEARLVAYEGWVAGKKK amide) was measured. Phosphorylation of this peptide was detected using the following procedure. GST-TIE2 was incubated for 30 minutes at room temperature with ₂ mM ATP, 5 mM MgCl ₂ and 12.5 mM DTT in 22.5 mM HEPES buffer (pH 7.4) for preactivation of the enzyme. This pre-activated GST-TIE2 was diluted with 1 μMD1-15 peptide, 80 uMATP, 10 mM MgCl ₂ , 0.1 mg / ml BSA in 1 mM HEPES (pH 7.4) and test compound (diluted from 10 mM stock solution in DMSO, final DMSO concentration 2.4% ) For 30 minutes at room temperature. The reaction was stopped by the addition of EDTA (final concentration 45 mM). Next, streptavidin-conjugated-APC (allophycocyanin, MolecularProbe) and europium labeled anti-phosphotyrosine antibody (Wallac) were added at final concentrations of 17 μg / well and 2.1 μg / well, respectively. APC signals were measured using an ARVO multilabel counter (WallacBertholdJapan). The% inhibition of activity compared to blank control wells was calculated.

Tie2 fluorescence polarization kinase activity assay: (TIE2-FP)
Activation of recombinant Tie2 activation:
Recombinant GST-Tie2 was activated by incubation of the enzyme for 2 hours at room temperature in 20 mM Tris-HCl, pH 7.5, 12 mM MgCl ₂ , 100 mM NaCl, 20 μM sodium vanide, 1 mM DTT and 300 μMATP. The activated mixture was then passed through a NAP-25 desalting column (Pharmacia Biotechcat. No. 17-0852-02) to remove free ATP. The activated enzyme was dispensed and stored at −80 ° C. in 20 mM Tris-HCl, pH 7.5 and 100 mM NaCl.

Assay conditions:
The final assay conditions were 50 mM HEPES, pH 7.5, 5% DMSO (for compound screening), 200 μMATP, 5 mM MgCl ₂ , 1 mM DTT, 50 μM sodium vanidoate, 1 nM activating enzyme and 200 μM peptide. The IC ₅₀ of the compound was measured by changing the concentration of activated Tie2 and peptide substrate (RFWKYEFWR-OH; MW1873Da, TFA salt) in subsaturated ATP (200 μM). The phosphorylated peptide was detected using panvera anti-phosphotyrosine antibody (Cat # P2840) and PTKGreenTracer (Cat # P2842). Polarization was measured for 30 minutes at room temperature on a TECANPolarion with a period of 138 seconds. Thereafter, IC ₅₀ was determined from the% polarization using the normal calculation method. The results are shown in Table 2 below.

Nonlinear regression (Levernberg-Marquardt) and the equation y = Vmax (1-x / (K + x)) + Y2 were used to interpolate the concentration (IC ₅₀ ) of the test compound that inhibited the activity by 50%. It was. Here “K” is equal to IC ₅₀ . The The IC ₅₀ values pIC ₅₀ values, i.e. converted into -log IC ₅₀ in molar concentration. The results are shown in Table 2 below.

Test compounds are used in free or salt form.

Although specific embodiments of the present invention have been described and described in detail, it should be clearly understood that the invention is not limited thereto. The detailed description of the above embodiments is provided by way of illustration only and should not be construed as constituting any limitation of the invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included within the scope of the claims.

Claims (34)

Compounds of formula (I), their salts, solvates and pharmaceutically acceptable derivatives:

Where A is H, alkyl, or aryl;
R ¹ is D ¹ , D ² , D ³ , D ⁴ , or D ⁵ ,
Said D ¹ is:

R ³ and R ⁴ are each independently H, alkyl, alkyl, alkylsulfonyl, or —C (O) — (CH ₂ ) _x —R ⁵ ;
R ⁵ is alkyl, acyl, alkoxy,-(O)-(CH ₂ ) _x- (O) -alkyl, or -NR ⁶ R ⁷ ;
R ⁶ and R ⁷ are each independently H or alkyl, or R ⁶ and R ⁷ are combined to form a 5- or 6-membered ring, which ring optionally further contains one or more heteroatoms. Optionally containing one or more degrees of unsaturation and optionally substituted one or more times by alkyl, hydroxy, carboxy, acyl, alkoxy or halogen,
Alternatively, R ³ and R ⁴ combine to form a 5- or 6-membered ring, which optionally further contains one or more heteroatoms, and optionally contains one or more degrees of unsaturation, Substituted one or more times by alkyl, hydroxy, carboxy, alkoxy, acyl or halogen;
D ² is:

And R ⁸ is alkyl or —NR ⁹ R ¹⁰ ;
R ⁹ and R ¹⁰ are each independently selected from H, alkyl, or — (CH ₂ ) _x —NR ⁶ R ⁷ ;
R ⁶ and R ⁷ are each independently H or alkyl, or R ⁶ and R ⁷ are combined to form a 5- or 6-membered ring, which ring optionally further contains one or more heteroatoms. Optionally containing one or more degrees of unsaturation and optionally substituted one or more times by alkyl, hydroxy, carboxy, acyl, alkoxy or halogen;
Said D ³ is:

And the dotted line represents any double bond;
When R ¹¹ is — (CH ₂ ) _x , there is no double dotted double bond, and R ¹² is alkylsulfonyl or —NR ¹³ R ¹⁴ ,
R ¹³ and R ¹⁴ are each independently selected from H, alkyl,-(CH ₂ ) _x -R ¹⁷ (R ¹⁷ is alkoxy or -NR ¹⁵ R ¹⁶ );
R ¹⁵ and R ¹⁶ are each independently H or alkyl;
Or R ¹³ and R ¹⁴ combine to form a 5- or 6-membered ring, optionally further containing one or more heteroatoms, optionally containing one or more degrees of unsaturation, Substituted one or more times by alkyl or — (CH ₂ ) _x —OH by
When R ¹¹ is-(CH)-, there is an optional dotted double bond, and R ¹² is-(CH) -C (O) -OH;
Said D ⁴ is:

And R ¹⁷ is hydroxy, alkoxy, or —NR ¹⁸ R ¹⁹ ,
R ¹⁸ and R ¹⁹ are each independently selected from H, alkyl, — (CH ₂ ) _x —R ²⁰ ,
R ²⁰ is alkylsulfonyl, hydroxy, aryl (aryl is optionally substituted with hydroxy or alkoxy), heteroaryl, or —NR ²¹ R ²² ;
R ²¹ and R ²² are each independently selected from H, acyl, and alkyl, or R ²¹ and R ²² combine to form a 5- or 6-membered ring, optionally further comprising one or more rings Contains a heteroatom, optionally contains one or more degrees of unsaturation and is optionally substituted by alkyl or — (CH ₂ ) _x —OH;
Alternatively, R ¹⁸ and R ¹⁹ combine to form a 5- or 6-membered ring, optionally containing one or more heteroatoms, optionally containing one or more degrees of unsaturation, Substituted by-(CH ₂ ) _x -R ²³ by
R ²³ is alkoxy, hydroxy, —C (O) —R ²⁴ (R ²⁴ is a 5- or 6-membered ring, this ring optionally further containing one or more heteroatoms and optionally one or more unsaturateds. Or -NR ²⁵ R ²⁶ (R ²⁵ and R ²⁶ are each independently H or alkyl);
D ⁵ is
A 5- or 6-membered ring, optionally further containing one or more heteroatoms, optionally containing one or more degrees of unsaturation, and optionally another 5- or 6-membered ring ( This ring optionally further contains one or more heteroatoms and optionally contains one or more degrees of unsaturation),
Said ring or fused ring system is optionally: halogen, alkyl, haloalkyl, alkylsulfonyl, alkylthio, hydroxy, alkoxy, oxo, sulfonyl, sulfate, nitro, cyano, carboxy, alkoxycarbonyl, aryl (aryl is optionally sulfamoyl) Optionally substituted), heteroaryl (heteroaryl optionally substituted with alkyl), or —NR ²⁷ R ²⁸ ,
(Wherein R ²⁷ and R ²⁸ are each independently H, alkyl, acyl, alkoxy, alkoxycarbonyl, carboxy, or — (CH ₂ ) _x —NR ²⁹ R ³⁰ (R ²⁹ and R ³⁰ are each independently H and Selected from alkyl) or
Or R ²⁷ and R ²⁸ combine to form a 5- or 6-membered ring, which optionally further contains one or more heteroatoms, and optionally contains one or more degrees of unsaturation, Is substituted with one or more alkyl, hydroxy, carboxy, acyl, alkoxy, or halogen. )
Alternatively,-(O) _y- (CH ₂ ) _x -R ³¹ (wherein R ³¹ is hydroxy, alkoxy, haloalkyl, aryl (optionally substituted with halogen), or -NR ²⁷ R ²⁸ (R ²⁷ and R ²⁸ is as defined above) and may be substituted one or more times by
For each of the above cases, x is independently 0, 1, 2, or 3;
For each of the above cases, y is independently 0 or 1; and
R ² is phenyl, substituted with one or more alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ³¹ R ³² ;
R ³¹ and R ³² are each independently selected from H, alkyl, acyl, or-(CH ₂ ) _z -R ³³ ;
Said z is 0, 1, or 2; and
R ³³ is cycloalkyl. The compound of claim 1, wherein R ¹ is D ⁵ . D ⁵ is pyridyl, compound of Claim 2. D ⁵ is 4-pyridyl A compound according to claim 3. The compound of claim 1, wherein R ² is phenyl substituted with alkoxy. 6. A compound according to claim 5, wherein alkoxy is methoxy. R ² is the formula, A compound according to claim 6:

For each case, the alkyl is C ₁ -C ₆ alkyl, A compound according to claim 1. The compound of claim 1, wherein R ¹ is D ³ and R ¹¹ and R ¹² are combined to form — (CH) ═ (CH) —C (O) —OH. 10. A compound according to claim 9, wherein the stereochemical configuration is cis. 10. A compound according to claim 9, wherein the stereochemical configuration is trans. The compound according to claim 1, wherein A is H. 2. A compound according to claim 1 wherein A is alkyl. _14. A compound according to claim 13, wherein A is C1-6 alkyl. 15. A compound according to claim 14, wherein A is selected from propyl or isopropyl. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1-15. The pharmaceutical composition of claim 16, further comprising one or more pharmaceutically acceptable carriers, diluents, or excipients. 16. A method of treating a mammalian disorder characterized by the misregulation of one or more protein kinases, comprising administering to the mammal a therapeutically effective amount of a compound according to claims 1-15. 19. The method of claim 18, wherein the kinase is a serine / threonine kinase. 20. The method of claim 19, wherein the kinase is GSK3. The method of claim 18, wherein the kinase is a tyrosine kinase. 24. The method of claim 21, wherein the kinase is TIE2. 16. A method of treating a mammalian disorder characterized by the misregulation of one or more protein kinases, comprising administering to the mammal a therapeutically effective amount of a compound according to claims 1-15. 24. The method of claim 23, wherein the protein kinase is GSK3. 24. The method of claim 23, wherein the protein kinase is TIE2. 16. A compound according to claims 1-15 for use in therapy. Use of a compound according to claims 1-15 in the preparation of a medicament for use in the treatment of disorders characterized by misregulation of one or more protein kinases. A method of treating the following disorders comprising administering to a mammal a therapeutically effective amount of a compound according to claims 1-15: Type 2 diabetes, hyperlipidemia, obesity, CNS disorders, neurotrauma, immunity Augmentation, baldness or hair loss, atherosclerotic cardiovascular disease, hypertension, polycystic ovary syndrome, ischemia, immune dysfunction, and cancer. A therapeutically effective amount for a mammal,
(i) the compound of claims 1-15, and
(ii) at least one other antidiabetic agent,
A method for treating type II diabetes, comprising administering 16. A compound according to any one of claims 1 to 15, corresponding to any of the examples. Compounds of formula (II) and their salts, solvates and pharmaceutically functional derivatives:

Where A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2; and
R ^d is cycloalkyl. Compounds of formula (III) and their salts, solvates and pharmaceutically functional derivatives:

Where A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2; and
R ^d is cycloalkyl. Compounds of formula (IV) and their salts, solvates and pharmaceutically functional derivatives:

Where A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2; and
R ^d is cycloalkyl. Compounds of formula (V) and their salts, solvates and pharmaceutically functional derivatives:

Where A is H, alkyl, or aryl;
R ^a is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro, or —NR ^b R ^c ,
R ^b and R ^c are each independently selected from H, alkyl, acyl, or — (CH ₂ ) _z —R ^d ;
Said z is 0, 1, or 2;
R ^d is cycloalkyl; and
^Re is H or —C (O) — (O) —C— (CH ₃ ) ₃ .